June 21-25, 2013, Chicago, IL Day #4 Highlights – Draft

Executive Highlights

Greetings from Chicago, where we took our last walk through the poster hall and exhibit hall – and tonight, watched the Blackhawks win the Stanley Cup!

The big debate of the day concerned a scenario familiar to many healthcare providers: how to treat a type 2 diabetes patient who is failing oral therapy. Dr. Vivian Fonseca (Tulane University Medical Center, New Orleans, LA) argued convincingly in favor of using a GLP-1 agonist, noting that the class significantly lowers glucose, causes weight loss, improves cardiovascular biomarkers, and comes with a low risk of hypoglycemia. (We also all may have in the back of our minds that GLP-1 may prove to be cardioprotective.) Dr. Paresh Dandona (State University of New York, Buffalo, NY) countered that patients with an A1c of 8.5% and above should start on basal insulin to address elevated fasting glucose, and that patients with an A1c of over 10% would not benefit enough from a GLP-1 agonist. However, both speakers agreed that GLP-1 agonists and basal insulin could work very well in combination – an increasingly common theme at major meetings, and in clinical care. Of course, basal-bolus insulin therapy remains a bulwark of type 2 diabetes therapy, and an active area of research. For example, in the FullSTEP study discussed by Dr. Helena Rodbard (Endocrine and Metabolic Consultants, Rockville, MD), stepwise initiation of basal-bolus therapy (one meal at a time) provided non-inferior glycemic control compared to full basal-bolus therapy at 32 weeks. The stepwise approach also had a lower risk for hypoglycemia and provided better treatment satisfaction. One historic concern about basal insulin was potential carcinogenicity, and we were encouraged to see Dr. Louise Bordeleau (McMaster University, Hamilton, ON) present results from a cancer-focused subanalysis of the ORIGIN trial. This analysis revealed no significant difference in cancer death rates or adjusted incidence of cancer between the study's glargine vs. standard care arms, nor any significant difference in the incidence of several common subtypes of cancer (e.g. lung, colorectal, breast, prostate). The data are in line with what we heard at ADA 2012, and they help further underscore glargine's to-date neutral cancer profile.

In the poster hall, we came across several posters of interest on novel drugs: a new, more concentrated formulation of insulin glargine (U-300) was found to have comparable A1c-lowering efficacy to U-100 insulin glargine while lowering the risk of nocturnal hypoglycemia (43-LB), a new glucagon analog was shown to be stable in a liquid formulation (404-P), and detailed data from AWARD-5 comparing the once-weekly GLP-1 agonist dulaglutide versus sitagliptin was released (1004-P). We also immersed ourselves in a phase 2a study of dapagliflozin in type 1 diabetes (70-LB); the SGLT-2 inhibitor improved both glycemic control and variability while decreasing total daily insulin requirement. Day #4’s technology presentations included fresh findings on Medtronic's predictive low glucose management pump, which prevented exercise-induced hypoglycemia (<63 mg/dl) in 12 of 15 clinical experiments (80%). Today's report also includes the full write-up of the ASPIRE in-home study of low glucose suspend, published this week in the New England Journal of Medicine. Of course, new products are not the only way to reduce hypoglycemia, as proven by Dr. Stephanie Amiel (King’s College London, London, UK) in a pilot study of behavioral interventions for patients with persistent hypoglycemia unawareness. At the end of the six-week study, patients' moderate hypoglycemia was reduced by 16-fold and severe hypoglycemia was eliminated. We cannot wait to see what modern diabetes technologies and behavioral interventions could do in combination!   

 

Devices

Oral Sessions: Emerging Evidence in Pediatric Type 1 Diabetes

Feasibility Data of the Predictive Low Glucose Management Algorithm – The Pilgrim Study (357-OR)

Thomas Danne, MD (Kinderkrankenhaus, Hannover, Germany)

Dr. Thomas Danne presented encouraging feasibility data on Medtronic’s predictive low glucose management (PLGM) algorithm from the PILGRIM study. The study used a 30-minute predictive horizon with a sensor threshold of 70 or 80 mg/dl. Twenty-two adolescents (14-20 years of age) exercised with the PLGM system until either the system suspended insulin delivery or until the reference blood glucose value (HemoCue) reached the predictive suspension threshold setting. Of the 16 patients who reached the hypoglycemic threshold for PLGM activation, PLGM was successfully activated in 15 of the experiments and prevented hypoglycemia (reference blood glucose ≤63 mg/dl) in 12 of the 15 experiments. Dr. Danne commented that in one of the cases of hypoglycemia, the patient had restarted basal delivery manually. Notably, suspension time averaged 90 minutes. Dr. Danne underscored that this was 30 minutes less than the fixed two-hour suspension time of the Veo (Medtronic’s low glucose suspend [LGS] system). He attributed the lower post-suspension nadir (HemoCue) of 77 mg/dl (vs. 91.4 mg/dl in ASPIRE in-Clinic, which tested LGS [now called threshold suspend]) to the more flexible length of suspension provided by the PLGM algorithm. Dr. Danne reminded the audience of an in-silico modeling experiment of the PLGM system (Roy et al., Diabetologia 2012), which had similar results to the PILGRIM study. He suggested, therefore, that it was reasonable to extrapolate clinical outcomes from the in-silico experiment. Roy et al. found that the number of hypoglycemic events with PLGM was 18.3% less than on CSII and that the time spent in hypoglycemia with PLGM was significantly less than the time spent in hypoglycemia with LGS (p<0.001). Dr. Danne concluded his talk with his perspective on where the field stands on the path towards an artificial pancreas. “I think we’re just a step away from treatment with PLGM in the day and closed-loop control during the night,” said Dr. Danne.

 

Oral Session: Inpatient Management of Diabetes

Safety and Efficacy of Automated Closed-Loop Glucose Control in the Critical Care Unit (313-OR)

Lalantha Leelarathna, MBBS, MRCP, MSc (University of Cambridge, Cambridge, UK)

Dr. Lalantha Leelarathna presented a compelling feasibility study on the safety and efficacy of automated closed-loop control in critical care patients. Twenty-four patients were randomized to 48-hours of automated closed-loop control (n=12) or local protocol (intravenous sliding scale insulin; n=12). The closed-loop system was comprised of a bedside laptop running an MPC algorithm, FreeStyle Navigator sensor and receiver, and both insulin and dextrose (20%) pumps. Both groups had hourly arterial blood gas (ABG) taken and sensors were calibrated with ABG every one to six hours. Based on reference glucose values, closed-loop control led to a significantly greater time in range (6.0-8.0 mM [108-144 mg/dl]; 54.3% vs. 18.5%; p=0.001) and significantly decreased time above range (39.0% vs. 78.4%; p=0.001). Neither group recorded any reference glucose readings below 4.0 mM (72 mg/dl). Dr. Leelarathna concluded that the findings support conducting a larger closed-loop trial in a more diverse patient population.

• “Although there is no agreement about the correct [blood glucose] target, there is general consensus that we need better methods for glucose control,” said Dr. Leelarathna. As such, his group set forth to investigate whether closed-loop control could provide superior glycemic control to standard protocols.
• The study was conducted in the neurosciences critical care unit at Addenbrooke’s Hospital and enrolled 48 patients. Inclusion criteria included having blood glucose ≥10 mmol/l (180 mg/dl) or being on insulin therapy. Exclusion criteria included irreversible organ failure, therapeutic hypothermia, or major blood clotting abnormalities. Patients had similar baseline characteristics, including age (standard arm vs. closed-loop arm: 58.3 vs. 62.8 years), BMI (27.8 vs. 27.1 kg/m2), Apache II score (a measure of illness severity; 11.2 vs. 12.9); prior diabetes (n=6 vs. n=5); and insulin infusion at baseline (n=10 vs. n=10).
• The components of the closed-loop system included the FreeStyle Navigator sensor and receiver, a bedside computer running an MPC algorithm, an insulin pump, and a dextrose (20%) pump. The system was initiated with approximate body weight; no nutritional information was provided.
• Impressively, closed-loop control resulted in 54.3% of time 6.0-8.0 mM (108-144 mg/dl) and 92.2% of the time 5.6-10.0 mM (100.8-180 mg/dl). By both metrics, time in range was significantly greater with closed-loop control than local protocol (p=0.001); however, as pointed out in Q&A, sliding scale insulin therapy is not the best available care. Looking forward, Dr. Leelarathna hopes to test the system against more dynamic care protocols.
  
  • Blood glucose less than 4.0 mM (72 mg/dl) were not recorded in either group; seven patients required dextrose intervention in the closed-loop group (six of those seven required less than 10 g per 24 hours). During Q&A, Dr. Leelarathna attributed at least part of the dextrose intervention to care changes. For example, the algorithm wasn’t aware when nutrition stopped, he said.
     

Metric	Results Based on Reference Glucose
	Standard Care	Closed Loop	p-value
Starting Glucose	10.8 (194.4)	10 (180)	0.219
Time in Target (6.0-8.0 mM [108-144 mg/dl])	18.5%	54.3%	0.001
Time Above 8.0 mM (144 mg/dl)	78.4%	39.0%	0.001
Time Below 4 mM (72 mg/dl)	0	0	NA
Time in Target (5.6-10.0 mM [100.8-180 mg/dl])	73.2%	92.2%	0.001
Mean Glucose (mM [mg/dl])	9.1 (163.8)	7.9 (142.2)	0.001
SD of Glucose (mM [mg/dl])	1.8 (32.4)	1.3 (23.4)	0.089
Total Insulin (24 hours; U)	40.9	57.4	0.478

 

• The sensor recorded a median absolute relative deviation of 7.0% and an absolute deviation of 0.5 mmol/l (9 mg/dl). Median bias was -0.1 mmol/l (-1.8 mg/dl). Eighty-eight percent of readings fell in Clark Error Grid Zone A. During the first 24 hours, the sensor was calibrated at a median interval of 152 minutes; during the second 24 hours, the sensor was calibrated at a median interval of 205 minutes. Sensor accuracy was a point of discussion during Q&A; Dr. Leelarathna commented that his group was able to achieve the accuracy by calibrating more than recommended by the manufacturer. When the algorithm detected that sensor values were deviating too far from reference values, it would calibrate more frequently.

Questions and Answers

Q: How long did you treat the patients for?

A: The study duration was 48 hours. At 48 hours, they went back to usual treatment. If they left the critical care unit, the experiment was terminated. At least 24 hours was required to be included in the analysis.

Q: Many will argue that in critical care populations, sensors cannot capture hypoglycemia. How did you achieve the accuracy?

A: The majority of previous studies looking at the accuracy of sensors have looked at Medtronic. And out of the three sensors Medtronic has the highest MARD. The science behind Navigator is less susceptible to medication and less dependent on tissue oxidation. We also calibrated the sensor much more frequently than recommended by the manufacturer. The algorithm detected when sensor glucose started to deviate.

