American Association of Clinical Endocrinologists 23rd Annual Scientific and Clinical Congress (AACE 2014)

May 14-18, 2014; Las Vegas, NV Day #2 Highlights - Draft

Executive Highlights

We’re back with Day #2 of AACE 2014, the meeting’s first full day of scientific sessions. Here, we outline our top 10 highlights of the day, followed by detailed reports on each of the highlights listed below.

1. AACE’s exhibit hall opened today, and at the Dexcom booth, we learned that the company signed a contract with CVS/Caremark last week to get CGM covered as a pharmacy benefit.

2. In the exhibit hall we also got our first demo of AZ’s new Bydureon dual-chambered pen. It’s a bit larger in person than we would have expected and definitely easier than the current process! More detail below.

3. Dr. Zachary Bloomgarden (Mount Sinai, New York, NY) faced off against the infamous Dr. Peter Butler (UCLA, Los Angeles, CA) in a debate over benefit/risk of incretin-based therapies. Dr. Butler’s spirited presentation was actually quite balanced (though Q&A was less so), and he was careful to emphasize that he is not advocating that people stop taking incretins based on the currently available data, but rather urging the scientific community to further investigate a phenomenon he believes to be quite concerning. Mass media did not pick up the balance last year, of course, and the impact on HCPs and patients was not addressed. In Q&A, Dr. Butler argued the benefit of SFUs on the basis of price, not mentioning differences in hypoglycemia or weight gain, or benefits inherent in branded drugs going generic over time.

4. In a meet-the-expert session, Drs. Irl Hirsch (University of Washington, Seattle, WA) and Barry Ginsberg discussed BGM accuracy and shared strong concerns over the new FDA point-of-care draft guidance.

5. During AZ’s breakfast symposium on SGLT-2 inhibitors, Dr. Stanley Schwartz (University of Pennsylvania, Philadelphia, PA) commented on real-world usage of SGLT-2 inhibitors, saying that he and other providers “in real life” are generally seeing fewer infections than expected and that the infections can be proactively prevented (details below on exactly how). He also endorsed the off-label use of SGLT-2s in type 1 diabetes (surprisingly even noting that it has reduced some of the need for pumps in some of his type 1 patients).

6. During the President’s Plenary lecture, the leadership of various endocrinology professional societies discussed the challenges they see the specialty facing, including formularies restricting the treatment options available to HCPs.

7. Valeritas shared a poster with positive interim results from a 12-month, real-world observational study of the V-Go. Patients saw an overall 1% drop in A1c from an 8.9% baseline, including a striking 2.4% A1c decline in patients on the V-Go 40, where the baseline was 10.2%.

8. During a crowded Farxiga (dapagliflozin) product theater, Dr. Parresh Dandona (SUNY Buffalo, NY) led a lively Q&A session. At one point he stated that Dr. Steve Nissen and the Avandia saga have kicked off a new era of cynicism in diabetes drug development, which he thinks was reflected in the initial bladder cancer concerns for dapagliflozin (AZ’s SGLT-2 Farxiga/Forxiga).

9. In a Vivus product theater for Qsymia, Dr. Alan Garber presented market research (n=422 surveyed obese or overweight people) suggesting that a remarkable 83% of people would be willing to take Qsymia if their HCP recommended it to them, but that 45% did not see their HCP as a solution to their weight struggles.

10. Finally, we got to sit down for 15 minutes with AACE President, Dr. Jeffrey Mechanick who riffed on AACE’s leading position in the effort to improve the state of obesity care in the US. We were concerned that AACE’s newest leadership did not address obesity at all in their address.

Table of Contents 

Detailed Discussion and Commentary

Point/Counterpoint: Incretin Hormone Therapy: Panacea or Plague?

Incretin Hormone Therapy: Panacea or Plague? Neither

Peter Butler, MD (UCLA, Los Angeles, CA)

The infamous Dr. Peter Butler offered a resolute, yet balanced, explanation of his journey to becoming the lone whistle-blower on the pancreatic safety of incretin-based therapies. He won a bit of credibility at the beginning of the session by describing the history of how it all began – it does not seem that he ever prospectively set out to vilify incretins, but that his rodent-model findings caught him by surprise, according to him. The presentation was very similar to the one he delivered at the 2013 NIH/NIDDK Pancreatitis and Pancreatic Cancer Workshop; the presentation he gave today built upon his previous presentation at the NIH workshop by providing preliminary data from new donor pancreases that he has added to his 2013 morphological study published in Diabetes and some additional suggestions for how to move forward. His expanded dataset, which seemed about twice as large as the original, supports the conclusions of the original study and also addresses some of the short-comings of the original study (namely the age discrepancy between groups). In his expanded dataset, the pancreata of people with type 2 diabetes who had taken incretin therapies were still larger than the pancreata of people with type 1 or type 2 diabetes who had never taken incretin therapies and larger than those of people without diabetes. Dr. Butler also performed a new analysis in which he sectioned the pancreata into three parts – head, body, and tail – and found that most of the increase in pancreas size is accounted for in the head (this is problematic because most pancreatic cancer is derived from the head). We are clearly not specialists on the biology behind pancreatitis and pancreatic cancer, but Dr. Butler’s presentation seemed fairly convincing. We appreciate that he was very careful to emphasize that he does not believe his evidence establishes proof of a causal relationship, but simply that the scientific community should more closely examine these concerning issues. We wish that he had exercised as much caution with the popular media, or encouraged the mass media to exercise as much nuance with their coverage of his call to action, so that patients would not have been scared off of their medications – and so that primary care and other doctors would not have sounded alarm bells. It is obviously hard to know how Dr. Butler addressed the media and what the media itself did. The New York Times headline was “A Lone Voice Raises Alarm on Lucrative Diabetes Drugs” (the piece itself was much more balanced than the headline, as respected New York Times writer Andrew Pollack pointed out to us).  Other medial experts were less enthusiastic about his work – for example, Dr. Michael Nauck who was quoted last year in MedPage Today noting that Dr. Butler’s work was “inconsistent.” Dr. Butler seemed to be a bit on the defensive about his work in his talk at AACE, highlighting the CVs of the other scientists he’d worked with to establish their repute. In closing, we thought that Dr. Butler made some sound suggestions for future steps to further elucidate the effect of incretins on the human pancreas. For example, he suggested using the relatively a relatively simple MRI, CT or ultrasound study to measure pancreas size in live patients to see if his findings can be replicated. On a bit of a surprising note, he remarked that if the signal is not there, we could likely dismiss the nPOD group he used in his donor study as an aberrant one. If that happens, of course, it will likely be hard to get the attention of mass media.

