American Diabetes Association 73rd Scientific Sessions

June 21-25, 2013, Chicago IL Day #2 Highlights – Draft

Executive Highlights

Hello again from Chicago, where the sun stayed out all day, the exhibit hall opened its doors, and we saw a host of promising new data – especially on novel drugs and combination therapies. There was also valuable new data on the 30th Anniversary symposium on DCCT/EDIC.

In the morning, we saw an excellent oral session on GLP-1 therapies, which spilled eager attendees into an overflow room. Here we got our first, long-awaited look at Dr. Ralph DeFronzo’s triple-therapy trial, as presented by Dr. Muhammad Abdul-Ghani (University of Texas Health Science Center, San Antonio, TX). The study compared triple therapy (metformin plus pioglitazone plus exenatide) to conventional therapy (metformin followed by a sulfonylurea and then basal insulin). At 24 months, the triple-therapy group posted a lower mean A1c (6.0% vs. 6.6%) – an encouraging result, though interpretation is complicated given how unusually well conventional therapy performed. Another highlight was Dr. John Buse’s (University of North Carolina, Chapel Hill, NC) presentation of DUAL-1, a study of once-daily insulin degludec and liraglutide in a coformulation (IDegLira). Over 80% of patients taking IDegLira got their A1c to the goal of 7.0% or below, and IDegLira was better than degludec alone in terms of hypoglycemia (one third less than with degludec) and weight (slight weight loss, instead of weight gain with Tresiba). Also in GLP-1 news (but in a later session), Dr. Stephanie M. Gustavson, PhD (TransTech Pharma, High Point, NC) presented the results of a four-week phase 1 trial examining the safety and efficacy of TTP054, a phase 2 oral GLP-1 agonist that caused consistently greater declines in fasting plasma glucose and two-hour postprandial glucose versus placebo-treated patients, with no hypoglycemic events and with a similar rate of GI adverse events to the placebo arm.

During a morning corporate symposium on SGLT-2 inhibition, Dr. Zachary Bloomgarden (Mount Sinai Medical Center, New York, NY) commented on the potential of SGLT-2 inhibitors for the treatment of type 1 diabetes, and expressed optimism for the use of SGLT-2 inhibitors in combination with TZDs. SGLT-2 inhibitors were also a major featured in the morning session on novel therapeutic targets: Dr. Bernard Zinman (University of Toronto, Toronto, Canada) gave a strong, optimistic overview of the class and voiced interest in the eventual results from ongoing CV outcomes trials with the drugs. Finally, he also previewed an eight-week pilot study evaluating the use of empagliflozin in type 1 diabetes patients that demonstrated an A1c decline of 8.0% to 7.6% as well as reductions in insulin dosing and the incidence of hypoglycemic events, to be presented in poster 1074-P.

Obesity drugs generated interest today as well, and we were especially interested by an Eisai survey on Belviq (lorcaserin). Of the product theater’s attendees, 53% indicated that they would reconsider waiting to use pharmacotherapy in their patients who are obese or overweight, 28% stated that they would not reconsider this, and 20% indicated that they need more information. They were not the only ones to voice concerns about new agents – during a panel discussion on obesity pharmacotherapy, Dr. Robert Eckel (University of Colorado, Aurora, CO) remarked that he did not think 3.0 mg liraglutide’s (Novo Nordisk’s Victoza for obesity) side effects were worth its weight loss benefit or at least were “limiting.”

The main device talk of the day came from Dr. Boris Kovatchev (University of Virginia, Charlottesville, VA), who shared data from two recent studies of outpatient closed-loop control (including two US centers!). The results were somewhat modest in themselves, but we are thrilled at what they presage: a world where outpatient artificial pancreas research is the norm.


Table of Contents 



Symposium: Hypoglycemia in Clinical Practice (Supported by an Unrestricted Educational Grant from Merck)


Irl Hirsch, MD (University of Washington School of Medicine, Seattle, WA)

Before beginning, Dr. Irl Hirsch dedicated his presentation to Dr. Richard Rubin: “I have nothing but amazing memories over the years. He was a true inspiration to many of us. I miss him greatly.” Dr. Hirsch then proceeded with a stellar review of hypoglycemia and CGM, emphasizing a few key points: 1) hypoglycemia remains a major barrier to glycemic control (and is linked to a 4-10% lifetime risk of death); 2) CGM has the potential to reduce this burden; 3) CGM accuracy is less than perfect, especially in hypoglycemia, but it’s improved from earlier generations (he was particularly psyched about the 90% “severe hypoglycemia detection rate” with Dexcom’s Gen 4); 4) CGM accuracy is lower on day one; 5) like many aspects of diabetes therapy, patients need to be active participants with use of CGM; and 6) as CGM continues to evolve, it appears possible that there could be major improvements in the burden of hypoglycemia in type 1 diabetes. In the immediate future, Dr. Hirsch believes benefits on hypoglycemia should be most obvious with CGM activated insulin interruption (i.e., low glucose suspend). However, “the major” unanswered question for him is whether this technology will be available to the people who need it most.

  • Hypoglycemia is not a benign problem – 4-10% of the population of pediatric and young adults with type 1 diabetes actually die from hypoglycemia. This point was disputed in Q&A, though Dr. Hirsch clarified that this represents lifetime risk of death (he went back to the original studies to double check). He also showed T1D Exchange data on the 12-month frequency of severe hypoglycemia, which ranges from 6% in the youngest age group up to 14% in those over 50 years old. “This is absolutely huge,” he noted.
  • Although the DCCT established a clear inverse relationship between severe hypoglycemia and A1c, the link has not been confirmed in the T1D Exchange. Patients in the Exchange have a rate of severe hypoglycemia ranging from 6-9%, quite consistent at all A1c levels. This was puzzling to Dr. Hirsch, and after offering a few unlikely explanations, he admitted the real answer to this question – “We don’t know, but these numbers are too high.”
  • Dr. Hirsch highlighted two things that are required to reduce or eliminate the risk of severe hypoglycemia: 1) an accurate CGM device and 2) a knowledgeable patient that is proactive and makes adjustments for food and insulin. He emphasized that a “knowledgeable” patient is NOT synonymous with “compliant” or “adherent.”
  • Current CGM technology has improved over less accurate early generation devices, though there are still a few key areas for improvement: accuracy in hypoglycemia is still lower than that at more in range values, day one accuracy is worse (an “Achilles heel”) than accuracy on subsequent days, and accuracy is lowest during times of rapid glucose change. Dr. Hirsch emphasized that the inaccuracy of initial CGM devices led to lots of initial frustration with the technology (overall MARDs of 20-26% with the Guardian RT, GlucoWatch, and Dexcom STS);
  • Dr. Hirsch reviewed the accuracy data on Dexcom’s Gen 4 CGM; he was quite positive on the device’s 90% “severe hypoglycemia detection rate.” The severe hypoglycemia detection rate is defined as the percentage of CGM values that are <70 mg/dl when the YSI reads <55 mg/dl. This is poster #391 (Peyser et al.) at ADA 2013. He also highlighted the~80% of values in Zone A of the Clarke Error Grid. Still, he noted that Dexcom’s accuracy canimprove in hypoglycemia and on day one.
  • Dr. Hirsch also summarized the accuracy of Medtronic’s Enlite sensor from an ADA poster last year (“not in the US, but available in most countries”). He showed a display of the accuracy data based on rate of glucose change (a “smart way to present”; Bailey et al., Poster 30LB at ADA 2012). As would be expected, lower rates of change had better accuracy: MARD was 13.6% at <1 mg/dl/min and 12.9% at 1-2 mg/dl/min, much better than 16.3% when glucose changed rapidly at >2 mg/dl/min. He reiterated the same limitations as those covered on the Dexcom slides: worse accuracy in hypoglycemia (a 17% MARD for <75 mg/dl vs. 12.6% for 70-180 mg/dl) and worse accuracy on day one (15.9% vs. 11.8% on day three and 13.6% overall).
  • “Even the best CGM won’t help if the patient is not able to or interested.” Dr. Hirsch reviewed the now commonly accepted belief that level of CGM use predicts A1c decline – this finding has been demonstrated in STAR-1, STAR-3, the JDRF CGM trial, and in T1D Exchange data.
  • Per JDRF CGM trial data, the technology is beneficial for patients who have already achieved excellent glycemic control (“A very important trial that I must continually point out to payers in Washington”). At baseline, those in the JDRF CGM trial with an A1c<7% spent a median of 91 minutes per day in hypoglycemia; after 26 weeks on CGM, this dropped to just 54 minutes, while the control group had no improvement (JDRF Study Group, Diabetes Care 2009).

Questions and Answers

Q: Can you discuss the problems of CGM detecting hypoglycemia at night vs. during the day?

A: The big issue with nocturnal hypoglycemia is that even when everything is working perfectly, the patient is in too deep a sleep. The CGM doesn't wake the patient up and do its job. It’s often a spouse or a parent that wakes up. The other thing is that patients don’t want to be bothered with it, so they turn the alarms off during the day and forget to turn them back on at night. Regarding the problem of accuracy if the device is slept on, I don’t think that’s as big of a problem now as it was with previous generations. The big issue is people sleep through the alarms.

Dr. Robert Engler (GlySens, San Diego, CA): With implantable CGM, we find that with falling glucose, the implanted sensor actually leads the blood YSI, whereas with a rise in glucose it trails it. Timing is very important for hypoglycemia detection. Can you say whether the MARD and statistical data you showed is different for a rising vs. falling glucose?

A: You’d have to ask the engineers. I showed rate of change for Enlite. I did not have access to data for Dexcom. Data anecdotally shows that this is not as big of a problem. I want to be clear – there is still a lag time for interstitial fluid. Given the physiology of interstitial fluid, I’m not sure that’s a problem that can go away with this technology.

Q: I’m a little confused with the mortality rate from hypoglycemia – 4-10% of patient die? I’m certainly not losing 4-10% of my patients to hypoglycemia.

A: It’s not per year. It’s risk of death in lifetime. I went back to each of these studies and made sure I was reading it right. If I’m recalling it correctly, I got this from Phil Cryer’s review article. It wasn’t every year – it was in someone’s lifetime. And these are relatively recent data. Phil did I get that right?

Dr. Phil Cryer (Washington University School of Medicine, St Louis, MO): Yes.

Q: Is it known whether lower accuracy on the first day is a function of the sensor chemical reaction itself? Is it calibration?

A: I’m going to leave that for the engineers at Medtronic and Dexcom. My understanding is that it has to do with the wound produced when the catheter goes in. There is inflammation around that wound, and that happens until that wound heals up. That’s why it may be difficult to get that first day MARD a lot better. In our institution, we are thinking about using CGM in non-ICU settings. What’s really hurting us is the fact that the first day is not as accurate as we would like it to be. That’s a big reason why it has been decided not to use CGM for surgical procedures and short stays in the hospitals.

Q: I had an educator tell me to put on a new sensor the day before or 12 hours before taking off the previous one. This allows time to warm up. Do you recommend that?

A: I haven’t been recommending it. However, if the issue is the wound and inflammation causing the inaccuracy, maybe that would be nice. That would be a very nice and easy study to do – it would be great to do that study. It makes a lot of common sense.



Stephanie Amiel, MD (Kings College London, London, United Kingdom, London, UK)

Dr. Stephanie Amiel gave a whirlwind review of nocturnal hypoglycemia studies tracking all the way back to 1936 and the Somogyi phenomenon, which suggests that nocturnal hypoglycemia precipitates hyperglycemia. Dr. Amiel undermined this hypothesis by demonstrating the lack of a counterregulatory stress response to hypoglycemia in deep sleep (Jones et al., NEJM 1998). Instead, she argued that nocturnal hypoglycemia is associated with morning hypoglycemia and often precedes diurnal hypoglycemia by blunting patients’ stress response and symptom response to daytime lows. Her historical overview showed how the field’s understanding of this topic has improved and also how the insulins used to manage hypoglycemia have improved. However, as Dr. Amiel said in her introduction, nocturnal hypoglycemia is still common. The nighttime poses a particular challenge to patients because it represents the longest interval between meals, the longest interval between self monitoring, and the time of maximal insulin sensitivity. She pressed that nocturnal hypoglycemia needs to be actively sought we still don’t routinely ask our patients about their hypoglycemia experience, said Dr. Amiel. “[Nocturnal hypoglycemia] can be diminished,” she concluded, “even pending the availability of new technologies.”

Questions and Answers

Q: With kids it is important for them to get frequent exercise. One of the things we found helpful was reducing insulin during exercise. We also found that if blood sugar was above 180 mg/dl at bedtime, there was low risk for hypoglycemia. And above 130 mg/dl greatly reduced the risk.

A: We need to understand how to use insulin and teach our patients that knowledge.

Q: Is there data to suggest that giving Levemir (insulin detemir) in the morning instead of at bedtime works?

A: That is a common response for people who experience hypoglycemia at night. I feel strongly that once- daily background insulin is not ideal. My preference is to use Levemir in the morning and at bedtime. It also gives you the ability to adjust the dose.

Q: You implied that the Somogyi rebound isn’t so. Could you elaborate?

A: What he was describing was in a very different era. With current studies, there is very little evidence that hypoglycemia in the night is a major driver of hyperglycemia in the morning. My own interpretation comes from perhaps the fact that we know in deep sleep hypoglycemia doesn’t have a counterregulatory response.

Q: Do you think “dead in bed” occurs in patients with type 2 diabetes?

A: I have never been asked that before. I can’t see why it would be different once a patient with type 2 diabetes has the same kind of insulin deficiency as in type 1 diabetes. Hypoglycemia-related death can certainly occur in patients with type 2 diabetes on SFUs, but whether it’s the same mechanism, I don’t know. But death certainly can occur.

Q: Nocturnal hypoglycemia has become a major focus for new basal insulins. Do you think there is a real pathophysiological difference between hypoglycemia in the day and nocturnal hypoglycemia?

A: The most important difference is the lack of a counterregulatory stress response. One of the nice things about new agents intended to cause less hypoglycemia is that they raised the awareness among health care professionals.



Joel Zonszein, MD (Montefiore Medical Center, Bronx, NY)

Dr. Joel Zonszein provided a comprehensive review of outpatient and inpatient studies investigating intensive insulin therapy (IIT), hypoglycemia, and mortality. The collection of inpatient trials to date has not presented a uniform message as to the relationship between IIT and mortality; however, he stressed that the association between hypoglycemia and increased mortality is clear. Further, Dr. Zonszein said that hypoglycemia has been associated with greater hospital cost, length of stay, and morbidity. He reminded the audience that blood glucose monitoring is an important component to preventing hypoglycemia. We were struck by the statistic that fingerstick testing costs ~$2.5 million dollars per year in a large institution like Montefiore (Bronx, New York). This doesn’t mean we should test less, said Dr. Zonszein, it means we should make sure we test in a meaningful way. Dr. Zonszein spent the remainder of his presentation comparing iatrogenic to spontaneous hypoglycemia and suggested that iatrogenic hypoglycemia is associated with lower mortality (Boucal, Am J Med 2011).


Symposium: ADA Diabetes Care Symposium


Boris Kovatchev, PhD (University of Virginia, Charlottesville, VA)

Dr. Boris Kovatchev reviewed his group’s progress toward outpatient closed-loop control and shared data from two recent multi-site, outpatient trials (n=20 each) – an early feasibility study and an efficacy study with randomized crossover design. Each study compared open-loop and closed-loop control during roughly 40-hour sessions that included unrestricted, announced meals and used the University of Virginia’s smartphone-based platform (DiAs). The first study’s primary endpoint was simply the percentage of time that inter-device communication was maintained (98.9% for closed-loop and 97.1% for open-loop). In this study, closed-loop control gave slightly worse time in target at night (72% vs. 80%), but it reduced exposure to overnight hypoglycemia (0.27 vs. 0.53 events per 24 hours). The second study used a more advanced system and had a primary endpoint of hypoglycemia reduction, as measured by low blood glucose index. By this metric, closed-loop control outperformed open-loop control with a highly statistically significant effect size of 0.64 – better than the 0.4 effect size that the researchers had anticipated.

  • Between November 2011 and July 2012, Dr. Kovatchev and collaborators conducted a multicenter feasibility study of outpatient closed-loop control, the results of which will be published in Diabetes Care in July. The study was conducted at the University of Virginia, the University of Padova, the University of Montpellier, and Sansum Diabetes Research Institute (n=5 patients per site). Each study visit was 42 hours long.
    • The system included a DiAs-enabled smartphone, a Dexcom Seven Plus CGM, an OmniPod, and a separate handheld device to link the CGM and pump with each other and the smartphone. The algorithm architecture included a range- correction module, a meal bolus calculator, and a safety system.
  • In Europe, once closed-loop control was begun, it continued for the rest of the trial; in the US, the system was placed in an overnight safety mode (i.e., basal insulin delivery rate, plus the safety module). As the time that the study designs were submitted to the FDA, the agency would have allowed nocturnal closed-loop control only if blood glucose measurements were taken throughout the night. A benefit of the Europe-US difference was that to allow rough comparison between closed-loop and quasi-open-loop control in the overnight period. Another difference was that in Europe, closed-loop control was initiated in the hospital, whereas in the US, control was entirely outpatient (e.g., at a hotel or guesthouse).
  • The researchers succeeded with regard to their prespecified primary endpoint – to maintain inter-device communication for at least 80% of the time. Altogether, the study included 830 hours of data (277 hours of open-loop control and 550 hours of closed-loop control). Inter-device communication was maintained for 98.9% of the time in open-loop mode and 97.1% of the time in closed-loop mode. Dr. Kovatchev showed how often each system component malfunctioned and caused data loss. Measured in events per 24 hours, malfunction frequency was as follows for: sensor components (0.0 in open-loop, 0.04 for closed-loop), pump components (0.17 in open- loop, 0.09 in closed-loop), and DiAs (0.17 in open-loop, 0.04 in closed-loop). The control algorithm performed as intended, producing a dose recommendation 100% of the time.
  • Closed-loop control and open-loop control were roughly comparable in terms of time in target range, but closed-loop control did reduce the number of overnight hypoglycemic events. In the overnight period (11:00 pm to 7:00 am), time in target was slightly better with open-loop control (80% vs. 72%) – Dr. Kovatchev noted that the patients in the study were good at managing their diabetes. However, open-loop control led to more nocturnal hypoglycemic events below 70 mg/dl (0.53 vs. 0.27 events per 24 hours). Dr. Kovatchev also noted that the outpatient closed-loop results compared favorably to inpatient closed-loop data from a previous study with a similar system (Breton et al., Diabetes 2012). The studies had differences in design that prevent a straightforward comparison. Still, we thought it generally encouraging to see such similarities with inpatient and outpatient results, respectively, for overall time in range (74% vs. 70%), overnight time in range (74% vs. 72%), and the frequency of overnight hypoglycemic episodes (0.24 vs. 0.27).
  • Dr. Kovatchev highlighted the system’s ability to allow remote monitoring. The remote monitoring function was tested most thoroughly at the Sansum Diabetes Research Institute, where all five patients performed their study visits simultaneously. Their data could be viewed in real-time via computer and even on Dr. Howard Zisser’s iPad. The main screen included each patient’s top-line glucose data and a traffic light to indicate whether the system was functioning properly (e.g., no pump occlusions). Researchers could also click on each patient’s icon to get a more in-depth look at the study data.
  • Following up on interim results shown at ATTD 2013, Dr. Kovatchev shared top-line data from his consortium’s most recent outpatient closed-loop trial. (He noted that full results could be seen in the poster hall, at poster 993-P.) The study enrolled five patients at each of the same four clinical centers from the feasibility study (total n=20). Patients took part in two 40-hour sessions: once using a closed-loop system, and once using the same system in open- loop mode. Patients had dinners and restaurants and had no restrictions on meal size, as long asthey announced meals to the system and estimated carbohydrate content. The other main challenge to the system was 45 minutes of walking.
    • Patients used a DiAs-enabled smartphone that was linked to a Dexcom G4 receiver by USB cable and linked to a Tandem t:slim pump by Bluetooth low energy. Remote monitoring was possible via WiFi and the cellular network. The algorithm featured an enhanced version of the feasibility study’s range-correction module, as well as insulin-on-board constraints.
    • During the study, roughly 1,400 hours of data were collected: 700 hours each for open- and closed-loop control. Dr. Kovatchev said that approximately 96.5% of the data were valid, with 3.5% lost to pump occlusions and other technical problems.
    • Closed-loop control was a success according to the study’s primary efficacy endpoint: reduction in the risk of hypoglycemia, as defined by the low blood glucose index (LBGI). By this metric, closed-loop control had an effect size of 0.64 – a highly statistically significant result, and better than the 0.4 effect size that the researchers had anticipated.
    • The Dexcom G4 performed with a mean absolute relative difference of 11.5 mg/dl, as compared to self-monitoring of blood glucose (SMBG) tests taken during the study. The correlation between the CGM and SMBG was r=0.95. Dr. Kovatchev noted that these results were consistent with a paper on the G4’s accuracy that was written by Christiansen and colleagues and published online just a few days before ADA (Diabetes Technol Ther 2013).


Symposium: Continuous Glucose Monitoring (CGM) in the Management of Diabetes in Pregnancy


Jane Harding, DPhil (University of Auckland, Auckland, New Zealand)

Dr. Jane Harding discussed the possibility of using continuous glucose monitoring (CGM) to detect hypoglycemia in newborns. To set the stage for her presentation, she explained that hypoglycemia is the commonest metabolic disorder in newborns and the only common preventable cause of brain damage in newborns. Hypoglycemia (blood glucose <47 mg/dl) is estimated to occur in 5-15% of all births. Dr. Harding believes that CGM can potentially uncover the duration, frequency, and severity of hypoglycemia and can be used to better understand the effects of interventions. Currently, said Dr. Harding, we do lots of blood tests and treatments without being sure they are changing the outcome. However, the inaccuracies of today’s CGM technology are particularly un-ideal in newborns. CGM tends to be least accurate in the first 24 hours and most problems in newborns occur during this time period, especially in the first two to four hours after birth. Dr. Harding concluded that CGM is a “wonderful research tool” in newborns, but it is not yet a “day-to-day tool.”

  • “Either we are missing a whole lot of hypoglycemia or CGM is detecting a whole lot of hypoglycemia that doesn’t matter. It is very important to know which one of these is true before we start using CGM clinically.” In the BABIES study cohort (n=102 babies ≥ 32 week old and at risk of neonatal hypoglycemia), newborns received routine clinical care (intermittent blood glucose measurement) plus blinded continuous interstitial glucose monitoring. CGM detected 266episodes of low blood glucose lasting five to 475 minutes and only 19% of these episodes were detected by intermittent blood glucose measurement. Further, of the 107 hypoglycemic episodes lasting >30 minutes (an arbitrary threshold, she said), only 27% were detected by intermittent blood glucose measurement (Harris et al., J Pediatr 2010).
  • Dr. Harding highlighted three CGM inaccuracies that make it less valuable to newborn patients: 1) CGM takes one to two hours to initialize and tends to be least accurate in the first 24 hours; however, most problems in newborns occur in the first 24 hours; 2) CGM has a delayed response to rapid changes in blood glucose, but babies often have rapid changes in glucose concentration; and 3) CGM needs calibration at extremely low glucose concentrations (blood glucose <2.2 mM [40 mg/dl]) and this is where glucose concentration is of most concern in newborns. In one of Dr. Harding’s studies, she applied a modified retrospective calibration algorithm to the CGM, such that the CGM trace had to go through each individual blood glucose value taken by intermittent monitoring.
  • “It would be nice to know if [47 mg/dl] is the right number.” Dr. Harding explained that she defined hypoglycemia as 47 mg/dl because it is widely regarded as the threshold for considering treatment, “not because I can defend it strongly.” An underlying theme to Dr. Harding’s presentation was the need for greater understanding of the clinical significance of low blood sugar in newborns. We were also impressed by the novelty of CGM research in newborns and were excited to see CGM being applied to this patient group. Neonatologist Dr. Harding began working with CGM just five years ago.

Questions and Answers

Dr. Ken Ward (Oregon Health and Science University, Portland, OR): I would like to comment that we’ve been doing some work with newest Dexcom gen 4 sensor and it has a low delay time and I know the new Enlite sensor [editor’s note - Medtronic; CE marked, but not yet FDA approved] has a low delay too. New-generation sensors might make the delay less. My question was about the recalibrated data. Can you only do that retrospectively or can you apply it real time?

A: At the moment, we have only done it retrospectively. I am sure it could be built into a real-time algorithm but the question is how many points do you want to draw in? With regard to the delay, perhaps it would be better to wait a little bit to respond with treatment, so perhaps it might work in our favor.



Teri Hernandez, PhD (University of Colorado Anschutz Medical Campus, Aurora, Colorado)

Dr. Teri Hernandez discussed the goals of using CGM in pregnant women without diabetes and the limitations of research to date. Throughout her talk she emphasized the value of CGM as a clinical and research tool that gives a wealth of granular data, as well as a “Gestalt” picture of overall glycemic control. However, she pointed out that CGM-based metrics can be tricky to define (e.g., what exactly is “fasting glucose”?), and she called for her colleagues to develop standardized metrics. She also lamented the dearth of good glycemic data in pregnant women without diabetes – as of 2011, only 12 such studies had ever been conducted (total n~250), only six had used CGM (total n~150), and hardly any of the patients studied had been obese. Thus healthcare providers have a hard time knowing what the “normoglycemic” targets should be for women with diabetes. However, even based on published data, Dr. Hernandez made a strong case that normoglycemic glucose excursions tend to be much smaller than the targets that are currently recommended for one-hour and two-hour postprandial glucose values (120 and 140 mg/dl, respectively). Another notable finding has been that obese women tend to have higher glucose values than non-obese women, both early and late in pregnancy (Harmon et al., 2011 Diabetes Care).

Questions and Answers

Q: It is important to take into consideration the type of CGM. The algorithms for retrospective CGM may not be the same as real-time systems.

A: This is how geeky I am: I have learned the physiology of the sensors we are using, and the engineers for that company are sick of talking to me. Yes, that is a great point – retrospective vs. real-time matters.



Elizabeth Mathieson, MD (University of Copenhagen, Copenhagen, Denmark)

Dr. Elizabeth Mathieson reviewed a randomized trial of intermittent use of Medtronic’s Guardian REAL-Time CGM in pregnant women with type 1 or type 2 diabetes (n=154; Secher et al., Diabetes Care 2013). Women in both groups performed rigorous glycemic management using seven daily tests of plasma glucose; indeed, Dr. Mathieson remarked several times that she was proud of the control group’s results. Unfortunately, more women in the CGM group had newborns that were large for gestational age (45% vs. 34%), even in the per-protocol analysis (49% vs. 34%). The incidence of severe neonatal hypoglycemia was similar in the CGM group and control group (13% vs. 14%), though CGM use showed a tendency toward improvement in the per-protocol analysis (11% vs. 19%). Dr. Mathieson concluded that the results do not support routine, intermittent use of real-time CGM in unselected pregnant women with diabetes. She instead said that the study highlights the importance of improving CGM sensor accuracy and patient friendliness. She noted that sensors have improved beyond the Sof- Sensor used in this study, and during Q&A she said that she still even prescribes the Sof-Sensor for women who are at especially high risk of severe hypoglycemia during pregnancy.

Questions and Answers

Comment: I think that the study shows the remarkably good care you have given to these patients in the control group. It is interesting that there was no improvement compared to the control group. Maybe the problem was data overload, similarly to when a patient gives you 15-to-20 fingerstick tests a day – you don’t know what to do with them. Maybe data interpretation is a problem as well.

A: I had been working with CGM for 5-to-10 years prior to initiating this study. I thought that I knew what I was doing.

Q: The performance of the sensors was considerably worse than what we usually see in a real-time setting with non-pregnant people. Might this be due to using them in a pregnant population?

A: In this lecture I gave you some accuracy data from a non-pregnant published study. I have seen similar results in non-pregnant studies – that the accuracy is around 20 mg/dl different. Not only is the average sensor different from the meter, but this bias is not consistent. A recent paper looked at precision in the hypoglycemic range and found it not useful. In this study we used the Sof-Sensor. Since then, other, more precise sensors have come out. Even though I have these results, I still use these devices in selected women with high risk of severe hypoglycemia, and I do find them useful.

Q: Despite equivalent values with A1c, you have 45% incidence of LGA in the CGM group and 34% in the self-monitoring group. I wonder – is it possible that we are looking at the wrong analyte with regard to fetal growth? I recall research showing a stronger relationship of gestational outcomes with maternal triglycerides than with glucose. I think Dr. Harmon’s study showed the same thing. Did you measure triglycerides?

A: You are right – we have to look at other things apart from glucose. We also have to look at different time periods of glucose – before pregnancy, during pregnancy, and right before delivery. We are going to publish that we saw a correlation between the SED score and plasma glucose of newborn, as well as mean glucose in the eight hours before delivery and neonatal hypoglycemia. I didn’t bring those data. Within the sensor group, we looked at the percentage of time when women had glucose above 7 mmol/l (126 mg/dl). Among those who had values above 7 mmol/l within eight hours of delivery, the duration of time above 7 mmol/ correlated with the neonatal glucose of the newborn.

Q: CGM is not a therapy, it is a tool. The benefits depend on how CGM used. Given the fact that the CGM in this study was inaccurate, my assumption is that people didn’t trust it. What instructions did you give patients about how to use CGM to manage diabetes? You showed data about how it’s a tough decision whether to give an extra bolus, for example. Did you measure compliance?

A: CGM was not approved to use without testing plasma glucose, and in this study we had both women test their plasma glucose seven times a day, every day. My patients are excellent in using plasma glucose to obtain strict metabolic control. With CGM, I asked patients mainly to focus on getting rid of hypoglycemia at night, and to look at the glucose curves in the morning to see how the night worked.

Q: So patients were not using the direction or rate of change of glucose?

A: Not in any systematic way.



Helen Murphy, MD (University of Cambridge, Cambridge, UK)

What do we do in pregnancy?” asked Dr. Helen Murphy in her discussion of closed-loop systems. “Do we accept the limitations of current technologies and work with the sensor and pump manufacturers and algorithm engineers to improve them?” Dr. Murphy and her clinic believe they should have this dialogue and have begun to explore how closed-loop systems can best be applied to patients with type 1 diabetes in pregnancy. “As with any new field,” said Dr. Murphy, “it is best to start with something smaller and more achievable.” As such, her team has focused their closed-loop investigation on reducing nocturnal hypoglycemia. Dr. Murphy and colleagues are about to embark on the first outpatient feasibility study investigating overnight closed-loop control in pregnant women with type 1 diabetes (n=16). Patients will be randomly assigned to either four weeks of overnight closed-loop control or sensor-augmented pump therapy. Previous pilot studies in the clinical research facility suggested that nighttime closed-loop control could indeed adjust insulin delivery safely and effectively in both early- and late-stage pregnancy.