Q: How do you view hypoglycemia with the dextrose infusions – 58% received dextrose?

A: The infusion was to prevent hypoglycemia. For example the algorithm wasn’t aware when nutrition was stopped.

Q: Were any of those patients close to sepsis? Did you see worse performance there?

A: We haven’t analyzed sensor performance in that way. We need a bigger study with a more diverse population, and we need to assess whether the sensor varies with diagnosis.

Q: The exclusion criteria said permanent organ failure was excluded. What about acute organ failure?

A: Yes, we had patients on vasopressors included in the study.

Q: Most people do use a dynamic protocol. Moving forward, you need to compare closed-loop control to a dynamical protocol [vs. sliding scale].

A: That is a fair point. It will be more informative to compare it to a more advanced insulin infusion protocol.

Oral Session: Cost-Effective Health Care/Economics

Impact of a Hospital-Wide Inpatient Glucose Management Program on Economic and Clinical Outcomes in the Non-Critical Care Setting (261-OR)

Elias Spanakis, MD (Johns Hopkins University, Baltimore, MD)

Dr. Elias Spanakis discussed the clinical and cost impact of Johns Hopkins’ glucose anagement quality improvement interventions, which were implemented in a step-wise fashion beginning with a glucose steering committee in January 2006. Johns Hopkins next implemented a hospital-wide hypoglycemia policy in July 2006, a diabetes nursing superuser program in January 2007, a hospital-wide hyperglycemia orderset and policy in December 2007, and a hyperglycemia smart orderset in January 2008. Staff education was ongoing over this timespan. Dr. Spanakis and his team conducted a retrospective cohort study comparing hospital outcomes in January - June 2006 (baseline; steering committee only) to December 2008 - December 2009 (post-hyperglycemia smart orderset implementation); the study population included non-critical care adults with a diagnosis of diabetes or hyperglycemia at admission. When adjusting for age, sex, and race, the glucose management intervention significantly improved mortality rate, length of stay, and hospital cost per admission (p <0.05). The results remained significant when also adjusting for hyperglycemia (p <0.05). However, when further adjusting for mortality risk index, severity of illness, and hospital unit, only the improvement in hospital cost per admission remained significant (p <0.05); as noted in Q&A, program implementation expenses were not incorporated into the cost analysis. Curiously, Dr. Spanakis commented that hospital cost per admission and length of stay in adults admitted to non-critical care units without diabetes increased over this same time period. We also wonder how readmission rate was related to cost and length of stay in these patient groups.

Model Adjustments	Mortality Rate		Length of Stay		Total Hospital Costs/Admission
	Rate Ratio vs. baseline	p-value	Rate Ratio vs. baseline	p-value	Rate Ratio vs. baseline	p-value
Model 1: Age, sex, race	0.42	0.01	-0.93	0.03	-$3,834	0.02
Model 2: Model 1 + hyperglycemia	0.42	0.01	-0.90	0.03	-$3,718	0.02
Model 3: Model 2 + mortality risk index, severity of illness index, hospital unit	0.53	0.08	-0.54	0.15	-$3,276	0.04

Questions and Answers

Q: We have what I consider to be excellent protocols. But the general attitude of the usual physician is ‘you’re not going to tell me what to do.’ How do you get this through to the administration and to the non-users? The protocols are there but they don’t have to use it.

A: In the smart overset, the provider has to fill out this information in order to prescribe insulin. This is how we manage to bypass the issue.

Q: How did you account for program costs in your analysis? For the cost of training?

A: This was not a cost-effective analysis. The cost was the cost of hospitalization.

Dr. Guillermo Umpierrez (Emory University School of Medicine, Atlanta, GA): Did you look at the difference between medicine and surgery units or did you look at everyone?

A: We didn’t do a subgroup analysis. But we adjusted for hospital units per se.

Dr. Umpierrez: Who writes the orders for the patients in your hospital? The house staff?

A: The house staff is providing the orders.

Q: How many deaths occurred over this three-year period?

A: I don’t remember exactly.

Q: The question is, did you look at the change in causes of death? You need to look at the distribution of deaths over time.

A: We looked at mortality rate. There was a decrease in model 1 and model 2. After we adjusted for the mortality risk index and severity of illness, the results were not statistically significant.

Q: But reducing the rate ratio by half is still important, even if it’s not statistically significant.

A: Good point. We will look at that.

Q: Were the orders totally automated? How do you take into account if patients were post-op? Or throwing up? Were you able to account for how much of the meal they ate?

A: In order to say that someone is getting a full tray, they need to eat more than 50% of the tray.

Q: Overall cost for patients are going up and cost for diabetes are going down. Is it that the overall care of patients is different and glucose effects are being washed out?

A: As we said, there was an increase in total hospital cost and length of stay in patients without diabetes. We wanted to see the general trend in the hospital.

Posters

Reduction in Hypoglycemia and No Increase in A1c with Threshold-Based Sensor-Augmented pump (SAP) Insulin Suspension: ASPIRE In-Home (48-LB)

Richard Bergenstal, David Klonoff, Bruce Bode, Satish Garg, Andrew Ahmann, Robert Slover, Melissa Meredith, and Francine Kaufman

This poster detailed the results from the ASPIRE In-Home study of low glucose suspend (called “threshold suspend” in this poster), simultaneously published in the New England Journal of Medicine by Dr. Richard Bergenstal et al. The three-month in-home study was a randomized, controlled trial of 247 patients comparing sensor-augmented pump (SAP) therapy alone to SAP plus “threshold suspend” (i.e., low glucose suspend set at 60-90 mg/dl). Results showed that nocturnal hypoglycemic events per patient week occurred 32% less frequently in the threshold suspend group (p <0.001). Moreover, mean area under the curve (magnitude plus duration) of nocturnal hypoglycemia events decreased 38% in the threshold suspend group compared to control (p <0.001). Strikingly, four severe hypoglycemia events were observed in the three-month study, with ALL occurring in the control group – this really resonated with us, and we hope payers will also appreciate this technology’s power to improve healthcare costs over the long term. Significantly, there was no change in A1c levels between the groups, both maintaining baseline A1cs of ~7.2% after three months in the study – that’s a huge win given the improvements in hypoglycemia. We think this data will build an even stronger case for the FDA to approve this device. (Approval is expected “this calendar year” per the last update in Medtronic F4Q13.)

• ASPIRE in-home was a 19-site, open label, randomized controlled study comparing sensor-augmented pump therapy with the threshold suspend feature (n=121) to sensor-augmented pump therapy alone (n=126). The study had a two-week run-in phase for all patients, followed by randomization and a three-month study phase. The run-in established eligibility for the study, as subjects were required to have experienced two or more episodes of nocturnal hypoglycemia during the run-in phase. An episode of nocturnal hypoglycemia was defined as a sequence of sensor glucose values ≤65 mg/dl, lasting >20 min, between 10:00 pm and 8:00 am, and with no evidence of user-pump interaction. For those in the intervention group, the threshold to suspend insulin was set at 60-90 mg/dl. Runs of sensor glucose levels <65 mg/dl ad < 20 minutes were not included in the primary analysis. Full study details and methods were published on June 23, 2013 in the Journal of Diabetes Science and Technology.
• The study randomized 247 patients with a mean A1c of 7.2%, a mean age of 42-45 years, a mean diabetes duration of 27 years, and a mean BMI of 27-28 kg/m2. Patients in the two groups were 38-40% male.
• Mean area under the curve (magnitude plus duration) of nocturnal hypoglycemia events decreased 38% in the threshold suspend group compared to control (p <0.001). Mean AUC declined from 1,547 mg/dl x min to 980 mg/dl x min in the threshold suspend group vs. 1,406 to 1,568 mg/dl x min (an increase) in the control group.
• Nocturnal hypoglycemic events per patient-week occurred 32% less frequently in the threshold suspend group (p <0.001) – these declined from 2.4 to 1.5 events per week in the threshold suspend group vs. 2.5 to 2.2 events per week in the control group. Since the pump is not predictively suspending, we would guess this reduced number of events per week could be attributed to a couple factors: 1) the previous finding that hypoglycemia begets hypoglycemia (i.e., reducing the magnitude and duration of nocturnal hypoglycemia reduced the susceptibility and occurrence of subsequent events); or 2) since the threshold can be set from 60-90 mg/dl, those using the higher end of the threshold suspend range would see a reduction in events, particularly if the sensor was biased to read low).
  
  • Combined day and night hypoglycemia events per patient week happened 30% less often in the threshold suspend group (p<0.001). Day-only data was not shown, which we suspect means it was not significant. Of course, since the vast majority of two-hour suspends occurred at night, this is not very surprising.
• The percentage of sensor glucose values <70 mg/dl decreased 40% overnight in the threshold suspend group compared to the control group – in absolute terms, this represented a decline in values <70 mg/dl values from 10% of the time in the control group to 6% of the time in the threshold suspend group. As might be expected (given the nature of threshold suspend at 60-90 mg/dl), the biggest boost came in the <50 mg/dl range – a 57% reduction with threshold suspend vs. the control group.
• Following two-hour suspend events, insulin delivery resumed at an average of 93 mg/dl, rising to an average of 169 mg/dl two hours later (and then leveling out). We expect predictive low glucose management will markedly improve that two-hour average of 169 mg/dl. Two hours after insulin delivery resumed, 26% of values were >200 mg/dl, 70% of values were 70-200 mg/dl, and only 4% of values were <70 mg/dl. Consistent with previous data, most (77%) of the 1,873 two-hour suspends occurred at night.
• In a huge win, there was no significant change in A1c in either group. To us, this is a testament to the power of preventing hypoglycemia – we’d speculate it had positive ripple effects on hyperglycemia as well (e.g., less hypoglycemia meant less tendency to overcorrect and go high).

	A1c at Baseline	A1c at three months
Threshold suspend group	7.26	7.24
Control group	7.21	7.14

 

• There were four occurrences of severe hypoglycemia in the control group vs. zero in the threshold suspend group. Previous data on blinded CGM has shown that seizures typically occur overnight after several hours of hypoglycemia – though threshold suspend is not preventative in nature, it does reduce the number of hours a sleeping patient would spend hypoglycemic. It was welcoming to see the positive severe hypoglycemia results in this study. From a cost-effectiveness perspective, this certainly seemed attractive.
  