  • Dr. Butler first began working with incretins when Merck approached him to study sitagliptin (Januvia) in a type 2 diabetes rat model that his group had developed. After treating rats with sitagliptin, metformin, or both for 12 weeks, he said that his post-doc came to him saying that there was something strange about the pancreases and that he could recognize whether the rat had been on sitagliptin or not after opening it up. Dr. Butler was surprised at this finding, and indeed they found that the sitagliptin pancreases were 30% larger and exhibited acinar to ductal metaplasia (acinar cells changing into ductal cells). Further studies confirmed the finding and also showed increased cellular replication in the pancreases from rodents on sitagliptin.
    • The acinar to ductal metaplasia is significant because a recent study published in Cancer Cell found that the acinar to ductal transition may be associated with premalignancy (Kopp et al., 2012).
  • Subsequently, Dr. Butler repeated these experiments with exendin-4 (the exenatide precursor) in non-diabetic rats. The exendin-treated animals had a marked increase in replication of the pancreatic duct gland structure in the main pancreatic duct, about three-times higher than that of the control group. He concluded that GLP-1-induced proliferation in the exocrine pancreas was focal and might accelerate development of dysplastic lesions when present.
  • He then studied the effects of exendin-4 in a rat model of chronic pancreatitis (so the animals were genetically prone to pancreatic cancer), which found that the GLP-1 agonist accelerated formation of premalignant PanIN lesions. Again he found increased replication in the exendin-4 treated animals and also an increase in lipase indicating that the animals had chronic pancreatitis.
  • As far as human data, Dr. Butler pointed to the FDA AERS database study, which found an increase in pancreatitis and pancreatic cancer associated with exenatide or sitagliptin therapy. Notably, he remarked that this increase was observed in 2006 and prior, before incretins had any public notoriety for being associated with pancreatic adverse events (which counters the argument that the imbalance could be caused by reporting bias). Dr. Butler remarked that the EMA, WHO, and German databases all came to the same conclusion.
  • Dr. Butler then turned to the JDRF’s nPOD (Network of Pancreatic Organ Donors with Diabetes) study at the University of Florida where he studied the 34 human pancreas that are the subject of his most recent 2013 publication in Diabetes. He obtained whole pancreases from brain dead organ donors with type 2 diabetes not on incretins, type 2 diabetes on incretins, and no diabetes. He found that the average weight of pancreas from people with type 2 diabetes on incretins was significantly larger than the control groups, had significantly greater alpha cell hyperplasia, and had a greater number of PanIN lesions. 
  • Dr. Butler presented preliminary new data from an expansion of his organ donor pancreas study confirming the original results. The expansion seems to have at least doubled the previous sample size (n estimated from a scatterplot) and also added a type 1 diabetes control arm.
    • Dr. Butler performed a new analysis in which he sectioned the pancreas into three parts – head, body, and tail – and found that most of the increase in pancreas size is accounted for in the head. He suggested that this was problematic because most pancreatic cancer is derived from the head.
    • He also performed a subset analysis of pancreases from people of the same age and BMI. His original paper had been criticized for the large age difference between the incretin group and the control groups, but this new subset analysis shows that even across the same age and BMI, there is still a clear increase an mean pancreas size in the incretin arm.
  • Dr. Butler explicitly acknowledged that none of the data he presented can prove a causal relationship between incretins and pancreatitis or pancreatic cancer, but he emphasized that his human pancreas study suggests that something troubling may be happening in patients we’re treating now that we haven’t been detecting because we obviously cannot dissect the pancreases of live patients. Dr. Butler was careful not to say that we should withhold incretin treatment from anyone, but concluded that the balance of benefit vs. side effects of GLP-1-based therapies has not been established. In Q&A, he remarked, “At present, the consensus is that there is no reason to change treatment recommendations, and I don’t disagree. All we’ve been saying through this sequence of studies we’ve been engaged in is that we found something we didn’t expect, we pursued it in animal models, and in humans, through our pathology studies.”
  • Dr. Butler made several suggestions for future steps. He remarked that current CVOTs are not powered to detect pancreatic cancer, so we cannot rely on them to reassure us.
    • Dr. Butler remarked that pancreas size in humans is easily measured by an MRI, CT, or ultrasound, so one could establish an independent study to easily determine whether his findings can be replicated on a large scale in live patients. He very candidly remarked that if the signal is not there, we could likely dismiss the nPOD donors as a strange group of people, but seemed pretty confident that such a study would confirm his findings.
    • Furthermore, ~2,000 pancreata per year from organ donors with type 2 diabetes are potentially available for research. This offers a larger study population than his small donor study.
    • Finally, he suggested additional studies of GLP-1-based therapies in relevant models of chronic pancreatitis.

Should We Fear Incretin Treatment? NO!

Zachary Bloomgarden, MD (Mount Sinai School of Medicine, New York, NY)

Dr. Zachary Bloomgarden provided a well-structured defense of the incretin class, devoting the first half of his presentation to a comparison of incretin therapies versus sulfonylureas – while some may argue that it would be hard for most drug classes to not seem relatively strong when compared to SFUs, SFUs are what most patients still use today after metformin. He made the point that incretin therapies are at least as effective as SFUs (in the case of GLP-1 agonists, more effective) and come with weight and hypoglycemia benefits relative to SFUs. He shared data indicating an increased risk of CV events with SFUs (Schramm et al., Eur Heart J 2011 & Dr. Craig Currie’s somewhat controversial UK database studies presented at EASD), while the well-known Monami et al. meta-analyses of DPP-4 inhibitors and GLP-1 agonists show cardioprotection or a trend towards it. Moving on to pancreatitis, Dr. Bloomgarden discussed some now-familiar weaknesses of Dr. Butler’s pancreatic morphology study (poorly matched controls) and his FDA AERS study – reporting of adverse events to a database is subject to a number of biases, and appeared (according to Raschi et al., Acta Diabetol 2013) to positively correlate with FDA safety announcements on the issue. To learn more about incretins and pancreatitis/pancreatic cancer, you can read our primer.

  • Although most of Dr. Bloomgarden’s presentation focused on clinical data, we were glad that he concluded with some commentary involving the media, as it was the broader media that fanned most of the flames of the incretin-pancreatitis controversy – and it is the media that unfortunately guides practice. He quoted an email to Reuters Health from Dr. Victor Montori (Mayo Clinic, Rochester, MN), who researches the dissemination of scientific and medical knowledge. “Early evidence often exaggerates benefit,” Dr. Montori wrote. “Sometimes, early evidence may exaggerate harm. Clinicians should avoid falling prey to novelty, whether it comes from science or from marketing…” We agree with Dr. Bloomgarden that these were wise words, especially in light of the negative impact that the framing of clinical data had on the lives of countless patients on incretin therapies.

Panel Discussion

Q: Peter if I may ask, you submitted some of these data to the FDA, and recently the FDA said that at this point they feel the indication should be changed. The EMA said something similar. Did they finish checking your stuff or is it in between?

Dr. Peter Butler (UCLA, Los Angeles, CA): FDA has their own database, and most of what they have is not available to us who are not in the pharmaceutical industry. What a lot of us are pushing for is more open access to clinical trials. What the FDA has looked at to reassure themselves is data that’s not available to you or I. Our data is a very small piece of the pie.

Q: Do you think that the data held in these databases might prompt a change in treatment recommendations?

Dr. Butler: I’m not a drug toxicology expert. At present, the consensus is that there is no reason to change treatment recommendations, and I don’t disagree. All we’ve been saying through this sequence of studies we’ve been engaged in is that we found something we didn’t expect, we pursued it in animal models, and in humans, through our pathology studies – it’s a good thing my wife is a pathologist. I think the FDA would agree that there are some signals that we don’t understand, but until we have more data, it’s difficult to make specific recommendations one way or another. We know that every drug has side effects, and it’s always a challenge to find the balance.

Q: Is that pancreatic metaplasia reversed when medication is discontinued? Second was there metformin data presented last year about metformin decreasing amount of metaplasia that occurred?

Dr. Butler: That is a great question. A big problem is no one funds studies to look at adverse events for the obvious reasons. The kinds of studies you described, stopping the drug to see if the effects go away would be fascinating and interesting to do. I have no data on that. I would say, however, that I use GLP-1 mimetic drugs prior to gastric bypass surgery. I use that to see if I can avoid gastric therapy for six months, and if at the end of six months the patient still needs surgery or has stopped taking the drug anyway then I give them surgery. I figure you cannot do too much harm in six months. Maybe that’s where you can do an on/off experiment.

Dr. Zachary Bloomgarden (Mount Sinai, New York, NY): An interesting point that occurred to me as you were speaking, Dr. Butler, is that if you take an overall population of individuals treated with incretin-based therapy, you may well choose a population that differs systematically from individuals getting other diabetes treatments. For example, regarding the likelihood that some specimens from your study actually had type 1 diabetes… 

Dr. Butler (interrupting Dr. Bloomgarden): We addressed that. That’s absolute nonsense.  We had three experienced pathologists on this paper. Type 1 and type 2 diabetes have very different pathologies. This has been brought up repeatedly, and we addressed it to the editor of Diabetes. They did not have type 1 diabetes.