Oral Sessions: GLP-1 Agonists in Practice


Muhammad Abdul-Ghani, MD, PhD (University of Texas Health Science Center, San Antonio, TX)

Most people in the GLP-1 agonist oral session remained for the last presentation, during which Dr. Muhammad Abdul-Ghani presented the results of Dr. Ralph DeFronzo’s triple therapy trial. The open label, randomized controlled trial assigned 155 drug naïve, newly-diagnosed type 2 patients to either triple therapy (metformin plus pioglitazone plus exenatide) or conventional therapy (metformin followed by the sequential addition of a SFU and then basal insulin). The drug doses were titrated to avoid hypoglycemia and to achieve an A1c <6.5%. At 24 months, those in the triple therapy arm experienced a lower average A1c (6.0%) compared to those in the conventional therapy arm (6.6%; p<0.001) from a baseline A1c of 8.6%. Compared to the conventional group, the triple therapy group had a greater proportion of participants who achieved an A1c <6% (27% vs. 60%; p<0.001) or an A1c <7% (72% vs. 92%; p<0.001). The triple therapy approach also provided greater improvements in body weight (-1.2 kg [-2.6 lbs]) compared to the conventional therapy approach (+4.1 kg [+9.0 lbs]). On the safety front, Dr. Abdul-Ghani highlighted that the triple therapy group had a lower rate of hypoglycemia compared to the conventional group (15% vs. 46%, respectively), despite having a lower average A1c. However, triple therapy was associated with a higher rate of GI side effects compared to conventional therapy (33% vs. 21%, respectively), as well as a higher rate of edema (5.3% vs. 1.3%, respectively), though Dr. Abdul-Ghani commented that no cases of heart failure were observed. Based on these results, Dr. Abdul-Ghani concluded that HCPs should “treat the disease, not the symptoms, and treat the patient, not his blood sugar.”

  • Dr. Abdul-Ghani discussed the rationale for evaluating a metformin/pioglitazone/exenatide triple therapy. He noted that both the ADA and EASD now recommend lowering the A1c to as close to normal as possible while avoiding hypoglycemia; however, despite this guidance, no previous study has examined the optimal therapy to achieve this goal. Dr. Abdul-Ghani’s group hypothesized “that in newly diagnosed type 2 diabetes, initiating therapy with agents that correct known pathophysiological defects will produce a greater, more durable A1c reduction while avoiding hypoglycemia compared to the currently- recommended approach of sequential addition of agents that lower plasma glucose but do not correct the underlying metabolic defects.” Dr. Abdul-Ghani highlighted that pioglitazone and exenatide were chosen because of their favorable effects on insulin resistance and progressive beta cell failure, respectively.
  • The open label, randomized controlled trial assigned 155 drug naïve, newly- diagnosed type 2 patients to either triple therapy (metformin plus pioglitazone plus exenatide) or conventional therapy (metformin followed by the sequential addition of a SFU and then basal insulin to maintain A1c ≤6.5%). At baseline, participants had an average age of 46- 47 years, BMI of 36-37 kg/m2, diabetes duration of 5 months, A1c of 8.6%, and fasting plasma glucose (FPG) of 190-192 mg/dl. In both arms, investigators up-titrated the drug dose to achieve an A1c of <6.5%. The primary endpoint was the difference in A1c between the triple therapy and conventional therapy groups at 24 months. The investigators also measured a range of secondary endpoints pertaining to glycemic control, body weight, and hypoglycemia.
  • Participants visited the clinic every month for the first three months, after which they had a follow-up visit every three months. At the follow-up visits, physicians would decrease the medication doses if a patient experienced hypoglycemia (blood glucose <60 mg/dl) or symptoms of hypoglycemia.
  • In the triple therapy arm, participants received metformin (1,000 mg/day, titrated to 2,000 mg/day at month one), pioglitazone (15 mg/day titrated to 30 mg/day), and exenatide (5 g twice daily titrated to 10 g twice daily). If the patient did not achieve an A1c <6.5% at three months, the pioglitazone dose was increased to 45 mg/day.
  • In the conventional therapy arm, patients started with metformin 1,000 mg/day; if the patient’s FPG exceed 100 mg/dl after the first month, the metformin dose was increased to 2,000 mg/day and glyburide was initiated at 5 mg/day. If the patient had a FPG >100 mg/dl or an A1c >6.5% at month two, the glyburide dose was escalated to 10 mg/day. If the patient was unable to achieve FPG <100 mg/dl or A1c <6.5% at month three, insulin glargine was initiated at 10 units/day and the dose was increased based on FPG levels.
  • Treatment failure was defined as an A1c >6.5% on two consecutive visits three months apart despite maximum dosages. The rescue therapy for the conventional therapy arm was Humalog 4-6 units before meals, with a dose escalation to maintain a two-hour post-prandial glucose level under 140 mg/dl. The rescue approach in the triple therapy arm was two fold: 1) insulin glargine 10 units in the morning with dose escalation to maintain FPG <100 mg/dl and an A1c <6.5%; and 2) the initiation of Humalog after reaching the maximum glargine dose of 60 units per day.
  • At 24 months, the average A1c in the triple therapy arm (6.0%) was significantly lower than the average A1c in the conventional therapy arm (6.6%; p<0.001). While both groups had a similar average A1c at six months (~6.0%) , those on triple therapy maintained the A1c reduction while those on conventional therapy experienced a rise in A1c. Median A1c levels were 5.8% and 6.4% for the triple therapy and conventional therapy groups, respectively, at 24 months.
  • Kaplan Meier curves show that roughly 50% of those who failed the triple therapy approach failed within six months; in contrast, the failure rate in the conventional therapy arm was relatively steady over the course of the 24-month study. To Dr. Abdul-Ghani, this result indicates that the triple therapy affects the course of the disease, in particular beta cell failure – i.e., the primary defect behind hyperglycemia.
  • A greater proportion of patients in the triple therapy arm achieved an A1c<6% or an A1c <7% compared to those on conventional therapy (60% vs. 27% for an A1c <6%; 92% vs. 72% for an A1c <7%; p<0.001 for both comparisons).
  • Triple therapy was associated with a 1.2 kg (2.6 lbs) weight loss while conventional therapy was associated with a 4.1 kg (9.0 lbs) weight gain.
  • Dr. Abdul-Ghani highlighted that while the mean A1c with triple therapy was 0.6% lower than that observed with conventional therapy, the triple therapy arm had a much lower risk of hypoglycemia (15%, vs. 46% for conventional therapy). No serious hypoglycemia events were observed in the trial.
  • The triple therapy arm was associated with slightly higher rates of GI side effects, as well as higher rates of edema, though Dr. Abdul-Ghani noted that no cases of heart failure were observed.

Adverse Events


Conventional Therapy

Triple Therapy

Any adverse event (%)



Hypoglycemia (%)



Serious hypoglycemia (%)



Edema (%)



GI side effects (%)



Deaths (#)*



Fractures (#)



* not treatment related

Questions and Answers

Moderator [Dr. Julio Rosenstock]: This controversial data is now open to discussion.

Q: The number of patients was small and the A1c range at baseline was very wide. I’m wondering if the treatment differed in people with lower vs. higher A1c levels at baseline.

A: It’s impossible to say because we don’t have the statistics to stratify response by A1c; however, anecdotally, patients with higher A1c levels at baseline did less well than those with lower A1c levels to start.



John B. Buse MD PhD (University of North Carolina, Chapel Hill, NC)

Dr. John Buse presented an excellent summary of the phase 3 DUAL-1 trial, which compared a fixed dose combination of insulin degludec and liraglutide (known as IDegLira) with insulin degludec (Tresiba) and liraglutide (Victoza) alone (all from Novo Nordisk). The concept of IDegLira is to combine the benefits of both therapies, with each agent mitigating the side effects of the other. The trial showed this approach was valid, yielding excellent results. In fact, the (nearly a third) lower hypoglycemia of the combination allowed participants to achieve 0.5% lower A1c levels with a lower total daily dose of insulin. GI side effects of the combination were also lower than with liraglutide alone and the combination yielded a small but sustained weight loss (of,0.5kg [1.1 lbs]) compared to a weight gain with insulin. The trial studied over 1,600 participants for a 26 week period titrated to target in the case of the IDegLira and insulin degludec arms, and titrated in the usual ramp-up fashion for liraglutide. After 26 weeks, the IDegLira group was taking 38U/day of insulin, compared to 53U/day in the degludec group. However, A1c reduction from a baseline of ~8.3% was 1.9% for IDegLira, compared to a reduction of 1.4% with degludec and 1.3% with liraglutide. The IDegLira group achieved and maintained a very low A1c of 6.4%. Even better was the result that 81% of the IDegLira group reached the target of a7.0% A1c (compared to 65% of the degludec group). IDegLira used a ratio of 50U of insulin degludec to 1.8 mg of liraglutide. Dr. Buse concluded that IDegLira resulted in better glycemic control with a lower risk of hypoglycemia and weight gain than either of its components alone.

  • The combination of a basal insulin and a GLP-1 agonist has the potential to combine their benefits while also mitigating the adverse effects of the two agents used individually. The post-prandial effects of GLP-1 can be combined with the fasting glycemic control of basal insulin. The weight loss of GLP-1 can mitigate any weight gain with insulin. The observed low hypoglycemia with GLP-1 can mitigate the potential for hypoglycemia with insulin and therefore allow patients to achieve lower A1c levels.
  • The open label DUAL-1 trial studied 1,663 people with type 2 diabetes randomized to IDegLira (Novo Nordisk), insulin degludec (Tresiba, Novo Nordisk) and liraglutide (Victoza, Novo Nordisk). IDegLira is Novo Nordisk’s once-daily injectable combination of insulin degludec and liraglutide. The IDegLira used in this study was fixed at a ratio of 50U degludec to 1.8 mg of liraglutide. Participants at baseline were inadequately controlled on metformin with or without pioglitazone (Takeda’s Actos). Liraglutide was titrated up from an initial 0.6 mg dose to a maximum dose of 1.8 mg as per the label, although the average dose at the end of the trial was 1.4 mg. IDegLira and degludec were titrated twice a week in two unit steps to a target fasting plasma glucose of 72-90 mg/dl (4.0-5.0 mmol/l). At baseline, BMI was roughly 31 kg/m2 and duration of diabetes was seven years. Eighty-three percent of the participants were taking metformin and 17% were taking metformin plus pioglitazone.
  • After 26 weeks, A1c reduction was 1.9% for IDegLira, 1.4% for degludec, and 1.3% for liraglutide from a baseline of 8.3%. Remarkably, IDegLira participants had an average A1c of 6.4%. In the IDegLira group, 81% of participants reached a target A1c of ≤7%, and 70% reached a target of ≤6.5%. While IDegLira and degludec provided an equivalent reduction in fasting plasma glucose (65 mg/dl) at 26 weeks, those in the IDegLira group were taking much less insulin (38 units/day, vs. 53 units/day for degludec). Nine point blood glucose profiles established that the post-prandial control of IDegLira was similar to that of liraglutide alone.
  • The rate of hypoglycemia in the IDegLira group was only 68% of the rate in the degludec group. Rates in the IDegLira group were around two events per patient year of exposure. The rates of hypoglycemia in the liraglutide group were ten times lower (around 0.2 events per patient year). Since hypoglycemia is usually the limiting factor in treating to target, Dr. Buse presented a model of the relationship between A1c and hypoglycemia rate for IDegLira and degludec, which supported the argument that a patient taking IDegLira can achieve a lower A1c at the same risk of hypoglycemia, (or that patients with the same A1c have a lower risk of hypoglycemia with IDegLira).
  • Participants taking liraglutide exhibited a weight loss of 6.6 lb (3 kg) after 26 weeks, compared to those taking degludec, who gained 1.5 kg (3.3 lb). Those taking IDegLira exhibited a slight weight loss of 1.1 lb (0.5 kg). This small weight loss was sustained to the end of the trial (and even out to 52 weeks in the DUAL-1 extension, according to Novo Nordisk).
  • Nausea for IDegLira was much better than liraglutide alone. For the first four weeks, nausea peaked at over 10% of subjects in the liraglutide group, but resolved to a sustained level of 3% after 13 weeks. In comparison, nausea for IDegLira declined steadily from roughly 3% of participants initially to 1% by the end of the trial. Dr. Buse commented that this reduction isprobably related more to the titration program and the lower starting dose than to the total amount of exposure to liraglutide.
  • Compared to insulin degludec, IDegLira exhibited reduced hypoglycemia, leading to a lower A1c with better post-prandial control and no weight gain. Compared to liraglutide, IDegLira had a better reduction in A1c and fasting glucose, with a reduced amount of nausea.

Questions and Answers

Q: [Dr. Rosenstock] The trial would have been nicer if it had been blinded…

A: [Dr. Buse] Later this year, we plan to present the results from the DUAL-2 study, which is blinded. (Note that Novo Nordisk has already announced some top level results for DUAL-2, which compares IDegLira and degludec. In DUAL-2, IDegLira also achieved a 1.9% A1c reduction over baseline, which was reported to be statistically significantly better than degludec (A1c reduction not yet disclosed)..

Q: Do you have any data regarding nocturnal hypoglycemia?

A: I can’t remember it all off the top of my head, but it’s more or less equal across degludec and IDegLira.

Q: What was the washout protocol?

A: I don’t know what you are referring to. There was no washout period. I suspect that you were referring to the concern raised at the FDA Advisory panel on degludec on CVD events during the washout period. There was one adjudicated cardiovascular event in each of the three arms, but no issues with washout protocol.

Q: Can we combine U500 insulin with GLP-1?

A: I think that Wendy Lane from Asheville NC will be presenting on the combination with severely insulin resistant patients.

Q: There is an impressive reduction in hypoglycemia – what is the reason?

A: It’s related perhaps to the lower amount of insulin, but I remember the GWCO trial adding exenatide to glargine where we saw a similar thing. I suspect that it is also related to an improvement in alpha cell function.



Carol H. Wysham MD (University of Washington, Spokane, WA)

Dr. Carol Wysham presented the results of the phase 3 AWARD-1 study, which compared dulaglutide at two doses (1.5 mg and 0.7 5mg) to exenatide twice daily (BMS/AZ’s Byetta) and placebo on a background of maximal doses of metformin and pioglitazone (Takeda’s Actos). After 26 weeks, dulaglutide 1.5 mg provided an A1c reduction of 1.5% from baseline (compared to a reduction of 1.0% with exenatide), which was roughly 1% lower than the placebo group. Nearly 80% of the patients in the high dose dulaglutide group reached an A1c target of 7%, compared to 54% in the exenatide group and 45% in the control group. Weight loss for dulaglutide 1.5 mg was similar to exenatide, while dulaglutide 0.75 mg was weight neutral.

  • Dulaglutide (Lilly) is a once-weekly GLP-1 agonist that links recombinant human GLP-1 to a human IgG4 Fc fragment in order to obtain longer plasma half-life (~5 days) in an injectable solution. This study, AWARD-1, is part of a series of five phase 3 trials,leading up to Lilly’s FDA submission, scheduled for 2013. Lilly has previously announced top-line results for the AWARD trials that are covered in this session (see our report at
  • The primary objective of the AWARD-1 trial is to prove superiority of once-weekly dulaglutide versus placebo in people with type 2 diabetes treated with metformin and pioglitazone (Takeda’s Actos). Metformin and pioglitazone were optimized to maximum doses before the start of the trial, and dulaglutide was investigated at two doses – 1.5 mg and 0.75 mg. The AWARD-1 trial also includes twice daily exenatide (BMS/AZ’s Byetta) as a comparator. The trial randomized 978 type 2 diabetes patients to dulaglutide 0.75 mg or 1.5 mg for 52 weeks, to exenatide for 52 weeks, or to placebo for 26 weeks followed by dulaglutide (0.75 mg or 1.5 mg) for 26 weeks. A1c at baseline was roughly 8.1% and participants had an average BMI of 33 kg/m2.
  • Dulaglutide 1.5 mg achieved an A1c reduction of 1.05% compared to placebo, demonstrating superiority. A1c reduction from baseline was 1.5% for dulaglutide 1.5 mg, 1.3% for dulaglutide 0.75 mg, 1.0% for exenatide and 0.4% for the placebo. In addition, 79% of participants taking dulaglutide 1.5 mg reached a target A1c of ≤7%, compared with 67% for the0.75 mg dose and 54% for exenatide. Both doses of dulaglutide were better at lowering fasting serum glucose than either placebo or exenatide.
  • Participants in the dulaglutide 1.5 mg group achieved a weight loss of 3.3 lb (1.5 kg) after 26 weeks, which was similar to exenatide. The weight loss was achieved after four weeks and was then maintained throughout the study. Dulaglutide 0.75 mg was weight neutral and the placebo group gained 3.1 lb (1.4 kg).
  • The majority of adverse events were GI related but reduced over time for dulaglutide. Dulaglutide 1.5 mg had the most nausea, at 28% of participants, dulaglutide 0.75 mg had a nausea rate of 16%, and exenatide was in the middle at 26%. There was one case of pancreatitis and one case of pancreatic cancer in the pooled dulaglutide group (five months of exposure).
  • The A1c reductions in all three GLP-1 groups were sustained out to 52 weeks.

Questions and Answers

Q: Longer acting GLP-1 agonists tend to be associated with lower GI side effects, but that’s not the case here. Can you explain?

A: The answer is probably in the chemistry of the compound. We see a reduction in glucose earlier, this shows earlier efficacy, maybe just after first injected.



Michael Nauck, MD, PhD (Diabeteszentrum Bad Lauterberg, Harz, Germany)

Dr. Michael Nauck presented the results of Lilly’s AWARD-5 study, which compared dulaglutide 1.5 mg and 0.75 mg to sitagliptin and placebo in 1,098 type 2 patients. At 52 weeks, both dulaglutide doses provided superior A1c reductions compared to sitagliptin (1.11%, 0.86%, and 0.39%, respectively), as well as larger improvements in body weight (-3.22 kg [-7.1 lbs], -2.7 kg [-6.0 lbs], and -1.63 kg [-3.6], respectively). Furthermore, a greater proportion of people in the dulaglutide 1.5 mg and 0.75 mg arms achieved the A1c goal of <7% (58% and 49%, respectively, vs. 33% for sitagliptin), as well as the A1c goal of 6.5% (42% and 29%, respectively, vs. 19% for sitagliptin). While dulaglutide was associated with a higher rate of GI side effects, Dr. Nauck noted that the rates fell within the range typically observed for long-acting GLP-1 agonists.

  • The doubled blind RCT enrolled type 2 patients who had been on either monotherapy (metformin or an oral anti-diabetic medication [OAM]) or combination therapy (metformin plus one OAM) with an A1c between 7.0% and 9.5%. Participants were first placed on metformin during the 11-week run-in period and then randomized to multiple doses of dulaglutide (ranging from 0.25 mg to 3.0 mg) for 13 weeks. Dr. Nauck explained that this phase mimicked a dose-ranging phase 2 trial and allowed Lilly to select the optimal doses for the subsequent phase 3 trial (AWARD-5). Patients not assigned to the selected doses were exclude from the phase 3 study. Lilly chose the 0.75 mg and 1.5 mg doses using a Clinical Utility Index, which takes into account efficacy and safety measures, with a focus on blood pressure and pulse rate effects – Dr. Nauck remarked that the full details of this process are being presented in poster 1045-P.
  • The phase 3 trial compared dulaglutide 0.75 mg and 1.5 mg (n=302 and 304, respectively) to sitagliptin (100 mg; n=315) and placebo (n=177). Patients randomized to placebo took the placebo capsule for 26 weeks (“for ethical reasons”) before switching to sitagliptin. At baseline, the participants had an average age of 55 years, weight of 86-87 kg (190- 192 lbs), and A1c of 8.1-8.2%. Dr. Nauck noted that while Lilly obtained both 52-week and 104- week data, his presentation would focus on the former. The 104-week data is detailed in poster 1004-P.
  • At 26 weeks, greater improvements in A1c were observed with dulaglutide 1.5 mg (- 1.22%) and 0.75 mg (-1.01%) compared to sitagliptin (-0.61%) and placebo (+0.04%). This pattern was also observed at 52 weeks, with larger A1c reductions observed for dulaglutide1.5 mg (-1.11%) and 0.75 mg (-0.86%) vs. sitagliptin (-0.39%; p<0.001 for both comparisons). At 52 weeks, the three treatment groups had ending mean A1c values of 6.83%, 7.08%, and 7.57%, respectively. Both dulaglutide doses also provided greater reductions in fasting plasma glucose (- 43 mg/dl for 1.5 mg and -29 mg/dl for 0.75 mg) compared to sitagliptin (-16 mg/dl).
  • Not surprisingly, greater weight loss was observed with dulaglutide 1.5 mg (-3.22 kg [-7.1 lbs]) and dulaglutide 0.75 mg (-2.7 kg [-6.0 lbs]) compared to sitagliptin (-1.63 kg [-3.6]).
  • On the safety front, dulaglutide 1.5 mg and 0.75 mg were associated with slightly higher rates of adverse events (77% for both groups) compared to sitagliptin (70%). Dr. Nauck commented that while dulaglutide was also associated with higher rates of GI side effects, the numbers fall within the range typically observed with long-acting GLP-1 agonists. All three groups experienced a similarly low rate of injection site reactions (1%), as well as comparable rates of hypoglycemia (1.6% for dulaglutide 1.5 mg; 2.6% for dulaglutide 0.75 mg, and 1.1% for sitagliptin). No cases of severe hypoglycemia were reported in the study.
    • The trial also tracked cases of pancreatitis and pancreatic cancer over 104 weeks. The rate of pancreatitis was zero cases for the dulaglutide arms and 3 cases/1,000 patient-years in the sitagliptin arm. No cases of pancreatic cancer were reported.

Questions and Answers

Q: Can you tell us something about the biodistribution of the compound? It might be more concentrated in certain compartments such as the lymph nodes. We know that GLP-1 can act on T cells and B cells.

A: I can’t give you a detailed account of how this molecule is distributed in circulation. I can tell you that the half life is 5 days, so it’s in the circulation for quite a period of time. It’s thought to be degraded within the circulation. So I think the question you ask is very justified and it would be interesting to know such details – i.e., what is the concentration of dulaglutide in lymph vessels. I think we need to ask the company to do such details.

Q: Is it degraded in kidney?

A: It is not degraded in the kidney. All the large, once-weekly agonists are somewhat coupled to a big protein. The purpose is to circumvent the fact that the original peptide related to GLP-1 is cleared in the kidney. This is also another compound that could be tested in renally-impaired patients.

Q: Regarding the adaptive design, it was very interesting, very nice. I’m guessing that because of the short timeframe, the reason for choosing the doses of the drug was the side effect profile. You have 17% nausea, 13% vomiting. What happened when you tested the higher doses?

A: I think we should go to poster 1045-P for these details. The major reason for not selecting the 3 mg dose was cardiovascular parameters – e.g., pulse rate and blood pressure. It wasn’t because of GI side effects.

Q: Was there a change in pulse rate in this trial?

A: We saw minor changes in pulse rate that are typical for most long-acting GLP-1 agonists.



Guillermo E. Umpierrez, MD (Emory University, Atlanta, GA)

Dr. Guillermo Umpierrez treated us to the full results of the AWARD-3 trial, part of the phase 3 package for dulaglutide (Lilly) that was presented at this session. AWARD-3 compares dulaglutide to metformin in monotherapy, for patients with an average duration of 2.6 years of diabetes, and an A1c of 7.6%. Results indicate that dulaglutide has a superior A1c reduction at 26 weeks (around 0.2% better than metformin, but statistically significant), together with a higher percentage of patients reaching target. The dulaglutide 1.5mg dose had an identical effect on weight as metformin at 26 weeks, although the data suggested that it weight was trending less favorably than metformin at 52 weeks. Adverse events were comparable (mainly GI in nature), so Dr. Umpierrez was able to conclude that dulaglutide was superior to metformin in monotherapy. However, in the Q&A Dr. Rosenstock (chairing the session) admitted that while dulaglutide was statistically superior, he didn’t think it was clinically superior. Dr. Umpierrez countered that since a significantly greater percentage of people reach target, then by definition it has to be clinically superior.

  • This study, AWARD-3, is part of a series of five phase 3 trials, leading up to Lilly’s FDA submission for dulaglutide (a once-weekly injectable GLP-1 agonist) scheduled for 2013. Lilly has previously announced top-line results for the AWARD trials that are covered in this session (see our report at
  • This double blind randomized controlled study is designed to compare dulaglutide at two doses (1.5 mg and 0.75 mg once weekly) with metformin in monotherapy over 52 weeks. Participants were randomized to dulaglutide plus oral placebo (two doses) or metformin (1,500 or 2,000 mg/day according to tolerability) plus injectable placebo. The 807 treatment naïve participants were randomized, and at baseline, A1c was low at 7.6%, BMI was 33 kg/m2, average age was 56 years, and duration of diabetes a relatively short 2.6 years, since it was an early trial.
  • At 26 weeks, patients taking dulaglutide 1.5 mg experienced a mea 0.8% A1c reduction from baseline, which was 0.22% better than metformin (p<0.025). Dulaglutide was also superior at 52 weeks vs. metformin (A1c reduction for dulaglutide 1.5 mg was 0.7% lower than baseline and 0.17% lower than metformin). However, the lower dose dulaglutide was non-inferior, but not superior to metformin at 52 weeks. For the high dose dulaglutide, A1c showed a rapid reduction over the first 13 weeks, with a slight rise from week 26 to week 52. At 26 weeks, 62% of patients achieved a target of ≤7% A1c in the dulaglutide 1.5 mg arm, compared with 54% of metformin patients.
  • At 26 weeks, both the metformin and dulaglutide 1.5 mg arms showed the same weight loss, around ~4.4 lb (2 kg). By 52 weeks, dulaglutide patients appeared to be gaining weight compared to metformin patients, but the difference was non-significant. Overall adverse events were similar in all three arms – GI side effects were the largest component.

Questions and Answers

Q: [Dr. Rosenstock] Dulaglutide maybe be statistically superior, but maybe not clinically superior – I would conclude that dulaglutide is effective, but you would never use it in monotherapy instead of metformin.

A: The number of people achieving A1c targets was significantly greater than metformin so it is clinically better. On A1c, dulaglutide is up to 0.4% better, and we think that this is clinically significant.

Q: Do you have any blood pressure data?

A: I didn’t show blood pressure data but there is 2mmHg difference in favor of dulaglutide - but it’s not significant.

Q; Did you ever consider the cost efficacy of this drug? Because metformin is very cheap…

A: [Dr. Rosenstock] Obvious!



Michael Trautman, MD (Eli Lilly, Indianapolis, IN)

Dr. Michael Trautman presented three-year results from the DURATION 3 study, which compared the safety and efficacy of exenatide once weekly and insulin glargine in people with type 2 diabetes. Overall, treatment with exenatide once weekly was associated with greater reductions in A1c (7.3% vs. 7.5%; p=0.033) and weight (-2.49 kg vs. +2.0 kg; p<0.001) than with insulin glargine in the ITT groups. However, insulin glargine provided greater improvements in fasting glucose than exenatide once weekly (-47.4 mg/dl vs. -31.2 mg/dl; p<0.001). Expectedly, incidence of minor hypoglycemia was significantly lower with exenatide once weekly compared to insulin glargine throughout the three-year period. No new safety signals were detected, with one incidence of pancreatitis in both treatment groups. Finally, exenatide antibodies were found to decrease over time, with 80% of individuals anti- body negative at three years. There was no association between exenatide anti-body status and degree of clinical effect.

  • DURATION 3 was a three-year open label, randomized controlled study that compared the safety and efficacy of exenatide once weekly with titrated insulin glargine. Insulin glargine was continuously titrated following a treat to target algorithm. Exenatide once weekly was administered as a fixed 2.0 mg dose. The study randomized 223 individuals to receive insulin glargine and 233 individuals to receive exenatide once weekly. At three years, 140 individuals remained in the exenatide once weekly arm and 147 individuals remained in the insulin glargine arm. Both arms were balanced at baseline, with an average A1c of 8.3%, body weight of 90 kg, and average duration of diabetes of eight years. 70% of patients in both arms were inadequately controlled on metformin alone, whereas the other 30% were inadequately controlled on metformin and a sulfonylurea. These baseline drugs were continued throughout the trial. Importantly, there were no differences in baseline characteristics between the intent to treat and the completer populations.
  • Exenatide once weekly provided a greater average reduction in A1c over three years vs. insulin glargine. Rapid reductions in A1c through week 36 were observed in both arms. Following week 36, A1c steadily increased with both treatments at approximately the same rate. At three years, however, average A1c remained statistically significantly lower in the ITT group with exenatide once weekly treatment (7.3%) vs. insulin glargine (7.5%; p=0.033). The average insulin glargine dose at three years was 39 IU/day. In the completer population, a similar result was observed with an average A1c of 7.1% in the exenatide once weekly arm vs. 7.4% in the insulin glargine arm (p=0.022). A greater percentage of patients were found to achieve the A1c goals of 7.0% and 6.5% with exenatide once weekly than insulin glargine at three years. In the ITT population, this result was only significant for the 6.5% target (24% v 15%; p=0.02). The 7.0% target was achieved by 40% of patients in the exenatide once weekly arm and 33% of patients in the insulin glargine arm (p=0.12).
  • Insulin glargine was associated with greater reductions in fasting plasma glucose. At three years, there was a -47.7 mg/dl reduction in FPG in the insulin glargine arm vs. a -31.16 mg/dl reduction in the exenatide once weekly arm. Dr. Trautman noted that this result was not surprising and suggested that the much of the glycemic benefit associated with exenatide once weekly is due to its impact on post-prandial control.
  • Exenatide once weekly provided significantly greater weight loss at three years vs. insulin glargine. In the ITT population, there was a weight gain of 2.0 kg with insulin glargine vs. a weight loss of 2.5 kg with exenatide once weekly (p<0.001). The weight loss achieved by exenatide was rapid, with maintenance beginning around week 36 through the end of the trial.
  • No surprising new tolerability and safety findings were reported. Minor hypoglycemia was reported less frequently with exenatide once weekly treatment than with insulin glargine. In the metformin subgroup, 12% of patients treated with exenatide once weekly vs. 40% of patients treated with insulin glargine reported one or more minor hypoglycemic episodes over three years. There was one event of pancreatitis in both groups. Anti-exenatide antibodies were found to decrease overtime, with 80% of the exenatide once weekly treatment group anti-body negative at three years. Further, there was no association between anti-body status and degree of glycemic effect.