  • A six-month study presented by Dr. Trang Ly was also presented at ADA, which tested use of the Medtronic Veo over a six-month period in patients with hypoglycemia unawareness. That study also demonstrated an impressive reduction in severe hypoglycemic events. Please see our write-up of abstract 228-OR in our ADA Day #3 coverage.
• Severe hyperglycemia (blood glucose>300 mg/dl with ketones >0.6 mmol/l) occurred three times in the threshold suspend group vs. zero times in the control group. These were labeled “infusion set related,” so we would guess they were caused by infusion set failure and were not linked to pump suspension. DKA was of course a worry of the FDA, so this was encouraging to see.
• ASPIRE In-Home only included patients prone to hypoglycemia (see eligibility criteria above), meaning that these results may not be generalizable to all populations. Still, we think this was a rationale study design choice, as this group stands to benefit the most from this device.
• This study was published in the New England Journal of Medicine on June 22, 2013. More information is at http://www.nejm.org/doi/full/10.1056/NEJMoa1303576?query=featured_home

Symposium: Intensifying Therapy Using Technology and Teams

Promoting Patients’ Enthusiasm about Blood Glucose Monitoring

William Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA)

Dr. William Polonsky gave a stirring talk on the motivation underlying self-monitoring of blood glucose, framing the problem realistically: “If you’re asked to collect numbers for something having to do with your health, and you feel like you cannot do much with those numbers, and it makes you feel bad about yourself, would you keep collecting them?” He then provided a valuable literature review to highlight some of the most common feelings about SMBG that patients endorse. Dr. Polonsky also offered four tips to motivate patients to perform SMBG, followed by a short discussion of gamification/apps and CGM. He concluded that “blood glucose monitoring is just a tool. It’s not a therapy.”

• Dr. Polonsky reviewed some of the most commonly endorsed (and fairly discouraging) patient beliefs about SMBG. In his own 2009 study of 483 poorly controlled insulin naïve type 2s, a striking 81% of patient said they blame themselves when a reading is high. Additionally, 32% said SMBG results makes them feel bad, 34% find the results discouraging, 21% believed there was nothing they could do with the result, and 22% felt there was no rhyme or reason to the numbers.
  
  • In a survey of ~1,000 type 2 patients (in press), there were three major contributors to the belief that SMBG is not worth doing: 1) burdensome (expensive and painful); 2) pointlessness (“I can’t do anything about the number anyway” and “my doctor’s comments aren’t helpful”); and 3) discouraging (“I often know it will be high, and I’d rather not have to see it,” “the result often makes me feel bad, so I’d rather not check,” and “it makes me think about diabetes more than I want”). Measures of avoidance and pointlessness were most strongly predictive of how often patients tested.
• Dr. Polonsky shared four tips than can promote patients’ enthusiasm to test:
  
  • First, SMBG must address a perceived patient need (e.g. elevated A1c, worries about hypoglycemia, making sure the right medications are being used).
  • Second, it’s key to use structured SMBG testing so that actionable data patterns may be observed. Dr. Polonsky supports using very simple paired testing (e.g., pre- and post-meal), which promotes behavior changes that can make a huge difference. He shared a case study of an obese man with type 2 diabetes that refused to exercise. The man’s one week experiment of paired testing before and after walking made him realize something “really shocking”: exercise lower blood glucose! Dr. Polonsky recommends that this type of discovery learning approach be practiced in seven-day experiments (i.e., there is “too much noise” in blood glucose meters to do it just once).
  • Third, help patients see how SMBG data is actionable – not chaos, not blame. Dr. Polonsky supported the use of problem-focused coping: “Not ‘what did you do wrong?’ but ‘what do you/we do next.’”
  • Last, somebody has to do something useful with the data (“This is what drives me nuts about recent review articles that say blood glucose monitoring isn’t useful in non-insulin-using type 2s”; he just wrote an editorial on this topic in Diabetes Care). Dr. Polonsky showed the Accu-Chek 360 view blood glucose paper tool, noting that the graphing “makes it pop” for patients and physicians (i.e., seeing the results on a chart helps make things visible and guide changes in therapy). In the STeP study, this tool made the biggest difference for physicians, who were much more likely to make aggressive, targeted changes in therapy. Dr. Polonsky also reviewed the St. Carlos study (Duran et al., 2010) of structured testing, calling it “really amazing data.”
• What about apps and gamification? Dr. Polonsky expressed cautious optimism in this area, though noted that most apps out there are logbooks. Still, he “hope(s) this is going to turn into something wonderful.” We listened carefully for any mention of his favorite app(s), though he didn’t comment on this front.
• “CGM changes everything…we’re turning blood glucose into a worthwhile activity.” Dr. Polonsky enthusiastically highlighted the benefits of CGM, especially trend arrows. He reviewed his 2011 study of users and ex-users, highlighting that CGM users feel more confident they can avoid hypoglycemia, feel safe when they exercise, feel safe when they are sleeping, are more confident they can control their diabetes.

Questions and Answers

Q: Would you like to come to Little Rock, Arkansas?

A: Yes!

Q: Often what I see is like your case study – when patients quit testing because they don’t perceive any value from it. They stop testing and then they are labeled as non-compliant.

A: Thank you so much. When people stop testing, we have certain labels – they are non-compliant, stupid, etc. Instead, we should remember that our patients are acting rationally. Just like us, I f you’re doing an activity that seems like a waste of time, you will give it up. We need to refrain from using those labels.

Q: What’s your philosophy behind paired testing? Why is it so powerful when patients can see the before and after?

A: The major reason is because we want people to see that their actions make a difference. One of the biggest problems in diabetes is that it is a relatively invisible disease. It’s easy to ignore. This is the ultimate tool – it’s a very simple technique and can be done with very little testing. We find that it’s really empowering for patients.

Reducing Clinical Inertia Through an Insulin Clinic

Susan Cotey, RN, CDE and Andrea Harris, RN, CDE (Cleveland Clinic-Stephanie Tubbs Jones Health Center, East Cleveland, Ohio)

Ms. Susan Cotey and Ms. Andrea Harris described the weekly insulin clinic that they began at their family health center last summer, in an effort to address their high prevalence of people A1c greater than 9.0% (discouragingly, this is roughly 30% of the center’s diabetes population). Every week, the clinic is open for 30-minute, one-on-one free visits with patients who have been referred by primary care doctors. The clinic’s goal was to identify patients requiring frequent insulin adjustment by PCPs, and to reduce clinical inertia. The clinic is an adjunct to, rather than a replacement for, diabetes education and visits with doctors. (For example, any dose adjustments must still be made by the doctor, and no standing algorithms are allowed.) Still, by encouraging patient engagement and reducing clinical inertia, the clinic staff has achieved amazing early success: of 24 patients who visited the clinic between July 2012 and March 2013, mean A1c dropped from 11.4% to 8.6%! The presenters noted that these data are from a small, uncontrolled, short-term intervention, but they certainly seemed happy with the results so far. Ongoing assessments of the clinic’s success will include A1c change as well as patient satisfaction, provider satisfaction, and a decrease in visits to the hospital and emergency room.

Using Paired Testing – Educating Patients on Self-Monitoring of Blood Glucose

Deborah Greenwood, MEd, CNS, BC-ADM, CDE (Sutter Medical Foundation, Sacramento, CA)

Ms. Deborah Greenwood, the “president elect elect” of the American Association of Diabetes Educators, described her group’s study of self-monitoring of blood glucose (SMBG) in type 2 diabetes patients not using insulin. The 12-week randomized, controlled trial enrolled people who had been involved in a telehealth diabetes program for at least one year, but still had A1c between 7.0% and 10.9% (n~1,000). Patients were randomized to receive standard care or an intervention that included education, automated and personalized feedback via an electronic tablet, and structured SMBG (pre-and-postmeal tests every day, switching to different meals in different weeks). Ms. Greenwood did not reveal top-line data but did share the story of one study participant named Maria. Maria was initially intimidated by her blood glucose data, but then experienced a “transformation” midway through the trial. By eating differently and exercising more (even running a 5k race at week 10), Maria dropped her A1c from 7.3% to 6.6% during 12 weeks. “Not till I tested in pairs did I REALLY see how important my eating and activity was,” Maria wrote in her journal. “In many ways this study has saved my life, it has given me the tools to give years to my life living with diabetes.” These quotes certainly attest to the power of structured SMBG, and we hope that many other patients in the study have had similar epiphanies.

Symposium: Moving Toward a Cure in Type 1 Diabetes

Closed-Loop Therapy Update

Andrew Bremer, MD, PhD (Vanderbilt University School of Medicine, Nashville, TN)

Dr. Andrew Bremer provided a basic background presentation on recent closed-loop research and approaches. His talk did not share any highly novel opinions or new data, but did remind us of the sheer breadth of approaches in development by various groups (similar to Dr. Aaron Kowalski’s opening remarks at the JDRF/NIH Closed-Loop Research Meeting on Day #3 of ADA). He also briefly discussed future directions for closed-loop research. We appreciated his view that we should avoid thinking of these devices in isolation – for him, improvements will not depend on small differences between devices, but on real life interactions between people and the technology. We believe this area of human factors – especially as systems become more autonomous – will become increasingly important as systems move from feasibility to commercialization.

• Dr. Bremer summarized some of the key future directions for closed-loop research: 1) expanding identifiable virtual patient models and in silico studies; 2) combine insulin delivery and CGM into a single device (interestingly, he called two sites a “big detriment” of current systems”); 3) combining insulin delivery with other agents; 4) developing new insulin formulations and routes of delivery; and 5) moving to the outpatient setting (“the big one”).

Questions and Answers

Q: How did families deal with getting a pump and sensor at diagnosis? [In reference to the DirecNet/TrialNet metabolic control study]

A: In our experience at Vanderbilt, the families in these studies were extraordinarily high functioning. Where we felt most scared was when they went home. They went from knowing nothing to being taught how to use the sensor and pump. That was often 48 hours after beginning to cope with a son or daughter’s new disease. We offered 24-hour patient support.

Q: Have you looked at changes over time in these patients?

A: That data is being processed. These patients are being followed. I did not put it on the slide, but our primary endpoint is changes in C-peptide at one year. The hope was that early intervention would preserve beta cell function. Two-year data will be forthcoming. [Editor’s Note: Dr. Bremer did not share the disappointing one-year results of this study shared by Dr. Bruce Buckingham at ATTD]

Q: Moving into commercial availability, what is the FDA pathway?

A: The FDA has accelerated the development of diabetes devices, especially with LGS currently pending FDA approval for use in the commercial setting. [Editor’s Note: Given the Veo’s three-plus-year delay in the US, we thought this was an odd example of the FDA accelerating device approvals.]

Q: Are any closed-loop devices available commercially?

A: To my knowledge there is not one that is FDA approved and available here in the US.