Dr. Bloomgarden: …To finish my previous point, look at obesity, which is a condition that leads one to be more likely to use incretin-based therapies. Obesity, in a surrogate fashion, is associated with pancreatic changes. We need to have controlled trials, and the data you presented does not seem highly suggestive at this time.

Dr. Yehuda Handelsman (Metabolic Institute of America, Tarzana, CA): To your question about metformin, some studies point out that maybe metformin may reduce the development of cancer. Those are very observational. There is a study going on now led by Dr. Pollack and Dr. Goodman from Canada looking at 4,000 patients and maybe in five years or so we’ll get some answers.

Q: I have a quick question about the negative profile of sulfonylureas as presented by Dr. Bloomgarden. I wonder if the studies have actually looked at the doses of the SFUs. Because in our practice, if you’re using a small dose of glimepiride, 1 mg twice daily, it is very different from 4 mg twice daily. So the question is about studies that have talked about all the negative effects – have they looked at these doses or combined all patients on SFUs? I think it’s very different if they’re on a low vs. maximum dose.

Dr. Bloomgarden: If I could paraphrase Joslin’s famous saying, the treatment of diabetes is for the wise, not the foolish whether they be patients or doctors. Certainly that pertains to incretin-based therapy and sulfonylureas. I have many patients to whom I give glimepiride 0.5 mg every other day thinking I may be avoiding adverse outcomes. However I think what we have to do is look at what the drug is that’s being accused of adverse outcomes, what are the other choices, and then what’s the real data in the population for benefit or harm with incretin-based therapy. What’s the real data on benefit or harm with the other drugs that are commonly used in place of such therapy? Then of course if there are some subtle signs that may not be currently available to us, an adverse effect on the pancreas would be an area of exploration yet I think we have to focus on the clinical use of the drugs, the safety that’s been established, and that was really the thrust of my argument.

Dr. Butler: I don’t think you can use the word “subtle” to describe a 40% growth in the head of the pancreas – that’s more than subtle. There has been a tendency to criticize efficacy findings that aren’t from randomized control trials, but to laud safety findings from database studies like the studies done on sulfonylureas and mortality. Clinical-type studies need to be done over a long period of time to show favorable benefit of a drug. Maybe SFUs would show more of a benefit in those type of studies, but no studies are available. There was a Mayo Clinic study published in Diabetes Care that studied sulfonylureas and incretins head-to-head, and there was no difference in outcomes, although there was a difference in cost. (Editor’s note: Dr. Butler did not mention if there were differences in hypoglycemia or weight gain or edema, etc. He also did not discuss benefits that could stem from incretins that are generic, as they ultimately will be.) There is no solid evidence yet from incretin studies that these drugs are more beneficial. What we do know is that they are more expensive.

Workshop/Meet-the-Experts

Diabetes Technology: An Update of Potential Limitations and (?) Solutions

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

Dr. Irl Hirsch gave an impassioned talk on BGM accuracy, sharing concerns about off-shore meters, generic strips, and the new FDA draft guidance (especially the highly stringent point-of-care requirements). He was especially concerned about the implications of reverting to central lab blood glucose testing in the ICU, which stands to put patients at risk. He concluded that “this topic is not going to go away,” and there is only one conclusion to draw at this point: “Keep calm and stay tuned, and we’ll be back soon.”

  • “I always thought Shasta was a diet soda. I did not even know that [generic strips] were possible.” Dr. Hirsch expressed his concerns over the April 29 FDA safety communication issued to Shasta regarding its generic GenStrip (for use with LifeScan Ultra meters). See our initial coverage here and the parent company’s confident response here.
  • Regarding the new FDA guidance for over-the-counter (home use) meters, Dr. Hirsch said, “When I talk to people in industry, they think they can do this” (i.e., meet the accuracy criteria for home-use meters). However, the impact of this guidance will likely be higher costs of strips, according to Dr. Hirsch. Moreover, it raises two key questions in his view: 1) What about competitive bidding? 2) Who is going to police all of this, especially off-shore meter accuracy studies? The latter, for Dr. Hirsch, “is the big issue.”
  • Regarding the point-of-care guidance, Dr. Hirsch was more troubled, “The problem: ZERO tolerance for statistic outliers. Even the laboratory YSI can’t achieve these criteria.” He was near-outraged at the new point-of-care requirement that significantly tightens the CLSI standards and will now require 99% of results within 10% (>70 mg/dl) or 7 mg/dl (<70 mg/dl) and 100% within 20% of reference. Added Dr. Hirsch, “the criteria appear to stretch beyond the limits of current technology” – indeed, he noted that reference methods have a ~2% error, and the new proposed criteria leave no room for the imprecision of reference methods. He added that the hematocrit (10-65%) requirement for 100% within reference is “also not possible.”
    • According to Dr. Hirsch, the FDA has said, “Current devices put [hospital] patients at risk as not evaluated for their current use” (i.e., meters were not previously tested in the ICU setting, so using them in this way is off label). His slide summarized the public comments on this front: “No data to support that. More likely, hospital meters with current accuracy (quite good) protect from potential fatal hypoglycemia.”
    • “Could you imagine waiting up to one hour in an ICU for a blood glucose for an insulin drip? I don’t know what’s going to happen.” The FDA guidance document says that glucose meters have not been previously assessed in the ICU setting, so technically they have always been used off label. The alternative to using a meter is central lab testing; however, this would take at least an hour at Dr. Hirsch’s hospital, which puts patients on IV insulin, in the ER/ICU, etc. at risk.
    • Dr. Hirsch also addressed the FDA’s concern over hypoglycemia due to the inaccuracy of current meters. In his view, hypoglycemia is quite uncommon in ICUs where hourly blood glucose levels are measured. The real issue is not meter accuracy but testing frequency, understanding protocols, etc. As an example, he pointed to NICE SUGAR, where some protocol violations included patients on IV insulin being tested every four hours.
  • Dr. Hirsch projected three potential outcomes of the draft guidance going forward: 1) the FDA will decide current CLSI criteria are sufficient; 2) the FDA will decide to implement more lax criteria; 3) the FDA will make no current changes. In any case, “the implications are huge for everybody” – non-ICU patients, smaller hospitals, emergency department, patients performing their own fingersticks; and nursing homes/skilled nursing facilities.
  • Similar to previous presentations he has given, Dr. Hirsch shared concerns over offshore meters. He supported this point with disturbing accuracy data on offshore meters (Brazg et al., JDST 2013) – none of the four offshore meters (Advocate RC, Embrace, True Balance, Element) and 12 lots tested met the 2013 ISO Standard.

Glycemic Safety Issues in Type 1 Diabetes: New Technologies and Old Problems

Barry Ginsberg, MD, PhD (CEO, Diabetes Technology Consultants, Wyckoff, NJ)

Dr. Barry Ginsberg gave a valuable general overview of blood glucose meter accuracy and the latest standards. We appreciated his translation of ISO criteria into MARD values, which put into perspective the accuracy of current meters and lab instruments (and by extension, how CGM compares). He also gave a valuable summary of the factors that cause meter inaccuracy and how to overcome them. Dr. Ginsberg concluded with a vague slide on how current meters can be improved using “pulse technology” – the approach took the same meter/strip (“very popular in the US today”) from not passing the ISO 2003 criteria to passing the most stringent 95% within 10% criteria.