Lawrence Leiter, MD (University of Toronto, Toronto, Canada)

Dr. Lawrence Leiter presented 26-week results from the HARMONY 8 trial, which evaluated the efficacy, safety, and tolerability of albiglutide (n=246) compared to sitagliptin (n=240) in people with type 2 diabetes and renal impairment inadequately controlled on lifestyle modifications or other oral diabetes agents. Through week 26, albiglutide (-0.8%) provided significantly greater reductions in A1c than sitagliptin (-0.5%; p=0.0003). Further, numerically greater reductions in A1c were observed with albiglutide regardless of renal impairment severity, although the result only reached significance for the moderate renal impairment group. However, Dr. Leiter noted that the trial was not adequately powered to detect these differences. Greater weight loss was also achieved with albiglutide than with sitagliptin (-0.8 kg vs. -0.2 kg; p=0.028). Both treatments were generally well tolerated and safe. The most common adverse side effects included diarrhea (8.8% with albiglutide vs. 6.1% with sitagliptin), constipation (6% vs. 2%), and nasopharyngitis (5.2% vs. 6.5%). Notably, nausea (4.8% vs. 2.8%) and vomiting (1.6% vs. 0.8%) rates were low in both groups. Although a greater proportion of people experienced hypoglycemia with albiglutide than with sitagliptin (20.5% vs. 13.4%), the majority (>90%) of cases in both arms occurred in participants who were also using an SFU. Antibodies to albiglutide were found in 2.8% of participants, but none of the antibodies were determined to be neutralizing. There was one incidence of pancreatitis in the albiglutide group, but it was determined to be non-related to treatment.

  • HARMONY 8 is a 52-week randomized, double blind, active controlled phase 3 study that will evaluate the efficacy, safety, and tolerability of albiglutide compared to sitagliptin in people with type 2 diabetes and renal impairment (eGFR <90 and>15 ml/min/1.73 m2) inadequately controlled on lifestyle modifications (11%) or oral diabetes agents (metformin, TZD, and/or SFU). After a four-week run in period, participants were randomized to 30 mg albiglutide once weekly (n=246) or sitagliptin (n=240). Albiglutide was uptitrated to 50 mg beginning at week four if glycemic targets were not met. Sitagliptin was dosed by degree of renal impairment according to product label. The treatment arms were balanced at baseline, with an average age of 63 years, BMI of 30 mg/kg2, A1c of 8.1%, and duration of diabetes of 11 years. Further, 8% of each group had a prior MI, 51% in each group were determined to have mild renal impairment (eGFR of 60-89 ml/min/1.73 m2), 40% moderate renal impairment (eGFR 30-60 ml/min/1.73 m2), and 9% severe renal impairment (eGFR <30 ml/min/1.73 m2).
  • Through week 26, albiglutide (-0.8%) provided significantly greater reductions in A1c than sitagliptin (-0.5%; p=0.0003). Further, numerically greater reductions in A1c were observed with albiglutide regardless of renal impairment severity, although the result only reached significance for the moderate renal impairment group. Dr. Leiter noted that the trial was not powered to detect statistically significant differences between these subgroups. In the mild renal impairment group, albiglutide provided an average A1c reduction of -0.72% vs. a -0.66% reduction with sitagliptin. In the moderate renal impairment group, a -0.88% reduction with albiglutide was observed vs. a -0.37% reduction with sitagliptin. In the severe renal impairment group, a -1.08% reduction in A1c was observed vs. a -0.65% reduction with sitagliptin. With regards to FPG, albiglutide provided statistically significantly greater reductions than sitagliptin(-26 mg/dl vs. 4 mg/dl; p<0.0001). A greater proportion of participants were also able to achievea target A1c of 7.0% with albiglutide (24.5%) than with sitagliptin (19.2%). 34% of participants in the albiglutide arm required uptitration to the 50 mg dose during the trial.
  • Greater weight loss was achieved with albiglutide than with sitagliptin. The albiglutide arm achieved an average weight loss of 0.8 kg vs. an average weight loss of 0.2 kg in the sitagliptin arm (p=0.028).
  • Both treatments were demonstrated to be generally well tolerated and safe. Drug related adverse effects were slightly more frequent in the albiglutide arm than the sitagliptin arm (19.7% vs. 13.0%). The most common adverse side effects included diarrhea (8.8% with albiglutide vs. 6.1% with sitagliptin), constipation (6% vs. 2%), and nasopharyngitis (5.2% vs. 6.5%). Notably, nausea (4.8% vs. 2.8%) and vomiting (1.6% vs. 0.8%) rates were low in both groups. Dr. Leiter attributed albiglutide’s low rate of nausea and vomiting to its long half-life, slow ramp up to therapeutic blood levels, and limited access to the CNS given its large size. With regards to hypoglycemia, there were no severe cases of hypoglycemia with albiglutide vs. two severe cases with sitagliptin. 20.5% of people in the albiglutide arm experienced hypoglycemia (94% of whom were also using an SFU) vs. 13.4% with sitagliptin (91% of whom were also using an SFU). Antibodies to albiglutide were found in 2.8% of participants, but none of the antibodies were determined to be neutralizing. There was one incidence of pancreatitis in the albiglutide group, but it was determined to be non-related to treatment. There were no incidences of pancreatitis in the sitagliptin group.

Questions and Answers

Q: How is albiglutide metabolized?

A: It is cleared by the reticuloendothelial system.

Q: What are your thoughts regarding the minimal GI side effects observed?

A: These results are consistent with previous data for albiglutide which showed a low incidence of nausea and vomiting. It is related in part to its once weekly injection, the gradual increased in blood drug levels, and the molecules large size, which possibly prevents CNS entry.

Q: Was there any difference in nausea rates with changing levels of renal impairment?

A: No, there was not.



Michaela Diamant, MD, PhD (VU University Medical Center, Amsterdam, Netherlands)

Dr. Michaela Diamant presented the results of a study directly comparing a prandial GLP-1 receptor agonist (exenatide BID) with a standard prandial insulin (insulin lispro T1DM). Following 12 weeks of basal insulin titration, participants who did not achieve A1c levels below 7.0% were randomized 1:1 to receive exenatide BID (5 g, titrated up to 10 g after four weeks, n=315) or insulin lispro treatment (n=312) for 30 weeks. This phase-3b 44-week open-label randomized, comparator-controlled interventional study found that both treatment arms achieved similar A1c reductions, but with lower fasting glucose, greater weight loss, less daytime hypoglycemia, and reduced systolic blood pressure observed among patients receiving exenatide BID.

  • In addition to establishing non-inferiority in A1c reduction (baseline after basal titration A1c 8.5%; exenatide 7.0% vs. 7.1% with insulin lispro at 44 weeks), while individuals receiving insulin lispro gained 2.1 kg (4.6 lbs), individuals receiving exenatide BID lost an average of 2.5 kg (5.5 lbs) after 30 weeks into treatment intensification. The change in fasting glucose was also 0.64 mmol/L (11 mg/dl) lower among patients receiving exenatide BID compared to patients receiving insulin lispro. Self-monitored blood glucose was also lower, except at lunch due to insulin lispro delivery at each meal, versus exenatide’s twice-daily delivery. At this time, approximately 15 more units of basal insulin were required daily by participants receiving exenatide BID (57 vs. 42).
  • Daytime hypoglycemia was found to be less frequent among individuals receiving exenatide BID than insulin lispro (15.2% vs. 33.7% incidence; p<0.001). Minor hypoglycemia was also less common; 40.7% incidence was reported among patients receiving insulin lispro, whereas only 29.5% incidence was observed among patients receiving exenatide BID (p<0.004). Given these results, Dr. Diamant believes that a short-acting GLP-1 receptor agonist may be a novel and efficacious treatment strategy for patients who fail on insulin and further intensification.


Oral Sessions: Novel Therapeutics


Alexander Fleming, MD (President & CEO, Kinexum, Harpers Ferry, WV)

As a fitting introduction to the session, Dr. Alexander Fleming discussed ways to facilitate the approval of promising diabetes therapies. As a former senior FDA official, Dr. Fleming was able to present a particularly insightful and pragmatic view of the diabetes drug approval process. He began his talk by discussing diabetes drugs that have recently been red-flagged for potential safety concerns, noting that the FDA seems to be erring on the side of caution due to fears of cardiovascular and cancer risks. He predicted that the regulatory environment would only grow more arduous in future years. To facilitate the development of novel therapies in the face of these challenges, Dr. Fleming recommended the use of Large Simple Trials (LSTs) conducted within healthcare systems, which retain the rigor of more commonly used clinical trial designs while reducing costs and accelerating trial timelines. He also cited the need for a stepwise approval system at the FDA, rather than the one-size-fits-all protocol that currently exists.

  • The FDA will always struggle with the balance between ensuring drug safety and facilitating rapid approval. Dr. Fleming noted that the pace of diabetes drug development has accelerated rapidly in the new millennium, with an accompanying increase in drug safety concerns. As examples, he cited the concerns regarding insulin analogs and tumors, liraglutide and thyroid cancer, and rosiglitazone and cardiovascular death. Regarding the latter case, he expressed his support for the FDA’s new cardiovascular safety protocol for diabetes drugs, but noted that the Avandia controversy was overblown. He emphasized that the results of non- prospective approaches such as epidemiological studies or meta-analyses should not be overstated or overly accepted, given the limitations of these study formats.
  • Dr. Fleming forecasted that moving forward, the FDA regulatory process for diabetes drugs will not get any easier. He noted that cancer signals have been raised in most classes of diabetes drugs, and that cancer risk is harder to rule out than cardiovascular risk due to the low frequency of cases and the long latency periods. He also recognized that large outcometrials like SYNCHRONY (a phase 2 study of aleglitazar’s CV risk) are typically not practical due to resources limitations. Regarding efficacy trials, he acknowledged the potential merits of using postprandial glucose levels as an endpoint instead of A1c reductions. However, he noted that postprandial glucose spikes only contribute to about one-third of overall glycemia, and that A1c would continue to be the primary endpoint recognized by the FDA Large Simple Trials (LSTs) can help facilitate the approval of novel therapies. Dr. Fleming noted that LSTs are prospective and randomized, and fulfill many of the criteria for standard phase 3 clinical trials. Although such trials cannot be used in the place of phase 3 trials, he noted that they have been used to satisfy FDA safety guidance in past cases. LSTs differ from standard trial paradigms in that they are conducted within healthcare networks, participation is facilitated through simple web-based documentation, and per-patient costs are lower. These factors enable larger trials that can be completed sooner, with easier FDA adjudication and greater data interpretability.
  • The FDA must embrace a stepwise approval system for diabetes drugs. Dr. Fleming stated that in such a system, drugs could initially be given a limited indication for a high-need group in which the risk-reward balance is more favorable; following this, the review process would proceed in a stepwise manner toward unrestricted approval. He noted that such a system would allow for larger outcome studies that could be completed earlier and with more favorable economics. He also emphasized that the FDA needs to move beyond indications that simply palliate the late-stage manifestations of diabetes, and instead focus more on treating prediabetes.

Questions and Answers

Q: To do a cardiovascular study, you are pressured to get patients who are closer to having events. They are more likely to have underlying cardiovascular disease, to be older, and to have various impairments. What are your thoughts on testing the new class of drugs in patients who have more advanced disease?

A: I believe this is exactly the rationale for a Large Simple Trial in the target population. Why do stress tests for the drug in a population where the drug may not be important?

Q: One of the issues about the need for huge studies is that A1c as a risk factor is so much weaker than other factors affecting cardiovascular disease such as cholesterol, meaning that glucose-lowering studies must enroll three to six times as many subjects to show significance compared to a cholesterol or blood pressure study. If you look at the data from trials in terms of the number needed to treat as opposed to percentage reductions, we need to treat over a hundred patients to prevent a cardiovascular single event.

A: I agree with just about everything you said, but I think we also have to agree that control of microvascular complication risk is also important. We can do that with available products, but to your point, cardiovascular residual risk is very difficult to address as simply a glycemic play.

Q: If you’re 60 years old, with a hemoglobin A1c of 9%, you have a lifetime risk of blindness of less than 1%. The number needed to treat for that group would be about 400. Because macrovascular disease dominates the classical diabetes population, don’t you think the main focus has to be the macrovascular profile, and that we shouldn’t get too bewitched with microvascular factors?

A: I think we agree it’s all about benefits and risk. Certainly, residual cardiovascular risk is a major issue in people with diabetes, and that does overwhelm what you can do in an elderly patient in terms of microvascular complications.



Thomas Jax, PhD (Profil, Neuss, Germany)

Dr. Jax presented steady state pharmacokinetics and pharmacodynamics results with a novel 300 U/ml formulation of insulin glargine (GlarU300) as compared to the current 100 U/ml formulation. Though single subcutaneous injections of GlarU300 have demonstrated prolonged duration of action and a flatter profile versus standard glargine in previous studies, this trial aimed to examine if these effects persist once patients are in the steady state. In the trial, patients with type 1 diabetes were randomized to receive either an eight-day regimen of 0.4 U/kg daily (n=18) or 0.6 U/kg daily (n=12) GlarU300, with crossover to an eight-day regimen of 0.4 U/kg daily dose of standard U100 glargine. When patients were monitored with a euglycemic clamp after the last injection at the end of each eight-day regimen, euglycemia was maintained for longer with the 0.4 U/kg U300 formulation (~32 hours) and 0.6 U/kg U300 dose (~34 hours) versus standard U100 glargine (~29 hours); these results were supported by a flatter and more constant profile of serum insulin glargine concentrations with GlarU300 at both doses versus standard U100 glargine as well. Dr. Jax suggested these changes could improve control while reducing the risk of hypoglycemia, though we await clinical outcomes data from the EDITION-I study, to be presented later in this meeting.

  • In the trial, patients with type 1 diabetes were randomized to receive either an eight- day regimen of 0.4 U/kg daily (n=18) or 0.6 U/kg daily (n=12) GlarU300, with crossover in 2x2 design to an eight-day regimen of 0.4 U/kg daily dose of standard U100 glargine. Patients were monitored with a euglycemic clamp for 36 hours after the last injection at the end of each eight-day regimen.
  • Using the euglycemic clamp, euglycemia was maintained for longer with the 0.4 U/kg U300 formulation (~32 hours) versus standard U100 glargine (~29 hours), with a lower maximum glucose infusion rate as well (2.6 mg/kg/min vs. 3.4 mg/kg/min). The 0.6 U/kg U300 patients demonstrated an even longer 34 hours of euglycemia, though a higher maximum glucose infusion rate (4.4 mg/kg/min).
  • These clamp results were supported by a flatter and more constant profile of serum insulin glargine concentrations with GlarU300 at both doses versus standard U100 glargine. Similarly corroborative, glargine exposure was quantifiable with 0.4 U/kg GlarU300 for 32 hours and with 0.6 U/kg GlarU300 for 36 hours, with 28 hours of quantifiable exposure with 0.4 U/kg U100 glargine. The half-life for the 0.4 U/kg dose of GlarU300 was 14.4 hours, 13.8 hours for the 0.6 U/kg dose, and 11.2 hours for 0.4 U/kg standard U100 glargine.

Questions and Answers

Q: There is a lot of variability in the environments of patients, particularly with type 1 diabetes. How would you adjust for when patients need to change their dose on the fly?

A: The concept of the basal insulin is you want a steady state as much as possible. The theory is if you have a duration of action for a longer period you have a more stable glucose control. That said, this is clearly

intended for once-daily subcutaneous injection, not necessarily for pump patients with rapid changes in dosing.

Q: I was a little surprised that the duration of action was not so different from standard glargine. Any comment on that?

A: Although there may only seem to be a small difference, it may make a large clinical difference. Those studies are on the way.

Comment: The duration of action is dose-dependent, so one should look at the basic insulin requirements of the people in this study beforehand.

Q: When comparing the two formulations, it looks like your data showed a peak with glargine standard when compared to the new formulation, but no peak with older studies versus NPH. Have you been able to identify populations that show more pronounced curves or others in whom it is truly flat?

A: To our knowledge, we don’t know certain populations. But there are two things to remembers here. The data there was from two different studies; the graphs here also have a different scale, so the curves look a little more pronounced.



Christof Kazda, MD, PhD (Eli Lilly and Company, Suresnes, France)

Dr. Christof Kazda presented phase 2 data on Lilly’s once-daily competitive glucagon antagonist LY2409021. The 24-week study randomized 254 type 2 patients (treatment naïve or on metformin) to one of three LY2409021 doses (2.5 mg, 10 mg, 20 mg) or placebo. At baseline, the participants had an average age of 56 years, diabetes duration of six years, A1c of 8.0%, and BMI of 32 kg/m2. Notably, the completion rate was quite low (ranging from 46% in the placebo group to 67% in the LY2409021 20 mg group) due to very stringent criteria for loss of glycemic control (at which point patients were required to drop out). At 24 weeks, LY2409021 20 mg and 10 mg provided significantly greater A1c reductions (0.92% and 0.78%, respectively) compared to placebo (0.15%; p<0.001 for both comparisons). The proportion of patients achieving an A1c ≤6.5% was statistically significantly greater in these two LY2409021 arms compared to placebo. The main safety analysis centered on the drug’s effects on serum alanine aminotransferase levels: while mild elevations in hepatic aminotransferases were observed, levels returned to baseline with continued treatment or after drug discontinuation. Consistent with previous observations, LY2409021 treatment led to increases in fasting plasma glucagon (three-to-four fold greater than baseline values), which stabilized after four weeks of treatment and resolved with drug discontinuation. LY2409021 had no clear effects on body weight, blood pressure, heart-rate, or plasma lipid levels, and the rates of hypoglycemia were similar across all the study groups.

Questions and Answers

Q: Interesting study. I guess the baseline liver enzymes were in the normal range. Unfortunately, many type 2 diabetes patients have elevated levels. So you have to study the drug in more detail in such patients. Do you have any idea of the mechanism behind the transient increase in transaminases?

A: We’ve been studying the mechanism very closely. It’s a mechanism-of-action-based phenomenon because other companies like Merck have also developed glucagon receptor antagonists and they saw the same phenomenon. Obviously, it’s not a toxic effect of this molecule itself; it’s obviously related to the mechanism. We have an ongoing study using magnetic resonance spectroscopy. In the animal experiments, even at doses significantly higher than those used in humans, we didn’t see any increase in ALT levels or any increases in liver fat in the animals, so it’s difficult to speculate on the mechanism behind this, but most likely it’s linked to the blockade of glucagon.

Q: You didn’t see any significant hypoglycemia in your study here. If you took this drug with a medication that causes hypoglycemia, would you expected a reduced counterregulation for hypoglycemia?

A: That’s an important question. We studied this in a hyperglycemic clamp study – under the presence of this glucagon antagonist, in concentrations that were equal to the concentration of the molecule in the body at the highest dose, we saw no change in the recovery from insulin-induced hypoglycemia. I agree that we still have to do studies of this drug in combination with hypoglycemia-inducing agents.

Q: In all the animal models you will have hyperglucagonemia and alpha cell hyperplasia. Is that a concern here and if so, how do you monitor for it?

A: What we are monitoring is plasma glucagon levels. These are the data I’ve shown to you. We have a three-to-four-fold increase in glucagon levels at this dose; this is a competitive antagonist to the receptor. The animal model you’re pointing to is a complete knockout of the receptor where the increase in glucagon is 500-times as much as what we observed with our model. So I think that you cannot compare the two.

Q: When you have drug withdrawal, do the drops in glucagon levels match the drug PK?

A: That’s completely right. The glucagon levels drop and the drop in glucagon nicely reflects the PK profile of the compound. The half life is about 25 hours.

Q: Very nice presentation. You mentioned that you didn’t see any steatosis in the animal models. Did you study diabetic animals?

A: We didn’t study diabetic animals.

Q: That’s something you should do, because it makes a difference.

A: Yes, that’s why we’re doing magnetic resonance spectroscopy.

Q: Did the drug affect any parameters such as glycerol, ketone bodies – any of that sort?

A: We looked at free fatty acids, and the triglycerides did not change; the free fatty acids did not change at all.

Q: In your clamp studies, did you measure different hormones? Was there a difference in the response?

A: Good point. When you measure all these response hormones, interestingly, there was absolutely no difference in cortisol, growth hormone, or epinephrine. The only difference was a higher response in glucagon to hypoglycemic events. The theory is that since this is a competitive antagonist, not an antibody, it could be pushed from the receptor by elevated glucagon concentration. That’s why we think that the response to the recovery of hypoglycemia was not different.



Stephanie M. Gustavson, PhD (TransTech Pharma, High Point, NC)

Dr. Gustavson presented the results of a four-week trial examining the safety and efficacy of TTP054, a phase 2 oral GLP-1 agonist currently in development by TransTech Pharma. In the trial, patients with type 2 diabetes on background metformin were randomized to receive either TTP054 400 mg QD (n=9), TTP054 200 mg BID (n=10), TTP054 200 mg QD (n=11), or placebo (n=18). TTP054-treated patients demonstrated consistently greater declines in fasting plasma glucose (-15 mg/dl with 200 mg QD, -18 mg/dl with 200 mg BID, and -20 mg/dl with 400 mg QD vs. -5 mg/dl with placebo) and two-hour postprandial glucose (-30 mg/dl, -32 mg/dl, and -35 mg/dl vs. no change with placebo) versus placebo- treated patients; while not long enough in duration to produce change in A1c, predictive models estimated A1c change at three months at about 0.6-1.0% across doses, which Dr. Gustavson suggested was a conservative estimate given the study design. Notably, TTP054-treated patients demonstrated no hypoglycemic events, with incidence of GI adverse events similar to those observed in the placebo arm. Dr. Gustavson noted that all phase 1 studies with TTP054 have completed, with one 12-week phase 2 study just recently completed. Given the reduction in GI adverse events and convenience, we will be interested to follow TTP054 as further clinical data is released. The company currently has another oral GLP-1 candidate, TTP273, in development; other companies known to have oral GLP-1 candidates include Zydus Cadila (ZYOG1; phase 1), Arisgen (preclinical), Heptares (preclinical), and Novo Nordisk (NN9924, NN9926, NN9927; all phase 1).

  • TTP054 is a phase 2 oral GLP-1 agonist currently in development by TransTech Pharma. In addition to the convenience of oral administration, given administration is through the intestine, it is expected the drug will have a lower incidence of GI adverse events versus injectable GLP-1; additionally, the oral drug is a small molecule agonist rather than a peptide, so it is believed it will not incur antibody formation. Dr. Gustavson noted that TTP054 has completed phase 1 studies, with one 12-week phase 2 study recently completed. An additional candidate TTP273 is in development with proof of mechanism demonstrated and phase 2b trials to begin in early 2014.
  • In this trial, patients with type 2 diabetes on background metformin were randomized to receive either TTP054 400 mg QD (n=9), TTP054 200 mg BID (n=10), TTP054 200 mg QD (n=11), or placebo (n=18) for four weeks. Evidencing proper absorption, TTP054 had a median Tmax of ~3 hours and mean terminal half-life of ~6 hours.
  • TTP054-treated patients demonstrated consistently greater declines in fasting plasma glucose (-15 mg/dl with 200 mg QD, -18 mg/dl with 200 mg BID, and -20 mg/dl with 400 mg QD vs. -5 mg/dl with placebo) and two-hour postprandial glucose (-30 mg/dl, -32 mg/dl, and -35 mg/dl vs. no change with placebo) versus placebo-treated patients. As the trial was too short in duration to show A1c change, Dr. Gustavson relied on various models to estimate A1c change at three months using these effects on glucose variables. Across four models of predicted change, declines in A1c were roughly -0.7% with 200 mg QD, -0.6% with 200 mg BID, and -1.0% with 400 mg QD versus -0.2% versusplacebo (baseline A1cs 8.1%, 8.1%, 8.3%, and 7.7%, respectively). Additionally, she suggested these estimates were conservative, given the meal challenge in this trial was small with no stabilization of diet prior to assessment and glucose lowering was continuing to decline with treatment at the time of assessment.
  • TTP054-treated patients demonstrated no hypoglycemic events, with incidence of GI adverse events similar to those observed in the placebo arm (2/11 patients [18%] with 200 mg QD, 0/10 patients [0%] with 200 mg BID, and 1/9 patients [11%] with 400 mg QD vs. 1/18 [6%] with placebo). Dr. Gustavson suggested all GI adverse events were mild in severity with investigators indicating adverse events were due to diet rather than the study treatment. While not powered to assess changes in lipids, Dr. Gustavson suggested that the maximum change in triglycerides with TTP054 was -50 mg/dl versus -10 mg/dl with placebo and that the maximum change in total cholesterol was -15 mg/dl versus +5 mg/dl with placebo, indicating a potential benefit.

Questions and Answers

Q: Do you have evidence of effect on GI motility?

A: We did look at GI motility in other studies and saw reduction. We also saw reduction in gastric emptying, so we think the drug is acting in the same way as the mimetics.


Current Issues: Should Sulfonylureas Remain an Acceptable First-Line Add-On Therapy to Metformin? (Supported by an unrestricted educational grant from Merck)

Session chair, Dr. Fred Whitehouse, opened by remarking upon how history repeats itself – at the ADA scientific sessions in the 1970s they argued about what to do with SFUs, and here we are in 2013 debating whether SFUs are an appropriate second-line agent.



Martin Abrahamson, MD (CMO, Joslin Diabetes Center, Boston, MA)

In front of a standing-room-only audience of roughly 1,000 people, Dr. Martin Abrahamson presented his argument for why sulfonylureas should remain an acceptable add-on to metformin: the crux of his argument was “why not” keep SFUs around when no good evidence exists for stopping their use? He argued that, when used appropriately 1) there is no clear evidence that SFUs accelerate beta cell decline; there is no evidence of increased beta cell apoptosis when used with metformin; 3) there is no evidence that they are less safe than other medications when used appropriately; and 4) there is evidence that they are effective, cheap, and well-tolerated. In our view, the caveat of “if used appropriately” is a huge one and represents a major challenge for prescribers today – since other second-line agents like DPP-4 inhibitors that require less prescriber hassle now exist, we would argue that this is a meaningful argument against using SFUs except in the very poor where there is no other economic choice and metformin is contra-indicated. Dr. Abrahamson identified the appropriate population for SFUs as younger patients early in disease progression with low risk for hypoglycemia. Overall, while we found Dr. Abrahamson’s argument to be well-prepared and thoughtful, we did not find the arguments terribly convincing. After the panel discussion, a consensus seemed to form between Drs. Abrahamson and Genuth that not all SFUs are created equal – they agreed that glyburide (aka glibenclamide), should definitely not be used – and that SFUs are most appropriate for only a select group of patients early in disease progression. See the table below for a summary of Dr. Abrahamson’s comparison of efficacy, tolerability, safety, durability, and cost of the various diabetes drug classes.

  • Efficacy: Dr. Abrahamson presented data demonstrating that SFUs have great A1c- lowering efficacy compared to other anti-diabetic agents. He presented data from a newly-published meta-analysis demonstrating that SFUs lowered A1c by 1.5% when used asmonotherapy (median study duration was 16 weeks; baseline A1c ranged from 4.7-13.6%; Hirst et al., Diabetologia 2013). In the same study, SFUs added onto metformin or TZD lowered A1c an additional 1.6% (n=4 studies; duration 16-52 weeks; baseline A1c 7.5-9.5%). We note that these are relatively short studies that would not capture SFUs’ lack of durability. Additionally, he cited head-to-head comparative effectiveness studies of liraglutide vs. glimepiride and liraglutide vs. sitagliptin, demonstrating that while liraglutide and glimepride showed similar efficacy over 26 weeks, sitagliptin demonstrated inferior efficacy to liraglutide (Nauck et al., Diabetes Care 2009; Pratley et al., Lancet 2010). He concluded that SFUs, TZDs, GLP-1 agonists, and insulin are highly effective and that DPP-4 inhibitors are moderately effective. Most notably, Dr. Abrahamson presented evidence demonstrating that half-maximal doses of glyburide and glipizide were just as effective as full doses, suggesting that lower doses could be prescribed to minimize side effects (Hurren et al, Diabetologia 2013).
  • Tolerability/side effects: Dr. Abrahamson argued that sulfonylureas were “highly tolerable” with the side effects of weight gain and moderate risk of hypoglycemia. He stated that in studies where SFUs have been used as comparators, there are usually no difference in overall rates of adverse events – we speculate that this is because these trials are designed to demonstrate that new agents are non-inferior to the existing standard of care, not to assess the safety of SFUs. He acknowledged that glyburide is the one SFU associated with more hypoglycemia than the other SFUs. However, he cited UKPDS hypoglycemia data as evidence that other SFUs have acceptable rates of hypoglycemia: in the UKPDS long term follow up, the rate of hypoglycemia in the conventional, chlorpropromide, glyburide, and insulin groups, respectively was 0, 1.0, 1.4, and 1.8 per year. We found it quite odd that the rate of hypoglycemia on insulin would be so low and would argue that relatively speaking, a hypoglycemia rate of >50% that of insulin is still quite undesirable. Dr. Abrahamson concluded that SFUs are highly tolerable, more so than TZDs or GLP-1 agonists; that the relevant side effects are hypoglycemia and weight gain; and that the risk for hypoglycemia is moderate compared to a high risk on insulin and a low risk of TZDs, DPP-4 inhibitors, and GLP-1 agonists.
  • CV safety: Dr. Abrahamson argued that CV safety of newer-generation SFUs is neutral. While the UGDP study in the 1970s suggested that sulfonylurea use was associated with increased CV harm, Dr. Abrahamson pointed to the UKPDS long-term follow up to show that the insulin/SFU arm actually experienced a legacy effect reduction in overall mortality, any diabetes- related endpoint, and myocardial infarction. Additionally, he stated that the BARI-2D study showed that patients randomized to “insulin-sensitizing therapies vs. insulin-providing therapies” experienced no difference in rates of survival or CV events. He concluded that SFUs, TZDs, and insulins have neutral CV safety, whereas the CV safety of DPP-4 inhibitors and GLP-1 agonists is unknown (he did not mention the recently-announced neutral results of Onglyza’s SAVOR-TIMI trial [see more detail at nor the fact that pooled analyses of CV risk for these classes suggest the possibility for CV benefit). Overall, given the chatter about beta cell burnout in at least some SFUs, and given that almost everyone on SFUs gains weight (negative for CV health by any definition) we thought arguing for neutrality was a leap – this may be just because other classes have no questions.
  • Durability: Dr. Abrahamson acknowledged that that there was evidence for lack of durability when using glyburide as monotherapy, but stated that there was no evidence for lack of durability of a metformin/SFU combination. In ADOPT, the time to drug failure (defined as A1c ≥7%) was 2.75 years for glyburide, 3.7 years for metformin, and4.75 years for rosiglitazone. He emphasized that this was not a combination therapy study andthat glyburide actually conferred better average glucose control during the first year. Dr. Abrahamson suggested that since none of the drugs tested were sufficient as monotherapy, it was perhaps a moot point to discuss monotherapy data and that combination therapy early in disease progression will be necessary to get more people to goal. He showed that while glyburide by itself at supraphysiological doses has produced beta cell apoptosis in in vivo models, this result has not been reproduced with other SFUs. In addition, metformin appears to be protective on beta cell apoptosis, and there is no data on the effect of metformin and SFU together on beta cell apoptosis.
  • Finally, Dr. Abrahamson discussed the economic burden of treating hyperglycemia: he argued that with diabetes costing the US $245 billion/year, and $18 billion of that going towards antihyperglycemic medications, that cost was a significant factor to consider. However, we would counter his argument by saying that since the costs of hospitalization, inpatient care, and treating complications far outweighs the costs of medications and supplies, that actually spending more on the best treatment options would be a better use of money and potentially save money in the end. On an individual level, however, for patients who do not have insurance and cannot afford any non-generic diabetes medications, of course we would argue that cost for the individual becomes a significant consideration.
  • Dr. Abrahamson’s comparison of the efficacy, tolerability, safety, durability, and cost associated with diabetes drugs:




















Side effects

Hypoglycemia Weight gain

Edema, CHF, Fractures

Weight gain

Rare pancreatitis


Rare Pancreatitis

Hypoglycemia Weight gain

Risk of Hypoglycemia






CV Safety




















Saul Genuth, MD (Case Western Reserve University, Cleveland, OH)

Dr. Saul Genuth represented the con argument in the sulfonylurea debate. While he began by acknowledging the merits of sulfonylureas, he then noted that many other drug classes are as effective as SFUs (if not more) and also safer. He shared a wealth of data drawn from numerous clinical studies which indicate that SFUs have comparable efficacy to TZDs, DPP-4 inhibitors, and GLP-1 agonists. He cited the ADOPT study as an example, as it showed that glyburide provided inferior glycemic control compared to rosiglitazone. Importantly, all three alternative drug classes have demonstrated a lower risk of hypoglycemia compared to SFUs; furthermore, two classes (DPP-4 inhibitors and GLP-1 agonists) have neutral or beneficial effects on body weight, compared to the weight gain seen with SFUs. Dr. Genuth remarked that the cardiovascular data on SFUs to date has been generally poor and thus not conclusive. As a result, he recommended that SFUs be moved to a lower tier in the ADA/EASD algorithm for type 2 diabetes. In concluding Dr. Genuth noted that the low cost of SFUs has real-world significance, and that the medical community should fight to lower the prices of newer and safer therapies to increase patient access.  