 

Biodel Luncheon

Glucagon Rescue Delivery Device Demonstration

Gerard Michel (CFO and VP Business of Development, Biodel, Danbury, CT)

We had the privilege of attending a small luncheon hosted by Biodel to demonstrate its new prototype glucagon rescue delivery device. As we noted in our recent Closer Look, the company’s new glucagon rescue product will use a dual chamber, automatic reconstitution device – pictures of the device can be found at http://www.biodel.com/glucagondevicee. The device contains a lyophilized cake of glucagon, which can be delivered in three steps: 1) remove a cover and twist (reconstitutes the glucagon and unlocks the front needle cover; 2) remove the needle shield; 3) push plunger to give dose (the needle automatically retracts into the barrel following completion of a full dose). The device is expected to have two-year dating and come in 1 mg and 0.5 mg (children) doses. As of the update in early June, the goal was an NDA filing in 2015 under the 505(b)(2) regulatory pathway. After getting a demo and seeing the device in person, we believe it offers strong ease-of-use improvements over the current Lilly and Novo Nordisk glucagon kits, though Biodel’s solution is not yet as simple as an EpiPen-like auto-injector. Still, we thought it did a good job of guiding a new user with arrows and number marked on the device itself. CFO Gerard Michel described the design goal as making it “intuitive and panic proof.” We note that will neither yet knocks either criterion out of the park (it’s first generation!), it does make important strides forward on the simplicity and training fronts – standard of care right now has major shortcomings on these fronts. As expected, we understand that Biodel is going to make further modifications to simplify the device based on feedback from the diabetes community. Mr. Michel said the feedback has been “very positive” on the device and its form factor (about 60 people total have attended over three days), though some have not been fans of the twist (step one above). We particularly enjoyed the questions this session stimulated, summarized below. As a reminder, Biodel is separately developing stable liquid glucagon presentation for pump usage (and potential emergency usage); as of the last update, formulation work was close to being finalized.

• What is the biggest barrier to more widespread glucagon rescue device penetration? The training required? Unawareness that severe hypoglycemia is an important issue? Cost? Patient perceptions that there is no reason to have a glucagon kit, as no one would know how to use it? An unwillingness to train loved ones/friends on how to use the glucagon device, perhaps because it self-identifies diabetes or suggests one is not managing diabetes well?
• Is there a market for a glucagon mini-dose indication for moderate hypoglycemia? How do patients feel about this vs. just eating food? What is the optimal delivery presentation – pen, patch, sublingual, intranasal?
• Have Lilly and Novo Nordisk contributed to the under-penetration of their glucagon kits? Since both companies make insulin, is it really in their best interests to emphasize the dangers of insulin and severe hypoglycemia?
• Who is the target market for a glucagon rescue product? Does it make more sense to market to HCPs or direct to patients? We would argue for the latter, since a pull strategy from patients has more potential to drive demand than a push strategy through already-busy HCPs.
• What role could a public awareness campaign play in expanding glucagon penetration? Does it make sense to do this on a broad, societal scale, or focused on people with diabetes?
• What color should a rescue device be? Should it be red to identify it easily during an emergency, or perhaps a color/skin of one’s choice to de-medicalize it?
• What are unique ways to train users on how to use a glucagon delivery device? Could a training app be created for a smartphone, perhaps downloadable via a QR code on the outside of the device?
• How have other rescue products, such as defibrillators and EpiPens, been widely adopted? What lessons can be learned from the adoption of these technologies?

Drugs

Posters

Delayed-Release Metformin May Be Suitable for Use in Diabetes Patients with Renal Impairment Who Are Contraindicated for Currently Available Metformin Formulations (75-LB)

Ralph DeFronzo, John Buse, Jon Monteleone, Terri Kim, Sharon Skare, Alain Baron, and Mark Fineman

Metformin, the most commonly prescribed agent for people with type 2 diabetes, is contraindicated in patients with renal impairment due to the elevated risk of lactic acidosis caused by heightened plasma metformin concentrations. Recently, however, it was discovered that metformin need not be systemically circulated to exert its full effect. Instead, it can be directed to enteroendocrine L-cells in the small intestine. A delayed release metformin (Met DR) was developed to minimize bioavailability and streamline metformin delivery directly to the distal small intestine, which could help make this drug available to people with renal impairment. A daily dose of 1000 mg Met DR significantly reduced systemic metformin exposure while providing non-inferior in plasma glucose lowering relative to immediate release metformin (Met IR), leading researchers to predict that Met DR may be tolerable in patients with renal impairment as well as people who have difficulty taking metformin due to GI side effects. A population PK model was used to predict metformin exposure (using AUC) after administration of Met DR, Met IR, or Met extended release (XR) in normal patients and those with varying degrees of impaired renal function. Results of the model indicate that 2,000 mg/day and 1,000 mg/day of Met DR in patients with severe renal impairment had lower total metformin exposure than 2,000 mg daily Met IR or Met XR in patients with normal renal function, with no diminishment in its ability to control glucose levels. The reductions in metformin exposure and comparable glycemic efficacy anticipated with Met DR position it as a potentially viable and safe treatment option for patients with type 2 diabetes and severe renal impairment. At the 7th annual TCYOD and Close Concerns forum on day #4 at ADA, two notable panelists, Dr. Jim Gavin and Dr. Robert Henry, spotlighted the enhanced metformin formulation as the most exciting unapproved drug in development. In the words of the acclaimed Dr. Garvin, this advancement represents an “optimal way to repurpose a lifecycle drug.” Assuming early results carry out to phase 3, we are very excited about the improvements this could bring to patients using this drug in monotherapy and in a variety of fixed dose combinations.

• By targeting Met DR (1,000 or 2,000 mg/day) delivery directly to the lower bowel of patients with type 2 diabetes, Met plasma exposure was decreased by 45%-68% compared to a 2,000 mg dose of commercially available metformin formulations. The minimized metformin exposure with Met DR did not compromise its glucose-lowering capacity. In fact, Met DR was as effective as Met IR at lowering plasma glucose and increasing concentrations of gut satiety hormones, such as fasting and postprandial PYY and GLP-1. Furthermore, because the entire dose of Met DR evaded the highly absorptive upper bowel and was delivered straight to the site of action, smaller concentrations of metformin achieved the same glucose regulatory effect as a maximum dose of currently available Met IR and Met XR (see ADA Poster 1087-P at http://ada.apprisor.org/epsAbstract.cfm?compid=1&id=1 for a complete summary of this facet of the study).
• The median predicted AUCs (ng*h/ml) for 1000 mg Met DR in patients with normal, mild, moderate and severe renal impairment were 2,936, 3,152, 3,497, and 4,144, respectively. These predictions were significantly lower than those for 2,000 mg/day of Met XR or IR (20,607 and 22,659 for normal renal function, and 29,074 and 31,606 for severely renal impairment). Across all patients with any measure of renal impairment, the 1,000 mg/day and 2,000 mg/day doses of Met DR predicted substantially reduced total and peak metformin exposures relative to 2,000 mg/day of Met IR or XR. Because the 1,000 mg/day of Met DR had lower total metformin exposure but equivalent glycemic efficacy outcomes as the 2,000 mg/day Met DR, the former concentration boasts the preferable risk/benefit profile and is being carried forward to future studies.

Exploring the Potential of Dapagliflozin in Type 1 Diabetes: Phase 2A Pilot Study (70-LB)

Robert Henry, Julio Rosenstock, Alexandros-Georgios Chalamandaris, Sreeneeranj Kasichayanula, Allyson Bogle, and Seven Griffen

This double-blind phase 2a study evaluated the short-term safety, tolerability, and pharmacokinetics and pharmacodynamics (PK/PD) of dapagliflozin (BMS/AZ’s Forxiga) after two-weeks as an add-on to insulin in 70 patients with type 1 diabetes. These are the first clinical results we have seen for an SGLT-2 inhibitor in type 1 diabetes. Patients on insulin (mean baseline A1c 8.5%) were randomized to receive dapagliflozin (1 mg, 2.5 mg, 5 mg, or 10 mg) or placebo once-daily for two weeks. Treatment resulted in a reduction in total daily insulin requirement (-19% on the 5 mg and -16% on the 10 mg doses) while also producing a trend towards reduced glucose levels and reduced glycemic variability (both measured by CGM): mean 24-hour glucose decreased by ~10-20 mg/dl relative to placebo on dapagliflozin 5 mg and 10 mg (no decrease was observed relative to placebo for the lower doses), and placebo-adjusted MAGE decreased by ~50-60 mg/dl on those same doses. Hypoglycemia appeared slightly elevated in the treatment groups compared to placebo, though there was no dose-dependent effect (i.e., the highest rate was observed in the 1 mg group; in contrast, there was a clear dose-dependent urinary glucose excretion effect). As elated conference attendees with type 1 diabetes expressed during the poster session, these findings (though preliminary) are exciting because of the possibility of increasing treatment options for a population challenged by a deficiency of therapies. However, the findings of this study, while encouraging, are very limited due to sample size and would be considered pilot data for larger and longer trials testing dapagliflozin (which Dr. Henry was confident will be underway in the near future).

• Seventy patients (62 completed trial) with inadequately controlled type 1 diabetes were randomized to receive daily doses for 14 days of placebo or dapagliflozin (1, 2.5, 5, or 10 mg) in addition to their insulin regimen. Baseline characteristics across all treatment arms were comparable and included a mean A1c of 8.5%, BMI of 25 kg/m2, and age of 35. The mean duration of type 1 diabetes ranged from 16-22 years across all groups. The primary objective was to assess the safety and tolerability of dapagliflozin after 14 days. Secondary objectives included change from baseline to day seven in 7-point monitoring profiles and pharmacokinetics. Exploratory objectives consisted of change from baseline at seven days in 24-hour CGM profiles, total daily insulin dosing (%), fasting plasma glucose (FPG), and 24-hour urine glucose output.
• Dapagliflozin appeared to improve glycemic control and diminish glycemic variability while also decreasing total daily insulin requirement. FPG levels were significantly lowered in the treatment arms compared to placebo (-26, -20, -42, -36 vs. -8 mg/dl for the 1, 2.5, 5, and 10 mg doses vs. placebo, respectively). CGM data suggested a dose-dependent improvement in glycemic control through a decrease in 24-hour average glucose levels relative to baseline (-16, -14, -30, and -41 mg/dl for the 1, 2.5, 5, and 10 mg doses of dapagliflozin, respectively, compared to -20 mg/dl in placebo). There was also a significant reduction in total daily insulin needs (-16, -11, -19, and -16 units for the 1, 2.5, 5, and 10 mg doses, respectively, compared to +2 units in placebo).
• Despite a dose-dependent increase in urine glucose from baseline to day seven (41.9, 48.5, 72.4 and 88.8 g/24 h for the 1, 2.5, 5 and 10 mg doses, respectively and-21.6 g/24 h on placebo), there was no dose-dependent effect on hypoglycemia. The percentage of patients that experienced hypoglycemia was 62% for the placebo group and 92%, 60%, 79% and 67% for the dapagliflozin 1, 2.5, 5 and 10 mg groups, respectively. There were no apparent effects of dapagliflozin on urine output, total fluid output, or fluid intake. 
• Genitourinary events, such as genital and urinary tract infections, were rare. One such event was recorded in the placebo arm, one each in the dapagliflozin 1 mg, 2.5 mg, and 5 mg arms, and zero in the 10 mg arm. Dr. Henry mentioned that, in his opinion, the rate of hypoglycemia was the greatest potential safety concern in the use of dapagliflozin.
• Treatment with dapagliflozin appears to have a neutral to slightly positive effect on body weight, though the short duration of the study may be the cause of this meager outcome.