  • Dr. Ginsberg gave a useful breakdown of ISO accuracy criteria by MARD, an expression we had not ever seen before. ISO 2003 (95% within 15 mg/dl or 20%) equates to ~8% MARD. ISO 2013 (95% within 15 mg/dl) equates to ~6% MARD. What he called the “extended ISO 2013 standard” (95% within 10 mg/dl or 10%) equates to an MARD ~4%. For context, lab instruments have an MARD of about 2%. These would seem incredibly challenging standards to meet.
  • “The problem is that the FDA does not generally remove older systems from the market.” According to Dr. Ginsberg, the FDA can only remove meters from the market that are contaminated or misbranded/mislabeled. As a result, if the Agency approved a device in 1998 that doesn’t even come close to the accuracy required today, it cannot be removed from the market on this point alone. However, Dr. Ginsberg noted in Q&A that the FDA does have the power to require companies to put an accuracy claim on the box – that could offer an avenue to eventually take meters off the market.
  • “A lot of our meters on the market today aren’t accurate by our own current standards.” Dr. Ginsberg reminded the audience of Dr. Guido Freckmann’s data on the accuracy of 34 different CE marked meters. He found that 79% of meters passed ISO 2003 criteria, but only 52% passed the updated ISO 2013 standard.
  • Dr. Ginsberg shared a list of factors that cause meter inaccuracy [and the methods to overcome them]:
    • electrode noise [nobel metal electrodes; bi facial geometry];
    • manufacturing variance [dynamic/pulse electrochemistry];
    • chemical variance [multiple measurements; dynamic/pulse electrochemistry];
    • coding [no code systems];
    • sample application [capillary fill;];
    • handwashing [education];
    • hematocrit [AC/multiphasic current];
    • urate, citrate, acetaminophen [GDH PQQ; dynamic/pulse electrochemistry];
    • altitude [GSH PQQ];
    • temperature [temperature compensation]; and
    • humidity [stability].

Posters: Diabetes Mellitus/Prediabetes

Initiating V-Go in Patients Using Long Acting Insulin

George Grunberger; Cheryl Rosenfeld, Bruce Bode, Kenneth Hershon, Poul Strange

It was exciting to see positive interim results from a 12-month observational study of Valeritas’ V-Go disposable insulin patch pump (SIMPLE), given how many type 2 patients have problems with insulin initiation and delivery and adherence. This poster presented six-month interim data from 40 patients with type 2 diabetes who switched to V-Go therapy from baseline treatment with long-acting insulin. At the study midpoint, patients experienced significantly improved A1c levels in all dosage groups (an overall 1% decline from an 8.9% baseline) and a reduction in total daily insulin dose in the V-Go 30 and V-Go 40 dosage groups. Most notable was the V-Go 40 group, which saw a staggering 2.4% drop in A1c from a 10.2% baseline, with a corresponding 7% reduction in insulin dose. Only five hypoglycemic events <70 mg/dl were reported, and there were no severe hypoglycemia episodes. We’d note that the trial does not have a control group, though the results are very real-world and do look quite encouraging, particularly for those who are very uncontrolled on long-acting insulin – this has been a very large group, given the difficulties of moving patients to mealtime insulin. 

  • After six months, A1c levels improved for all dosage groups from baseline (p<0.001).

Dosage group

A1c Change at 6 months

Baseline A1c at screening

V-Go 20 units

-0.6%

8.9%

V-Go 30 units

-0.8%

8.5%

V-Go 40 units

-2.4%

10.2%

  • Mean total daily insulin dose after six months also improved for both the V-Go 30 and V-Go 40 dosage groups, but not in the V-Go 20 dosage group.

Dosage group

TDD Change at 6 months

Baseline TDD at screening

V-Go 20 units

+14.4 units

33.1 units

V-Go 30 units

-2.6 units

50.7 units

V-Go 40 units

-4.2 units

57.6 units

  • Additionally, total basal dose (TBD) decreased in all dosage groups at month six from baseline.

Dosage group

TBD Change at 6 months

Baseline TBD at screening

V-Go 20 units

-4.1 units

32.6 units

V-Go 30 units

-13.8 units

44.9 units

V-Go 40 units

-18.9 units

57.6 units

  • Patients starting V-Go 20 had the greatest bolus insulin change, from a mean of 7 U/day to 19 U/day at six months. Patients starting V-Go 40 initiated at a mean of 10 U/day and increased to 15 U/day at six months. Patients starting V-Go 30 initiated at a mean of 13 U/day and received a mean of 17 U/day at six months. However, even after six months, the bolus to basal ratio was very low and the authors added that “mealtime bolus (clicks) could and should be optimized across all cohorts to attain better glycemic control.”
  • The SIMPLE study is an ongoing, observational, open-label, multicenter study. Patients with type 2 diabetes and a baseline A1c greater than 7% were enrolled. Study participants were then switched from one of five baseline treatments (5 cohorts) to V-Go for their basal and mealtime insulin delivery. One cohort (the basal cohort) included patients previously treated with a long-acting insulin (with or without oral anti-diabetic medication). The primary objective of the observational study is to compare change of average glycemic control as measured by A1c from baseline to the end of V-Go use for all patients combined, as well as each of the individual cohorts. Patients in the study were followed on their previous therapy for up to six weeks before initiating therapy with V-Go. The study, observational in nature, has no mandated or forced titration instructions to guide insulin therapy with the exception of recommended starting doses for V-Go basal rate options.
    • Patients in SIMPLE are divided according to their diabetes therapy at baseline: 1) OADs only; 2) OADs in combination with either exenatide, pramlintide, or liraglutide; 3) once or twice daily of an intermediate or long acting insulin with or without OADs and/or an incretin; 4) one to three daily injections of premix insulin with or without OADs and/or an incretin; or 5) any insulin with three or more insulin injections a day with or without OADs and/or an incretin. This poster only included patients previously on long-acting insulin.
    • While V-Go basal rates are preset, it was recommended that patients starting insulin start with the 20 U/day V-Go dosage. The authors did note that a better dosing and titration mechanism might be needed to show consistent improved response across different patient types with more of a focus on body weight than on previous insulin dose at initiation and improved bolus titration.

Plenary Sessions

The Future of CGM and the Bionic Pancreas

Jay Skyler, MD (University of Miami, FL)

After accepting this year’s well-deserved ACE Distinction in Endocrinology award, Dr. Jay Skyler shared an overview of CGM and the bionic pancreas in a very packed plenary session. His presentation was a combination of what he presented at Keystone 2013 and his recent review of the field in the Annals of the NY Academy of Sciences. He first covered a number of publications on CGM (especially the JDRF CGM trial, “the most important study related to CGM”), emphasizing that CGM can reduce A1c, hypoglycemia, and even severe hypoglycemia (Choudhary et al., Diabetes Care 2013 showed the latter). After briefly touching on reimbursement, Dr. Skyler focused on CGM accuracy and reviewed head-to-head results from three academic groups (Dexcom’s G4 Platinum and Abbott’s Navigator were the best; he did not offer any commentary on Medtronic’s Enlite). Dr. Skyler also summarized Dr. Irl Hirsch’s 2013 editorial from DT&T, which pointed out several questions related to the ASPIRE trial of the MiniMed 530G. Dr. Skyler concluded with a review of recent outpatient closed-loop studies from the DREAM group, the Boston/MGH group, and the University of Virginia. He shared that artificial pancreas “progress is moving at a dramatic pace…,” and “within the next three years we’ll have bionic pancreases for our patients.”