  • Sulfonylureas are no more effective than other drug classes at lowering A1c values. Dr. Genuth acknowledged that combination therapy with SFUs and metformin led to a sizeable reduction in A1c compared to either agent alone; however, the efficacy profile of this combination is comparable to (or worse than) those of other drug classes. He began by comparing SFUs with TZDs – two studies comparing glimepiride to pioglitazone showed comparable efficacy, while another comparing gliclazide to pioglitazone also showed similar reductions in A1c. Dr. Genuth cited the results of the ADOPT study, which showed that glyburide led more significantly more monotherapy failure (sustained A1c above 8%) than TZDs. Moving on to incretin mimetics, he presented evidence from clinical trials demonstrating incretins provide similar glycemic control compared to SFUs.
  • Several studies indicate that SFUs have a worse safety profile compared to other drug classes. To Dr. Genuth, this issue is the primary argument against the use of SFUs. Anatomical studies have shown that SFUs lead to an increase in atheroma volume, increasing the risk for adverse cardiovascular events. Dr. Genuth cited an epidemiological study that demonstrated a higher cumulative incidence of cardiovascular disease death with SFUs compared to metformin (Roumie et al., Ann Intern Med 2012), although he noted that the UKPDS did not show a similar finding. Dr. Genuth then turned to the topic of hypoglycemia, starting with the joint ADA/Endocrine Society workgroup statement that SFUs are the oral agents with the greatest risk for hypoglycemia. Many of the same studies that investigated the comparative effectiveness of diabetes drug classes showed that TZDs, GLP-1 agonists, and DPP-4 inhibitors resulted in substantially less hypoglycemia than SFUs. Dr. Genuth mentioned other safety concerns associated with SFUs, including the potential for adverse interactions with a wide range of drugs such as allopurinol, warfarin, ASA, and sulfonamides. He noted that SFUs can cause weight gain, while drug classes such as GLP-1 agonists generally promote weight loss. Of note, one study showed that SFU use led to an increase in the albumin/creatinine ratio compared to TZD use (Matthews et al., Diabetes Metab Res Rev 2005). Dr. Genuth argued that these safety data convincingly demonstrate that SFUs should not occupy the same tier on the FDA/EASD algorithm as other safer drug classes.



Martin Abrahamson, MD (CMO, Joslin Diabetes Center, Boston, MA); Saul Genuth, MD (Cleveland Clinic, Cleveland, OH)

Q: In this day and age, when people come in with shopping bag of medications, why add another pill? Why not get back on diet and lose some weight?

Dr. Abrahamson: I would be the first person to advocate for lifestyle as a major aspect of managing type 2 diabetes. I think the reality of what we’ve seen in clinic, what we see from clinical studies, is that diet and exercise work to some degree, but adherence to that is difficult. Ultimately the majority of patients are going to need medications in addition to metformin to manage their diabetes and get to goal. I think the challenge when considering use of a SFU is to determine which patients are least likely to develop hypoglycemia. I will commend my colleague Dr. Genuth for focusing on hypoglycemia as an issue, and I would agree with him. But not withstanding that issue, for patients unlikely to develop hypoglycemia using low doses and who start therapy early in the natural history of the disease, you’ll have a positive impact on A1c, which will result in favorable outcomes.

Dr. Genuth: SFUs are most effective early in the disease. The UKPDS study began SFU treatment at time of diagnosis. Already, though, these people had had type 2 diabetes probably 5-10 years before they showed up. Lifestyle modification certainly is effective, but it doesn’t last. My argument is it’s not perverseness of patients that we have to fight against; it’s not that our physicians don’t know how to teach people about exercise. I believe that the inability to restrict caloric intake and the inability to exercise consistently are symptoms of type 2 diabetes. I think patients are struggling against their disease. We’re not struggling against their perverseness.

Q: It seems like we have a hung jury. Since both speakers mentioned that the real bad actor is glyburide, is the appropriate compromise to say that SFUs are still a reasonable option if we’re talking about the newer ones and we eliminate glyburide from the list?

Dr. Genuth: I think we should add to the compromise that we should restrict their use to people under age 70.

Dr. Abrahamson: It’s amazing how early we are coming to consensus in this debate. I would concur. I would say that glyburide is an inappropriate drug to use and should be removed from the market, and I agree with Dr. Genuth that restrictions should be placed on its use regarding age. Still, the sad thing is that we’ve got a lot of people developing this disease much earlier on than we would have like to imagine.

Q: I would like to add three comments – first, one big mistake is that we mix all SFUs in one bag. It is very clear that glimepiride and longer-acting glipizide have much lower weight gain than glyburide and short-acting glipizide. I refuse the argument for hypoglycemia and weight gain with longer-acting SFUs. The other comment for Dr. Genuth – in trying to scare people from hypoglycemia, you said that SFUs had a six-times higher risk for hypoglycemia than DPP-4 inhibitors, but the absolute number of cases was low (about 1% in the DPP-4 arm). Additionally, you mentioned hypoglycemia in the VADT and ACCORD trial, though everyone in the audience understands that most hypoglycemia in those trials was caused by insulin. A final point to Dr. Abrahamson – why do you say that CV safety is neutral? The UKPDS showed very clearly that there was a cardioprotective legacy effect, so doesn’t that show a CV benefit for SFUs?

Dr. Genuth: Those are some valid points. I think any one case of serious hypoglycemia that results in death, is too many because it’s iatrogenic. So I’m less interested than you are in the actual incidence being low. I’m more impressed that some people have died and still can die when SFUs are used inappropriately. I think we’re beginning, as pointed out, to develop a consensus, which is a terrific outcome of this discussion, and maybe we all should write the next paper with a little more common sense than the last one [Editor’s note: we believe he was referring to the 2012 ADA/EASD position statement].

Dr. Abrahamson: I think we must not draw too many conclusions about SFUs’ cardiovascular benefit. The UKPDS extension demonstrated that those randomized to intensive therapy had fewer CV events – that was a manifestation of improved glycemic control rather than the specific impact of a drug. At least from my argument perspective, I think these drugs are neutral, which to me is adequate grounds to say there’s no evidence to support that these drugs pose cardiovascular risk.

Dr. Genuth: You may have to remind me, Martin, but my memory for the legacy effect was that the legacy effect was in the SFU/insulin group, so I’m reluctant to say that that demonstrates purely a SFU effect.

Q: We’re looking here at only second-line drugs in trials that last only five years, which in terms of this disease is relatively short term. In the long game, the thing that’s going to limit us in controlling our patients is hypoglycemia, and specifically hypoglycemia awareness. I think we know that the more hypoglycemic patients have, the more they develop hypoglycemia awareness. So if we’re looking at how we responsibly give our patients drugs, I think we need to accelerate hypoglycemia awareness.

Dr. Abrahamson: I think the point here is that nobody wants to cause hypoglycemia in the first place. What you’re referring to is the phenomenon of repeated episodes of hypoglycemia that increase hypoglycemia awareness. We’re all trying to prevent hypoglycemia in the first place. We want to use drugs safely and effectively. I think, as Dr. Genuth said, we’re coming to a consensus. A bad workman blames the tools, but in reality we agree that glyburide is the one that shouldn’t be used, but there are other sulfonylureas that, when used appropriately, and particularly at low doses, especially to start off with, would be much less likely to cause hypoglycemia. And then the issue of hypoglycemia awareness doesn’t become an issue.

Dr. Genuth: That’s very important. Also, we also haven’t talked about insulin. It’s clearly the most effective at lowering glucose levels. One survey that surprised me showed that people with type 2 diabetes taking insulin had one third the incidence of severe hypoglycemia compared to people with type 1 taking insulin. So insulin treatment is even more dangerous compared to sulfonylureas. We have to use it, but we need to work hard to educate our patients to help them avoid troublesome behavior.

Q: I just want to bring to your attention a recent JCEM paper that has shown if you give SFU as a monotherapy, there is an increased risk of CV mortality. Obviously it is registry data, not an RCT, but this is a recent paper.

Dr. Abrahamson: I’ll allude to Dr. Genuth’s work in the Annals of Internal Medicine showing that SFUs may be associated with increased CV events compared to metformin. The point I’d like to make from that paper is that the relative increase in CV events compared to metformin may be because metformin is associated with a reduction in CV events. I think that’s something none of us spoke about today because we all assume metformin is the appropriate first-line drug. So with epidemiologic studies, you have to ask whether metformin is reducing CV events, which may cause the comparator to show a relative increase.

Dr. Genuth: We can’t make the separation, I agree.

Q: The first question I have is about the idea of taking the first generation sulfonylureas out of use, or restricting their use like what we’re doing right now with rosiglitazone. I was wondering regarding second generation sulfonylureas, Dr. Genuth, don’t you think that what we need to do is prioritize and come in with another consensus and move sulfonylureas to a second or third-line treatment rather denying them to patients who cannot afford more expensive drugs?

Dr. Genuth: I am beginning to wonder if the sun is starting to set on sulfonylureas after 70 to 80 years of their use. If we have a lot of alternatives, and if their price comes down, and if they prove to have CV safety, I think sulfonylureas will have had their day.

Dr. Abrahamson: I think we’re all coming to broad agreement that you have to look at any particular drug and compare it to what else is on the market, and look at the pluses and minuses of using the particular product. I think that the GRADE study is going to be an important study, because includes all the common players, although SGLT-2 inhibitors are unfortunately not going to be in the study because they are too new. This study will ultimately help us determine which of the drugs we should be recommending as the most appropriate first line therapy. It’s a challenge for people in clinical practice to be given that wealth of information to have to decide which drug is most appropriate to use first.

Dr. Genuth: I have another regret about the GRADE study. I think it should have included pioglitazone. The reason I say that is that all these drug classes lower glucose by various mechanisms, but I think that TZDs are unique in that they get at one of the primary pathophysiological problems of type 2 diabetes. They attack insulin resistance directly through various in vitro pathways. I think that that reason alone should have meant they were included, also because the GRADE study is studying pathophysiology.

Comment: Most of the rest of the world, like Korea where I come from, uses glipizide. In studies, the risk of hypoglycemia with glipizide is the same to that of sitagliptin. The newer SFUs do not have the same risk of hypoglycemia or weight gain.

Q: You pointed out that some of the sulfonylureas that are shorter acting may have a higher risk of hypoglycemia. Data on glipizide are mostly on studies where they use the standard release preparation rather than the longer preparation. Can you comment on that?

Dr. Abrahamson: I’m not aware that long preparation of glipizide is associated with increased risk of hypoglycemia. If someone has data to refute that I’d be happy to see it.

Q: One additional argument about the risk analysis. In your data, glimepiride’s risk was 0.8/1,000 with glimepiride. At the same time we know lactic acidosis is 0.3/1,000. Then for pancreatitis, about 2% of cases of pancreatitis can also cause death. With pioglitazone, there is recent data on potential bladder cancer. In that risk analysis, are we willing to accept 0.8/1,000 of severe hypoglycemia that can be treated?

Dr. Genuth: If your point is that the absolute risk of severe hypoglycemia is low with SFUs, yes you can define low any way you want. But I would agree that the absolute risk is low. My point is simply that as a physician we each have to decide whether we even want to impose that low risk on any individual patient we are treating.

Dr. Abrahamson: I think there is ultimately is a risk/benefit analysis for any drug and any condition. Every single drug you take, including metformin, has a risk associated with its use. If you use the drug when you shouldn’t use the drug, you increase the risk enormously. The data says there is a 0.3/1,000 rate of lactic acidosis, but I haven’t seen it in anyone with normal renal function. SFU has a risk of severe hypoglycemia, so there is a higher risk for people susceptible to hypoglycemia. There is a risk of pancreatitis with incretin mimetics; we don’t know exactly the magnitude, but we as physicians need to tell patients about these risks, however small they may be, and we need to do our damnedest best to avoid using drugs in people who might develop complications.

Dr. Genuth: If we finally conclude that TZDs, when we have pioglitazone’s PROActive results, have a CV benefit, then the benefit/risk ratio of that drug will be considerably greater than SFUs – long or short acting.

Q: But we don’t have the CV benefit with DPP-4 inhibitors or GLP-1 agonists – there is no longer-term data.

Dr. Abrahamson: There is no long-term data yet. We await that data with interest.

Q: I just take up the point about glibenclamide. You’re aware the WHO has recommended the removal of glibenclamide from the essential drugs list for 65 and over. I really can’t see any justification for having glibenclamide on the market. The other point I wanted to challenge is the comment that metformin has clearly been shown to have CV benefits. If you set aside the epidemiological studies, the UKPDS is the only RCT that has shown a cardiovascular benefit for metformin, and systematic meta-analyses of metformin don’t show a cardioprotective effect.

Dr. Abrahamson: I was referring to the UKPDS data, and was only making the comment that when you look at epidemiological comparator studies, and show a relative increase of an event of one particular product, that you could say that the relative increase may be related to the fact that there was a relative decrease of the other product. But your points are well taken. Most of the data from metformin showing a cardiovascular benefit comes from UKPDS.

Dr. Genuth: This is unrelated, but I had showed proactive data showing that there was a reduced rate of stroke and other outcomes with pioglitazone. But I meant to also warn that if you look at the whole population studies, there is no advantage of pioglitazone over placebo regarding the primary outcome. It’s hard to put too much emphasis on a secondary finding when the primary finding wasn’t significant.

Q: The point that I would make is in between the exchange of both speakers: for me, in choosing an SFU I would consider three things: 1) Try to choose the right SFU. What I mean by this is I tend to go for the newer agents or the second or third generation agents. 2) I need to use the right dose of the SFU. Specifically what I mean is that in many studies out there, there is actually clear data supporting use of SFUs at 50% of their maximal recommended dose, which actually the speakers alluded to. 3) Choosing the so-called right patients. Again the speakers mentioned this. You want to get the younger patient and patients without renal impairment. Looking at these three facts, and probably cost as the fourth – maybe in a developing country cost would be #1 – the net result is that you want to maximize benefits and minimize risks while still keeping cost as an issue.

Dr. Abrahamson: We are all in what we call violent agreement. Thank you for those comments. I think we all ideally like to practice that way.


Symposium: New Therapeutic Targets in Type 2 Diabetes Mellitus (Sponsored by BI and Lilly)


Bernard Zinman, MD (University of Toronto, Toronto, Canada)

Dr. Zinman discussed the modulation of glucose absorption and excretion in the treatment of type 2 diabetes, with a focus on the SGLT-2 inhibitors. Following a review of the role of SGLT-2 in glucose reabsorption in the kidney and the rationale for its use as a therapeutic target, he highlighted topline results from a recent review (Taylor et al., Pharmacotherapy 2013) that summarized trial data from various SGLT-2 inhibitors (BMS/AZ’s dapagliflozin, J&J’s canagliflozin, Lilly/BI’s empagliflozin), suggesting in general just less than 1.0% declines in A1c with consistent 2-3 kg (4-7 lbs) weight loss. Given the low risk of hypoglycemia, weight loss, and declines in blood pressure observed with the class, he also voiced interest in the eventual results from ongoing CV outcomes trials with the drugs; he additionally previewed an eight-week pilot study evaluating the use of empagliflozin in type 1 diabetes patients that demonstrated an A1c decline of 8.0% to 7.6% as well as reductions in insulin dosing and the incidence of hypoglycemic events, to be presented in poster 1074-P.

  • Dr. Zinman opened with a brief update on the alpha-glucosidase inhibitors as modulators of glucose absorption. While widely used in Asia, these drugs (acarbose, voglibose, miglitol) are used infrequently in the US, primarily due to GI adverse events. Dr. Zinman highlighted, however, the results of the STOP-NIDDM trial, which suggested thatacarbose may produce a potential reduction in CV events (HR 0.51) versus placebo. This is currently being followed up by the more appropriately powered ACE (Acarbose Cardiovascular Evaluation) trial, which if positive, Dr. Zinman noted, could resurrect the drug class in the US.
  • Dr. Zinman moved to the SGLT-2 inhibitors as modulators of glucose excretion. Following a review of the role of SGLT-2 in glucose reabsorption in the kidney and the rationale for its use as a therapeutic target, he detailed a recent study (DeFronzo et al., Diabetes Care 2013) that explored the physiology of SGLT-2 inhibition. Using a stepped hyperglycemic clamp, the study demonstrated increased glucose reabsorption in type 2 diabetes patients versus healthy controls, with dapagliflozin (BMS/AZ’s Forxiga) able to reduce reabsorption in both populations. The study also confirmed the mechanism of action, showing that dapagliflozin could produce glucosuria in both populations, even at very low glucose levels.
  • Looking to clinical data, Dr. Zinman noted a recent review (Taylor et al., Pharmacotherapy 2013) that summarized trial data from various SGLT-2 inhibitors (BMS/AZ’s dapagliflozin, J&J’s canagliflozin, Lilly/BI’s empagliflozin). Highlighting topline results, he suggested while in a wide range, in general the drug class produces just less than 1.0% declines in A1c with consistent 2-3 kg (4-7 lbs) weight loss. Looking to canagliflozin’s and empagliflozin’s phase 3 data, he also stressed that the drugs could be combined with relatively any other diabetes therapy and provide supplementary benefit, including metformin, sulfonylureas, and thiazolidinediones.
  • While no head-to-head comparisons of the SGLT-2 inhibitors exist, Dr. Zinman highlighted comparisons between the drug class and sitagliptin and glipizide. The first (Schernthaner et al., Diabetes Care 2013) was 52 weeks in duration and showed an initial similar decline in A1c (~8.1% to ~7.2%) with both sitagliptin and canagliflozin, though sitagliptin patients demonstrated more regain in A1c over the trial period. A 52-week trial of dapagliflozin versus glipizide indicated an initial greater reduction in A1c with glipizide (-0.8% with glipizide vs. -0.5% with dapagliflozin; baseline ~7.7%) though by 52 weeks there was no difference in A1c decline in both groups (-0.5% vs. -0.5%) with more frequent hypoglycemic events in the glipizide- treated patients.
  • Though still theoretical, Dr. Zinman suggested there is reasoning to believe the drugs could produce CV benefit, including the low risk of hypoglycemia, consistent weight loss, and reduction in blood pressure observed with the class. Though he noted it was still unclear when these trials would complete given their dependence on event rate, he looked forward to the results of ongoing CV outcomes trials with the drugs including Empa-reg outcome (empagliflozin vs. placebo; estimated completion March 2018), CANVAS (canagliflozin vs. placebo; estimated completion June 2018), and DECLARE (dapagliflozin vs. placebo; estimated completion April 2019).
  • Dr. Zinman concluded by briefly touching on the potential use of SGLT-2 inhibitors in type 1 diabetes. He previewed a poster to be presented this Sunday at ADA (1074-P) that was an eight-week, open-label, single-arm pilot study of empagliflozin in type 1 diabetes patients. While without a control arm, patients showed an A1c decline of 8.0% to 7.6%, a reduction in insulin dosing from 55 to 46 units per day, and a decline in incidence of hypoglycemic events from0.12 to 0.04 events per day. Given the dearth of therapies for type 1 diabetes, we remain veryinterested in this potential application.

Questions and Answers

Q: You should lose a pound a month by the calculation of carbohydrate loss. Why don’t you see continued weight loss?

A: I think it relates to homeostatic mechanisms that respond when the weight is lost.

Q: How can you justify the usage of these drugs when they don’t really attack the underlying pathophysiology of the disease?

A: It’s true that you want to define the abnormality and attack the abnormality. The fact is that SGLT-2 is upregulated in type 2 diabetes and an increased absorption is maladaptive, so in some ways I do think it changes in the underlying pathophysiology.



John Leahy, MD (University of Vermont, Burlington, VT)

In a very engaging overview of specific pancreatic pathways that could serve as novel therapeutic targets, Dr. Leahy emphasized the importance of restoring beta cell function rather than attempting to control glucose after beta cells have deteriorated. Dr. Leahy praised recent endeavors that have taken a closer look at current biological knowledge to redefine therapeutic targets. Specifically, he cited the progress of GPR40 agonists such as TAK-875, which has demonstrated significant A1c reductions as well as impressive improvements in beta cell insulin secretion (Takeda reported the first phase 3 data on TAK-875 in late May; for full details, see our report at Dr. Leahy also reviewed his own work on the FoxO1 pathway, as well as the pathways involving Them27/Bace2, fractalkine, betatrophin, GPR119, and glucokinase. He concluded that current drugs are limited, and that new therapies which target the pancreas and beta cells should focus on ways to recover lost function while maintaining specificity to ensure efficacy and safety.

  • Dr. Leahy began by reviewing possible mechanisms of beta cell dysfunction and current diabetes agents. Insulin, TZDs, and SGLT-2 inhibitors address glucotoxicity and metabolic stress; incretin therapies correct for impaired incretin regulation; and IL-1 receptor antagonists address islet inflammation. Dr. Leahy noted that none of these agents is necessarily perfect, and that the bar for future therapies has risen to include weight stability, little or no incidence of hypoglycemia, cardiovascular safety or protection, and a patient-friendly delivery system.
  • For the majority of his talk, Dr. Leahy discussed GPR40, a free fatty acid receptor that promotes insulin secretion. GPR40 is expressed in beta cells, the hypothalamus, and intestinal cells. While there is limited information on the involved signaling pathway in humans, Dr. Leahy reviewed a study showing that GPR40 mRNA expression is significantly reduced in people with type 2 diabetes. Referencing the 12-week phase 2 trial of Takeda’s TAK-875 (n=426), Dr. Leahy noted that patients on all doses of TAK-875 with or without metformin experienced significant A1c reductions compared to placebo from baselines A1c levels of 8.2-8.6%; furthermore, this glycemic control was obtained without significant weight change. In addition, treatment with the 25 mg, 100 mg, and 200 mg doses of TAK-875 significantly improved insulin secretion from beta cells (for further information, see our March 9, 2012 Closer Look at
  • Dr. Leahy believes some of the most exciting biology work has come out of identifying potential pathways. Specifically, inhibitors of Them27/Bace2 lead to increases in beta cell mass and soluble forms of fractalkine (CX3CL1) circulate and regulate beta celldifferentiation. His own lab focuses on methods of activating the FoxO1 and PPARγ signaling network – type 2 patients exhibit diminished FoxO1 expression in their beta cells, a deficit which incretin hormones could potentially address. Early research has shown recovery of normal cytoplasmic localization and re-expression of FoxO1 upon treatment with a DPP-4 inhibitor. Dr. Leahy also mentioned the recently-discovered molecule betatrophin, a widely publicized finding out of Dr. Doug Melton’s lab.
  • In concluding, Dr. Leahy briefly addressed a few other possible pancreatic targets, including GPR119, glucokinase activators, and zinc. GPR119 binds short-chain fatty acids and has a very different, lesser-known biology than GPR40 (though Dr. Leahy noted that the receptor has direct beta cell effects likely mediated through cyclic AMP). Glucokinase activators presented problems with controlling hypoglycemia, and Dr. Leahy remarked that they are now directed toward suppression of hepatic glucose production.



Robert Henry, MD (University of California at San Diego, La Jolla, CA)

Dr. Henry gave a strong review of the role of inflammation in adipose tissue and skeletal muscle in the development of type 2 diabetes. When fat calorie intake exceeds the buffering capacity of adipose tissue, as seen in obesity, free fatty acid and triglyceride levels increase in circulation, interfering with insulin action. Within the adipose tissue, obesity leads to progressive adipocyte hypertrophy, inflammation, and macrophage and immune cell activation, creating a pro-inflammatory state. Evidence suggests these pathways are all mediated through NF-κB, a downstream protein complex that controls the transcription of inflammatory mediators; studies have suggested that this pathway can be manipulated to potential benefit in type 2 diabetes.

  • When fat calorie intake exceeds the buffering capacity of adipose tissue, such as seen in obesity, free fatty acid and triglyceride levels begin to increase in circulation. Adipose deposition can begin to occur in ectopic areas, with overflow stored in the viscera, liver, muscle, pancreas, and heart, all leading to deleterious effects. There is a strong relationship between visceral adipose tissue and insulin resistance as well as inflammatory cytokines, though it is still unclear if visceral fat is a marker or cause of cardiovascular disease.
  • Increased accumulation of fat can also alter the phenotype of adipose tissue, creating a pro-inflammatory state. As known, adipose tissue is not dormant but produces numerous endocrine and inflammatory signals. In addition to adipocytes, adipose tissue contains immune cells, endothelial cells, and fibroblasts. Adipocyte hypertrophy induces cell stress and initiates an inflammatory process, with increased macrophage and T cell recruitment and increased production of pro-inflammatory adipokines; it is now known that once this process begins it is continually maintained by leukocyte recruitment in a self-sustaining fashion. While data is more conflicting, there is evidence that macrophage infiltration is increased in muscular tissue in obesity as well, with increased inflammation as an intrinsic property of skeletal muscle in type 2 diabetes.
  • Numerous stimuli initiate the inflammatory process, converging upon NF-κB, a downstream protein complex that controls the transcription of inflammatory mediators and serves as a regulator of pathways implicated in insulin resistance and premature CVD. Dr. Henry noted stimulation by TNF, RAGE, Toll-like receptors, and IL-1extracellularly and ceramide, reactive oxygen species, protein kinase C, and ER stress intracellularly. The role of these signals in the development of diabetes, he suggested, was evidenced in the TINSAL study, which demonstrated efficacy with salsalate (known to reduce NF- κB activity in adipose tissue) in type 2 diabetes. Similarly, a recent study in high fat diet-induced obese mice showed increased weight loss and improved insulin sensitivity with amlexanox, an inhibitor of the NF-κB pathway.
  • Based on this mechanism, Dr. Henry briefly concluded with a list of numerous potential anti-inflammatory drug targets for type 2 diabetes. Many of these have been or are being pursued in clinical trials and included anti-CD3 antibodies, CCR2 antagonists, IL-1 inhibitors, IKK inhibitors, NF-κB antagonists, and anti-TNF antibodies.



Abd Tahrani, MD, PhD (University of Birmingham, Birmingham, UK)

Dr. Abd Tahrani gave a thorough overview of potential therapeutic targets in the complex insulin- signaling cascade, emphasizing that insulin resistance is a multifactorial problem that requires multiple approaches. Current approaches to insulin resistance include metformin, PPARγ agonists, and bromocriptine. On this front, he believes that targeting both the insulin receptor and post-receptor signaling pathways will lead to novel therapeutics. Dr. Tahrani emphasized the need for insulin specificity, since these signaling pathways have multiple downstream effects. He began with a discussion of insulin receptor activators, including DMAQ-B1, Compound 2, and TLK16998, an insulin receptor sensitizer that enhances tyrosine kinase activity only in the presence of insulin. Protein tyrosine phosphatase 1B (PTP-1B) inhibitors prevent dephosphorylation of the insulin receptor beta subunit, relieving the negative regulation of the insulin receptor – experimental studies have shown that mice on a high-fat diet treated with a PTP-1B inhibitor exhibited glucose levels that approached those of mice on a low fat diet, suggesting that the drug increased insulin sensitivity. Dr. Tahrani then discussed two approaches to targeting the post-receptor signaling pathway: 1) activating the pathway’s key activators (PI3K and AMP kinase); and 2) inhibiting its inhibitors (PTEN) to restore insulin sensitivity. Noting the breadth of possibilities, he listed several other targets currently under research, including 11βHSD inhibitors (glucocorticoid metabolism), resveratol (inflammatory pathway), zinc, lithium, and various vitamins. He concluded with a look into his own research on how sleep disorders increase insulin resistance, heighten inflammation, and impair glucose control, suggesting that these sleep problems may be a novel treatment target to improve insulin resistance at the metabolic level


Product Theater: Exposing Sodium Glucose Co-Transporters (SGLTs) – A Hidden Contributor to Persistent Hyperglycemia in Type 2 Diabetes (Sponsored by BI and Lilly)


James Gavin, MD, PhD (Emory University, Atlanta, GA)

Dr. James Gavin attracted a standing-room only crowd for his presentation on the role of glucose co- transporters in the kidney in glycemic homeostasis and the implications for type 2 diabetes. Projecting over the noise of the exhibit hall, Dr. Gavin reviewed the physiological mechanisms behind plasma glucose level regulation, highlighting the kidney as a major player in this process, where normally, 162 g of glucose is filtered and reabsorbed per day until a threshold level is reached (180 mg/dl), when excess glucose is removed by glycosuria. Dr. Gavin emphasized the danger in persistent hyperglycemia, which he stated could cause impaired beta-cell function and decreased insulin sensitivity. He explained that in patients with type 2 diabetes, renal glucose reabsorption increases due to overexpression of SGLT-2, causing the threshold for glucose excretion to increase. Dr. Gavin provided data on the increase in glucose excretion in animal models of type 2 diabetes after treatment with the SGLT inhibitor phlorizin, and an overview of SGLT-2 mutations in patients who experience decreased renal glucose absorption and increased glycosuria without adverse effects. Dr. Gavin concluded by expressing excitement over “a new set of therapeutic possibilities.”

Questions and Answers

Q: When you experience glycosuria, this comes with a loss of calories. If you calculate this, it comes out to a calorie loss of 100,000 calories a year. This is 11-12 kilograms a year, but when we look at new products, we only see a loss of two to three kilograms. Can you comment on that?

A: I can’t tell you what the physiologic answer is. There likely is some form of adaption that occurs. One of the reasons why we don’t expect that kind of weight loss is when we go back to the experience of familial renal glycosuria patients. They don’t become wasted away, and they don’t lose enormous amounts of weight as a result of glycosuria, so clearly there is some adaption that occurs. Having said that, it is still a benefit to this approach to therapy that calorie loss does result in another one of the benefits that we like to see in the vast majority of patients with type 2 diabetes.