A Novel Glucagon Analogue, ZP-GA-1, Displays Increased Chemical and Physical Stbility in Liquid Formulation (404-P)

Ditte Riber, Francesca Macchi, Lise Giehm, Mette Svendgaard, Torben Østerlund, Pia Nørregaard, Anders Valeur, and Trine Skovlund Neerup

Currently, native glucagon cannot be stored in liquid form for patient use due to its high incidence of fibrillation and low solubility at physiologic conditions. Native glucagon can degrade in solution in less than two weeks. Zealand Pharma investigated the comparative profiles of ZP-GA-1, its proprietary novel glucagon analog, to native glucagon. ZP-GA-1 showed superior physical stability, excellent chemical stability, comparable pharmacokinetics, potent glucagon receptor activation, and a similar pharmacodynamics profile compared to native glucagon. This suggests ZP-GA-1 is a candidate for the treatment and prevention of severe hypoglycemia, whether as a readily accessible rescue solution or in an artificial pancreas.

• Solubility of ZP-GA-1 and native glucagon was screened in various buffers and at different pH values. Native glucagon has low solubility (<1 mg/ml) at physiological conditions (pH=7) and in the 5-7.5 pH range. In the studies, enhanced solubility ( ≥1 mg/ml) of native glucagon was only found at pH 2.5-4. In contrast, ZP-GA-1 achieved enhanced solubility at physiological conditions as well as at pH 2.5-7.5. Both forms of glucagon were assayed in Thioflavin T (ThT) for 14 days at 40oC at physiological pH to test for fibrillation and turbidity. Native glucagon fibrillated within 24 hours and a notably higher turbidity than for ZP-GA-1 was observed. The chemical stability was measured by placing the substances in buffer at 1 mg/ml at physiological pH for 90 days. Just after one week, glucagon showed a 51% degradation, whereas ZP-GA-1 degradation was only 1.8%.
• The pharmacokinetics of native glucagon and ZP-GA-1 were comparable, each with a short half-life and appropriate time to maximum concentration. When tested intravenously and subcutaneously, the half-lives were more similar (5.21 minutes for glucagon and 5.15 minutes for ZP-GA-1) than when tested subcutaneously (13.0 minutes for glucagon and 32.4 minutes for ZP-GA-1). Time until maximum concentration in subcutaneous administration was identical (8.33 minutes).
• ZP-GA-1 activated the glucagon receptor similarly to native glucagon, as evidenced by the nearly superimposable graphs of concentration (nM) versus percent activation. Acute glucose release was tested in rats using both forms of glucagon. The injection of ZP-GA-1 versus native glucagon showed comparable blood glucose releasing effects: time to maximal efficacy, maximal glucose excursion, and time until blood glucose returns to normal/baseline levels. Overall, the pharmacodynamics profile of native glucagon was retained in ZP-GA-1.

Improved Glycemic Control Despite Reductions in Bolus Insulin Doses with Basal Inuslin LY2605541 Compared with Basal Insulin Glargine in Patients with Type 1 Diabetes (915-P)

Julio Rosenstock, Richard Bergenstal, Thomas Blevins, Linda Morrow, Yongming Qu, and Scott Jacober

LY2605541 (LY) is a long-acting novel basal insulin analog designed to have a large hydrodynamic size that may contribute to slower insulin absorption and reduced clearance. A phase 2, randomized, open-label, 2x2 crossover study found a greater improvement in glycemic control and reduction in prandial insulin requirements with LY compared to insulin glargine (GL) in patients with type 1 diabetes (n=108). The present analysis sought to further interrogate these initial results in order to explain the need for lower mealtime insulin doses. In the trial, LY-treated patients had significantly reduced daily mean blood glucose levels vs. patients receiving insulin glargine (143.0 mg/dl vs. 151.7 mg/dl compared to baseline of 161.8 mg/dl; p<0.001) at eight weeks. LY use was also associated with numerically more total hypoglycemia, but total hypoglycemia rates were significantly lower. Patients in both treatment arms required comparable doses of basal insulin, whereas the decrease need for bolus insulin use was consistent for every meal. Researchers concluded that these findings are perhaps related to LY’s prolonged duration of basal insulin action and/or greater suppression of hepatic glucose production related to a preferential hepatic effect.

• Subjects with type 1 diabetes (n=108) received a once-daily basal insulin (either LY [n=56] or GL [n=52]) plus prandial insulin for eight weeks, followed by crossover treatment for an additional eight weeks. Patients were comparable in terms of baseline demographics. Overall, 64.8% were men and 94.4% were Caucasian. Mean baseline age was 38.5 years, and mean duration of diabetes was 17.9 years. For both treatment groups, the mean BMI was 27.4 kg/m2, weight was 84 kg (185 lbs), and baseline A1c level was 7.6%.
• At eight weeks, Ly met statistical criteria for superiority vs. GL in lowering daily mean blood glucose levels (143.0 mg/dl vs. 151 mg/dl compared to a baseline of 161.8 mg/dl; p<0.001). The improvements in glycemic control during LY treatment were not found to be due to over-dosing, because fasting plasma glucose elvels were comparable between the two treatment groups.
• Following eight weeks of treatment, basal insulin doses were comparable between the two treatment groups, but bolus insulin doses were significantly lower in LY-treated patients compared with GL. In the first treatment period (2-6 weeks after randomization), patients receiving LY used significantly less basal insulin than those on GL; however, this difference dissipated during the second treatment period (after crossover). LY-treated patients needed significantly less bolus insulin compared with GL. This reduced use occurred primarily during the second treatment period (when basal doses for both groups was comparable) and was consistent for all meals (least-squares mean differences between LY and GL): breakfast (-0.9 IU; p=0.021), lunch (-1.4 IU; p<0.001), dinner (-2.0 IU; p<0.001), and total daily bolus dose (-4.3 IU; p =0.005).
• LY treatment was associated with significantly fewer nocturnal hypoglycemia events (0.9 vs. 1.2 events/30 days; p=0.007) and a numerically higher total hypoglycemia rate (9.2 vs. 8.1 events/30 days; p=0.074) than GL. Even though the incidence of total hypoglycemia (BG≤70 mg/dl) was higher in LY than GL (RR=1.20), the rate of early morning hypoglycemia was lower (RR=0.73). This trend was consistent throughout the eight-week treatment period.

New Insulin Glargine Formulation: Glucose Control and Hypoglycemia in People with Type 2 Diabetes Using Basal and Mealtime Insulin (Edition I) (43-LB)

Matthew Riddle, Geremia Bolli, Monika Ziemen, Isabel Muehlen-Bartmer, Florence Bizet, and Philip Home

This six-month phase 3a study compared the efficacy and safety of a new long-acting 300 U/ml (U-300) insulin glargine formulation to insulin glargine 100 U/mL (U-100) in patients with type 2 diabetes previously using both basal and mealtime insulin. U-300 has a longer and flatter pharmacokinetic profile than U-100, suggesting a possible advantage in diabetes treatment. Study subjects (n=807) were randomized to once-daily evening U-300 (n=404) or U-100 (n=403), while continuing their mealtime regimen. At baseline, subjects had a mean age of 60 years, BMI of 36.6 kg/m2, duration of type 2 diabetes of 15.8 years, and A1c of 8.15%. Following six months of treatment, U-300 was non-inferior to U-100 in A1c-lowering efficacy (both groups lowered A1c an average 0.83% from baseline). Patients receiving U-300 showed a significant 21% reduction in severe or nocturnal confirmed hypoglycemia from month three to month six (36.1% with U-300 vs. 46.0% with U-100; p=0.0045). Furthermore, the occurrence of any hypoglycemic event was numerically lower, but not statistically significant, in patients receiving U-300 vs. U-100. Given the comparable glycemic efficacy of U-300 and U-100, the potential of U-300 to reduce the risk of hypoglycemia indicates that it is an improved basal insulin that should be considered, especially for people with high insulin requirements.

Safety and Efficacy of Dulaglutide versus Sitagliptin After 104 Weeks in Type 2 Diabetes (AWARD-5) (1004-P)

Ruth Weinstock, Guillermo Umpierrez, Bruno Guerci, Michael Nauck, Karen Boleyn, Zachary Skrivanek, and Zvonko Milicevi

This 104-week, randomized, multi-center, double-blind trial examined the efficacy and safety of dulaglutide (DU) versus sitagliptin (SITA) in patients with type 2 diabetes treated with metformin. Patients were randomized to 1.5 mg DU (n=304), 0.75 mg DU (n=302), 100 mg SITA (n=315), or placebo (n=177) (to 26 weeks). At baseline, subjects had average BMI of 31 kg/m2, age of 54 years, A1c 0f 8.1-8.2%, and weight of 87 kg (191 lbs). At the end of 104 weeks, DU provided significantly greater A1c reductions than SITA (p<0.001). In the 1.5 mg DU, 0.75 mg DU, and SITA arms, A1c decreased an average 1.0%, 0.7%, and 0.3%, respectively, over 104 weeks. The 1.5 mg DU group was associated with greater body weight loss than SITA (1.1 kg [2.4 lbs] beyond placebo) (p<0.001) at 104 weeks. There was a higher rate of GI adverse events in the DU arms compared to SITA, including nausea, vomiting, diarrhea, constipation, and abdominal distension. The incidence and rates of hypoglycemia were similar across treatment groups and there were no reports of severe hypoglycemia episodes.