  • “You can improve both A1c and hypoglycemia if you use CGM on a continuing basis.” Dr. Skyler covered the following studies in his sweeping review of the literature: the JDRF CGM trial (NEJM 2008; Diabetes Care 2009); the SWITCH study (Battelino et al., Diabetologia 2012); Battelino Diabetes Care 2011; Dr. John Pickup’s widely cited individual patient data meta-analysis (BMJ 2011); and Choudhary et al., Diabetes Care 2013. He emphasized on the latter that severe hypoglycemia declined whether patients used low glucose suspend or not.
  • Concerning the ASPIRE in-home trial of the MiniMed 530G, Dr. Skyler referred to Dr. Irl Hirsch’s 2013 editorial in DT&T – in that piece, Dr. Hirsch expressed surprise that the median duration of suspension was only 11.9 minutes. He also acknowledged two limitations of the trial: a short duration (i.e., reduction of hypoglycemia over time is not known) and an inability to extrapolate benefits in adolescents, young adults, or geriatrics.
    • Dr. Skyler wondered whether basal insulin suspension was actually effective in reducing hypoglycemia, or patients were simply waking up to alarms and consuming glucose. He highlighted the key implication of a median 11.9-minute cessation of insulin in ASPIRE in-home – 50% of cessations were less than 11.9 minutes. Given the short duration, he hypothesized that these patients were being alerted to lows, performing SMBG, treating their low with glucose, and resuming insulin delivery. Assuming basal insulin delivery of one-unit per hour, the 11.9-minute suspension equates to 0.2 units of insulin (he questioned, “Do you really think that would be enough?”). We thought this was an astute point, though it is also largely in line with what Medtronic has found in other studies of LGS – the vast majority of suspends are less than ten minutes (and mostly during the day), while most two-hour suspends occur at night. Dr. Skyler did not specifically address full two-hour suspensions of insulin at night, which is what many believe is the real value of the LGS device. Broadly speaking, we think it’s extremely challenging to tease out whether the overall study effect of the device in ASPIRE was due to patients responding to alarms and treating their lows (in the case of short suspends), the longer two-hour MiniMed 530G suspends, or some combination. 
    • Dr. Skyler also questioned the value of suspending basal insulin delivery to correct hypoglycemia. According to Dr. Lutz Heinemann, it “takes 2.5-4 hours until a considerable change in basal infusion rate leads to a new steady state level in the induced metabolic effect.” Dr. Skyler’s take on ASPIRE is that impending/current hypoglycemia needs to be detected with “accurate CGM” and treated with glucose. Others point out the benefits with incremental change of course and point to improved accuracy over time with all CGM.
  • Dr. Skyler mentioned his recent article in the Annals of the New York Academy of Sciences: The Artificial Pancreas – Current Status and Future Prospects in the Management of Diabetes. Read our detailed coverage of the piece, which shares valuable commentary on the future of AP development, advocates for creation of a new company to integrate best-in-class tech, and discusses the latest in CGM and debates over smartphones and the role of glucagon.
  • He also highlighted head-to-head accuracy studies of CGM from three academic groups: (i) Freckmann et al. (JDST 2013) and Pleus et al. (JDST 2013); (ii) Kropff et al. (DTT 2014); and (iii) Damiano et al. (JDST 2014). He first shared this data in Dexcom’s Corporate Symposium at Keystone 2013. The table below summarizes the Freckmann and Pleus data; see our recent coverage of the Damiano paper here, which was consistent with the below (a MARD of 10.8% for the G4 Platinum, 12.3% for the Abbott Navigator, and 17.9% for the Medtronic MiniMed 530G/Enlite). These trials were small: 10 patients in Pleus et al., 12 patients in Freckmann et al., and 24 patients in Damiano et al. We look forward to larger studies in the future and to studies that include the next-gen Enlite.

CGM System

MARD

Abbott Navigator

12.4%

Medtronic Enlite

16.4%

Dexcom Seven Plus

16.7%

Dexcom G4 Platinum

10.9%

  • Dr. Skyler briefly touched on reimbursement, noting that almost all major carriers approve CGM for patients with type 1 diabetes. He told the audience that a prior authorization might be required, however – definitely perceived as a disadvantage by some doctors. And, of course, levels of reimbursement vary, and the percentage of co-pays and the levels of deductibles that patients must cover continues to climb. There are two reimbursement codes for providers to remember, said Dr. Skyler: 95250 to place a CGM, and 95251 to interpret CGM. Regarding the latter, the interpretation must be written down, and it will “potentially” get reimbursed – he was frank in acknowledging that not all insurance companies pay for this code. Notably, Dr. Skyler said that one center in the US increased its revenues by $250,000 per year by routinely submitting these codes.
  • Dr. Skyler disclosed his conflicts of interest at the beginning of his talk. He was on the Board of Directors of MiniMed prior to its acquisition by Medtronic. He is currently on Dexcom’s Board of Directors and is an investor in Tandem Diabetes Care.

My Exendin-4 Journey

John Eng, MD (Associate Professor of Medicine, Mount Sinai School of Medicine, New York, NY)

The inspiring Dr. John Eng was presented with the well-deserved AACE Frontiers in Science Award today for his exemplary contribution to diabetes drug discovery, specifically for his discovery of exendin-4, now licensed as Byetta (exenatide). Dr. Eng’s charisma was not lacking this morning, beginning with a wry disclaimer slide reading: “receiving royalties from Amylin Pharma, BMS/AZ, AstraZeneca,” and he noted that it may change to Pfizer soon. Dr. Eng shared his research journey, from his fortuitous finding of the hormone in gila monster venom to the grueling and often disheartening patenting and licensing process. This was an excellent reminder of the dedication and gumption needed in diabetes drug discovery today, particularly noting the necessity of smaller biotech companies like Amylin that took a risk that made all the difference (especially when bigger players like Lilly weren’t willing to bet on exenatide at first). We were very fortunate to have interviewed Dr. Eng back in 2005 for Diabetes Close Up, in which you can read his full story on exenatide’s discovery, patenting, licensing, and launch.

Presidents’ Plenary

Endocrinology Directions for the Future

Daniel Einhorn, MD (President, ACE); Jeffrey Mechanick, MD (President, AAC); Samuel Dagogo-Jack, MD (President-Elect, Medicine & Science, ADA); William Young Jr., MD (Immediate Past-President, Endocrine Society); Hossein Gharib, MD (President, ATA)

During a morning plenary session, leadership from AACE, ACE, ADA, ENDO, and ATA (the American Thyroid Association) briefly discussed the challenges in endocrinology they can collaborate on improving. Notably, Dr. Daniel Einhorn expressed concern about the “dumbing downing” of endocrine practice, through formularies limiting the treatment options available to HCPs. This fear has been raised increasingly more frequently of late, and we are worried such formulary restrictions will reduce ability of HCPs to individualize diabetes care as called for by ADA and EASD. Dr. Hossein Gharib highlighted the issues endocrinologists face with reimbursement, and pressed that the professional organizations should work together to effectively negotiate rates for their members. Additionally, Dr. Gharib described the need for endocrinologists to “sell ourselves as a practice that is gratifying in terms of service and income (this was a bit confusing because we hear so many challenges on these fronts).” Dr. William Young warned that funding for basic and clinical research in endocrinology is “under siege.” He therefore wanted to see the other societies join Endo in advocating on the Hill to prevent further research cuts. The ADA’s Dr. Samuel Dagogo-Jack stressed the need to prevent type 2 diabetes, and to aggressively diagnose new cases of type 2 diabetes as this might put the disease into regression. Unfortunately, a significant portion of the plenary was dedicated to the speakers detailing the leadership and mission of each organization; we feel that the conversation could have been more nuanced and informative had there been more time alloted to panel discussions. Overall, this was not the most satisfying session.

Exhibit Hall

Dexcom

In stopping by the busy Dexcom booth (coffee was a big draw!) at the back of the hall, we learned that the company signed a contract with CVS/Caremark last week. Notably, Dexcom CGM will now be covered as a pharmacy benefit for an impressive ~25 million covered lives. As we understand it, there is more to come on this front, which already builds on Dexcom’s addition to Express Scripts’ Preferred Drug List in January (pharmacy benefit coverage for ~5 million members). This is significant news, as it means patients would only need to pay a copay to get CGM, rather than the average ~20% co-insurance on sensors, transmitters, and receivers. The additional benefit of moving to a pharmacy benefit is it helps patients avoid the high deductibles typically associated with DME. Major kudos to Dexcom for continuing to move the needle on reimbursement, especially as more and more costs get shifted to patients through healthcare reform. On a related note, Dexcom CEO Terry Gregg was on CNBC's popular finance show, Mad Money today. We were in sessions and didn't catch it, but will be on the lookout for the clip.