Product Theater: Choosing a Therapy for the Individual Patient – Takeda’s Powerful Portfolio of Treatments for Type 2 Diabetes (Sponsored by Takeda)

Eugenio Cersosimo, MD, PhD (University of Texas Health Science Center, San Antonio, TX)

In this lightly attended product theater, Dr. Eugenio Cersosimo reviewed the efficacy, safety, dosing, and administration of Nesina (alogliptin), Kazano (alogliptin/metformin), and Oseni (alogliptin/pioglitazone). He emphasized that alogliptin is effective as monotherapy, in dual and triple therapy, and in fixed-dose combinations, and that Nesina, Kazano, and Oseni all address multiple defects of type 2 diabetes. In addition, he highlighted that the Takeda Diabetes Advantage Program offers support programs for patients; eligible patients who are enrolled in the program pay no more than $4 per month for up to 12 months for Nesina, Kazano, or Oseni.


Corporate Symposium: New Frontiers and Emerging Treatment Paradigms for Optimizing Cardiovascular Outcomes in Type 2 Diabetes (Sponsored by BMS/AZ)


Derek LeRoith, MD, PhD (Mount Sinai School of Medicine, New York, NY)

Dr. Derek LeRoith summarized the current experimental data that provides evidence for a beneficial CV effect of incretin therapies. Addressing the direct effects of incretins on the CV system first, Dr. LeRoith presented results from human and animal studies that showed that GLP-1 can: 1) act on cardiomyocytes to reduce myocardial insulin sensitivity, decrease apoptosis, increase ventricular function post-MI, and reduce infarct size post-MI; 2) act on endothelial cells to reduce NO vasodilation and inflammation; and act on vascular smooth muscle to decrease proliferation. Turing to cardiometabolic (indirect) effects of GLP-1 on the CV system, Dr. LeRoith reviewed clinical trial results for currently available GLP-1 agonists and DPP-4 inhibitors. In particular, he highlighted that GLP-1 agonists are capable of reducing visceral body fat, reducing systolic blood pressure, enhancing sodium excretion, improving various biomarkers of CV risk (PAI-1, BNP, CRP, triglycerides), and improving dyslipidemia (total cholesterol, LDL, HDL, and triglycerides). Similarly, with DPP-4 inhibitors, he shared evidence that highlighted the ability of saxagliptin to reduce blood pressure and provide modest weight reduction. The ability of saxagliptin to improve dyslipidemia appears to be limited. Overall, Dr. LeRoith concluded that incretins appear to have positive direct and indirect effects on the CV system; however, he stressed that any further conclusions on the CV protective benefits of these drugs would have to wait until results from the several ongoing CV outcomes studies for GLP-1 agonists and DPP-4 inhibitors were available.



Ralph DeFronzo, MD (University of Texas Health Science Center at San Antonio, San Antonio, TX)

After briefly discussing the physiology of renal glucose handling and the role of the kidney in the pathogenesis of type 2 diabetes, Dr. DeFronzo highlighted new results from a small clinical trial conducted by his group that examined the effects of dapagliflozin (n=10) vs. placebo (n=5) treatment for 14 days in people with type 2 diabetes (n=15). Overall, the results demonstrated the ability of a short course of dapagliflozin to significantly reduce FPG and PPG, significantly improve muscle insulin resistance, and significantly improve beta cell function. He believed that these findings were the result of the drug’s ability to reverse glucotoxicity by increasing urinary excretion of glucose. Turning to the effects of SGLT2 inhibitors on CV risk factors, Dr. DeFronzo noted that clinical trial data have shown that dapagliflozin provides significant improvements in A1c, body weight, and blood pressure. The drug appears to have a neutral to slightly positive impact on plasma lipid levels, providing a small increase in HDL, small increase in LDL, and moderate reduction in triglycerides. While an analysis of data from 14 dapagliflozin trials found a hazard ratio of 0.67 for CV outcomes with dapagliflozin vs. comparators, Dr. DeFronzo cautioned that the overall CV effect of SGLT-2 inhibitors will remain unknown until long- term data from the ongoing dedicated CV outcomes studies for this class report. Nonetheless, Dr. DeFronzo noted his optimism for the class, arguing that SGLT2 inhibitors meet an unmet need in diabetes care as they: 1) correct a novel pathophysiological defect; 2) reduce A1c; 3) complement the action of other antidiabetic agents; 4) reverse glucotoxicity; 5) do not increase the risk for hypoglycemia; 6) reduce blood pressure; and 7) promote weight loss. He concluded his talk by suggesting that SGLT2 inhibitors hold promise as monotherapy agents, add-on agents to metformin, SFUs, pioglitazone, or DPP-4 agents, agents to use in combination therapy with metformin, DPP-4 inhibitors, and pioglitazone, add-on agents to insulin in type 2 diabetes and type 1 diabetes, agents for use in IGT/IFG, and possibly as an add on to GLP-1 agonists (although data is lacking).



Vivian Fonseca, MD (Tulane University, New Orleans, NO)

Dr. Fonseca closed the session with a brief summary of the preceding talks. Because of the apparent irreversibility of complications, he argued that it is imperative that we begin to focus more intently on diabetes prevention and the earlier prevention of CV outcomes in the pathology of diabetes. Further, he noted that beyond aiming for improved glucose control to prevent CV events, it is important that we also address blood pressure control and dyslipidemia, as these measures are even more effective at CV risk reduction. Finally, he expressed excitement for the answers that will be provided in the numerous ongoing CV outcomes studies for GLP-1 agonists, DPP-4 inhibitors, pioglitazone, and SGLT-2 inhibitors as well as the TINSAL-CVD study, which is currently examining the CV protective effects of salicylate in individuals with metabolic syndrome and stable coronary disease.

* Editors Note: Our Full Report will contain our complete coverage of this symposium, including the panel discussion.


Corporate Symposium: Scientific Horizons in Diabetes Management – The Emerging Role of the Kidney as a Target for Therapy


George Bakris, MD (University of Chicago, Chicago, IL)

Dr. George Bakris reviewed the physiology behind the role of the kidney in the regulation of blood glucose, and its implications in patients with diabetes. The kidney contributes to gluconeogenesis, and also is involved in glucose reabsorption through sodium glucose co-transporters 1 and 2 (SGLT-1 and SGLT-2), which account for 10% and 90% of tubular reabsorption, respectively. He outlined the major differences between the two co-transporters, noting that SGLT-1 is mostly found in the intestine with some expression in the kidney, and has a high affinity (Km=0.4 mM) for glucose and a low capacity for its transport, whereas SGLT-2 is found almost exclusively in the kidney, and has a low affinity (Km=2 mM) for glucose, but a high capacity for transport. Because of its location, inhibiting SGLT-1 may cause significant GI side effects. Dr. Bakris discussed the rationale behind SGLT-2 inhibition to combat hyperglycemia in patients with diabetes, noting that it helps to lower the renal threshold for glucose excretion, effectively allowing for patients to urinate excess glucose. In addition, Dr. Bakris highlighted that SGLT-2 inhibition can reduce fasting plasma glucose and improve hyperglycemia even in the absence of substantial amounts of insulin (Rosetti et al., J. Clin Invest 1987).



Mark Molitch, MD (Northwestern University, Chicago, IL)

After defining the stages of chronic kidney disease (CKD), Dr. Mark Molitch systematically reviewed current recommendations for oral agent use in patients with type 2 diabetes and CKD. In addition, he highlighted that both insulin sensitivity and insulin clearance are decreased in patients with progressive declines in glomerular filtration rate (GFR), so special considerations should also be taken for insulin users. In a prospective trial of insulin-using patients with type 2 diabetes with eGFR <45 ml/min/1.73 m2 (n=107), halving the insulin dose numerically reduced the incidence of hypoglycemia while maintaining glycemic control within the 100-180 mg/dl range a comparable proportion of the time (Baldwin et al., Diabetes Care 2012).

  • Sulfonylureas: Dr. Molitch noted that glyburide clearance is not affected, but renal clearance of its metabolites is reduced with CKD. As such, the risk of hypoglycemia is very high for those with CKD; glyburide should not be used in patients with estimated GFR (eGFR) <60 ml/min/1.73 m2. Similarly, glimepiride clearance is not affected, but renal clearance of its metabolites is reduced with CKD. The risk of hypoglycemia is increased (though not nearly as high as with glyburide), so glimepiride should be used with caution in patients with eGFR <60 ml/min/1.73 m2 and avoided in patients with eGFR <30 ml/min/1.73 m2. Finally, glipizide should be used with caution in patients with eGFR <30 ml/min/1.73 m2, even though less than 10% of glipizide is renally cleared.
  • Metformin: Dr. Molitch commented that the current FDA package insert recommendation against use of metformin for individuals with serum creatinine levels above 1.4 mg/dl (female) or1.5 mg/dl (male) seems too conservative. Moving forward, he thinks it would make sense: 1) tohave no limitations on dosing for individuals with eGFR ≥60 ml/min/1.73 m2; 2) to proceed with caution dosing patients with eGFR ≥45 and <60 ml/min/1.73 m2, and monitor eGFR every three- to-six months; 3) to cap dosing at 1,000 mg/day for patients with eGFR ≥30 and <45 ml/min/1.73 m2, and monitor eGFR every three-to-four months; and 4) to stop metformin for patients with eGFR <30 ml/min/1.73 m2. Meanwhile, metformin should be stopped for inpatients if they are unstable, hypotensive, hypoxic, septic, or have acute worsening of renal function (Lipska et al., Diabetes Care 2011; KDIGO Controversies, in preparation).
  • Thiazolidinediones: Clearance of pioglitazone is not affected by kidney function; no dose reduction is needed in CKD.
  • Incretins: It is recommended for patients with eGFR <30 ml/min/1.73 m2 to discontinue exenatide therapy. Meanwhile, no dose adjustments for liraglutide are necessary for progressing CKD. As for DPP-4 inhibitors, dose adjustments are recommended for sitagliptin, saxagliptin, and alogliptin for patients with eGFR <50 ml/min/1.73 m2, but no dose adjustments are required for linagliptin as it is not renally cleared.
  • SGLT-2 inhibitors: SGLT-2 inhibitors are less effective with eGFR <60 ml/min/1.73 m2, and those with eGFR <45 ml/min/1.73 m2 could potentially experience more adverse effects (e.g., volume loss, hyperkalemia). For eGFR <60 ml/min/1.73 m2, canagliflozin should be kept at the 100 mg/day dose, and the higher 300 mg/day dose should be avoided. Canagliflozin is not currently approved for use with eGFR <45 ml/min/1.73 m2.



Zachary Bloomgarden, MD (Mount Sinai Medical Center, New York, NY)

Following a high-level review of the ADA/EASD position statement and the AACE glycemic control algorithm, Dr. Zachary Bloomgarden discussed the benefits and potential safety concerns of drugs in the SGLT-2 inhibitor class. He emphasized that SGLT-2 inhibitors could be a useful addition to the treatment armamentarium, as they bring about improvements in glycemic control with low risk of hypoglycemia, cause modest weight loss, and have a unique mechanism that does not promote increased endogenous insulin secretion. Overall, Dr. Bloomgarden provided a thoughtful and balanced review of the SGLT-2 inhibitor class, along with helpful advice for clinicians to select appropriate patients who would be less likely to experience adverse effects when taking an SGLT-2 inhibitor.

  • Dr. Bloomgarden highlighted a number of benefits of SGLT-2 inhibitors, including weight loss, low hypoglycemia risk, and blood pressure lowering. In addition, he posited that SGLT-2 inhibitors could be a good complementary therapy to TZDs, given the incremental reductions in A1c and fasting plasma glucose dapagliflozin provided when added to pioglitazone in a 48-week trial, and the attenuation of weight gain conferred (Rosenstock et al., Diabetes Care 2012). Regarding canagliflozin, he stated that reductions in both A1c and weight appeared to be dose dependent when added to metformin (Rosenstock et al., Diabetes Care 2012). After briefly touching on empagliflozin (as the agent with the highest selectivity for SGLT-2 versus SGLT-1) and ipragliflozin (which brings about similar weight loss across doses), Dr. Bloomgarden discussed Lexicon’s dual SGLT-1/SGLT-2 inhibitor LX4211, noting that a recent phase 2 study documented increases in GLP-1 and PYY following its administration (Zambrowicz et al., Clin Pharmacol Ther 2012). He speculated that it could be possible for SGLT-2 inhibitors to have some action on SGLT-1 receptors in the GI tract, noting that canagliflozin was shown to decrease gut glucose absorption (Polidori et al., Diabetes Care 2013); however, GLP-1 and PYY were not measured in the study.
  • He discussed potential safety concerns of SGLT-2 inhibitors, including genitourinary tract infections, carcinogenicity, volume depletion, and hyperlipidemia. Dr. Bloomgarden noted that vulvovaginal candidiasis occurred more frequently with canagliflozin treatment versus comparator (Nyirjesy et al., Curr Med Res Opin 2012), and there appeared to be an increased frequency of urinary tract infections (Nicolle et al., Curr Med Res Opin 2012), although the data are less clear. He noted that questions remain regarding dapagliflozin’s potential cancer signal, that is, whether the results were a statistical fluke, a class effect, or specific to dapagliflozin; unfortunately, RCTs are simply impractical to assess these very low frequency events. Subsequently, he stated that there is thus far no evidence of carcinogenicity of canagliflozin treatment in humans. Dr. Bloomgarden pointed out that canagliflozin treatment can cause volume depletion, and as such, clinicians should be cautious when prescribing the drug to the elderly, patients on diuretics, renally impaired individuals, and those with low blood pressure. He stated that it does appear that LDL cholesterol increases 5-10 mg/dl with canagliflozin treatment; he does not know how much this may occur with other SGLT- 2 inhibitors. Finally, given the significant increase in CV events observed during the first 30 days of the CANVAS CV outcomes trial with canagliflozin treatment, Dr. Bloomgarden suggested clinicians to be cautious when initiating high-risk patients on canagliflozin.



Zachary Bloomgarden, MD (Mount Sinai Medical Center, New York, NY); George Bakris, MD (University of Chicago, Chicago, IL); Mark Molitch, MD (Northwestern University, Chicago, IL)

Q: If familial renal glucosuria is so rare, how do we know these people don’t carry another mutation, that there aren’t compensations for the deficit in glucose reabsorption? Is this a valid argument for the increase in glucose reabsorption?

Dr. Bakris: The fact is that these are very rare cases. I’m unaware of a full genetic analysis, I think it’s simply an observation that these patients have an absence of glucose reabsorption indicated by higher urinary glucose excretion. We don’t know if there is some compensatory effect. That’s why I hate genetic animal models, because there are compensatory mechanisms. I think we’re just going to have to accept it the way it is.

Q: What role do you see for SGLT-2 inhibitors in the treatment of type 1 diabetes?

Dr. Bloomgarden: The interesting thing is that the prevalence of insulin resistance is roughly 25% in the overall population, and roughly 25% among people with type 1 diabetes. This whole concept of dual diabetes is really important. There is a very significant subset of individuals with type 1 diabetes who have features of both type 1 and type 2 diabetes and are often the most difficult to treat for whom metformin may be useful, and maybe SGLT-2 inhibition might also be beneficial. I wouldn’t jump on using SGLT-2 inhibitors as a treatment across the board, but there may be an important subset for which it does matter.

Dr. Molitch: In studies in patients with type 2 diabetes, the use of SGLT-2 inhibitors with insulin was effective, so there’s no reason to think they wouldn’t be effective in type 1 diabetes, but we don’t have any studies with that data.

Q: What do you think will be the clinical effect of the increased genital infections? Will endocrinologists have to do pelvic exams? And are there studies with GLP-1 and PYY measured during the trials?

Dr. Bloomgarden: I haven’t come across any studies as far as this question of fungal infections. I think that we have some pretty effective standard treatments for symptomatic genital fungal infection, and I don’t think there’s anything that has to be done other than letting women know in advance that this is a potential side effect, and offering one or another appropriate treatments when women develop symptoms. We need more studies.

Dr. Molitch: I’ve started the medication in several patients. You have to talk to the patients, and if it’s a woman you ask, “Have you had multiple vaginal infections in the last several years?” If they only had one 20 years ago instead of multiple in the past few years, then that’s the patient to start it on. The data from some of these studies suggest that if you do develop one infection and you treat it, it rarely recurs. In patients that have reoccurrence, you stop. Uncircumcised men tend to get infections more often, so extra hygiene might be necessary to avoid the risk.

Q: What were the issues that caused the FDA initially not to approve the SGLT-2 inhibitor dapagliflozin?

Dr. Bakris: They came on the heels of all the this cancer and CV stuff with the glitazones, so there was a tremendous amount of pressure on the FDA from Congress not to put anything out there that was not pristine. Unfortunately, because they were in a hurry, and this is based on oncologists’ testimony, they probably let people into the trials who already had bladder cancer, and the whole issue with hematuria gave pause. So, at the end of the day, they really didn’t know, and even though they had experts in oncology testify that it was highly unlikely [patients developed cancer from dapagliflozin treatment] because they are slowly growing cancers, the FDA decided to be conservative and ask for longer follow-up. In Europe, they had [longer-term] data on file, and decided that patients probably already had bladder cancer [going into the trial], that this was just dumb luck. I think all of this stuff in the press hyped by colleagues of ours is great for news, but doesn’t help patients at all. It doesn’t really resolve anything. My comment on rosiglitazone is that it is now impossible to make an honest judgment on the data. Most patients discontinued the drug, so any chance to exonerate it is gone, because it was already accused.

Q: Do you have any ideas about what might mediate the increase in LDL that has been reported?

Dr. Molitch: Not really. The mild LDL elevation seems to be a class effect, and there’s also an increase in HDL, although it’s a more modest increase. If you look at the ratio, it’s not increased, but this doesn’t give us the answer all the time. The mechanism is not known. How clinically significant is it? I think only time will tell.

Q: Based on phase 3 data, it appears that canagliflozin is slightly more effective in A1c and body weight reductions than dapagliflozin and empagliflozin. Can you comment on this?

Dr. Bloomgarden: Without head-to-head trials, you simply can’t compare them. In [their respective] trials, there were differences in baseline A1c, differences in body weight, differences in the conduct of the trials, and so on. One can simply say that the class appears to have a remarkably similar set of characteristics with the published data. If we look in our abstract book, we’ll probably see 100 SGLT-2 posters and orals that we can all go visit over the next couple of days.

Q: Why might there be an interaction of canagliflozin with ACE inhibitors and angiotensin receptor blockers?

Dr. Bloomgarden: There’s likely not going to be an interaction, but it may be that in individuals susceptible to hypotension, those receiving ACE inhibitors could have a greater propensity to dehydration, renal insufficiency and so on. We know sometimes that is seen with these agents.

Dr. Bakris: There’s no drug interaction. Let’s be clear on that. The issue is that of people that are taking these, there’s additional volume loss. You’re going to great a great reduction in GFR and blood pressure. That’s all that you’re seeing here. When they stopped the drug, it came right back up to where it was, which is what you’d see with an ACE or ARBs. If you’re seeing a reduction in GFR or an increase in creatinine, you shouldn’t blink until gets above 30%. A little increase in serum creatinine is not going to hurt anyone, nor has it shown to be adverse. There are two additional papers encouraging nephrologists to not change ACEs or ARBs if GFR goes up. This is a volume effect. That’s why, when I give it to patients, I cut the dose of the diuretic in half, because I’m anticipating some volume issues. There’s no published data but it does make sense.

Dr. Bloomgarden: It would be interesting to look at SGLT-2 inhibitors as diuretics and their role in potentially tying the lowering effects of antihypertensive drugs, etc. They might be potent in people with diabetes.

Q: Why is SGLT-2 upregulated in diabetes?

Dr. Bloomgarden: One could say this is teleologically an appropriate adaptive response to avoid glucose loss. The fact that a mechanism is available biologically to increase the expression of glucose transporters in people with diabetes is fascinating. I don’t know that I have more of an explanation, but I think it is a very interesting observation.

Q: Is any caution necessary to prescribe SGLT-2 inhibitors for sexually active patients?

Dr. Bloomgarden: No more so than the very appropriate idea of asking patients before we initiate these drugs whether they have had recurrent infections or recent symptoms of vaginitis.

Q: A patient in her 90s on canagliflozin 100 mg lost weight after a month and her edema resolved, but her fasting glucose remained in the 200s. After increasing canagliflozin to the 300 mg dose, what will happen? She worries about hypoglycemia with sulfonylureas, and refused to take insulin.

Dr. Bloomgarden: The answer is nothing. This is not a panacea. If her blood sugar is in the 200s, she needs insulin (or possibly a GLP-1 receptor agonist). The reality is that this [canagliflozin] is probably going to be the wrong agent.

Dr. Molitch: Just to come back to the fact that she is in her 90s – older patients seem to be the ones at risk for volume depletion symptoms, so I probably wouldn’t go up to 300 mg with her because the higher dose is associated with more symptoms. I would advise against use in older individuals. Going back to the

infection issue, when you look at upper urinary tract infections (like pyelonephritis) and bladder infections, there is a slight increase or no increase. The major concern is mycotic infections. Clearly they increase, but perhaps they are avoidable if patients are selected appropriately.

Dr. Bloomgarden: With the proviso that we might not have enough experience in at-risk patients yet. Another point on what you had mentioned – the degree of volume depletion is probably going to be proportional to the degree of elevation of blood sugar and the degree of diuresis, so it may be particularly worrisome for those who the drug is just not likely to be potent enough. We’ve all had patients with blood sugar in the 200s, and there are appropriate treatments. Basically, these are people who need insulin to stabilize their blood sugar, and occasionally, they can subsequently withdraw insulin.

Q: Where will SGLT-2 inhibitors enter the treatment algorithm?

Dr. Molitch: I think it would be after metformin, and really in that second layer. It’s pretty much dealer’s choice after metformin, depending on what you want to accomplish with your patients. The efficacy profile is good.

Dr. Bakris: The patients that come to see me are already on a DPP-4 inhibitor and metformin, but if I see that their A1c values are in the eights, I see this as a beautiful add-on choice at that point, but I would probably use it as a second-line also. In my experience, people over 70 tend to not drink a lot of fluid, men especially, and if you use this agent in people who are 80 to 90 years old, you could run into volume issues.

Dr. Bloomgarden: The potential for these agents to be used in combo with TZDs is very intriguing. The fluid retention effect to TZDs could be combated with the diuretic action of these agents. In that one study I talked about, it really appeared that the progressive weight gain seen with the TZD was attenuated by the weight loss of SGLT-2. I think we’ve moved away from TZDs a little too much, and low-dose pioglitazone ought to be part of our own treatment plan, in those not at risk of heart failure or fractures. Maybe this a combination that will allow us to use metformin and pioglitazone in triple therapy in an appropriate fashion.


Corporate Symposium: Optimizing Vascular Outcomes in T2DM: Collaboration for Quality Care (Sponsored by Genentech)


Robert Henry, MD (University of California at San Diego, La Jolla, CA)

Dr. Henry opened the symposia with a brief overview of the current state of diabetes care in the US, with a focus on current governmental efforts to establish a systematic assessment of quality of care. Overall, he reinforced the importance of standardized reporting systems such as the Physician Quality Reporting System (PQRS) employed by CMS and encouraged physician participation. Though he highlighted progress in metrics of diabetes care quality in the past years, he noted the enduring need for continued improvements.

  • Current standardized metrics of care in diabetes include glycemic control, blood pressure control, lipid management, lifestyle modifications, foot care, and presence of diabetic retinopathy. Dr. Henry stressed that quality assessment programs, such as the PQRS (a reporting program that uses a combination of incentive payments and payment adjustments to promote reporting of quality information by health professionals) employed by CMS, are important to understand current quality of care and allow surveillance; data also serves to inform efforts to improve quality and assess physician competence. Dr. Henry encouragedphysicians to participate in reporting, both to avoid coming payment adjustments and to increase personal quality of care. He noted that participation in PQRS reporting amongst endocrinologists has been rising in the past years, though still low at 33.2% in 2011.
  • To assess the current state of diabetes care, Dr. Henry began with NHANES data from 1999-2004, suggesting declines in mean A1c from 7.8% in 1999-2000 to 7.47% in 2001-2002 and 7.18% with 2003-2004. In terms of CV risk factor management, he noted data on the control of hyperglycemia, blood pressure, and hyperlipidemia in two registries (Kaiser and Denver Health), which showed 70.8% of patients for Kaiser and 44.3% of patients for Denver Health simultaneously meeting targets of A1c 8%, blood pressure of 140/90 mmHg, and LDL of 130 mg/dl. For diabetic retinopathy screening, he suggested that roughly 50-60% of patients have received screening, though it is unclear from current data if patients are meeting guidelines for the frequency of screening.



Omesh Gupta, MD, MBA (Jefferson Medical College, Philadelphia, PA)

Dr. Omesh Gupta gave an overview of the current state of diabetic retinopathy in the US, providing recommendations for improvement of care. As he noted, 40% of patients with diabetes older than 40 years of age have diabetic retinopathy, with 8% having vision-threatening disease. While glucose levels play a key role in the development of retinopathy, other factors have been shown to be related, including duration of diabetes, blood pressure, BMI, and other various measures. Thus, in addition to early screening, Dr. Gupta stressed the need to manage risk factors beyond A1c, both to prevent development of disease and improve outcomes in later surgical interventions.

  • Dr. Gupta reviewed the foreboding state of diabetic retinopathy in the US, highlighting the need for improvements in care. As he noted, 40% of patients with diabetes older than 40 years of age have diabetic retinopathy, with 8% having vision-threatening disease. Diabetic retinopathy is the leading cause of blindness in Americans aged 20-74 years as well, with projected increases in the coming years.
  • Retinopathy risk is multifactorial in nature. While glucose levels play a key role (Dr. Gupta noted that each percentage point reduction in A1c correlates with a 35% reduction in microvascular risk) in the development of retinopathy, other factors have been shown to be related, including duration of diabetes, blood pressure, BMI, and other various measures (e.g., insulin levels, cholesterol, triglycerides). Intriguingly, given diabetic retinopathy likely begins prior to diagnosis at A1cs as low as 5.5%, he suggested possible initiation of glucose therapies in the prediabetic state to prevent development as well.
  • An ophthalmologist by training, Dr. Gupta moved to describe two tests used by ophthalmologists to assess for underlying retinal pathology in patients with diabetes following referral. The first was the fluorescein angiogram technique, in which an inert plant resin is injected into the arm and then circulates to the eye, providing imaging of the vasculature. This technique allows observation of changes before overt symptoms occur, such as small aneurysms heralding hypertension. The second was optical coherence tomography, a relatively new technology that takes high-resolution pictures of the retina to investigate for hallmark changes in the fovea consistent with diabetic eye disease.
  • Dr. Gupta concluded with recommendations for optimal diabetic eye care. He stressed the importance of screening for diabetic retinopathy at diagnosis and the need for referral to an ophthalmologist for patients with any degree of macular edema or proliferative diabetic retinopathy, or severe non-proliferative retinopathy. This is especially important as retinopathy can portend other vascular complications, such as diabetic nephropathy and later CV events. Given retinopathy’s multifactorial nature, Dr. Gupta also highlighted the need to manage risk factors beyond A1c to prevent development of disease; he stressed good management aids in treatment as well, with laser photocoagulation of proliferative diabetic retinopathy showing better outcomes in patients if they present with A1c and lipid values in range. For treatment, he suggested early intervention with anti-VEGF helps preserve visual potential for patients with diabetic macular edema and can also improve later results with surgical options.



Jorge Plutzky, MD (Brigham and Women’s Hospital, Boston, MA)

Dr. Jorge Plutzky discussed the complex relationship between metabolic parameters and the vasculature in type 2 diabetes patients. He began by arguing that the clinically important risk factors for diabetes-related cardiovascular complications exist well before the formal diagnosis, and that earlier intervention is needed. He also emphasized that the length of diabetes is a critical variable in the evaluation of the vasculature of a type 2 diabetes patient, one that many landmark studies failed to record. He then discussed clinical trial data showing that a number of factors play a role in the “artherosclerosis puzzle” in type 2 diabetes patients, including cholesterol, triglycerides, and blood pressure. Surveying the current diabetes landscape, Dr. Plutzky noted that aleglitazar (a PPAR co- agonist) appears to reduce A1c as well as triglyceride levels while also increasing HDL. He also mentioned canagliflozin, and its ability to simultaneously improve A1c and body weight. He shared the recent findings of SAVOR TIMI-53, which showed that saxagliptin demonstrated cardiovascular safety in its outcomes trial, along with the STENO-2 study that showed the potential to reduce CV events by targeting blood pressure, lipids, and A1c.

  • A linear relationship exists between A1c levels and the incidence of adverse cardiovascular events in type 2 diabetes patients. Dr. Plutzky cited UKPDS data showing that a reduction in A1c of just 1% is associated with a 15% decreased risk of cardiovascular complications. Dr. Plutzky argued that setting a threshold A1c value for treatment is illogical given that significant risk exists in the prediabetes phase, well before formal diagnosis. He did mention the paradoxical results of the ACCORD and ADVANCE studies, which failed to show a reduction in cardiovascular adverse events with more intensive glycemic control. He explained this anomaly by noting that the studies may not have lasted long enough for the effect to emerge or that they may not have intervened earlier. They also may have ignored the negative effects of severe hypoglycemia, or failed to account for the duration of diabetes.
  • A number of factors contribute to diabetic atherosclerosis. Dr. Plutzky presented data indicating that cholesterol, triglycerides, and blood pressure levels have important effects on cardiovascular outcomes in type 2 diabetes patients. He highlighted data from an autopsy study of young males indicating that significant atherosclerosis can begin at an early age, and is proportional to BMI.
  • Recent cardiovascular outcomes data for type 2 diabetes drugs is promising. Dr. Plutzky mentioned the results of the SAVOR TIMI-53 study, which demonstrated that saxagliptin was associated with cardiovascular safety, although the secondary goal of superiority was not achieved. He noted the promising results of the SYNCHRONY study on aleglitazar, which showed that the PPAR co-agonist lowered A1c and triglycerides while improving HDL cholesterol. He highlighted the ability of canagliflozin to both reduce A1c and reduce body weight. Finally, he mentioned the findings of the STENO studies, which showed that aggressive control of blood pressure, A1c, and lipids led to a half-percent significant decrease in A1c.


Obesity and Bariatric Surgery


Hsin-Chieh Yeh, PhD (Johns Hopkins University, Baltimore, MD)

Though obesity is known to be strongly associated with an increased risk of diabetes and cardiovascular disease, the benefit of weight loss on cardiovascular disease risk remains unclear. Dr. Hsin-Chieh Yeh conducted an observational analysis on data from the POWER trial (a 24-month behavioral weight loss trial; Appel et al., NEJM 2011), estimating the effect of weight loss over six and 24 months on 10-year cardiovascular risk using the Framingham Risk Score (FRS). In adults with and without diabetes, at both six and 24 months there was a direct, significant dose-response relationship between the magnitude of weight loss and CVD risk reduction. This finding was consistent with previous studies demonstrating that obese individuals should be encouraged to lose at least 5% of their body weight to reduce cardiovascular disease risk. Dr. Yeh noted that Healthways, Inc. is developing a commercial weight loss program based on the results of the POWER trial.