• At the end of 104 weeks, A1c decreased in the 1.5 mg DU, 0.75 mg DU, and 100 mg sitagliptin groups by an average 1.0%, 0.7%, and 0.3%, respectively. The percentage of patients who achieved an A1c <7.0% at the end of the study was 54%, 45%, and 31%, with a weight reduction of 2.9 kg (6.4 lbs), 2.4 kg (5.3 lbs), and 1.7 kg (3.8 lbs), in the 1.5 mg DU, 0.75 mg DU, and 100 mg SITA arms, respectively. We note that a high number of people dropped out in each treatment arm: 37% in the 1.5 mg DU, 39% in the 0.75 mg DU, 41% in the SITA, and 46% in the placebo arm, with the primary cause due to adverse events. We also note that serious adverse events were reported in 12% of patients in the 1.5 mg DU arm, 8% of patients in the 0.75 mg DU arm, and 10% of patients in the 100 mg SITA arm. No difference across treatment groups in systolic or diastolic pressure was observed.
• There were no reports of severe hypoglycemic episodes at any point during the study. The incidence of hypoglycemia was, however, prevalent and similar across treatment groups: 13% in the 1.5 mg DU arm, 9% in the 0.75 mg DU arm, and 9% in the 100 mg SITA arm. The authors concluded that the safety profile and superior A1c-lowering efficacy of DU vs. SITA after 104 weeks indicate an acceptable benefit/risk profile; however, it is important to note that significantly more patients in the DU arms experienced adverse events during the first 24 weeks of the study, with the highest incidence among the 1.5 mg DU group.

Current Issues: In a Patient Who Is Failing Oral Antidiabetic Agent Therapy, the Next Step Is To?

Add a GLP-1 Agonist

Vivian Fonseca, MD (Tulane University Medical Center, New Orleans, LA)

Dr. Vivian Fonseca began his talk by discussing the disadvantages and limitations of insulin treatment for type 2 diabetes, noting that it leads to weight gain, can increase the incidence of hypoglycemia, and can be a challenge for older patients. He characterized insulin as a somewhat blunt instrument in that it exerts a constant downward pressure on glucose levels. Dr. Fonseca remarked that GLP-1 agonists are an attractive, more flexible treatment option, reviewing multiple studies that have shown the superior efficacy of once-daily and once-weekly GLP-1 agonists compared to insulin glargine. He highlighted that GLP-1 agonists act in a glucose-dependent manner, thus improving patients’ postprandial glucose levels while maintaining a low risk of hypoglycemia. Other studies indicate that GLP-1 agonists reduce biomarkers of cardiovascular risk, improve endothelial function, lower blood pressure, and reduce body weight. Dr. Fonseca further emphasized that GLP-1 agonists can also improve disposition indices and insulin sensitivity in a durable manner, thought he noted that the therapies do not induce beta cell proliferation. Speaking briefly on the currently hot topic of GLP-1 agonists and pancreatitis, Dr. Fonseca acknowledged the recent concerns, though explained that he did not believe that the current body of evidence supports an association between the two.

• Dr. Fonseca noted that the treatment paradigm for type 2 diabetes begins with lifestyle modification and metformin and proceeds to oral agents. Framing this debate, he noted that if a patient requires further glycemic control, he or she can add an injectable agent – i.e., a GLP-1 agonist or basal insulin. Dr. Fonseca noted that basal insulins increase the risk of hypoglycemia, require frequent blood glucose monitoring (which can be expensive), promote weight gain, and can be challenging for older patients. He highlighted that unlike GLP-1 agonists, basal insulin cannot correct several defects observed with diabetes, including the reduced incretin effect, as well as abnormally elevated glucagon levels.
• Both once-weekly and once-daily GLP-1 agonists have been shown to provide greater A1c reductions compared to insulin glargine. Dr. Fonseca acknowledged that some studies may have used less-than-sufficient dosages of insulin glargine, and that basal insulins generally provide greater reductions in fasting plasma glucose levels compared to GLP-1 agonists. Looking beyond just glycemic control, Dr. Fonseca pointed out that GLP-1 agonists provide the added benefit of weight loss (compared to the weight gain typically observed with insulin therapy), and appear to be particularly effective at decreasing visceral fat mass.
• Dr. Fonseca noted that GLP-1 agonists have a better safety profile than basal insulins, particularly in respect to the risk of hypoglycemia. Multiple studies show that exenatide and liraglutide produce significantly fewer episodes of hypoglycemia compared to insulin treatment. Of interest, early data appear to indicate that GLP-1 agonists can improve biomarkers of cardiovascular risk such as triglyceride levels, blood pressure, and artherosclerotic plaques. On this front, Dr. Fonseca remarked that some of this data comes from animal studies, and that the ongoing cardiovascular outcomes trials for GLP-1 agonists will provide greater clarity in the upcoming years.
• “GLP-1 agonists versus basal insulin” may not be an either-or debate. Combination of the two drug classes may provide the best results, due to their complementary effects and synergistic actions. Dr. Fonseca explained that basal insulins contribute more to the regulation of fasting glucose levels while GLP-1 agonists are particularly effective at lowering postprandial glucose excursions. Dr. Fonseca highlighted the potential of Novo Nordisk’s IDegLira (insulin degludec/liraglutide), which has demonstrated a better efficacy/safety profile than both liraglutide and insulin degludec alone (these results were presented during the oral session on GLP-1 agonists; for further details, please see page our ADA Day #2 report).

Add Insulin

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

After briefly recalling the history of insulin treatment, Dr. Parresh Dandona focused the majority of his presentation dispelling commonly held misconceptions regarding the safety of insulin. He emphasized that insulin is the most potent glucose-lowering agent, and can be used any time during the natural course of diabetes. Dr. Dandona stated that insulin has no side effects other than hypoglycemia, which can be minimized with proper titration. Reviewing a number of mouse and in vitro studies, he highlighted that insulin confers profound anti-inflammatory action, cardioprotective action, potential anti-atherogenic action, and potential protection against Alzheimer’s disease. Though he did not discuss the use of a GLP-1 agonist versus basal insulin in great detail, he commented that patients with an A1c of 8.5% and above should start on basal insulin to address elevated fasting glucose, and that patients with an A1c of over 10% would not benefit much from a GLP-1 agonist because elevated fasting glucose is the main contributor to hyperglycemia at higher A1cs. Lastly, Dr. Dandona showed several CGM tracings demonstrating reductions in glucose variability in patients with type 1 diabetes when liraglutide (Novo Nordisk’s Victoza) was added on to their insulin therapy. In closing, Dr. Dandona noted that every drug has its own place, and that it is up to clinicians to make sure they use them appropriately to best help their patients achieve good glycemic control.

• Dr. Dandona stressed that insulin has a safe cardiovascular profile, and may actually be anti-atherogenic. He highlighted results from the ORIGIN trial, which showed no divergence of the incidence of cardiovascular events between those treated with insulin glargine versus standard care in the trial. In the GRACE study, a substudy of the ORIGIN trial, the maximum common cIMT and bifurcation cIMT were significantly improved with patients treated with insulin glargine versus standard care.
• Subsequently, he emphasized that there is no evidence of cancer risk in humans with insulin treatment. He noted that these concerns were drawn entirely from in vitro studies in which insulin was administered at concentrations far greater than physiologic levels, and that there is no data showing a mitogenic effect with insulin at physiologic or near physiologic concentrations. IN the ORIGIN trial, the incidence of various types of cancer was balanced versus standard care, reassuring Dr. Dandona of inulin’s safety regarding cancer risk.
• Though it has been suggested that insulin causes hyperlipidemia, Dr. Dandona noted that it could actually lower lipid levels. In a review of the literature, he found no good evidence of any increase in lipid levels with insulin treatment; rather, LDL and triglycerides decreased (Chaudhuri and Dandona, DOM 2011).
• Noting the relatively high contribution of fasting hyperglycemia to total hyperglycemia in patients with high A1cs (Monnier, Diabetes Care 2003), Dr. Dandona recommended for patients with A1c of 8.5% and above to start on basal insulin to address elevated fasting glucose. He recommended that using a GLP-1 agonist for a patient with an A1c over10% would not do much, since most of the hyperglycemia is a result of elevated fasting glucose; instead, basal insulin would be able to get patients down to target, with minimal hypoglycemia if titrated properly. For those who want to minimize weight gain, Dr. Dandona advocated for the use of basal-bolus therapy versus biphasic insulin with either basal or prandial insulin, given reduced weight gain with the therapy. In addition, he noted that basal-bolus insulin, given reduced weight gain with the therapy. In addition, he noted that basal-bolus therapy provided improved control compared to sliding-scale insulin (Umpierrez et al., Diabetes Care 2007), and reduced the rates of postoperative complications for those who underwent surgery (Umpierrez et al., Diabetes Care 2011). Dr. Dandona commented that newer insulins aren’t even necessary for good glycemic control – in the DEAN trial, regular insulin plus NPH provided similar control as insulin determir plus insulin aspart (Umpierrez et al., JCEM 2009).

Panel Discussion

Guillermo Umpierrez, MD (Emory University, Atlanta, GA); Vivian Fonseca, MD (Tulane University School of Medicine, New Orleans, LA); Parresh Dandona, MD (State University of New York, Buffalo, NY)

Q: No study has shown that GLP-1 agonists reduce the risk of cardiovascular complications. Can you predict whether they will reduce these risks?

Dr. Fonseca: I can only say, “give me a break.” It took nine years for DCCT to show such an effect. But we all accept that glucose levels and A1c are good surrogates for cardiovascular risk. I don’t see why there would be differences between drugs in that sense.

Dr. Dandona: I agree that GLP-1 agonists haven’t been given enough time. My prediction is that these agents will be shown to reduce complications independent of glycemia.

Q: I want to raise a question around weight change being seen as an important factor in late type 2 diabetes management. I’m not aware of any study except the obesity studies that were randomized and that show a strong association with weight loss from any pharmacologic agent in type 2 diabetes reducing microvascular or macrovascular disease risk. Conversely, out of the studies that show an increased macrovascular event rate with insulin, I’m not aware of evidence saying that it’s related to weight change. Do we have enough evidence to show that weight is a therapeutic target of its own in late type 2 management?

Dr. Fonseca: It is an important question. However, let me just say that you’re not primarily using these drugs to lower weight. You’re using it for glycemic control, but weight gain is distressing for the patient who is trying to lose weight. The point I’m trying to make is that it’s against what the patient wants and what you’re telling the patient – you’re telling patients that you want them to lose weight and then you give them agents that make them gain weight? There’s no data saying that you’re causing cardiovascular disease by making them gain weight. However, weight is linked to other diseases such as sleep apnea that affect the patient. Weight gain is contrary to what the patient may desire and I think it’s an important consideration.

Q: In terms of combination therapy, when orals are failing and we decide to put patients on insulin, there are some patients on high doses of insulin who remain on sulfonylurea treatment. What are your thoughts on this?

Dr. Fonseca: In terms of sulfonylurea use in the presence of a high dose of insulin, you might get some benefit if the patient is only on basal insulin. If the patient is using prandial insulin, I’m not sure you’d get much by continuing to use a sulfonylurea.

Q: Do you have any comments on the use of GLP-1 agonists in type 1 patients?