AstraZeneca

At AstraZeneca’s booth, we got our first in-person look at the Bydureon dual-chambered pen. This is the new Bydureon device developed to eliminate the need for manual patient-end reconstitution of the powdered drug. The FDA approved it in March, and AZ has guided for a 2H14 launch. At the booth, the pen was not overtly advertised, nor was it on display, but one could ask at the medical information desk for a demo. The representative at the desk took us through the preparation and injection process – as we wrote when the device was first approved, it is quite an involved process. The pen is fairly large – it seemed a bit more like a  wand than a pen, which would still certainly be an improvement. We estimate that it was about 8-9 inches long with a circumference roughly the size of a US quarter. The needle was also relatively large, a 23-gauge needle. We learned that the needle could not be any smaller due to the microsphere technology of the drug. For comparison, Lyxumia’s pen in the EU can be used with 29 and 32 gauge needles. Bydureon uses a 23-gauge needle as well, however, and we have not heard negativity around it, due to the needle technology as we understand it (we’ve used it and it didn’t hurt!) The instructions that the representative provided for use were as follows:

1) Take the pen out of the refrigerator and let it sit at room temperature for 15 minutes.

2) Inspect the powder through the chamber’s viewing window to ensure that the powder is not discolored.

3) Attach the needle to the pen.

4) Twist the knob at the bottom of the pen to combine the powder and solvent.

5) Shake until fully mixed. It is recommended to tap the pen against the palm about 80 times to ensure proper mixing (the representative acknowledged that this sounded like a lot of shaking), but patients may also check halfway through to see if the powder has been fully mixed (there is an image in the user guide to help patients determine what the window should look like fully mixed). There was no actual powder or solvent in the demo pen, but there were images placed in the viewing window showing what the patient might see if it were fully mixed or not. The fully mixed suspension should be homogeneously white with no particles or clumps.

6) Twist the knob at the bottom of the pen again until you hear another click.

7) Remove the cover for the needle and swab the injection site.

8) Inject, pressing down and holding for 10 seconds.

In general, we think the new pen will be a slight convenience upgrade over the old complex process. The representatives at the booth were not able to give us more specifics on when it might launch, although we did learn that it would likely be priced similarly to the old Bydureon system.

Corporate Symposium: A New Approach to Glycemic Control in Type 2 Diabetes: Targeting the Kidney (Sponsored by AstraZeneca)

Targeting the Kidney in Managing Hyperglycemic: Exploring the Evidence

Stanley Schwartz, MD (University of Pennsylvania, Philadelphia, PA)

Dr. Stanley Schwartz reviewed the evidence behind glycemic, weight, blood pressure, lipid, and other safety effects of SGLT-2 inhibitors. The most notable part of his presentation was his discussion of real-world experience with SGLT-2 inhibitor side effects. He remarked that he and other providers generally see fewer genitourinary infections with SGLT-2 inhibitors than expected from clinical trial data and that these infections can be proactively prevented (e.g., by pushing fluids to keep urine dilute, counseling women to urinate after intercourse, and counseling uncircumcised men to keep the tip of the penis dry). He also provided some practical advice on the clinical use of SGLT-2 inhibitors – for example, when initiating the agent in someone with very high blood sugar, it helps to start other medications and diet first and then start the SGLT-2 inhibitor three days later. This brings down the blood sugar substantially prior to starting the SGLT-2 inhibitor, which prevents the precipitous volume loss that would occur if starting the SGLT-2 inhibitor right away in someone with very high blood sugar. Finally, he enthusiastically supported the off-label use of SGLT-2 inhibitors in patients with type 1 diabetes; on a bit of a surprising note, he said that using SGLT-2 inhibition has reduced some of the need for pumps in his type 1 patients since the SGLT-2 therapy can flatten out glucose peaks.

Hyperglycemia Management and the Potential Role for New Therapies in Type 2 Management

Yehuda Handelsman, MD (Metabolic Institute of America, Tarzana, CA)

Dr. Yehuda Handelsman provided an overview of a number of diabetes drug classes, focusing on SGLT-2 inhibitors, but also including a number of classes that are less popular in the US. He characterized bromocriptine-QR as a very interesting drug, especially given that it is the only drug to have demonstrated a reduction in overall CV adverse events (Gaziano et al., J Am Heart Assoc 2012). He also pointed out that acarbose, while generally avoided in the US due to relatively severe GI side effects, is seeing much broader use in China. He also took a generally positive perspective on Daiichi Sankyo’s bile acid sequestrant Welchol (colesevelam), which has beneficial effects on LDL, no hypoglycemia or weight gain, and A1c lowering on par with many DPP-4 inhibitors (~0.5-0.6%). On SGLT-2 inhibitors, he suggested that the class was ranked conservatively on the 2013 AACE/ACE algorithm because it was relatively new when the guidelines were drafted, but that the class is under-ranked on the algorithm in light of more solid clinical data that has emerged in the past two years. More than any individual class, Dr. Handelsman was (rightly, in our view) most optimistic about combination therapy for type 2 diabetes. He noted that AZ’s Forxiga/Farxiga (dapagliflozin) demonstrated efficacy in combination with a number of agents, and expressed particular enthusiasm about the combination of SGLT-2 inhibition and DPP-4 inhibition (AZ recently released topline phase 3 results on its “saxa/dapa” DPP-4/SGLT-2 inhibitor combination; read our report).

Panel Discussion

Q: Could you speak about the risk of pancreatitis with SGLT-2 inhibitors? If you have a patient with triglyceride levels at or above 500 mg/dl, should you be concerned about the risk of pancreatitis, especially if the patient is already on a GLP-1 analog?

Dr. Yehuda Handelsman (Metabolic Institute of America, Tarzana, CA): SGLT-2 inhibitors are really not implicated in causing pancreatitis, so you should feel pretty comfortable using them in that regard. If you have a patient at 500 mg/dl, therapy should also focus on triglycerides. The GLP-1 agonists do have a small risk for pancreatitis; it is not a common occurrence, but it is there. However, there is no contraindication against using GLP-1 agonists in patients with high triglycerides.

Q: So in a patient with a history of high triglycerides, would you still be comfortable using a GLP-1 agonist?

Dr. Handelsman: I would be fairly comfortable using a GLP-1 agonist or DPP-4 inhibitor, as the risk is very slight. The one group I am most careful about is patients who drink a lot of alcohol, not only because of the pancreatitis risk there, but also because of effect on glucagon, because both alcohol and GLP-1 agonists reduce glucose output from the liver. I would be a bit concerned there.

Q: Can you speak to the safety in cardiac patients? We have a lot of patients with silent ischemia, and these new products have hypotension. What were the adverse events in these people that you may have seen underlying unstable angina being precipitated?

Dr. Stanley Schwartz (University of Pennsylvania, Philadelphia, PA): In the safety studies of heart attack, stroke, and death, neither dapagliflozin nor canagliflozin had any undue risk, period. They’re likely to be beneficial in the sense of the blood pressure and weight loss benefits, but they had slides at the FDA presentation on angina, etc. that showed no undue risk. The only signal was with canagliflozin in the first month. It had an increased stroke risk and within two months the two groups were equal. The difference in cases was 4-0 or 5-1, so that was very minor. We don’t feel that a patient who has a significant CV history has any undue risk of starting these agents. We do respect the volume issue, so that’s why we proactively advise to drink lots of fluids to prevent that risk. Other than that kind of concern I’ve had no issues or reticence in prescribing it.