  • Analysis was stratified by baseline diabetes status and weight change. Individuals in the analysis were grouped by weight change (>2% gain, <2% loss/ gain, 2-5% loss, 5-10% loss, and >10% loss), not by treatment arm as in the POWER trial. Mean weight change was between4.3 kg and 4.6 kg (9.5 lbs and 10.1 lbs).
  • There were 317 individuals without diabetes and 98 individuals with diabetes included in the study. Individuals without diabetes in the study were 53.4 10.2 years-old and weighed 103.3 17.9 kg (227.7 39.5 lbs) on average, were 37.2% male, 40.1% black, and had median 10-year cardiovascular risk of 6.8%. Individuals with diabetes in the study were 56.1 9.7 years-old and weighed 105.5 18.0 kg (232.5 39.7 lbs) on average, were 33.7% male, 43.9% black, and had median 10-year cardiovascular risk of 13.1%. Diversity in terms of diabetes status and race, as well as high follow-up rate (94.5%), were highlighted as strengths of the study.
  • A significant dose-response relationship between the magnitude of weight loss and cardiovascular disease risk reduction was observed at both six and 24 months among individuals with and without diabetes. Among individuals without diabetes, at six months, the relative risk ratio of cardiovascular disease was 0.89 per 5% weight loss at six months and 0.94 at 24 months. Among individuals with diabetes, at six months, the relative risk ratio was0.86 per 5% weight loss at six months and 0.94 at 24 months. However, relative risk ratio confidence intervals were slightly larger among individuals with diabetes.
  • Dr. Yeh noted some limitations to using Framingham Risk Equations. Absolute risk can be over- or under-estimated, and calculations include HDL and total cholesterol, but not LDL. Dr. Yeh also considered the potential for residual confounding.

Questions and Answers

Q: Do the weight loss categories correlate with clinical considerations?

A: In the current guidelines, we encourage people to lose at least 5% of their weight, and several previous studies show that if you lose more than 10% of your weight there is an even more substantial benefit. The other categories were based on the data distribution, as well as a previous paper in the LOOK AHEAD trial using the same categories. We wanted our data to be comparable with previous data.

Q: Can you talk about the distribution of participants across weight change categories?

A: I don’t have the data with me, but I remember that in the no diabetes group, most of the people are in the stable group and the other groups are evenly distributed. In both groups of people with and without diabetes, the stable group is the largest group.


Symposium: Improving Glucose Metabolism With Bariatric Surgery–Mechanisms of Action


Peter Havel, PhD (University of California, Davis, CA)

Bariatric surgery is “currently the most effective long-term treatment for obesity and results in rapid type 2 diabetes reversal,” said Dr. Peter Havel. He argued that the short-term metabolic changes after Roux-en-Y gastric bypass (RYGB) cannot be explained by caloric restriction alone; Dr. Havel presented data from 22 morbidly obese subjects (no diabetes) randomized to either RYGB or dietary restriction to show that RYGB increases hepatic insulin extraction, postprandial insulin response, and postprandial GLP-1 response. Dr. Havel hypothesized that liver fat content decreases after RYGB leading to the enhanced hepatic insulin extraction. He dedicated the latter half of his talk to murine models of ileal interposition (IT) and vertical sleeve gastrectomy (VSG) to explore the pathway by which IT and VSG can prevent type 2 diabetes. Backtracking momentarily, he showed that the UCD-T2D rat model is superior to the ZDF rat model in modeling type 2 diabetes in humans (Cummings et al., Am J Phsyiol 2008). Dr. Havel showed that IT surgery increased circulating bile acids and proposed that the increase in cholic acid may act by decreasing endoplasmic reticulum stress. IT had a number of other effects in UCD-T2D rats, including improved glucose tolerance, insulin sensitivity, and insulin secretion. In the VSG model, he demonstrated that the surgery had the additional effect of increasing adiponectin and posited that it was due to decreased ghrelin levels.



Karen K. Ryan, PhD (University of Cincinnati College of Medicine, Cincinnati, OH)

Bariatric surgery is extremely effective in reversing obesity and maintaining long-term weight loss relative to the modest efficacy of pharmacologic and lifestyle interventions. The Vertical Sleeve Gastrectomy (VSG) is a simple procedure that removes 80% of the stomach along its greater curvature, leaving the individual with a small tube linking to the intestine. Cumulative food intake is reduced and similar to Roux-en-Y gastric bypass surgery, weight loss can be maintained over time. Dr. Ryan stressed that the benefits of VSG are not due to restriction or malabsorption (there was no change in fat absorption as compared to controls). Rather VSG is a metabolic surgery and research shows not only a significant increase in bile acids but furthermore, there may also be a role for bile acid signaling to regulate metabolism. Both circulating bile acids and ileal bile acid receptor (FXR) activity are substantially increased following VSG. When investigating the targeted genes of bile acid signaling, research shows that the FGF-15 and FGF-19 hormones (mouse and human homologues, respectively) are dramatically increased and play roles in improved glucose metabolism. FXR knockout mice recover the initial body weight and fat lost following VSG. These mice compensate for the initial anoretic response to VSG, meaning there is no difference in cumulative food intake. These mice also show blunted improvement in glucose tolerance following VSG. Thus, Dr. Ryan demonstrated that FXR signaling is linked to improved glucose control following VSG and improved weight loss maintenance. Dr. Ryan mentioned, critically, that there are reciprocal interactions between bile acids and gut microbiota. While bile acids activate FXR and alter gene expression, the microbiota differentially deconjugate and dehydroxylate bile acids, which alters FXR signaling. While more remains to be seen, this complex interaction may contribute to the benefits of bariatric surgery and glucose metabolism.

Questions and Answers

Q: I imagine it’s been annoying for you to deal with the fact that the FXR knockout at baseline is lighter and more glucose tolerant than wild types. Why is that? It would seem if anything at baseline FXR knockouts would cause heavier and glucose intolerant animals - not the other way around?

Dr. Ryan: Now that’s a great question and I would love to have the answer to it and I would like to continue investigating. The FXR knockout mice have a strange phenotype, which is that on a chow diet they tend to have impaired glucose tolerance, and when they are on a high fat diet they have relatively improved glucose tolerance. Why this switch occurs, I’m not sure. I wonder if it has something to do with the interaction in gut microbiota. Moreover this is important for adipogenesis, so I think breaking this down into tissue-specific effects will be an important next step.

Q: Why is there an increase in expression of FXR target genes? Can you potentially use the bile acid to kick off the process?

Dr. Ryan: In the first case, that’s an interesting question that also will require some follow up studies. What we observe is a change in serum bile acids, which, as you are probably aware, does not necessarily mean a change in the total bile acid pool. In another study of metabolism, researchers saw an increase in the FXR target genes in the ileum in the presence of the gut microbiota, but there was actually a decrease of availability in the ileum. So it may not be a direct relationship between total bile acids and FXR signaling, there is probably some effect of the bile acid composition.

Q: I’m confused why bile acids remain elevated, because FXR seems to be activated. FGF-15 is also elevated so it seems like that would potentially over time bring the bile acid pool down to normal, or at least lower it significantly. Why do you see both increased bile acids levels and increased FGF19?

Dr. Ryan: I don’t have a great answer for you. We have been looking at longitudinal studies to address that looking at bile acid levels and compositionQ: Have you looked at the TGFR5 receptor?

Dr. Ryan: No.


Symposium: Joint ADA/EASD Symposium–Metabolic Effects of Bariatric Surgery– How Low Can You Go?


Philip Schauer, MD (Cleveland Clinic, Cleveland, OH)

Dr. Philip Schauer presented evidence that bariatric surgery could be a useful option for type 2 diabetes treatment. Four randomized controlled trials (RCTs; including one brand new study in JAMA [Ikramuddin 2013]) of various types of bariatric surgery compared to either conventional or intensive medical treatment have now shown that bariatric surgery consistently results in superior glycemic outcomes (e.g., diabetes remission) and improves cardiovascular risk factors. While no long-term RCTs have been done to date, a number of long-term studies beyond five years suggest that the benefit over medical therapy persists over the long term. Dr. Schauer reviewed the current guidelines and recommendations of major diabetes societies, expressing the greatest approval for the IDF’s guidelines, which voice the strongest support for the use of bariatric surgery in type 2 diabetes. In Q&A, Dr. Schauer urged the NIH and NHLBI to seriously consider larger, randomized trials to examine cardiovascular outcomes for bariatric surgery in type 2 diabetes.

  • Dr. Schauer reviewed results from the four randomized controlled trials (RCTs) that have compared the effects of bariatric surgery to medical therapy on clinical outcomes in type 2 diabetes. All showed that bariatric surgery was superior for diabetes remission and improving cardiovascular outcomes. Generally, adverse events observed were in the expected range.
    • The first RCT of this kind compared laparoscopic gastric banding (LAGB) with conventional medical treatment for type 2 diabetes (Dixon et al., JAMA 2008). Patients (n=60) had relatively new diabetes (<2 years from diagnosis; average baseline A1c 7.7%; none on insulin treatment). Remission rates of 73% in the LAGB group compared to 13% in the medical treatment group were observed after two years. Dr. Schauer noted that this was likely driven by weight loss of 21% vs. 2%, respectively in the two groups. Neither group experienced serious side effects.
    • Dr. Schauer’s STAMPEDE trial was next – this study compared Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (LSG) with intensive medical therapy targeting an aggressive A1c of 6.0%. Patients (n=50) were randomized to RYGB, LSG, or intensive medical treatment; they had relatively advanced diabetes (average baseline duration of eight years; average baseline A1c of 9%; most patients on more than 3 anti-diabetic agents). The primary endpoint was A1c ≤6% with or without medical treatment after 12 months; 12%, 42%, and 37% of the medical therapy, RYGB, and LSG groups, respectively, achieved this goal. The proportion of those achieving ≤6% A1c without medical therapy was 0%, 42%, and 27%, respectively. The surgical groups experienced superior glycemic control while almost eliminating the need for diabetes medications.
    • Geltrude Mingrone’s 2012 NEJM study compared two surgical cohorts (LAGB and biliopancreatic diversion [BPD]) with standard medical therapy. Patients (n=60; baseline A1c 8.5%; diabetes duration of six years) were randomized to LAGB, BPD, or standard medical therapy for two years. Remission rates for these three groups were 75%, 95%, and 0%, respectively. Dr. Schauer noted that some potential malnutrition may have been observed in the BPD group, while this was not a concern for RYGB.
    • A brand new study published in JAMA in June 2013 (Ikramuddin et al.) compared RYGB with intensive medical therapy. This was a multicenter (in theUS and Taiwan), 12-month RCT (n=120; baseline A1c of 9.6%). Notably, 60% of patients had BMI <35 kg/m2 whereas most people in the previous three RCTs had BMI over 35 kg/m2. The primary endpoint was a composite of A1c <7%, LDL cholesterol <100 mg/dl, SBP <130 mmHg (the ADA’s triple ABC recommendations); 49% of those in the surgical group vs. 19% of those in the medical group achieved these goals. In addition, 44% and 9%, respectively, achieved diabetes remission. One patient had a very poor outcome that resulted in brain injury. In total, there were 15 major adverse events (AEs) in the medical treatment group and 22 major AEs in the surgical group.
  • Dr. Schauer then reviewed evidence for the long-term benefit of bariatric surgery. The SOS study has now been running for more than 20 years. While the original results showed a 72% vs. 21% diabetes remission rate in the surgical vs. control cohorts, the number of patients in remission fell to 36% vs. 13% after 10 years. Dr. Schauer stated that while remission rates fall after time, the superiority over the control group still persists. Additionally, David Arterburn’s group (Obesity Surgery 2013) showed that the median duration of remission was 8.3 years – a substantial amount of time in our view.
  • Finally, he reviewed the ADA, AACE, and IDF positions on bariatric surgery for type 2 diabetes. The ADA is the most conservative, stating that surgery could be considered for patients with severe obesity and a BMI ≥35 kg/m2 but that there is insufficient evidence to recommend bariatric surgery for patients with BMI <35 kg/m2. AACE recently added bariatric surgery to their guidelines for the first time, recommending surgery after failure of lifestyle and medical therapies in patients with BMI ≥35 kg/m2. The IDF is the strongest proponent of the three – it says that surgery should be an accepted option for people with BMI ≥35 kg/m2 and type 2 diabetes and should be considered for people with BMI of 30-35 kg/m2. It even goes as far as to suggest that patients of certain ethnicities or otherwise predisposed to type 2 diabetes (e.g., Asians), should be considered candidates at a BMI as low as 27.5 kg/m2.

Questions and Answers

Q: Are you aware of three studies that have been published in the last three months comparing surgery with a very intensive low calorie diet? The results of the three studies show that in a short period of time, the results were the same. These studies you’ve been showing have been with traditional calorie diets. Could diet get the same effect as surgery?

A: While short-term diets have been known for many years to have very profound effects on type 2 diabetes, they have been very short term and very transient. None of those studies go much beyond a few months, especially not beyond a few years. To my knowledge, there is nothing comparing low calorie diet long term with clinical outcomes. That may be the value of bariatric surgery – sustainability. SOS is now out to 20 years showing that sustainability is quite dramatic. Clearly the mechanisms of what drives the benefit need to be studied further. Most would agree that weight loss and caloric reduction are factors. There are also lots of data suggesting other endocrine and neuroendocrine effects may have predominant effects as well. All this calls for larger RCTs to answer these questions.

Q: This question relates to CV endpoint studies. We’re doing them with DPP-4 inhibitors and GLP-1 agonists. Is it being done with bariatric surgery anywhere?

A: The SOS study’s primary endpoint was CV. It wasn’t randomized, but it clearly showed benefit for all- cause mortality for diabetic and nondiabetic patients. Currently to my knowledge no studies are large enough to realistically look at these CV endpoints. I do hope NIH and NHLBI look at this very seriously.



Geltrude Mingrone, MD, PhD (Catholic University, Rome, Italy)

Dr. Geltrude Mingrone first reviewed evidence suggesting that biliopancreatic diversion (BPD) and Roux-en-Y gastric bypass (RYGB) improve glucose metabolism in very different ways: whereas BPD has a greater effect on improving insulin sensitivity, RYGB’s major effect is improving insulin secretion. She then asked what might be the mediators of improved glucose metabolism after metabolic surgery – she presented evidence showing that neither of the two usual suspects, GLP-1 and ghrelin, were necessary for the improvements in glucose metabolism. In contrast, she believes that bypassing the proximal bowel (the duodenum), and instead delivering nutrients to the mid-bowel (the jejunum), is a relevant factor for improving glucose metabolism. Finally, Dr. Mingrone presented striking new data from her group suggesting that intestinal peptides other than GLP-1 or ghrelin may be involved in inducing insulin resistance in type 2 diabetes.

  • Dr. Mingrone presented evidence that neither GLP-1 nor ghrelin is necessary to mediate the glycemic effects of metabolic surgery. In a recent Diabetes paper (2013), sleeve gastrectomy had the same effect on GLP-1 receptor knock-out mice as wild type mice. In addition, rodents who were not able to secrete ghrelin had similar responses to sleeve gastrectomy (Chamber et al., Gastroenterology 2013).
  • Dr. Mingrone believes nutrient exclusion from the duodenum plays a large role in mediating the metabolic effects of RYGB. When diabetic rodents’ duodenums were protected by a sleeve, the OGTT response was normalized. However, when the sleeve had holes in it to allow nutrients to escape into the duodenum, the OGTT was typical of a diabetic animal (Rubino et al., Ann Rev Med 2010). In addition, Dr. Mingrone’s group recently published work showing that when delivering a mixed meal into the distal jejunum (mid-lower bowel), the proximal jejunum (mid-upper bowel), or the duodenum (upper bowel) on separate days, patients’ insulin response only improved when the nutrients were delivered to the distal jejunum (Salinari et al., Am J Physiol Endocrin Metab 2013).
  • Lastly, Dr. Mingrone presented striking new data from her group suggesting that proteins secreted by the duodenum-jejunum of db/db mice with type 2 diabetes might be responsible for inducing insulin resistance. After isolating these proteins and incubating them with normal mice soleus muscle tissue and L6 skeletal muscle cells, insulin resistance was induced. Additionally, injecting these proteins intravenously into normal Swiss mice was sufficient to induce insulin resistance as demonstrated by an insulin tolerance test.

Questions and Answers

Q: Could you comment again on the last experiment? I may have missed it. In humans did you take a jejunal biopsy or fluids? How did you show that some proteins secreted by the jejunum in humans induced insulin resistance?

A: We obtained the jejunum samples during bariatric surgery and also during enterectomy in patients with Crohn’s disease. Despite the fact that patients with Crohn’s should be more insulin resistance due to the inflammation, these proteins were unable to induce insulin resistance, while proteins obtained form insulin resistant subjects did.

Q: Are outcomes with sleeve gastrectomy and gastric bypass similar?

A: Gastric bypass is more effective in improving insulin sensitivity than sleeve gastrectomy, although there are fewer studies on sleeve gastrectomy than RYGB. Indeed the bypass of a larger portion of the gut could explain the improvement in insulin sensitivity. After gastric bypass there is a small improvement in insulin sensitivity. After BPD there is a large improvement of insulin sensitivity, probably due to the larger bypass of the small intestine. The sleeve gastrectomy is not so effective in either improving insulin sensitivity or increasing insulin secretion.



Allan Geliebter, PhD (Columbia University Medical Center, New York, NY)

Dr. Allan Geliebter explored the neural system’s response to food in obese versus lean individuals and the corresponding changes post-bariatric surgery. Following an introduction to gastric distension, Dr. Geliebter discussed how obese individuals have an altered reward response to meals. Post-bariatric surgery, the reduction in mesolimbic activation in response to high-energy dense food suggests a restoration of the brain’s normal response to high-energy dense food. Further, he noted how bariatric surgery altered the levels of hormones known to affect the brain’s response to food.

  • Using an intragastric balloon to distend participants’ stomachs, Dr. Geliebter’s group evaluated how the brain responds to gastric distension. In the study (n=18) the balloon was filled to 250 ml, then 500 ml, and then deflated stepwise. As the balloon was filled, they observed activation in the amygdala and then the insula, which usually detects signals from the gut; participants reported changes in fullness but not hunger or discomfort. Interestingly, they observed a significant inverse correlation between BMI and brain activation– the greater the individual’s BMI, the smaller the response to equivalent gastric distension.
  • Dr. Geliebter briefly reviewed mesolimbic dopamine reward pathways in the brain, before evaluating how obese individuals’ brains assess reward. In a PET study, obese individuals had reduced D2 receptor binding compared to normal individuals, indicating lower activation of the dopaminergic reward pathways. An fMRI study involving 10 obese (BMI=33 kg/m2) and 10 lean individuals (BMI=22 kg/m2) without diabetes demonstrated that high-energy dense foods (>3.5 kcal/g) led to greater dopamine reward system activation in obese individuals compared to lean individuals.
  • In an fMRI study comparing reward activation in women before and one month after surgery, investigators found that the reward response to high-energy dense foods decreased by a greater magnitude than did the reward response to low-energy dense foods following surgery. Dr. Geliebter concluded that the discordant reduction in mesolimbic activation in response to different energy dense foods appears to help restore the brain’s normal response to high-energy dense food cues.
  • A prospective study of 13 healthy women with BMI >40 kg/m2 evaluated GI hormones and gastric emptying pre- and post- surgery in response to a nutritionally complete liquid meal that followed an overnight fast. Post-surgery, there was a rapid rise in CCK (a neuropeptide involved in satiety signaling) after the meal compared to pre-surgery tests and an interesting decrease in leptin levels, all indicating an altered neural response. Additionally, gastric emptying was much faster post-surgery. Finally, Dr. Geliebter reminded the audience of Dr. David Cummings’ findings that post-surgery ghrelin levels stay flat after a meal compared to the normal rise.



Karine Clément, MD, PhD (ICAN, Paris, France)

Dr. Karine Clément discussed “the other genome” – the collective genome of gut microflora – and how it contributes to the effects of bariatric surgery. She noted that there are significant changes in the microbiome post-surgery that could be involved in weight loss. She reviewed a study (n=47) that demonstrated a positive correlation between two types of bacteria (Bifidobacterium and Lactobacillus) and BMI, percent fat mass, and leptin levels. F. prausnitzii was negatively associated with inflammatory markers, independent of food intake. Dr. Clément then presented data showing that obese subjects have a lower diversity of gut microflora and that a very low diversity can lead to impaired metabolic improvement even while dieting. After bariatric surgery, microflora diversity increases; about 58 new species were found post-surgery in one study. Dr. Clément posited that the changes in food intake, pH, intestine motility, and incretin levels create an environment that can modify the gut microbiome. Some of the beneficial effects of microflora changes are transmissible, as shown in a mouse study where the gut microbiome of a mouse post-surgery was transplanted into another germ-free mouse, resulting in weight reduction and reduced production of short-chain fatty acids. Dr. Clément concluded with a summary of current knowledge on the topic: microflora richness changes after gastric bypass surgery; there are strong associations between microflora and metabolic and inflammatory phenotypes; and changes in food intake explain only about 50% of these effects.


Symposium: Pharmacologic Management of Obesity


Robert Eckel, MD (University of Colorado, Aurora, CO)

Following Dr. W. Timothy Garvey’s (University of Alabama, Birmingham, Birmingham, AL) description of anti-obesity agents before 2012, Dr. Robert Eckel dove into the labels and phase 3 data for phentermine/topiramate ER (Vivus’ Qsymia) and lorcaserin (Arena/Eisai’s Belviq). Dr. Eckel detailed the need for 5 % to 10% weight loss to produce a cardiometabolic benefit and positively described the ability of these recently launched agents to achieve up to 10% weight loss and be used indefinitely. Dr. Eckel was careful to keep his description of Qsymia and Belviq factual; he explained during the subsequent panel discussion that he wanted attendees to decide for themselves which drug to use in their various patients. Still, when pressed by a questioner on the matter, Dr. Eckel stated that he would likely use phentermine in his case study of a “frustrated patient” (a 48 year old woman with a BMI of 34 kg/m2 despite having been on “every diet”), if she expressed feeling hungry, since in his observational experience phentermine works particularly well in such patients. Between Qsymia and Belviq, Dr. Eckel briefly explained that he would likely favor Qsymia for such a patient, since he would want the greater efficacy. Looking to the future of obesity pharmacotherapy, Dr. Eckel touched upon the current phase 3 findings for naltrexone/bupropion (Orexigen’s Contrave) and 3.0 mg liraglutide (Novo Nordisk’s Victoza for obesity). Strikingly, during the panel discussion, Dr. Eckel remarked that he did not think 3.0 mg liraglutide’s side effects (he appeared to be referring to GI adverse events) were worth the weight loss. Later, he softened his language slightly, describing its side effects as “limiting” for the higher dose.



W. Timothy Garvey, MD (University of Alabama, Birmingham, Birmingham, AL)

Dr. Timothy Garvey opened his presentation explaining that his talk’s sub-title, “The Good, The Bad, And The Ugly” was assigned by the ADA, and he thought it was “too trite.” Thus, Dr. Garvey renamed it “Something Old, Something New…” For “something old,” Dr. Garvey focused on phentermine and Orlistat, rather than the several of drugs that have been removed from the market. Looking at the gap that formed in obesity treatment, Dr. Garvey remarked that the weight loss associated with older drugs was not great enough for many people. Dr. Garvey dedicated much of his presentation to detailing BMI’s poor predictive power for comorbidities, such as type 2 diabetes. Instead, Dr. Garvey pressed that people should use AACE’s complications-centric approach for treating obesity in which the modality and intensity of treatment is determined by the amount of weight loss a person needs to improve their comorbidities. Dr. Garvey proposed that people use his group’s obesity staging system, the Cardiometabolic Disease Staging System, which is found to be predictive of complications and mortality risk. Concluding his talk, Dr. Garvey argued that weight loss is cost-effective and should be reimbursed by the government and payers.

  • Dr. Garvey explained that generic phentermine it is available at much higher doses (15-35.5 mg doses) than all but the highest dose of Vivus’ Qsymia (15 mg/92 mg phentermine/topiramate ER). We note that Vivus is a company for whom Dr. Garvey frequently authors posters and papers. Dr. Garvey continued to describe how phentermine is associated with 13% weight loss (8% placebo adjusted) and is only approved for three-months use.
  • Orlistat is approved for long-term use and is associated with weight loss of 5.8 kg vs. kg of weight loss on a “DPP-type” intervention (baselines not provided). Dr. Garvey presented data demonstrating that orlistat significantly reduces people’s progression to type 2 diabetes by 37.3%. This result was driven by a reduction in risk among people with IGT. In this population orlistat reduced progression to type 2 diabetes by 45.0%, which Dr. Garvey stated was better than a DPP-type intervention (Torgerson et al., Diabetes Care 2004). We note that the drug’s GI side effects (due to the malabsorption of fat) have significantly reduced its popularity despite this efficacy.
  • Dr. Garvey described a complications-centered model for treating obesity (as proposed by AACE) as being superior to an approach based purely on BMI. He had five points to support this hypothesis (details below). Furthermore, he underscored that the relationship between BMI and complications is complex, with up to 30% of obese patients being insulin sensitive and without cardiometabolic disease or another significant obesity-related complication. Based on the BMI model, these patients qualify for extensive weight loss treatments that may not be necessary.
  • Nearly 70% of American adults are overweight or obese. Thus, according to Dr. Garvey, it is not safe or fiscally feasible to treat all overweight or obese people (as defined by BMI) with anti-obesity pharmacotherapy or surgery.
  • A complications-centered model, in Dr. Garvey’s view, emphasizes medical, rather than cosmetic, outcomes.
  • Dr. Garvey explained that 10% weight loss is sufficient to improve many risk factors for comorbidities. These include insulin sensitivity, glucose homeostasis, lipid levels, blood pressure, and cardiovascular disease risk factors. This level of weight loss can also reduce the number of glucose and/or blood pressure control medications people require. Referencing the DPP trial, Dr. Garvey explained that the ability to prevent type 2 diabetes via weight loss appears to max out at 10%.
  • Medical and surgical interventions often provide better outcomes than lifestyle interventions in obese patients with complications.
  • Dr. Garvey believes that weight loss has the optimal benefit/risk ratio when it is used a tool to treat the complications of obesity.
  • Dr. Garvey encouraged attendees to use more efficacious (and higher risk) obesity treatment modalities and to intensify within a treatment modality, if a person is not losing substantial weight. Within medical therapy he ordered current options from least intense to most as follows: phentermine, orlistat, lorcaserin, recommended dose of phentermine/topiramate ER (7.5 mg phentermine/46 mg topiramate ER), and high dose phentermine/topiramate ER (15 mg phentermine/92 mg topiramate ER).
  • Concluding his talk, Dr. Garvey argued that weight loss is cost-effective and should be reimbursed by the government and payers. He cited data suggesting that 5% weight loss for two years results in a total financial benefit of $334, permanent 5% weight loss generates a total benefit of $3,150, and permanent 10% weight loss could save $6,400 (Dall et al., Am J Prev Med 2011).
  • Dr. Garvey’s Cardiometabolic Disease Staging characterizes a person’s obesity as being one-of-five possible stages of severity.
  • Stage zero is defined as a person having no risk factors (i.e., waist, blood pressure, triglycerides, HDL-c) meaning that the person is “healthy obese.”Stage one: the person has one or two risk factors. The rationale for this is that one or two risk factors elevates a person’s risk of future type 2 diabetes and cardiovascular disease.
  • Stage two: the person has metabolic syndrome or prediabetes.
  • Stage three: the person has metabolic syndrome and prediabetes.
  • Stage four: the person has end-stage cardiometabolic disease.



Michael Schwartz, MD (University of Washington, Seattle, WA)

Dr. Michael Schwartz opened the symposium by explaining current understandings of how weight is impacted by the central nervous system. Most obese bodies will biologically defend their size, meaning that nearly 90% of patients regain their lost weight within five years. The current neurological model of explaining when and how we feed is based on the idea of energy homeostasis controlled by neurocircuits including leptin. While there is no unified neurocircuit base of obesity pathogenesis, non-homeostatic feeding circuits (such as states of hypoglycemia or intense stress) are always in balance with normal energy homeostasis. Lastly, Dr. Schwartz hypothesized that obesity is associated with neuronal injury and subsequent gliosis in the mediobasal hypothalamic areas that control energy homeostasis. This injury could be a target for obesity treatment.

  • Energy homeostasis involves complex, highly integrated neurocircuits through which the control of short-term food intake is continuously adjusted in response to changes in the amount of body fuel stored as fat in order to maintain stability. Circulating signals like the leptin correspond with the hypothalamus to regulate the body’s energy intake and expenditure. Most obese individuals are leptin resistant, not leptin deficient, as leptinpromotes a decrease in energy intake and an increase in energy expenditures. When an individual is on a hypocaloric diet, leptin levels drop as a consequence. This stimulates receptors to increase food intake, enhance the reward value of palatable food, and blunt reception of meal satiety. Thus the body favors unwanted weight gain.
  • Under emergent conditions (hypoglycemia, external stress, trauma, injury, or illness), food intake can be potently altered to meet needs unrelated to energy homeostasis and mechanisms driving food intake can completely override homeostatic controls. For example, in the case of hypoglycemia sensed by the ventromedial nucleus (VMN), the brain increases the drive to eat by lifting tonic inhibition of VMN neurocircuits. On the other hand, inhibition of this powerful non-homeostatic response allows normal energy homeostasis to occur.
  • Finally, Dr. Schwartz showed data from rodent models of obesity that demonstrated damaged hypothalamic cells and reactive gliosis. He believes this injury may play a causal role in obesity pathogenesis and could be a target for obesity treatment.



Moderator: Samuel Klein, MD (Washington University, St. Louis, MO)

Panelists: Robert Eckel, MD (University of Colorado, Aurora, CO); W. Timothy Garvey, MD (University of Alabama, Birmingham, Birmingham, AL); Michael Schwartz, MD (University of Washington, Seattle, WA)

Q: Have you got any studies on whether these drugs combat the leptin effect?

Dr. Schwartz: I have not. I do not have anything useful to say on how helpful that would be.

Q: The thing that was left out was how many people stay on therapy versus drop-out due to the side effects with these drugs. How many suicides were there? Do we have five-year data yet?

Dr. Eckel: The dropout rate is of course less in lower doses. As you dose up they can get to the 20% range. In some of the earlier studies the dropout rate was quite higher.

Q: The thing that is interesting is that increasing the dose doesn’t seem to give you direct metabolic, HDL, LDL increases. Is that doubling of metabolic benefits suggesting some other drug benefit?