Dr. Dandona: We’ve used this agent in a limited number of patients with type 1 diabetes, no more than 100. We’ve published two papers in this area. One was in patients with well-controlled type 1 diabetes on both a continuous subcutaneous insulin infusion system and a continuous monitoring system. They were well controlled and got better controlled. The other group was patients that had badly-controlled type 1 diabetes, with an A1c around 8%, who were also obese. In that group, GLP-1 agonists worked too, and reduced A1c, body weight, and systolic blood pressure. There were spectacular falls in blood pressure. You can see that paper in Endocrine Practice. In both sets, it works. To pronounce a much more detailed sort of algorithm is still some time away; this is just the beginning of the story.

Dr. Fonseca: The issue of gastric emptying and its impact on A1c is an interesting one. I refer you to Michael Horowitz in Australia, who has done a lot of work in this area. Nutrient delivery is important in terms of glucose excursions, but I don’t know whether it affects A1c a lot. It may affect the variability of glucose, but whether that has an impact on A1c is also highly debatable. There is no study yet showing that flattening it out has an effect on A1c.

Q: Two questions for the experts. First, when you start either basal insulin or GLP-1 agonists, what do you usually do with the dosages of sulfonylureas? Because many patients in a clinical setting will be failing on metformin and sulfonylureas when you need to move to these agents. Secondly, when you add a basal insulin, what is your view of the optimal time at which to give the basal insulin?

Dr. Dandona: Let’s start with the basal insulin issue. In our unit, basal insulin is usually given at bedtime, but we sometimes find that patients fall asleep before they take it. If that happens, we ask them to take it at dinnertime. I’m reluctant to ask them to take it at breakfast time, because I’m not yet convinced that they act for a full day.

Dr. Fonseca: There was one study done where glargine was given in the morning or the evening, and the effect on A1c was essentially the same. To get back to your first question about sulfonylureas, there is no best option. If your A1c is high, it may be inappropriate to stop. If the A1c is low enough, because sulfonylureas have been shown to be associated with hypoglycemia, you may want to lower or stop sulfonylureas.

Q: For patients who are doing well on high-dose insulin, would they be good candidates for GLP-1 therapy? I’m thinking of people on 100 units of insulin a day.

Dr. Dandona: I don’t see why not. I personal believe – and I’ve had this hang up for decades now – that when you inject insulin, not all of it gets into your body. And therefore, in the obese patients in particular, you may be injecting a lot of insulin that’s not getting into the circulation. What is surprising is that when you give five micrograms of exenatide, it makes it to the target almost immediately. So therefore, what you just said is very very relevant. Usually when I start these patients on a GLP-1 agonist, the insulin dose comes down and glycemic control improves.

Dr. Fonseca: There’s a lot of interest in the use of high-concentrated insulin – e.g., U300 and U500. We need to explore this area further.

Dr. Umpierrez: There was an abstract last year that looked at very high doses of insulin and compared add-on placebo to add-on GLP-1 therapy. The GLP-1 agonist resulted in significant improvements in A1c with less weight gain.

Q: For patients on both metformin and a DPP-4 inhibitor, is it worth adding a GLP-1 agonist, or would you go to basal insulin?

Dr. Fonseca: You have to have a lot of money to add a GLP-1 agonist to a DPP-4 inhibitor. There’s just no data on it at this point.

Dr. Dandona: Also, remember that these molecules that we are using are manufactured on the basis that they are resistant to degradation by DPP-4.

Q: You talked a lot about the risk of cancer with insulin, but didn’t talk about the issue with GLP-1 agonists. In the UK in the popular media, we’ve been having a debate about whether GLP-1 agonists cause pancreatic cancer.

Dr. Fonseca: I like the way you used the phrase “popular media” to refer to the BMJ. But like I said, what we need to see are proper studies, not these little anecdotal reports drawn from databases based on sub-reporting. We need to take patient level data from many randomized control trials and put it all together to see what’s going on.

Q: Can you address the issue of the 24-hour or 24-hour-plus insulin? There’s a dawn phenomenon in type 1 diabetes, which exists to some extent in type 2 diabetes. The patients that take basal insulin in the evening are accustomed to titrating the dosage according to fasting glucose level. If you get the dose down before breakfast, that’s when patients are the most insulin resistant. And some are going to run into trouble before supper, when they are less insulin resistant and still have the same amount of insulin on board. We had some patients on glargine and their fasting glucose was at goal – 90 mg/dl – and they were getting hypoglycemia before supper and we had to switch them to Levemir. Do you think this will be a problem for degludec?

Dr. Dandona. You seem to imply with confidence that Levemir has a shorter duration of action.

Dr. Umpierrez: We’ve heard a lot about long-acting insulins at this meeting, and we’ve heard a lot about long-acting GLP-1 agonists that could be dosed once weekly or longer. What do you anticipate will happen with these new insulins and GLP-1 agonists? Will we stick with what we have, or shift to using these new drugs?

Dr. Dandona: I think time will tell. I’m trying to dodge the question, because we have so much on our plate right now. The menu is so large, the choices so many. We can be brainwashed for a while into using specific preparations. And of course, degludec would come up with the idea that it is stable, with highly predictable bioavailability, pharmacodynamics, and so on, but I think only time will tell what its utility is. The reason I included your [Dr. Umpierrez’s] slide is for the simple reason that you asked the question whether we are going overboard with these novel preparations. You showed that good old regular insulin and NPH worked as well as insulin detemir and insulin aspart. I think that only time will tell with these new agents. Clinical practice will tell. We can model utopia in clinical trials, but whether this utopia gets translated is another matter.

Dr. Fonseca: Predictions are usually wrong, especially when they are about the future.

Dr. Umpierrez: Could you provide any comment about long-acting GLP-1 agonists?

Dr. Fonseca: I think it’s very attractive for patients to have a long-acting preparation, as it improves compliance. I want to point out the Intarcia product – it’s subcutaneously implanted for six months, and may even go for one year. Compliance is assured for that duration [Editor’s note: we previously reported on ITCA 650’s phase 3 trial in our March 22, 2013 Closer Look].

Dr. Umpierrez: If I have a patient on metformin and sulfonylurea, what would you recommend next?

Dr. Dandona: If the patient’s A1c is above 8.5%, it has to be basal insulin. If it’s less than 8.5%, you have an argument, but you need basal insulin to bring it down to that. Normally, a GLP-1 agonist will not get you down to 7% when your A1c is greater than 8.5%.

Dr. Fonseca: I totally agree with that. You may get it in an occasional patient, but what is the chance of that effect?

 

Corporate Symposium: Targeting Glucagon in Type 1 and Type 2 Diabetes Mellitus (Sponsored by Eli Lilly and Company)

New Frontiers in Incretin Therapy: The Contribution of Alpha Cell Suppression

Tina Vilsbøll, MD (University of Copenhagen, Copenhagen, Denmark)

Dr. Tina Vilsbøll began her talk by noting that type 2 diabetes is a pathology of both alpha and beta cells. Type 2 diabetes patients experience fasting hyperglucagonemia, along with a twofold increase in glucagon secretion after meals because of L-cell action in the gut. Dr. Vilsbøll cited experimental evidence from Dr. Michael Nauck’s group demonstrating that GLP-1 inhibits glucagon secretion in a glucose-dependent manner in type 2 diabetes patients. Although early research had focused on GLP-1’s effects on insulin secretion, studies have shown that the hormone’s glucagonostatic and insulinotropic effects contribute equally to its glucose-lowering actions; in type 1 diabetes patients, the glucose-lowering effect of GLP-1 is mediated almost entirely by glucagon (Creutzfeldt et al., Diabetes Care 1996). Dr. Vilsbøll said that she favors long-acting GLP-1 agonists over shorter-acting alternatives because of their superior control of nighttime glycemia. In terms of safety, GLP-1 agonists do not impair the counterregulatory glucagon response, and some studies show that the alpha cell response during hypoglycemia is actually improved by GLP-1 therapy.

“Glucagon” the Forgotten Hormone

Alan D. Cherrington, PhD (Vanderbilt University, Nashville, TN)

Dr. Alan Cherrington outlined the normal physiologic roles of glucagon, and argued that excess glucagon contributes to the metabolic phenotypes of type 1 and type 2 diabetes. Glucagon is hepatocentric and pleiotropic, with effects ranging from positive regulation of glycogenolysis and gluconeogenesis to negative regulation of fatty acid and protein synthesis. It opposes the effects of insulin. Both dog and human studies have demonstrated that the liver responds quickly to rises in glucagon by increasing net hepatic glucose output; this is mediated by glycogenolysis rather than gluconeogenesis. Through its glycogenolytic effects, glucagon sustains two-thirds of glucose production in the fasting state. Notably, glucagon is also involved in glucose regulation in the postprandial state. In people with normal glucose tolerance, glucagon is typically suppressed after a meal. However, in those with impaired glucose tolerance or type 2 diabetes, plasma glucagon levels rise inappropriately in response to a meal, contributing to postprandial hyperglycemia. Interestingly, studies have shown that glucagon is also involved in regulating glucose uptake by the liver after a meal. Finally, in people without diabetes, glucagon protects against blood sugar falling too low; it is the first line of defense against hypoglycemia. However, in those with type 1 diabetes, glucagon levels are dysregulated, contributing to hypoglycemia. This landscape suggests that if we learned how to control glucagon, we could improve the lives of people with diabetes.

Direct Targeting of Glucagon Signaling in Type 2 Diabetes: Defining the Potential

David D’Alessio, MD (University of Cincinnati, Cincinnati, OH)

Dr. David D’Alessio began by reminding the audience of the glucagon-related defects seen in type 2 diabetes – an increased ratio of alpha to beta cells, hyperglucagonemia, and impaired alpha cell function. He then noted that preclinical studies have provided support for targeting glucagon as a therapeutic strategy and went on to discuss the clinical status of this approach. Thus far, glucagon receptor antagonists have been the main focus for drug development. Bayer was developing a glucagon receptor antagonist in the 1990s; in early trials, the compound was shown to suppress hepatic glucose production. However, the compound’s development was halted before it finished clinical testing. Merck was also previously developing a glucagon receptor antagonist; its compound lowered blood sugars in response to hyperglycemia, decreased fasting glucose in a dose-dependent fashion, and dropped A1c by 2%. This program was unexpectedly cancelled. Lilly is currently developing a glucagon receptor antagonist. Its compound LY2409021 suppresses fasting glucose and reduces A1c in a dose-dependent fashion. However, it seems to also increase plasma glucagon levels and GLP-1 levels. Dr. D’Alessio concluded by noting that although glucagon receptor antagonism seems promising, some concerns have emerged from preclinical and clinical trials. Preclinical studies have suggested risks of alpha cell hyperplasia, abnormal lipid metabolism, and loss of beta cell stimulation. Hyperglucagonemia and increases in LDL, blood pressure, body weight, and transaminases were seen in early clinical trials. Thus, glucagon receptor antagonists will have to be carefully scrutinized in trials.