Q: Were the studies powered to look at that? I was told from some behind-the-scenes folks that there was an increase in unstable angina during the first month, but nobody knew what the mechanism might be. Is it truly safe to use these agents in patients at risk for unstable angina or silent ischemia?

Dr. Schwartz: I have not seen the data on unstable angina or ischemia.

Dr. Handelsman: We need distinguish between fluid overload with TZDs, which poses a risk, with fluid loss, which SGLT-2 inhibitors cause. I am personally not familiar with the data on unstable angina. If I have a patient with documented silent ischemia, I would be careful with any agent that could cause volume depletion or overload.

Q: I wanted to get a little more information about the issue of bladder cancer. I understand there’s really no difference between dapagliflozin and canagliflozin, but from a legal standpoint I don’t see any real reason to use dapagliflozin. My understanding is the package insert comments about bladder cancer.

Dr. Handelsman: It’s a very interesting issue. It is true that dapagliflozin was initially rejected because of bladder cancer concerns. However, it came down to four cases, so it’s not too clear, and it’s still not definitely implicated. The FDA said something very strange, which was not to give it to someone with active bladder cancer. This was in contrast with what the recommendation was for pioglitazone, when if someone had it in the past, they did not seem to worry. So I may agree with you, but please if the package insert tells you not to give it to someone with active bladder cancer, just don’t give it. That represents very few patients, so it’s not worth it to go through that.

Q: But is there any reason to give dapagliflozin as the first choice?

Dr. Handelsman: That is your decision: it was studied as monotherapy and shown to be effective, and the FDA has approved it as a monotherapy drug.

Product Theaters

The Role of the Kidney in Glucose Homeostasis (Sponsored by AstraZeneca)

Parresh Dandona, MD (State University of New York, Buffalo, NY)

Dr. Parresh Dandona’s product theater presentation on AZ’s SGLT-2 inhibitor Forxiga/Farxiga (dapagliflozin) was one of the highlights of our day, but the credit does not go entirely to him, as the fairly full room (~120 attendees) asked some remarkably insightful questions during Q&A. In an answer to a question on the bladder cancer signal seen in dapagliflozin’s clinical trial program, which Dr. Dandona characterized as marginal and possibly nonexistent, he suggested that the Avandia saga (kicked off by Dr. Steve Nissen of the Cleveland Clinic) triggered a new era of cynicism in diabetes. He commented very positively on the potential of the SGLT-2 inhibitor class (as well as Novo Nordisk’s Victoza [liraglutide]) in type 1 diabetes. When asked about dapagliflozin’s contraindication in patients with moderate renal impairment (as opposed to J&J’s Invokana [canagliflozin]), he suggested that the distinction could be in part the outcome of how AZ and J&J designed their clinical trial programs – he did also characterize endocrinologists as “artisans” of treating diabetes. During his presentation, he emphasized the importance of proper hygiene for patients in Forxiga/Farxiga to prevent genital mycotic infections, and somewhat (though perhaps not completely) jokingly suggested that SGLT-2 inhibitors should be accompanied by sanitary wipes. Dr. Dandona does not feel optimistic about selective SGLT-1 inhibition due to the high possibility of GI side effects, and suggested that the pharmaceutical industry does not seem very interested in SGLT-1 inhibition at the moment.

Questions and Answers

Q: It seems to me that using SGLT-2 inhibitors and TZDs in combination could be beneficial, but it seems from your presentation that dapagliflozin, in addition to possibly pioglitazone, is associated with bladder carcinoma.

A: The signal for bladder carcinoma with dapagliflozin is so marginal that I’m not sure it exists. The FDA saw the two year data and still approved the drug. I don’t want to sound political, but ever since the rosiglitazone story, thanks to Steve Nissen, we’ve all become very cynical about the good things in life. My line would be that yes, we need to look at all the data appropriately, critically, and scientifically, but let’s not overblow things. We now have people threatening us if we prescribe SGLT-2 inhibitors. We are in that kind of era, and we need to be very careful.

Q: Are there any studies of this drug in type 1 diabetes?

A: There have been two studies published on the class, one from Bob Henry’s group in San Diego from two years ago, and one with BI’s drug empagliflozin, from Bernie Zinman’s group in Toronto. Both studies showed significant reduction in hypoglycemia with the class. From my own experience, we’re presenting evidence soon on the use of liraglutide in type 1 diabetes, and there have really been amazing results.

Comment: Why might there be an effect on hypoglycemia?

A: Why does hypoglycemia occur in type 1 diabetes? It is because you have no beta cell function and no endogenous insulin reserves. You are putting faith in your own calculations to administer the correct amount of rapid-acting insulin. The beta cell is much more clever than you or I – it delivers just the right amount of insulin. Our calculations for administering rapid-acting insulin are semi-bogus, although they are the best we have available. If, by using other agents, I can affect other mechanisms impacting hyperglycemia and take away some of the uncertainty caused by rapid-acting insulin, I will, by definition, reduce hypoglycemia. That is the expectation, and that is exactly what we’re seeing in the data.

Q: Do we have any studies on the use of GLP-1 agonists with SGLT-2 inhibitors?

A: There is nothing published as of yet, but this is a very important issue. GLP-1 agonist therapy has become a mainstay in recent times, and the class has absolutely changed my own practice. We’re awaiting data on that combination.

Q: Can you talk about the rise in glucagon seen with SGLT-2 inhibitors?

A: This is something that has arisen recently. Not only is there is a rise in glucagon, there are reports of increases in hepatic gluconeogenesis. My line as a practical clinical is that no matter what else is happening in the body, the drug is improving glucose levels. Sooner or later, we will discover the mechanisms and implications of this phenomenon, but overall it has not altered my practice.

Q: The weight loss seen with dapagliflozin appears to plateau despite a consistently elevated level of glycosuria. Why might that be?

A: Any weight loss strategy, including lifestyle intervention, eventually flattens out because the body has mechanisms to conserve calories. However, if you stop the drug, you will see patients regain the weight. I’ve seen this with discontinuation of GLP-1 agonists, and I think you will see it with SGLT-2 inhibitors as well. The fact that you are not getting any additional weight loss does not mean that the drug has stopped acting, as is proven when you discontinue therapy.

Q: You can still use canagliflozin in patients with eGFRs lower than 60 ml/min/1.73 m2, down to 30 ml/min/1.73 m2. Why can you not use dapagliflozin in those patients?

A: The differences are due to the way that the studies were designed and planned. You and I are expert endocrinologists, and we are artisans at treating diabetes – we can take some liberties. 

Q: Last year, the AACE guidelines stated that there was a question mark regarding bone health with some agents in the class, namely canagliflozin. Is there any data on bone health with dapagliflozin?

A: I am not aware of the data on that issue, but clearly that is important information.

Chronic Management of Obesity: The Role of a Unique, Once-Daily Treatment (Sponsored by Vivus)

Alan Garber, MD (Baylor College of Medicine, Houston, TX)

During a Vivus product theater for Qsymia (phentermine/topiramate ER), Dr. Alan Garber highlighted patients’ willingness to take an anti-obesity medication if their HCP recommends it. In a Vivus survey of 422 obese and overweight patients, 83% indicated that they would try Qsymia if their HCP recommended it. Troublingly, 45% of respondents did not view their HCP as a solution to their weight struggles. Dr. Garber concluded from this data that patients are motivated to treat their obesity, and that they do not expect their HCP to help them. Of course these results may be viewed as potentially slightly overstated, since they were gathered in a Vivus administered survey. However, it seems reasonable that a bigger challenge to greater uptake of anti-obesity medications might not be patient unwillingness to take them, but HCP reticence discussing obesity, and prescribing anti-obesity pharmacotherapies.