Dr. Garvey: In some cases the cardiometabolic benefits with the treatment dose are pretty close to what is seen with the maximum dose. There is a lot of individual variation here. Seeing the data from the Look AHEAD study we can assume that certain parameters will improve up to certain thresholds. We can intensify our therapy if we need more weight loss. With phentermine/topiramate, patients with depression and those on SSRIs were included. These patients had no complications; there was no suicide signal; these patients did quite well. Those patients were excluded so the FDA label has a warning for lorcaserin.

Dr. Klein: There is a definitely an expected, dose-dependent weight loss. Additionally, there is a gradual improvement of triglyceride and cholesterol levels.

Q: For topiramate you showed its kind of weird effect on A1c. Can you explain this?

Dr. Eckel: You seem to be a bit disappointed with the effect on A1c.

Comment: The A1c did not really change despite the weight loss.

Dr. Eckel: There was clearly an A1c effect for phentermine/topiramate and it was dose related. So I am not sure if I understand your question.

Q: Do you think it is worth it to go through all of the side effects with liraglutide just to lose the little weight it is associated with?

Dr. Eckel: I do not think that it is worth it. The higher dose does cause a more aggressive weight reduction. But yes, the side effects do limit the higher dose.

Q: How would you decide which of the new drugs to give the “frustrated patient”?

Dr. Eckel: I wanted you to make your own decision. I might fall back onto what I have done historically. If she were hungry I might give her phentermine. It is cheap and highly effective if a person is hungry. I may be looking for a bit better effect with the phentermine/topiramate combination but lorcaserin would also be a reasonable choice.

Q: You are right to point out that the expectations from patients are sometimes grossly exaggerated. I think that we fail to get across that the expectation of weight loss is small and that it takes a long time. I think we need to be responsible physicians to make sure their expectations are fair.

Dr. Eckel: Great point.

Q: My main question is the safety of these drugs. These studies have been done for about two years. The safety issues arise when you use the drugs long term. How do you deal with this limited data. Do you stop the drug after two years? If so, how do you deal with the weight regain?

Dr. Garvey: We don’t know what the long-term effects of these drugs are going to be. If these patients are removed from these medications, we know that patients will likely regain their weight so we keep them on the drug indefinitely. We will rely on clinicians making careful observations and figuring out how to most effectively use these drugs over the long term.

Dr. Klein: Two of these compounds have been around for a long time. They just have not been used together before. It is unlikely we will see something new with the lower doses.

Q: It seems like the medications are more effective in patients with complications. What do we do in our obese patients who don't have complications? How do we clear the gap for them?

Dr. Klein: Let me expand that a bit more. Dr. Garvey, you talked about a disease-centric approach, which becomes very complicated. You focused it very much on cardiometabolic disease and ignored cancer, arthritis, and other parts of the disease. So what do you do if this patient does not have active cardiometabolic disease but is obese?

Dr. Eckel: That is why I included a slide on prevention. We need to do a better job on that. I think that in terms of patients without comorbidities we need to be more aggressive about the prevention of complications.

Dr. Garvey: I would also stress sleep apnea. In the Look AHEAD study over 80% of patients who were obese and had type 2 diabetes had sleep apnea. This is a serious condition for which there is no approved pharmacotherapy. I do not want to just talk about the cardiometabolic disease and give the impression that the others are not important. When we are talking to an obese patient we should make sure that we

have goals in mind. If we are putting them on medicines or bariatric surgery we are exposing them to risks and we need to consider the benefits they might reap.

Q: My bias is that those with the most insulin resistance are the most difficult patients – they have the hardest time achieving success. I have not seen any insulin resistance data. Is lorcaserin or phentermine/topiramate more efficient at restoring insulin sensitivity?

Dr. Garvey: Fasting insulin and fasting glucose go down. That is indicative of improvements in insulin sensitivity. There have not been formal clamp studies but both of these drugs improve insulin sensitivity in association with weight loss. I do not know if one is better than the other, there have not been any head to head trials.

Dr. Eckel: I agree with Tim. I think the concept of insulin resistance being a defender of excess body fat is an interesting concept. I think what happens with weight reduction is that as patients become more insulin sensitive there tends to be more fat oxidation and less fat storage.

Q: Is there enough known about the different mechanisms so that we can use multiple agents that have different mechanisms to attack glucose homeostasis

Dr. Schwartz: I do think that is where the future lies but I thought that 20 yeas ago. I thought that these breakthroughs in understanding these neural circuits would lead to therapies that were somewhat effective on their own but more effective in combination. You would have one thing that promoted weight loss and than another that blocks the homeostatic response to weight loss. I do think that is where the future lies. Lorcaserin to some extent stands as being a mechanism-based drug. Really none of the other drugs do – someone discovered that they were associated with weight loss. I do not think we have a scientific understanding of how phentermine causes weight loss. If you do not have that, it is hard to use it in a mechanistic way. Really for all of the chronic medical conditions that we think about (hypertension or type 2 diabetes) one drug may be effective for some segment of the population but many people require more than one drug. I think that will be the case for obesity as well.

Dr. Klein: It is fascinating to me why some people stay lean while others are obese. Schwartz let me ask you – what about this other aspect, this executive function, that overrides all these other mechanisms. People come from Japan, they are skinny and then gain weight due to the food – their chemicals are overridden. People will not eat more dinner because they are full but they eat up the apple pie despite it hurting.

Dr. Schwartz: Mechanisms themselves can cause obesity. Probably the most important mechanism linked to obesity is that they allow weight to be gained. The mutation is not one that causes obesity, it is one that does not prevent against obesity as well. You don't have to work very hard in the environment to eat a variety of foods that have been engineered to be incredibly palatable and energy dense. You are confronted with an environment that favors positive energy balances. The average BMI continues to drift upwards. The genes are not changing. The genes determine the susceptibility to the environment and the environment is changing. Lifestyle intervention is a much better way to prevent obesity than to treat it, because the gained body weight is now biologically dependent. Even if you eat perfectly you are not going to lose weight. So it is a very complicated dynamic. The more you lose weight the more rewarding the idea of eating that extra sliver of pie becomes.

Dr. Klein: So what is the future for pharmacotherapy for obesity? Can you develop chemicals that will break these mechanisms without making people miserable?

Dr. Schwartz: I think there is a limit. The interesting thing with gastric bypass surgery is that those people can lose a lot of weight but they do not show the adaptive responses you see in people who lose weight through lifestyle. That suggests that there is a biological resetting to a lower weight. It is hard to see why that can’t be done with a pharmacological approach. It is a fascinating question. I am going to go to a symposium on bariatric surgery where I hope the mechanisms discussed will shed some light on this.


Product Theater: A Novel Treatment Option for Chronic Weight Management (Sponsored by Eisai)


Caroline Apovian, MD (Boston University Medical Center, Boston, MA)

A substantial line of people waiting for Eisai’s product theater on Eisai’s Belviq (lorcaserin) was already wrapping around the exhibit hall 20 minutes before Dr. Caroline Apovian’s presentation was to begin. Even though the FDA approved the drug last June, this was the first product theater we attended in which the speaker could openly discuss Belviq, as the drug was only effectively scheduled by the Drug Enforcement Agency on June 7, 2013. During her presentation based largely on Belviq’s phase 3 data and label, Dr. Apovian repeatedly described Belviq as the first and only selective 5-HT2c receptor agonist for chronic weight management. She positively characterized the drug’s 3-4% placebo adjusted weight loss. In line with Eisai’s stated belief that one of Belviq’s patient niches is people with type 2 diabetes, Dr. Apovian dedicated part of her presentation to detailing BLOOM-DM, the phase 3 trial of Belviq in people with type 2 diabetes. She stated that the weight loss seen in this population was “very good” and that the drug was associated with “nice” and significant drops in both A1c (0.5% placebo- adjusted) and fasting glucose (15.5 mg/dl placebo-adjusted). On the safety side, Dr. Apovian underscored Belviq’s differentiation from past anti-obesity medications associated with valvulopathy and her belief that the rate of valvulopathy regurgitation seen among people on the drug (2.4% vs. 2.0% on placebo) is due to obesity being associated with this condition. Following, Dr. Apovian’s one-hour long presentation, 53% of attendees said that they would reconsider waiting to use pharmacotherapy in their patients who are obese or overweight, 28% stated that they would not reconsider this, and 20% indicated that they need more information. We are curious what attendee’s reasons are for not reconsidering pharmacotherapy options and what additional information they would like before prescribing the drugs; unfortunately, the theater did not include a Q&A session during which people could express these concerns.

  • Dr. Apovian remarked that the American Medical Association’s (AMA) decision last week to designate obesity a medical disease, was the culmination of over 20 years of hard work by researchers and groups like The Obesity Society (TOS). She relayed her (and anti-obesity companies’) hope that the AMA’s announcement will lead to increased reimbursement of anti-obesity medications. Additionally, she believes that if obesity is a disease then a physician’s time diagnosing and treating it should be reimbursed. Currently, most physicians are reimbursed for treating obesity comorbidities not obesity itself.


Additional Topics

Oral Sessions: Islet Transplantation for the Treatment of Type 1 Diabetes


Eduardo Moraes Leao Peixoto, MD (University of Miami, Miami, FL)

Looking for a way to slow islet transplant graft’s loss of function without short-acting exenatide’s (BMS/AZ’s Byetta) tolerability issues, Dr. Eduardo Moraes Leao Peixoto investigated the impact of liraglutide on graft function and glycemic control. In a prospective study (n=6), Dr. Peixoto found that liraglutide did slow the deterioration of graft function and was well tolerated. Dr. Peixoto hypothesized that chronically higher GLP-1 levels (basal and stimulated) could lead to longer islet survival. However, he found that liraglutide also did not decrease gastric emptying to the extent of short-acting exenatide. Notably, the abnormal glucagon response to 300-minute mixed-meal tolerance test often seen among people with type 1 diabetes was inhibited by short-acting exenatide for up to 36 months of use but was not inhibited by liraglutide treatment. We are curious what impact (if any) these latter findings could have on the desirability for short-acting exenatide vs. liraglutide in type 1 diabetes – presumably since overeating is not generally a problem in type 1 diabetes, the lack of effect on gastric emptying may not be an issue.

  • In this prospective study on islet transplant recipients with positive C-peptide (n=6); at baseline five were on exenatide and one on sitagliptin (all exenatide was stopped prior to the study). Liraglutide was then started at 0.6 mg daily and increased to 1.2 mg daily after one week. The insulin dose was not changed (all participants were only on insulin glargine). Data on insulin, glucose, C-peptide, acetaminophen (to measure gastric emptying time), glucagon, and GLP-1 in response to a 300 minutes Mixed Meal Tolerance Test (MMTT) were collected at zero, six, and 12 months, in addition to body composition data, A1c, and glucose finger stick readings.
  • Dr. Peixoto found that liraglutide was well tolerated. Strikingly, no nausea was observed, and appetite increased in all patients. Additionally, weight loss was observed in 67% of patients after six months (3.6 +/- 9.5 lbs). 33% had weight loss at month 12 (1.4 +/- 4.9 lbs; baselines not provided). No severe hypoglycemia episodes occurred, and the liraglutide dose was reduced in two participants due to constipation or diarrheas.
  • For background, several years ago Dr. Rodolfo Alejandro’s (University of Miami, Miami, FL) group investigated the effect of short-acting exenatide treatment (BMS/AZ’s Byetta) following transplantation (n=16). They found that exenatide had a positive effect on glycemic control and islet graft function, however, 63% the patients discontinued the drug due to adverse events. Hearing about liraglutide’s superior tolerability Dr. Peixoto, now a member of Dr. Alejandro’s group, decided to investigate its use in people with islet transplants.

Questions and Answers

Q: Did you notice between the two cohorts you treated with exenatide and liraglutide if you had to use different doses of immunosuppressants?

A: There was no difference in immunosuppression or the absorption of medication.

Q: I was wondering if some of the results could be explained by the specific dose of liraglutide you chose. Did you have any way of doing a dose comparison? In terms of the timing of the testing that you were doing the A1c could be impacted.

A: We aimed to give them the highest dose that we could to improve their glucose control. It was a very small sample.



Karen Teff, PhD (University of Pennsylvania, Philadelphia, PA)

Dr. Karen Teff presented the results of a study examining the effect of intrahepatic islet cell transplantation on glucose counter-regulation and hypoglycemia symptoms in patients with long- standing type 1 diabetes. In this study, patients with type 1 diabetes (n=12; average duration 29 years) with evidenced hypoglycemia unawareness underwent hyperinsulinemic hypoglycemic and euglycemic clamp procedures prior and six months following intrahepatic islet transplantation. Results were compared to healthy controls (n=8). Clamp procedures demonstrated full to partial recovery of various metrics of glucose counter-regulation in patients post-transplant, including glucagon, epinephrine, pancreatic polypeptide, free fatty acids, and autonomic symptom scores; Dr. Teff indicated these results supported consideration of intrahepatic islet transplantation for patients with severe hypoglycemia unawareness.

  • Patients with type 1 diabetes are known to show a diminished response to low glucose levels as well as hypoglycemia unawareness, increasing the risk of severe hypoglycemia. Patients lose the first line of defense to hypoglycemia through the islet cells (increased glucagon release and decreased insulin release) and have been shown to have a diminished second line defense via the sympathetic response (increased epinephrine and autonomic symptoms) as well. This study aimed to confirm if intrahepatic islet cell transplantation has a restorative effect on these functions.
  • In this study, patients with type 1 diabetes (n=12) underwent hyperinsulinemic hypoglycemic and euglycemic clamp procedures prior and six months following intrahepatic islet transplantation; results were compared to healthy controls (n=8). Patients had a mean type 1 diabetes duration of 29 years with evidenced hypoglycemia unawareness (by Clarke hypoglycemic score of 6.3 and HYPO score of 2,564). Patients receiving transplantation were given on average 9,468 islet equivalents/kg by a portal vein infusion, with 10/12 patients becoming insulin-independent and an overall A1c decline from 7.0% pre- to 5.6% post-transplant. Baseline A1c in healthy controls was 5.5%.
  • Clamp procedures demonstrated full to partial recovery of various metrics of glucose counter-regulation in patients post-transplant. During hypoglycemic clamp, patients pre-transplant showed a reduced glucagon response, which was recovered post- transplant though still diminished versus healthy controls; pancreatic polypeptide and epinephrine showed similar patterns with near-complete recovery, whereas autonomic symptom scores and free fatty acid levels in response to hypoglycemia were fully recovered post-transplant. There was a restoration in endogenous glucose production post-transplant as well, lost in pre- transplant patients. During euglycemic clamp, post-transplant patients showed no difference versus normal controls in the amount of insulin or C-peptide production as well.

Questions and Answers

Q: I was interested in how it did not restore complete epinephrine response. Do you know why that is?

A: It’s probably due to the beta cell mass, which is still likely not equivalent.

Comment: The restoration in glucagon secretion you are observing is likely either due to alpha cells recognizing hypoglycemia or epinephrine causing the release. You could answer that by giving a beta blocker beforehand.

A: That would be a very interesting experiment. Thank you.


Special Lectures and Addresses: President, Health Care & Education Address and Outstanding Educator in Diabetes Award Lecture


Ann Albright, PhD (CDC, Atlanta, GA)

Movingly dedicated to Dr. Richard Rubin and her mother, Dr. Ann Albright’s impassioned speech commended the progress of self-management education, emerging recognition of psychosocial concerns, and the growth of the National Diabetes Prevention Program (National DPP). Playing off her message that the diabetes community needs to have fun while advancing education and prevention, she punctuated her presentation with music ranging from Seal to Buddy Guy and had the audience clapping along and dancing in their seats. Noting that while “it is a thrilling time to be working in diabetes,” she cautioned that managing and preventing diabetes is an ongoing process that will need to involve advocacy, partnerships, and education. Specifically, she pointed to the significant disparities that still exist between income brackets at the family and community levels, such as the higher percentage of income spent on treatment in low-income families compared to high-income families. Dr. Albright noted that general acknowledgement that diabetes is experienced beyond the individual is only the first step – now the community has the “awesome responsibility to address social determinants of health… one we cannot shy away from.” Looking forward, she believes this multi-target approach will involve investment in community development, expansion of the National DPP, further development of virtual support systems, and the implementation of learning from the Natural Experiments in Translation for Diabetes (NEXT-D). Dr. Albright called for attendees to refuse to settle for “fragmented efforts that will never bring intervention to scale” and to work together on research, implementation, and availability. As she herself declared, “I believe we can succeed. We must succeed. People are counting on us.”



Lurelean Gaines, RN, MSN (East Los Angeles College; President of Health Care and Education at American Diabetes Association, Los Angeles, CA)

Ms. Lurelean Gaines began by stating she has made an impact, her way, through her choice to work with the underserved, underrepresented, disadvantaged populations as a public health nurse and educator at East Los Angeles College (ELAC). She shared several touching stories from her work with patients and providers, and she concluded by calling on the audience to become volunteers to stop diabetes. We appreciated hearing Ms. Gaines’ view of diabetes in the real world and her emphasis on the difficulties of behavior change – especially among people with other pressing life challenges.

  • Near Los Angeles, challenges of diabetes management include lack of adherence, homelessness, and lack of insurance. Patients have trouble adhering to their treatments, Ms. Gaines noted, in part because of the high cost and varying accessibility of test strips and monitoring devices, as well as a dislike of recommended food choices. (Ms. Gaines emphasized that adherence can be difficult regardless of education level: she shared the sobering story of a Latino registered nurse who died of diabetes complications at age 28.) Additionally, Ms. Gainesexplained that culture, traditions, and fatalistic belief systems sometimes conflict with diabetes treatments, making it necessary for clinicians to work closely with the community.
  • Ms. Gaines has been working for years to improve the prevention and education of diabetes. In a joint initiative between the ADA, St. John’s, QueensCare, and ELAC, Ms. Gaines has helped to create foot-washing clinics where clients can be referred to QueensCare for further medical treatment. She has also worked to develop diabetes health fairs, handouts on nutrition, better follow-up care, and exercise programs.
  • Ms. Gaines tells the students in her psychiatric nursing class that “we can do and cover anything in psychology” – a proactive philosophy that led Ms. Gaines to develop a special program to help students understand the impact of diabetes on wellbeing. The program requires students to work with a community member with diabetes for eight weeks, helping them improve their understanding of their medication, their diet, their exercise, and other aspects of diabetes management. Ms. Gaines highlighted the importance of respecting the patients’ boundaries, diversity, culture, and ethnicity. She also shared the story of one 64-year-old Vietnamese-American patient, Mrs. V, who learned to appreciate brown rice and take longer walks with the help of one of Ms. Gaines’ students.
  • “Don’t just talk the talk, walk the walk.” Ms. Gaines challenged the audience to take action in the fight against diabetes. She remarked that it takes a team to accomplish all that ELAC and ADA has, and there is still much more work to be done. She highlighted her own action at junior high and high school events, as well as her role as a member of the Los Angeles Community Leadership Board. We applaud Ms. Gaines as a role model for her community involvement in an effort to stop diabetes.


Symposium: DCCT/EDIC 30th Anniversary Symposium–Contributions and Progress


David Nathan, MD (Massachusetts General Hospital, Boston, MA)

Dr. David Nathan reviewed the design and results of the Diabetes Control and Complications Trial (DCCT) and its follow-up study, Epidemiology of Diabetes Interventions and Complications (EDIC). From the first presentation of results in 1993, DCCT illustrated the beneficial effect of intensive glycemic control on early microvascular and neural complications, established the association and primacy of glycemia and complications, and identified the risks and benefits of intensive control. Then, the follow- on EDIC study demonstrated the durability of intensive therapy’s effects (“metabolic memory”) and showed that glycemic control also benefited patients with regard to longer-term clinical outcomes (e.g., advanced microvascular complications and cardiovascular disease). Dr. Nathan also noted that in both DCCT and EDIC, intensive control has not been found to decrease cognitive function – even in patients with frequent hypoglycemia. In a gesture of gratitude, he repeatedly acknowledged the study participants for their high rate of follow-up – as of 2012, 95% of the surviving cohort was still participating! The biggest takeaways we got from this set of talks were the following:

  • In the latest EDIC data, the researchers have observed high rates of musculoskeletal complications (such as cheiroarthropathy, which involves stiffening of the hands or fingers, and adhesive capsulitis, which is otherwise known as frozen shoulder). Dr. Nathan suggested that these complications affect 50% to 60% of the population but have been under-recognized because of high incidence among the general aging population. The rates were not different between theconventional and intensive DCCT groups. However, higher A1c is correlated with higher incidence.
  • Mortality data is forthcoming now that 50 deaths have been reached, but it remains embargoed – we think this data will be striking and are very eager to see this out.
  • Risk reductions for DCCT /EDIC for the intensive group were repeated and include 50% for impaired kidney function, 60% for heart disease and stroke, 50% for need for ocular surgery/eye disease, 50% for impaired GFR, 20% for hypertension.
  • Dr. Nathan and Dr. Lachin emphasized, as they have in the past, that this study speaks to long-term metabolic memory for glucose, where changes in A1c today have impact up to 10 years later, and this explains continued better health of DCCT subjects long afterward. They suggested epigenetic changes to genes or glycation of collagen as possible explanations. Notably, they found evidence of epigenetic change in "60 carefully selected extreme cases." They noted that oldest participant is only about 69/70, so they're still not at a stage where old-age complications can really be tracked in detail. They stressed that there is still no point of no return when it comes to A1c, and indeed changes may only become apparent later; they noted no difference in original DCCT between control and intensive for retinopathy and neuropathy over first 4-5 years of intensive therapy, but huge difference became apparent afterward.
  • The DCCT EDIC study group will be looking at glycemic variability – there was a single reference on a slide toward the very end of discussing what the Study Group will be focused on. We have always thought Dr. Kilpatrick’s paper on this showing no correlation with glycemic variability was unconvincing and we’re happy to see that this is going to be re-examined. We wonder how DCCT would have looked, indeed, had accurate CGM been available – perhaps the analysis would look quite different for glycemia variability – we will never know, of course.



John M. Lachin, ScD, (George Washington University, Rockville, MD)

Dr. John Lachin provided a thorough overview of the cardiovascular outcomes of DCCT/EDIC, noting that the benefits of intensive therapy on cardiovascular disease have increased through 2012 as the EDIC study continues. The 2005 results after 11 years of EDIC follow-up showed a 42% risk reduction for any cardiovascular outcome and a 57% risk reduction in the clinically important outcome of cardiovascular death, myocardial infarction, or stroke. A major theme of the talk was that glycemia explains the majority of differences in cardiovascular risk, ranging from surrogate markers of atherosclerosis to the major clinical cardiovascular outcomes. Dr. Lachin announced that the risk factor analyses for major cardiovascular clinical events are forthcoming now that 100 cardiovascular disease cases have occurred in the conventional glycemic control group. He told us to stay tuned, as the results are anticipated in the next few years. Another recent landmark occurred when the 50th patient from the conventional group died, triggering an analysis of mortality in DCCT/EDIC. This manuscript is still being prepared and the results are embargoed until publication, but Dr. Lachin was able to tell us there is no excess mortality risk in the former DCCT intensive therapy group.

  • The original DCCT study had too few outcomes to make significant conclusions about the benefit of intensive glycemic therapy on reducing macrovascular events and atherosclerosis. To achieve 85% statistical power the study was continued as the EDIC study with analyses triggered after 50 individuals experienced their first cardiovascular events in the conventional treatment group.
  • The 6.5 years of intensive therapy in DCCT decreased the subsequent progression of atherosclerosis as measured by carotid intima media thickness (CIMT) and coronary artery calcification (CAC). CIMT was measured by ultrasound during EDIC at years 1, 6, and 12, while CAC was calculated by CT at year 8. Furthermore, hyperglycemia during DCCT explained the vast majority of the variation in these atherosclerosis surrogate markers, with the DCCT A1c explaining 95% and 96% of the CIMT change at years 6 and 12, respectively, and 86% of the CAC effect.
  • The 6.5 years of intensive therapy reduced the risk of major cardiovascular events. The intensive glycemic control subjects showed a 42% reduction in risk of any cardiovascular event and a 57% reduction in the risk of the more clinically important composite of cardiovascular death, myocardial infarction, and stroke.
  • Cardiac MRI studies at EDIC year 15 showed no differences between the DCCT intensive vs. conventional groups in cMRI measures of cardiac structure, function, and remodeling. However, mean DCCT A1c and age did show significant associations with left ventricular mass, left ventricular mass divided by end diastolic volume, and aortic distensibility.
  • In conclusion, in the DCCT/EDIC type 1 diabetes population, intensive glycemic therapy was highly effective in decreasing the risk of cardiovascular disease. The long-term beneficial effects of intensive therapy on cardiovascular disease are largely mediated by changes in glycemia during the DCCT (A1c explains 97% of the group effect), while partially mediated by a reduction in the incidence of albuminuria (microalbuminuria and albuminuria explained 45% and 29% of the group effect, respectively).



Ian de Boer, MD (University of Washington, Seattle, WA)

Dr. Ian de Boer reviewed the well-established benefits of intensive glycemic control on nephropathy, and he showed unpublished data about how these data have continued to the present day. For the first 18 years of EDIC, patients in the intensive group enjoyed significantly reduced risks of microalbuminuria (39%) and macroalbuminuria (61%). Dr. de Boer noted that 100% of these benefits could be statistically explained by patients’ mean A1c during DCCT – still more clear evidence that early, intensive glycemic control in type 1 diabetes is effective for preventing or delaying kidney disease.

  • Early intensive glycemic control has been shown to reduce the risks of both microalbuminuria (≥40 mg/day) and macroalbuminuria (>300 mg/day). During DCCT, patients in the intensive group had their risk of microalbuminuria reduced by 34%, while the absolute rate of macroalbuminuria was too low for a benefit to be seen. In the first eight years of EDIC, highly significant risk reductions were seen for both microalbuminuria (57%) and macroalbuminuria (84%) (JAMA 2003). Dr. de Boer also presented unpublished 18-year data, showing that patients in the intensive arm of DCCT still enjoyed highly significant risk reductions for microalbuminuria (39%) and macroalbuminuria (61%). Remarkably, for each period of analysis, the benefits could be explained almost entirely (90-100%) by patients’ mean A1c during DCCT.
  • The only new data that Dr. de Boer showed were for micro- and macroalbuminuria, but he also reviewed how glycemic control has benefited several other markers of kidney disease. For example, the risk of new hypertension decreased by 24% after a median foll0w-up of 15.8 years after randomization (DCCT/EDIC, Arch Intern Med 2008). Intensive glycemic control also reduced the long-term risks of declines in estimated glomerular filtration rate; the risk reduction after a median follow-up of 22 years was roughly 50% (DCCT/EDIC, NEJM 2011).



Catherine L. Martin, MS, APRN, BC-ADM, CDE (University of Michigan, Ann Arbor, MI)

Ms. Catherine Martin provided a comprehensive overview of the neurological outcomes data from the past 30 years since DCCT/EDIC began. She noted that the prevalence of peripheral neuropathy and autonomic neuropathy at baseline were low and similar between the intensive glycemic control and conventional glycemic control groups. However, by the end of the 10-year DCCT study, the intensive control group showed a 64% reduced risk of peripheral neuropathy and 31% reduction in cardiac autonomic neuropathy. The differences between the intensive and conventional control groups persisted, albeit with smaller magnitudes by years 13 and 14 of the EDIC follow-up study. Intensive glycemic control also decreased the risk for other neurological complications in EDIC, with lower rates of erectile dysfunction and foot ulcers. The neurological results from DCCT/EDIC show that intensive therapy can reduce the risk of several different neuropathologic complications long-term.

  • In the Diabetes Control and Complications Trial (DCCT) examining the effect of intensive vs. conventional glycemic control on long-term complications in type 1 diabetics, peripheral neuropathy represented an important microvascular outcome. The original DCCT study tested for peripheral neuropathy using the neurological history and physical examination, as well as electrodiagnostic studies at baseline, at five years, and at the end of the study. In contrast, the follow-up Epidemiology of Diabetes Interventions and Complications study (EDIC) measured neuropathy only in annual tests with the Michigan Neuropathy Screening Instrument (MNSI), which lacked the sensitivity to compare the results between groups. At years 13 and 14, the full DCCT neurological examination was performed in the patients to enable a between-group comparison in the rates of neuropathy. The neurological information collected was used to construct a confirmed clinical neuropathy endpoint consisting of an abnormal exam consistent with peripheral sensory neuropathy and abnormal nerve conduction in at least two peripheral nerves or an abnormal autonomic finding.
  • By the end of DCCT, intensive therapy had reduced the risk of developing confirmed clinical neuropathy (CCN) by 64% and of developing cardiac autonomic neuropathy (CAN) by 31%. The prevalence of peripheral neuropathic complications rose greatly in both the intensive and conventional groups by EDIC years 13 and 14. However, the risk of developing CCN or CAN in EDIC by year 14 was reduced by 30% and 31% respectively in the former intensive control subjects. A higher mean A1c was associated with an increased risk for CAN, and differences in A1c explained 78% of the treatment group effect. CAN was again measured in EDIC years 16 and 17 and the prevalence continues to rise, with both groups’ prevalence greater than 35%. The difference between the intensive and conventional groups is starting to shrink, suggesting that metabolic memory can wane.
  • People with diabetes are at increased risk for erectile dysfunction (ED), and the prevalence of ED was 25% overall by year 10 of EDIC. The risk of developing erectiledysfunction by year 10 of EDIC was reduced by 67% in the intensive control group of the secondary prevention cohort (patients who at baseline had type 1 diabetes longer than 5 years or evidence of complications). However, in the primary prevention cohort (patients with diabetes for 1-5 years at the start of the study), the effect on erectile dysfunction risk was not statistically significant. The increased risk for erectile dysfunction per 10% higher DCCT/EDIC mean A1c was 74% for the primary prevention cohort and 97% for the secondary cohort.
  • Additionally, the risk of developing ulcers was reduced by 48% in the former intensive control group. The risk reduction for amputations was 28%, but this result was not statistically significant.



Lloyd Aiello, MD, PhD (Joslin Diabetes Center, Boston, MA)

Dr. Lloyd Aiello presented the newest data on retinopathy from the 18th year of the EDIC study. To begin, he reviewed the effects of intensive therapy in DCCT on primary prevention of retinopathy: 76% risk reduction after a three-to-four year delay. He then provided new EDIC data showing that the intensively treated group continued to have a significant risk reduction in many areas of retinopathy, including: proliferative diabetic retinopathy (47%), clinically significant macular edema (35%), scatter or focal laser treatment requirements , and total accumulative incidence (39%). Patients from the intensive control group had consistently lower risk at four, 10, and 18 years, but the between-group difference decreased over time (from approximately 70% to 48% risk reduction). Overall, the intensive group’s risk reduction for all severe retinal outcomes in either eye was roughly 50%. In summary, the EDIC follow-up study show that patients who were in the intensive treatment group continue to experience risk reduction at a significantly greater rate than those in the conventional group – another example of “metabolic memory.”



Rose A. Gubitosi-Klug, MD, PhD (Case Western Reserve University, Cleveland, OH)

Dr. Gubitosi-Klug provided a forward-looking discussion of the DCCT/EDIC study as it enters its 30th year. She began by summarizing the overall message of the results so far: early intensive glycemic intervention is most effective in type 1 diabetes patients, and if intensive therapy is delayed, the momentum of complications is difficult to slow. Recent results from EDIC have hinted the metabolic memory effect may wane over time as the relative risks for microvascular and cardiovascular disease have been decreasing over time. Dr. Gubitosi-Klug emphasized that cardiovascular outcomes must be the major focus going forward. Finally, she introduced new studies that will address the effects of residual insulin secretion, the effect of glycemic control on hearing impairment, and the effect of glycemic control on delayed gastric emptying. Other topics that must be addressed with the DCCT/EDIC cohort include the development of evidence-based frequency for screening of retinopathy and nephropathy, the effects of glycemic variability, non-glycemic risk factors and outcomes, cognitive function, and health economics.

  • An upcoming study with the DCCT/EDIC cohort will address questions relating to residual C-peptide: Is there residual beta cell function after an average diabetes duration of 30 years? What factors influence residual beta cell function? What is the physiologic significant of residual C-peptide? What is the effect on risk for complications? The DCCT/EDIC team has begun a pilot study of 58 patients from a cohort with near normal A1c levels and/or above average C-peptide at baseline. In year 20 of EDIC, 10 of 58 participants showed glucose stimulus response curves showing residual beta cell function. The next step is to expand this study to the full EDIC cohort to examine how this residual function affects outcomes such as A1c over time, rates of hypoglycemia, and long-term complications.
  • Hearing impairment is more common in patients type 2 diabetes than without. A question to be addressed is whether there is hearing impairment in type 1 diabetes as well, and if so, does it correlate with neuropathy, microvascular disease, or chiroarthropathy? Is there a relationship between prior DCCT treatment with intensive glycemic control or other risk factors? Dr. Gubitosi-Klug noted that a protocol with a standardized hearing study across all 27 EDIC sites is currently being developed.
  • People with diabetes can develop delayed gastric emptying. Questions being addressed in upcoming studies include determining the prevalence of disturbances in gastric emptying and whether this impacts glycemic control. A pilot study at seven EDIC centers with 80 participants using the 13C-Spirulina gastric emptying breath test is being developed.



Rose A. Gubitosi-Klug, MD, PhD (Case Western Reserve University, Cleveland, OH)

Dr. Gubitosi-Klug provided a forward-looking discussion of the DCCT/EDIC study as it enters its 30th year. She began by summarizing the overall message of the results so far: early intensive glycemic intervention is most effective in type 1 diabetes patients, and if intensive therapy is delayed, the momentum of complications is difficult to slow. Recent results from EDIC have hinted the metabolic memory effect may wane over time as the relative risks for microvascular and cardiovascular disease have been decreasing over time. Dr. Gubitosi-Klug emphasized that cardiovascular outcomes must be the major focus going forward. Finally, she introduced new studies that will address the effects of residual insulin secretion, the effect of glycemic control on hearing impairment, and the effect of glycemic control on delayed gastric emptying. Other topics that must be addressed with the DCCT/EDIC cohort include the development of evidence-based frequency for screening of retinopathy and nephropathy, the effects of glycemic variability, non-glycemic risk factors and outcomes, cognitive function, and health economics.

  • An upcoming study with the DCCT/EDIC cohort will address questions relating to residual C-peptide: Is there residual beta cell function after an average diabetes duration of 30 years? What factors influence residual beta cell function? What is the physiologic significant of residual C-peptide? What is the effect on risk for complications? The DCCT/EDIC team has begun a pilot study of 58 patients from a cohort with near normal A1c levels and/or above average C-peptide at baseline. In year 20 of EDIC, 10 of 58 participants showed glucose stimulus response curves showing residual beta cell function. The next step is to expand this study to the full EDIC cohort to examine how this residual function affects outcomes such as A1c over time, rates of hypoglycemia, and long-term complications.
  • Hearing impairment is more common in patients type 2 diabetes than without. A question to be addressed is whether there is hearing impairment in type 1 diabetes as well, and if so, does it correlate with neuropathy, microvascular disease, or chiroarthropathy? Is there a relationship between prior DCCT treatment with intensive glycemic control or other risk factors? Dr. Gubitosi-Klug noted that a protocol with a standardized hearing study across all 27 EDIC sites is currently being developed.
  • People with diabetes can develop delayed gastric emptying. Questions being addressed in upcoming studies include determining the prevalence of disturbances in gastric emptying and whether this impacts glycemic control. A pilot study at seven EDIC centers with 80 participants using the 13C-Spirulina gastric emptying breath test is being developed.


Symposium: New Insights Into Treatment of Diabetic Retinopathy and Other Complications


Anthony Keech, MD, PhD (University of Sydney, Sydney, Australia)

Dyslipidemia has long been associated with retinopathy. Even though statins are now a mainstay in the treatment of diabetes, according to Dr. Anthony Keech, statins do not appear to reduce rates of diabetic retinopathy. He presented evidence for fenofibrate’s powerful effect on reducing progression of diabetic retinopathy. The FIELD study and the ACCORD eye lipid arm were two large, prospective studies showed that fenofibrate use reduced progression of diabetic retinopathy and reduced the need for laser intervention: the FIELD study found a 31% reduction in the need for laser therapy amongst 10,000 patients with diabetic retinopathy, and the ACCORD eye lipid arm found a 40% reduction in progression of DR by fenofibrate compared to placebo (both on top of simvastatin). Dr. Keech cited fenofibrate’s known anti-inflammatory and anti-oxidative effects as putative mechanisms. FIELD and the ACCORD lipid study also found that fenofibrate reduced CV events (particularly in the subgroup with dyslipidemia), reduced amputations attributable to microvascular defects, and reduced albuminuria compared to placebo.



George King, MD (Joslin Diabetes Center, Boston, MA)

Dr. George King discussed the Medalist study conducted at the Joslin Diabetes Center in the context of diabetic retinopathy. The Medalist study seeks to explore what potential protective factors these patients may have had in halting the progression of retinopathy. He then proposed multiple mechanisms for diabetic retinopathy. The results of existing trials have not been very robust, but they have revealed that angiogenesis and leaking occurs very late in the retinopathy cascade. He concluded that there were no common protective factors identified between retinopathy and neuropathy, and called for additional study based on proteomics data.

  • Dr. King summarized the methods and results of the Medalist study, which identified 850 50+ year survivors of type 1 diabetes to identify potential protective factors that these patients may have had. He noted the success of the entirely voluntary Medalist trial and its 90% retention rate in the patients. One of the most remarkable characteristics of the patients was that about 45% of the medalists did not have significant proliferative diabetic retinopathy (PDR). Risk factors for PDR in this group did not correlate with A1C, C-peptide, or presence of autoantibodies. Medalists did not have kidneys typical of patients with type 1 diabetes; their kidneys did not lose function, but some still had retinopathy, indicating that protective factors in the eye and kidney may differ.
  • Dr. King revealed that based on cell-based assays, there were no common protective proteins between retinopathy and nephropathy. Patients with no kidney disease had 15 protective anti-oxidative and anti-inflammatory proteins, none of which are shared with the protective elements of retinopathy. Dr. King hypothesized that further proteomics data from donor organ studies would provide further clues about the protective factors.


Symposium: ADA Education Recognition Program Symposium–Making a Case for Diabetes Education–The Use of a National Diabetes Education Database


Linda Siminerio, PhD (University of Pittsburg Medical Center, Pittsburg, PA)

Dr. Linda Siminerio began by remarking that America is entering an era of accountable care. With annual healthcare costs at a staggering $2.5 trillion, Dr. Siminerio called for increased collaboration and incentives for quality care. She noted that with the new Affordable Care Act provisions, patients will make decisions about what services to use based on increased available information. Patients, she explained, are going to be concerned about the quality of services they are receiving. She emphasized that educators are going to “shine” in strengthening community health centers, where they will spend hours with patients. Dr. Siminerio additionally underscored that educators are going to “be graded whether we like it or not” because decisions about education use and reimbursement should be based on analysis of education outcomes – not made arbitrarily by Medicare, as in the past. She argued that an education national care report is necessary so that educators can act proactively. Indeed, Dr. Siminerio posed the question: Shouldn’t we be ahead of the game?



Paulina Duker, MPH, RN, BC-ADM, CDE VP (Diabetes Education/Clinical Programs at American Diabetes Association, Alexandria, VA)

Ms. Paulina Duker provided a detailed history and description of Chronicle Diabetes, an online software for documenting diabetes self-management education. Chronicle was developed in 2011 by the University of Pittsburgh and Flipside Media as a way to improve the process of education, which was being sought by only 10-15% of patients despite association with better outcomes and (partial) reimbursement. The program’s core objective set includes increasing engagement among patients, improving population health, and ensuring privacy. The long-term impact of course remains to be seen, but the system is being used in 47 states, and patients and providers are increasingly using Chronicle to facilitate educational efforts.

  • The features of Chronicle aim to meet a core set of objectives. These objectives include patient engagement, improvements in care coordination, improvements in public health, improvements in quality, safety, and efficiency, and guarantee of privacy and security for protected health information (PHI). Chronicle helps to achieve these core objectives through features such as patient portals, snapshot reports, and active medication lists. Ms. Duker especially underscored filter reports, which allows HCPs to create focus groups for specific populations. She also noted that Chronicle’s password access protects patients by allowing only credentialed staff to access information.
  • Ms. Duker discussed the increasing adoption of the Chronicle system, remarking that data points for many levels of evaluation have at least doubled in the past year, including A1c levels, lipid levels, foot exams, blood pressure data, and goals. Ms. Duker focused on Chronicle’s impact on goal sets – behavioral goals for diabetes patient – because she believes that Chronicle is the only system for documenting goals associated with diabetes education. She noted that these increases in data allow HCPs to determine if subjective observations in practice are real in analysis. Ms. Duker also emphasized that patient registration had doubled to about 600 in the past year even though the number of registered sites did not significantly increase. Chronicle is currently used in all states except for Rhode Island, South Dakota, and Utah, which Ms. Duker explained might be because only a few education sites are registered in those states. Additionally, she noted that rural sites, with approximately 65% of total sites, are using Chronicle more than urban and suburban sites.


Symposium: The Future Is Now – Changing Health Care Delivery Models


John Brooks, MS, BBA (Joslin Diabetes Center, Boston, MA)

After providing an overview of Joslin Diabetes Center, President and CEO Mr. John Brooks listed a number of technologies and programs Joslin is exploring, and discussed some of the center’s philosophies, principles, and initiatives.

  • Mr. Brooks listed some of the technologies and programs Joslin is currently exploring: smartphone/cloud-integrated physiologic measurement (i.e., glucose, food, exercise, and insulin) to drive decision support and enable predictive and adaptive algorithms; patient, healthcare team, and consumer dynamic portals; EMR linkage with full interoperability for robust data mining (Mr. Brooks commented that he is seeing a lot of companies starting to tackle inter- EMR communications); risk stratification and “big data” analytics (e.g., to gain better insights on medication use, comorbidities, etc.); metrics and feedback; apps, including reminders, care-plan tracking and real-time retooling, medication adherence and reconciliation, and insulin initiation and insulin adjustment tools (Joslin is both developing apps on its own and talking to companies); and prevention and wellness programs for weight management, healthy food/nutrition choices, exercise, stress mitigation, and goal tracking.
  • Subsequently, he discussed some of Joslin’s philosophies, principles, and initiatives. Joslin Inside is the principle that whatever the institution does, it wants to show clinical benefit and value from a best-practice-based standpoint. Joslin Everywhere is the broad concept that Joslin wants to use the best ways to engage people around the world (i.e., cell phones), and to use the power of connectivity and cloud-based analytics as they help tackle the global diabetes challenge. Joslin hopes to be a catalyzer or sparkplug for innovation, but does not think they can solve the diabetes epidemic singlehandedly. They believe in collaboration and collaboratories – working together, even if they’re not 100% sure where it leads. Mr. Brooks also mentioned that Joslin invites players from across the spectrum – payers, providers, industry, etc. – to collaborate, offering them access to Joslin patients and expertise. In the future, Joslin may also set up global centers of excellence for diabetes. Other initiatives include working with self- insured employers to help reduce healthcare costs, and engaging PCPs to help them with their challenges. In addition, Joslin has a Center for Technology, Connectivity, and Innovation, as well as an Office of Commercialization and Ventures.

Questions and Answers

Q: Could you share a little bit more about Joslin’s philosophy around partnerships? You mentioned that as a key element.

A: We look at partnerships at a number of different levels. For research, we are anxious and willing to set up collaborations with other research institutions on a global basis. A number of those are already under way. In terms of some of the clinical opportunities, we have been actively working with different companies, from established pharmaceutical companies all the way to start-ups. We have the ability at Joslin to incubate or accelerate ideas that entrepreneurs come to us with. We have lab space to allow people to leverage our animal models, assays, etc. We’ve invested a lot, but if we can drive new ideas, and leverage our knowledge to theirs, we think that’s a good thing. We have a mechanism through an independent company set up by friends of Joslin that makes us eligible to receive money to take ideas then de-risk them to the point where hopefully someone is willing to further fund, partner, or spin them out.

Q: Maybe there are allists, partialists, and gapists. In many healthcare systems, there’s none of the above. Or rather, doctors of different kinds, nothing along the lines of what you, Dudl, Gabbay, and McCulloch described. So for those of you that have it, what would you recommend that the have-nots do first?

A: Try to find pilots, drive a change, or a new initiative or clinic model. Get a couple of proactive clinicians, and find if there’s a way to prove a new approach – I think we saw some from the previous presenters. Do a pilot, test it, and show if it works.

Q: I don’t disagree that pilots need to be done, but in many institutions, everybody – nurses, assistants, and docs say, “I’m up to here with work.” There’s no dollars for IT that are free. So if the system is going to change, somebody is going to have to do something that they’re not doing, or somebody is going to have to be added. That costs money. What would you recommend as the cheapest pilot in terms of personnel and dollar cost?

A: I’ve heard those arguments, and I think it’s one of those situations where you need to look where all those IT dollars are being spent. One route could be to find tech companies out there interested in undertaking some sort of pilot or program. They’re starting to figure out that if they just bring technology into the environment, they’re not going to have it all figured out. Technology doesn’t exist in a vacuum. They need to understand he workflow, and how doctors, clinicians, and nurses engage. A lot of them are trying to figure out how they’ll deliver value in the new healthcare system. Find IT companies that are interested in partnering. You have to co-opt them into basically being a funder or an underwriter. We find a lot of people willing to underwrite pilots, if they’ll be able to demonstrate where it can go next.

Comment: The idea is to work smarter, but not necessarily harder. Having a more team- based approach where tasks are distributed across the team, and everyone practices at the top of their license frees up time. Who are the highest risk patients who have been doing poorly for some time? Proactively bring them in [to prevent more resources being needed further down the road].



Robert Gabbay, MD, PhD (Pennsylvania State University, Hershey, PA)

According to Dr. Robert Gabbay, within the field of diabetes there have been a lot of innovations in care regimens, but the current reimbursement model in the United States remains a barrier. Dr. Gabbay asserted that the passage of the Affordable Care Act (ACA) has changed the dynamics of the future of American healthcare. He highlighted three key aspects of the ACA that the symposium covered: shared decision-making; the patient-centered home; and the change in reimbursement to a value-based system. He emphasized that the change in reimbursement is now a “sweet spot” for diabetes care in that providers can really make a tangible difference. Since diabetes has been a testing ground for new approaches to care, the team-based approach that has gained popularity is now becoming a model for other areas of the medical sector. He concluded his overview by saying how exciting the following models were for diabetes care, giving HCPs the chance to bring about a wider change in patient outcomes through the evolving system.


Symposium: Behavioral Science Contributions to Understanding Diabetes (With Richard R. Rubin Award Lecture)


Richard Holt, PhD (University of Southamptom, Southamptom, UK)

Dr. Richard Holt presented the initial results from the DAWN2 study. Overall, data from the study showed that diabetes represents a major psychosocial burden for people with diabetes and their families. Dr. Holt noted that the study highlights numerous opportunities for improving diabetes care, education, and community support by placing people with diabetes and their families at the center of a new patient care model. He concluded by calling for a broad dialogue and collaborative action to raise the voices of people with diabetes and to improve their health and quality of life. Specific results from the study are highlighted below:

  • Impact of diabetes on quality of life: DAWN2 revealed that people with diabetes have an elevated risk for depression with 13.8% of respondents with diabetes reporting that they likely have depression. 39% of respondents indicated that their diabetes medication routinely interfered with their ability to live a normal life, and 55.5% indicated that they felt very worried about the risk of hypoglycemia. Further, people with diabetes reported a negative impact of their disease on reduced physical health (62%), reduced emotional well being (46%), finances (44%), leisure activities (38%), work studies (35%), and relationships with family, friends, and peers (20.5%). The study also found that better support was associated with better outcomes for wellbeing and quality of life and that psychosocial outcomes were worse for those who were in worse physical health or experienced greater diabetes burden.
  • The family perspective: DAWN2 showed that the burden of diabetes also impacts family members’ quality of life. Through the questionnaire, 35.5% of family members reported a moderate to a very large burden from caring for a relative with diabetes. Family members reported a negative impact of their family member’s diabetes on their emotional wellbeing (44.6%), finances (35.2%), leisure activities (31.0%), physical health (26.7), work studies (22.9%), and relationships with family, friends, and peers (19.8%). Additionally, the study showed that a substantial proportion of family members want to be more involved in helping their relative with diabetes (39%), but that they do not know how to help best (37%).
  • Active involvement of people with diabetes: DAWN2 demonstrated a need for improved self-management among people with diabetes. In particular, the study revealed that during an average week, people with diabetes follow a health eating plan for 5.3 days, participate in physical activity over 30 minutes for 3.8 days, test their blood sugar 3.4 days, checked their feet 3.2 days,and take their medications exactly as prescribed 6.1 days. Meanwhile, healthcare professionals generally recognized the value of actively engaged people with diabetes. In particular, 85% of healthcare professionals believed it was helpful when patients indicated how healthcare professionals could best support them, 84% believed it was helpful when patients prepared questions prior to the consultation, 71% believed it was helpful when patients were able to find self-management information for themselves. Finally, 60% of healthcare professional respondents indicated that there was a need for a major improvement in the availability of diabetes self-management education, and 61% believed that improving the availability of diabetes self-management education would reduce disease burden.
  • Quality diabetes care, including psychosocial support: DAWN2 revealed that there are prominent gaps in the care for the psychosocial and behavioral dimensions of diabetes. While 75% of respondents with diabetes reported that someone from their healthcare team measured their long-term blood sugar control level in the past 12 months, only 32% indicated that someone from their healthcare team asked if they had been anxious or depressed over a similar time frame. There also appears to be a difference in perspective on quality of psychosocial support provided by healthcare professional between patients and their providers. While 23.7% of patient responders believed that their healthcare provider asked them how diabetes affects their lives, 51.8% of healthcare providers reported that they had addressed this topic with their patients. In general, healthcare professionals called for increased resources to provide more person-centered care, including formal training in effective communication, increased availability of psychological support and care, and improved communication among healthcare teams. Notably, only 20% of healthcare provider respondents indicated that they had received training in the management of the psychological aspects of diabetes, and 59% indicated that they would like to receive more training in this area. Separately, another significant finding of the study was that less than 50% of people with diabetes had previously participated in any diabetes educational program.
  • Discrimination and societal issues: DAWN2 indicated that discrimination was an issue for people with diabetes. 19.2% of people with diabetes experienced discrimination, intolerance, and lack of support from their community. 21.5% of family members believed that people with diabetes experienced discrimination because of their diabetes. 32.5% of healthcare professional believed that discrimination was an issue for people with diabetes.



Mark F. Peyrot, PhD (Loyola University, Baltimore, MD)

The DAWN2 study was a questionnaire-based study conducted in 17 countries that sought to assess potential barriers and facilitators of active and successful management of diabetes among people with diabetes and their family members and healthcare providers. In total, 15,438 individuals were surveyed, including 1368 individuals with type 1 diabetes, 7228 people with type 2 diabetes, 2057 family members, 2066 primary care physicians or general practitioners, 1350 diabetes specialists, 827 nurses, and 542 dietitians. Participants were selected from online panels and databases, phone lists, general population directories, hospital/physician directories, referrals from other participants, and professional association lists. The questionnaire was conducted online, by phone, or in-person in the country’s local language. Questionnaire topics included: 1) health/quality of life (people with diabetes and family members); 2) diabetes profile; 3) active self-management; 4) attitudes and beliefs about diabetes; 5) care and support/involvement; 6) diabetes education and information; 7) diabetes training (healthcare professionals); 8 future needs; 9) demographic and practice characteristics.

  • The participating countries included: Algeria, Canada, China, Denmark, France, Germany, India, Italy, Japan, Mexico, Netherlands, Poland, Russia, Spain, Turkey, United Kingdom, and US.
  • Secondary objectives included: 1) to establish national benchmarks for health status, quality of life, and access to self-management education to measure national progress and promote cross- national comparisons; 2) assess the access to, and use and benefit of, support from healthcare teams, family and friends, and communities and society; 3) explore and pinpoint the most important facilitators and barriers to person-centered chronic care for each stakeholder group; and 4) identify successes, wishes, needs, preferences, and priorities for change among all key stakeholders in diabetes.


Symposium: China Medical Tribune Symposium–Updating Diabetes Research in China–From Bench to Real World


Jin Li (Guangdong Diabetes Center, Guangzhou, China)

Dr. Jin Li presented preliminary results from a multicenter registration study characterizing the current status of type 1 diabetes in the Guangdong province of China. In order to be included in the registry, individuals must have been diagnosed with type 1 diabetes by an endocrinologist, be insulin dependent, lived in the Guangdong province for at least a year, and must have: 1) obvious diabetes- related metabolic disorder symptoms; 2) previous diabetic ketoacidosis or ketosis; 3) tested positive for diabetes-related autoantibodies; or 4) fasting C-peptide levels of less than 200 pmol/l. Compared to Western populations, those with type 1 diabetes in the Guangdong registry were older (the median age of onset was 27.3 years), with lower BMI (only 11.8% were overweight or obese). In addition, people in the Guangdong registry tested their blood glucose much less frequently than people in the T1D Exchange in the US (0.4 vs. 5.5 times per day; Natl Med J Chin 2013; Diabetes Care 2013); Dr. Li explained that this was because test strips are not covered by reimbursement. A low percentage (13.4%) of patients used insulin pumps, as the majority were on MDI (50%) or took three or fewer injections per day (36.2%). Only 9% of patients achieved blood glucose, blood pressure, and lipid targets, and the prevalence of microvascular complications was high in the Guangdong population relative to the T1D Exchange population. In closing, Dr. Li highlighted the implementation of a nationwide registry, long- term follow-up with patients in the Guangdong registry, and epidemiological studies to characterize the incidence of type 1 diabetes in China as important areas of future research.

Questions and Answers

Q: How complete do you think the ascertainment was of type 1 diabetes in the Guangdong population? Would it be possible to use something like capture/recapture methodology of several different approaches to identify different patients?

A: It is very difficult to completely distinguish type 1 diabetes from type 2 diabetes in large-scale studies. In our studies, diagnosis was made by local endocrinologists. If the diagnosis was uncertain, endocrinologists at the Guangdong Diabetes Center could review the data and make a decision, since the data was on the Internet in the registry.

Q: Do you think we see such low numbers in type 1 diabetes in China because we lack a definition for diagnosis or have lack of awareness of type 1 diabetes in China?

A: Based on data from Western countries, type 1 diabetes accounts for approximately 5% of total diabetes cases. Maybe in the future we can explore some gold standard method or definition for type 1 diabetes.

Q: We know China has a very heterogeneous population. What was the ethnic makeup of the study population?

A: In our study, most of the patients were Han Chinese. Maybe in the future nationwide study we can analyze the different ethnic groups in China.

Q: In your autoantibody positive type 1 patients, have you noticed any hotspots in terms of environmental influences that may contribute to type 1 diabetes?

A: We haven’t done this yet, but we do plan to look into this.

Q: I was wondering if you could take a little bit more about who is entering data into the registries. Is it doctors in outpatient clinics? I ask this, because doctors in outpatient clinics in China are very busy.

A: Doctors or nurses in each hospital entered the data. We also hired a CRO to monitor.



Zhao Liebin, MD (Shanghai Jiao Tong University School of Medicine, Shanghai, China)

Dr. Zhao Liebin highlighted the importance of clinic-community collaborative care for diabetes in China. He noted that the prevalence of diabetes in China has grown from 5.50% in 2010 to 9.70% in 2012, and that the country currently has 94 million adults with the disease. He remarked that due to a weak primary care system, patients often turn to community programs as a source of diabetes care and support. His group’s one-year trial evaluated the efficacy of clinic-community collaborative care vs. the usual care found in either the community or hospital. The 415 type 2 patients (60-80 years old, baseline A1c ~7.0%) randomized to the “collaborative care” group experienced several forms of diabetes support, including guideline-based training, once-monthly telemedicine guidance, and a free blood glucose measurement at the clinic every month (this was their only blood glucose assessment, as patients did not test at home). Those in the collaborative group exhibited lower A1c and blood pressure levels at one year, and also demonstrated improvements in blood glucose monitoring, healthy eating, foot care, and diabetes knowledge. These benefits were also observed in those patients treated at the hospital, but not in those treated only in community programs. During Q&A, Dr. Liebin remarked that even once-a- month blood glucose monitoring appeared to make a difference for his patients – an unexpected and remarkable finding.

Questions and Answers

Q: I was particularly fascinated that these patients had rather good glycemic control. As I recall, the baseline A1c was around 7% or a little less. Yet with a very modest intervention – it seems as though blood glucose testing was essentially done once-monthly at the clinic – you were bale to get a small by appreciable reduction in A1c. This is a very nice model for

providing what we in the US might think of standard care, in an enthusiastic fashion with actual outcome benefit.

A: These patients did have a good A1c. We were very luck to have gotten those patients. Our acceptance criteria did not include an A1c cutoff. However, we chose the community; our community is the best- controlled community in Shanghai. Also, there are not newly-diagnosed patients. These patients have been cared for by a general practitioner or specialist so maybe they have a good start. We just gave once a month blood glucose monitoring. But I’m very excited – we think that if we can just give blood glucose monitoring once a month, they can have a good result. Although A1c doesn’t change much, it does change. Maybe in general, we have given patients too serious rules to monitor their blood glucose levels. With monitoring only once a month, we have seen changes.

Comment: That’s very interesting. The intervention was probably not just testing blood glucose levels – by asking them to come into the clinic once a month, you’re reinforcing awareness of diabetes.

Q: Do the patients learn how to test their blood glucose at home and if so, how frequently do they do it?

A: They only tested in the clinics but not in their homes.

Q: Regarding your patient program, was it difficult to get people to come into the clinic if these patients are working. People who are retired have the time to come in, but for patients who are still working, how do you attract them to your hospital for training?.

A: The average age of the study cohort was nearly 60 years old. A lot of them are retired in their community..

Q: What percentage of your patients were treated with insulin?

A: Maybe less than 10% in the study population I think.


Symposium: China Medical Tribune Symposium–Updating Diabetes Research in China–From Bench to Real World


Zhiguang Zhou, MD, PhD (Central South University, Hunan, China)

Called “Mr. LADA” in China, Dr. Zhiguang Zhou discussed the efforts of the LADA China Study Group to characterize the disease in China. The group’s nationwide, multicenter study aimed to determine the prevalence of LADA in China among patients with clinically diagnosed type 2 diabetes. Among the 4,880 patients enrolled, 287 (5.9%) were diagnosed with LADA based on positive GAD antibody screening (Zhou et al., Diabetes 2013). No age, gender, or ethnic differences were found between the LADA and type 2 diabetes groups. The investigators also collected genetic samples and performed HLA- DQ genotyping on the LADA patients, comparing the results to those of 174 type 2 patients and 495 OGTT-screened healthy controls. Dr. Zhou highlighted that the prevalence of LADA in China differs by geographic location, with the highest prevalence in the northern parts of China and the lowest in the southern regions. Interesting, genetic differences did not explain the north-south frequency gradient, suggesting that environmental factors may play a role in the disease progression.

Questions and Answers

Q: Some people in Sweden first described type 2 diabetes patients that were negative for antibodies at the time of diagnosis, but that tested positive later. Did you see this in China?

A: Yes, we have seen this type of patient in our clinical practice. Someone mentioned that autoimmune diabetes overlaps later onto type 2 diabetes.

Q: Did you get the chance to compare the family histories of those with type 2 diabetes to those with LADA to see the frequency of type 2 diabetes within the families?

A: Yes, we did; there was a similar percentage of type 2 diabetes in the family histories of these two groups.

Q: A couple of years ago, a publication suggested that China probably has 100 million type 2 patients. From your estimate, it would seem that China would then have roughly six million LADA patients. From a clinical practice perspective, if we can identify these six million patients, should we treat them differently than how we treat type 2 patients?

A: Yes, based on studies that looked at GAD-positive type 2 patients compared to antibody-negative type 2 patient, beta cell function decreases three-times as quickly in the GAD-positive patients. I think that if these patient meet the high titer criteria, we have to treat them actively and use insulin.



Renming Hu, MD, PhD (Fudan University, Shanghai, China)

Dr. Hu discussed the potential of microRNA-145 to modulate chronic inflammation in patients with type 2 diabetes by targeting the cytokine receptor osteoprotegerin (OPG). MicroRNAs, or miRNAs, are small, non-coding RNA molecules between 19 and 22 nucleotides long that base-pair complementary mRNA molecules to regulate their expression. miRNA-145 base-pairs with the 3’ untranslated region of the OPG gene, significantly inhibiting its expression. In mouse models, inhibition of OPG expression leads to a reduction of macrophage infiltration. This reduces the release of inflammatory cytokines that normally elevate blood sugar. Other downstream effects include improved glucose tolerance and reduced aortic plaque lesions. Collectively, these potentially lower the risk of complications from diabetes and can prevent or reduce cardiovascular disease. Dr. Hu is hopeful that miRNA-145 may be delivered to patients in an injectable form in order to reap the benefits of reduced OPG expression, though much translational research remains to be completed.

Questions and Answers

Q: You mentioned that this could become a potential drug target for type 2 diabetes. I was wondering if you could educate the audience about how this basic research can be developed into a drug?

A: It would be difficult; we’ve been working on this for six years. miRNA-145 would be injected into patients with type 2 diabetes.

Q: Would there be safety concerns, like the autoimmune response we’ve observed with GLP-1s?

A: We would only need very low levels of miRNA-145 in newly diagnosed patients, so I don’t think it would be like GLP-1s; one physiologic dose would be enough.


-- by Adam Brown, Eric Chang, Hannah Deming, Jessica Dong, Sam Haque, Stephanie Kahn, Ben Kozak, Kira Maker, Hannah Martin, Rajiv Narayan, Nina Ran, Joseph Shivers, Tony Thaweethai, Manu Venkat, Katrina Verbrugge, Vincent Wu, and Kelly Close