Improving Glycemic Control Through DPP-4 Inhibition-Treatment Considerations for Adult Patients with Type 2 Diabetes (Sponsored by Lilly/BI)

Farhad Zangeneh, MD (Endocrinology, Diabetes, and Metabolism Center, Sterling, VA)

Dr. Farhad Zangeneh introduced his presentation on Lilly/BI’s DPP-4 inhibitor Trajenta (linagliptin) by drawing a distinction between glucose-independent diabetes drugs and the more “elite” set of glucose-dependent drugs. He used the term “dirty A1c” to describe A1c benefits associated with agents that also cause weight gain and/or hypoglycemia. Regarding Trajenta specifically, he stated that the lack of a dose adjustment requirement in patients with renal impairment is the drug’s primary distinguishing factor against the crowded field of DPP-4 inhibitors. Why spend time adjusting a patient’s dose of a drug, he asked the audience, when one could use Trajenta and not have to worry about such adjustments in the event a patient develops renal impairment. He shared that in all his patients that have any degree of renal impairment, he prescribes Tradjenta.

Media Briefings: 15-Minutes with…

Dr. Jeffrey Mechanick, AACE President

Members of the media had the opportunity to sit down with AACE President Dr. Jeffrey Mechanick for 15 minutes for an open Q&A session. The passion that AACE and Dr. Mechanick have for improving the state of obesity care was abundantly evident through in this session. Dr. Mechanick will soon pass the mantle of his presidency to Dr. R. Mack Harrell (Memorial Healthcare System, Hollywood, FL). Dr. Harrell’s 15 minutes followed Dr. Mechanick’s – Dr. Harrell specializes in thyroid disease, and he did not mention obesity during his 15 minutes. We hope that as the mantle is passed, AACE can maintain its momentum on finding solutions for issues in obesity care – it was surprising to us this wasn’t raised..

Questions and Answers

Q: What were your priorities in your year as President, and did you accomplish those goals?

A: Most if not all of my priorities for the year have been met. One of the major priorities, within the AACE structure, was to create a mechanism where we could be more agile, more effective. We created this prism model that you may have seen during the President’s Plenary. We simply can’t do everything with limited resources. We need to prioritize what we do. The way we do it is scan the environment for opportunities, evaluate internally generated goals, pose codified decision analysis based on logistical ease and strategic fit. […] So that is one priority that was fulfilled. Another priority was to engage the effort in the obesity space in a way to be a leader, to make a difference and drive change. We spent a lot of time creating an obesity position paper and submitted Resolution 420 declaring obesity as a disease, got the AMA to adopt it, and translated that into a Consensus Conference on obesity [Editor’s note: read our report on the conference here]. We’ve now initiated the translation across the Emergent Concept One [identified at the AACE Consensus Conference] to redefine obesity through the new AACE Advanced Framework for a new definition of obesity that will then be vetted by the pillars that participated during the obesity conference. Then we’ll move on to phase 3, finding a manner to implement and develop a logistical basis for that implementation so it can be successful. We would track prevalence rates and metrics to see if it makes a difference. Once you get a critical mass of all this action then a complex disease is managed in a complex fashion. We believe obesity as a complex disease is not managed with simple solutions.

Q: Can you talk about the recent document from AHA and The Obesity Society? How are your documents the same or different, and how should physicians use them?

A: It is confusing for physicians to get different white papers from different bodies with different results, and we are against that. We spend a lot of time seeking out collaborative efforts to come up with one voice on particular topics. Because different agencies use different manners and methods of operation, a lot of times that’s not possible. We disagree with the conclusions being adopted by physicians in general. However those conclusions were logical and sound based on the methodology used. The methodology used, as mandated by NIH, was to only use Level I evidence (prospective RCTs). If you limit your conclusions to that much more contracted body of evidence, that is substantially different from how AACE does it. We look at a different evidence base, we rate it, and we transparently disclose that type of evidence. The method of going form methods to recommendations is tractable. You can follow it, and at any point you can change it. We will look at Level I evidence – prospective RCTs and strong meta-analyses­ – but we’ll also consider Level II studies, which can be some strong case-controlled or cohort studies. Even some experiential or expert opinion can be used if it’s transparently coated. And then you take the weight of evidence and draw conclusions and build a weight management plan. If you look at AHA/ACC/TOS – the only one pharmaceutical mentioned at the time was orlistat. There was some mention of lifestyle, but it really didn’t drill down into how to manage that at a granular level. There was a lot of tension based on bariatric surgery. It was a BMI centric approach whereas AACE espouses a complications centric approach. Which, getting back to previous question, reflects that our framework is based on pathophysiological correlates of disease. We disagree that the basis of that definition is a number.

Q: What impact do you hope declaring obesity as a disease will have?

A: Let’s zoom out and zoom in. Let’s look at the big picture. The big picture is clearly we’ve done a pathetic job at stemming the tide of the obesity epidemic. We’ve been watching it grow and grow. We understand the context of obesity much better yet it’s two/thirds of Americans are overweight or obese. That number is staying the same but pediatric obesity is getting worse, and obesity class III and IV is getting worse. We’re not really doing a good job. We’re not applying all this money in a good way. If you look at expenditures and growing costs, it will be rising up to $500-800 billion in a few decades. It is a national security issue that is pervasive and affecting almost all aspects of American culture. It is a complex disease with multiple drivers. There is the context of the obesogenic environment, and then there are the genes. There are multiple drivers in those groups. The previous paradigm was to approach it with singular interventions. Lower the BMI or lower the LDL or lower the A1c, yet if you look at our population we still have an obese and very sick American population.

Again from this long view, if obesity is a complex disease we need to address it in a complex manner. And not to be afraid of complexity, to view complexity really as something we can understand and deal with and we do have the knowledgebase to synthesize. We need reimbursement for lifestyle and obesity meds. We need better performance and innovations for surgical procedures, but really it’s lifestyle. The lifestyle component in my personal opinion and AACE’s is paramount to any successful addressing of the obesity epidemic.

In the short run, what do we need to do? We have to apply some of the Emergent Concepts from our Consensus Conference on obesity. We need to define obesity. We need to address shortages in obesity experts. There are very, very few bona fide obesity training programs – medical schools, residency programs, fellowships, etc. AACE is addressing it at the CME level trying to get the message out. We need to talk to program directors, deans of medical schools, and allied health professionals who can participate in the expert delivery of obesity care. We need to have reimbursement strategies and go to Capital Hill. We need to have legislative acts, socioeconomic committees. One the advantages of an organization like AACE is if you look at our committee structure, we’re equipped and poised to do it and now actually we‘re doing it. We have these things in motion to address the obesity epidemic much the same way we’re tackling diabetes and other chronic disease. We need endocrinologists and experts to take care of these diseases. And the role of the PCP? We recognize that – we have many programs that target high quality care for PCPs so that they as gate keepers can deliver expert obesity and diabetes care. Maybe not at the same technically expert level conferred upon an endocrinologist with all the training specialized in that area. But most of the cases do not make it to the endocrinologist. Being socially responsible and wanting to address this epidemic, a lot of the effort has to be at the primary care level.

R. Mack Harrell, MD (AACE President-Elect; Memorial Center for Integrative Endocrine Surgery, Memorial Healthcare System, Hollywood, FL)

Providing a stark contrast from current AACE President Dr. Mechanick’s emphasis on diabetes and obesity, AACE President-Elect Dr. Harrell (disappointingly) did not mention diabetes or obesity in his brief 15 minutes in the pressroom. Dr. Harrell’s background is in thyroid cancer and his integrated endocrine-surgery practice emphasizes transparency for patients and provider collaboration. While Dr. Harrell has said that AACE “will work to steer endocrinology toward a better endocrine care model, while maintaining the sanctity of the doctor/patient relationship,” we hope that the torches for diabetes and obesity aren’t dropped in this leadership transition.

-- by Adam Brown, Hannah Deming, Jessica Dong, Jenny Tan, Manu Venkat, and Kelly Close