Panel Discussion

Alan D. Cherrington, PhD (Vanderbilt University Medical Center, Nashville, TN); David D’Alessio, MD (University of Cincinnati, Cincinnati, OH); Tina Vilsbøll, MD (University of Copenhagen, Copenhagen, Denmark)

Q: Here’s a question for Tina. If GLP-1 increases somatostatin, shouldn’t it also impair insulin secretion?

Dr. Vilsbøll: That’s a good question. It is right that in general somatostatin suppresses insulin as well. My short answer is that we don’t really know, but in spite of the action on insulin, there is a definite suppression of glucagon.

Q: Is there dysregulation of glucagon secretion after bariatric surgery?

Dr. Vilsbøll: We have seen that GLP-1 does definitely go up after bariatric surgery, and there are discussions about what happens with GIP. In general, glucagon is not changed very much, which is somewhat surprising. There is a small decrease in some studies. But there are still many, many things that we do not know.

Dr. D’Alessio: Bariatric surgery is very confusing with regards to glucagon. In general we see improvements in glucose tolerance even though glucose enters the blood more rapidly. And the resolution of diabetes is fairly impressive. But what we see is that bariatric patients often have hyperglucagonemia after meals, which doesn’t fit with the rest of what we see. So that’s a big question in the bariatric field right now.

Q: Is there any effect of somatostatin on GLP-1 secretion?

Dr. Cherrington: Certainly if you inhibit GLP-1, you would argue that that is going to make the diabetic state worse. I think that as David said, when you use somatostatin as a tool or therapeutic agent, you need to be aware that it has a lot of effects, including effects on growth hormone. There are some groups working on developing a somatostatin that affects alpha cells.

Q: Would a combination of short- and long-acting GLP-1 agonists be worth considering?

Dr. Vilsbøll: It’s a good question, because short acting GLP-1 agonists have their main effect on gastric emptying, while longer-acting agonists act on insulin levels. We need to see some results, because it would be an expensive treatment. I also see potential combinations of basal insulins and GLP-1 agonists, like IDegLira, as very promising.

Q: Why did weight go up in some of the earlier studies on the Merck glucagon receptor antagonist?

Dr. D’Alessio: That’s not clear either, because generally hyperglucagonemia appears to be satiating, and generally leads to weight loss. In preclinical models, glucagon receptor agonists cause weight loss. So it’s not clear why that happened, but it didn’t look like a big effect.

Q: What about the future of these compounds?

Dr. D’Alessio: It’s looking like a tempting target. It seems like it’s a great way to lower glucose, but we need to know more. I think people are enthusiastic but are somewhat trepidatious about possible effects.

Q: What time of the day is best to prescribe DPP-4 inhibitors?

Dr. Vilsbøll: Overall the multiple DPP-4 inhibitors on the market are mostly the same, and are all generally effective. The clinical data seems to show that they cover a full day, so time of the day for administration shouldn’t matter much.

Q: Can you elaborate on the differences between GLP-1 agonists and DPP-4 inhibitors regarding type 1 diabetes?

Dr. Vilsbøll: As far as I know there aren’t any studies on DPP-4 inhibitors in type 1 diabetes patients, so I don’t think that current patients see it as a potential treatment. In terms of the difference, GLP-1 agonists are more effective, and can lead to weight loss. The combination of GLP-1s in obese type 1 patients is promising.

Q: What are glucagon’s actions in the brain?

Dr. Cherrington: Clearly the liver is the primary target of glucagon. Receptors elsewhere don’t end up doing much in terms of overall physiology. As David mentioned there are some receptors in the heart, but you need to get very high plasma levels of glucagon to see any effect there. But recently there has been a study in which glucagon was infused directly into the brain, and showed that it had an inhibitory effect on glucose production. There are a number of papers that also suggest this. The hypothesis has been put forward that glucagon has a dual action on the liver: directly it stimulates the liver, but there is a secondary effect that inhibits this stimulation. A related theory is that obesity in some cases can be caused by the failure of glucagon to shut down its own signal. It’s something to be aware of, as glucagon is a satiety factor.

Q: What types of individuals would benefit from a glucagon receptor blockade?

Dr. Cherrington: I think that it’s pretty much anyone who’s a type 2 diabetic. Whenever you lower glucagon, things get better in terms of glucose. At this point, I think it’s more important to get a glucagon receptor antagonist that has low risk, and then decide whether there are patient populations that would benefit more than others.

Q: What about people who have had pancreatectomies? What would happen treating these patients with GLP-1 agonists?

Dr. Vilsbøll: I have never treated these patients with a GLP-1 agonist. Just a month ago, we initiated a study on patients with total pancreatectomies. Here you have a model without beta cells or alpha cells either. The reason we are studying these patients is because, if we see an increase in glucagon, then it’s proof that it’s glucagon from the gastrointestinal tract. Regarding pancreatitis, we had wanted to do a study using DPP-4 inhibitors on patients with pancreatitis, but up until now it has been quite a challenge to do such a study.

Q: Do you know any association between dysregulation of glucagon secretion and insulin resistance?

Dr. Cherrington: I don’t think we know how the alpha cell goes wrong. Interestingly, if you create hypoglycemia without using insulin, glucagon responds normally. It’s the insulin-induced hypoglycemia that leads to a defect. There’s a lot about alpha cell biology that we don’t know. There is a prevailing incretin hypothesis that the alpha cell is bathed in the product of beta cells, so insulin made in the beta cells surrounds alpha cells and inhibits glucagon, and in a diabetic patient that restraint isn’t there. I’d be interested to see how the GLP-1 receptor works along with that.

Dr. Vilsbøll Well the action of GLP-1 on alpha cells is debatable. I definitely agree that there are many things we don’t know.

Q: What do we know about changes in the expression of the glucagon receptor?

Dr. Cherrington: There is no consensus in the field regarding whether glucagon receptor expression is higher in people with diabetes, nor is there data on glucagon sensitivity in individuals with diabetes. The strength of the data is that there is too much glucagon. Whether or not there are signaling or receptor abnormalities downstream is unclear. It’s very difficult to measure glucagon. Ideally you would measure glucagon levels in the portal vein rather than in arteries. It’s hard to study receptor action when you don’t have a great way of measuring glucagon levels at the target tissues. As with most physiology around glucagon, a lot remains to be determined, partially because it is such a forgotten hormone. I think you’ll see a lot of glucagon research over the next 10 years that will result in translation to therapeutic opportunities.

Dr. Vilsbøll: There is also lots of opportunity to improve the glucagon assay. There are lots of challenges involved with that, but we’re beginning to see the light at the end of the tunnel.

Q: You mentioned that GLP-1 acts through somatostatin. Are there GLP-1 receptors on the beta cell? Also, in patients taking GLP-1 agonists for a very long time, do you see delta cell hyperplasia or small adenomas? And third, in evolutionary terms, why is there no GLP-1 receptor on alpha cells?

Dr. Vilsbøll: To the first question: there are GLP-1 receptors on the beta cells. Regarding the long-lasting effects of GLP-1, I would imagine that sustained action on these cells could lead to some abnormalities, but the clinical data on this is unclear. The FDA is examining the data they have. More than 16,000 rodents have been evaluated, and in those animals there have been no signs of hyperplasia. We don’t know, but to my knowledge there is no evidence of delta cell tumors. And regarding the final question, I really don’t know.

Dr. D’Alessio: It’s a fair question though, because if you look at the studies that blocked physiological levels of GLP-1, the glucagon effect comes out strong. Most of us think that it is an indirect effect, but it is tightly regulated.

Q: If endogenous GLP-1 only exists in the body for a short time, and artificial analogs act for a prolonged period of time, I’m wondering if altering these levels is truly a good thing in the long term.

Dr. Vilsbøll: It’s a good question, because we really are playing with physiology here. Physicians did note that altering the expression of a hormone can alter the expression of the receptor, but studies do show that we’re seeing sustained effects. GLP-1 agonists have been on the market for a while now and we’re seeing sustained efficacy.

Q: Should glucagon only be inhibited during the daytime in order to avoid morning hyperglycemia?

Dr. Vilsbøll: Maybe in type 1 diabetes, but generally in type 2 patients we don’t see that much morning hyperglycemia, and there is an advantage to suppressing glucagon during the night.

Dr. Cherrington: I agree that suppressing glucagon through day and night will give you the most bang for your buck.

 

Sanofi Diabetes Update

Sanofi Diabetes Update

Sanofi held a conference call this morning to review results presented at ADA for its new U300 insulin glargine formulation and to provide an update on the Lyxumia/Lantus combination product. Management guided for phase 3 to begin in 1H14 for “lixi/lan;” disappointingly, management did not provide any detail on the functionality of the fixed-ratio device or details on the technical difficulties encountered with the fix-flex device, as was expected. Results of the U300 insulin glargine’s EDITION I and EDITION II studies were very impressive – EDITION I showed a 21% reduction in nocturnal hypoglycemia compared to Lantus. Topline EDITION II results confirmed this finding.

• Management highlighted that these two studies enrolled very difficult type 2 patients (in both studies, all participants required >42 u/day of insulin at baseline). In both studies, U300 provided non-inferior glycemic control to Lantus while significantly reducing hypoglycemia: specifically in EDITION I both Lantus and U300 provided a 0.8% A1c reduction while U300 provided a 21% relative reduction in number of patients experiencing nocturnal hypoglycemia (severe and/or confirmed) from month three to six.
• Management emphasized that measuring the number of people experiencing hypoglycemia rather than simply hypoglycemic events was a more stringent measure for hypoglycemia superiority.
• Notably, management confirmed during Q&A that the EDITION I extension study examining a flexible dosing schedule will report results later this year.
• Lastly, management provided a financial update showing that Lyxumia reached 8% of the GLP-1 market share by volume in Germany in its first 11 weeks. This was almost on par with BMS/AZ’s Bydureon. In Q&A management commented that Lyxumia is priced roughly at parity with Byetta across markets.
• While Sanofi continues to aim for becoming a comprehensive diabetes care company, the company remained very Lantus-centric on today’s call – the presentation closed out with a slide on multiple growth drivers to sustain Lantus growth, one of which was the opportunity for combination therapy with Lyxumia.

Questions and Answers

Q: There seems to be an extension study for EDITION I exploring an adaptable injection profile – when might that read out? You commented on the significance on nocturnal hypoglycemia, what about the non-significance on overall?

A: Identification of the benefit of a product takes a large volume study. Characteristics of the patients in EDITION I and II were quite unusual. One reason why did this study first was to stress test the product. If we were going to find something meaningful here, the probability of the product to deliver could be speculated to be really meaningful. These studies will be followed by other ones. What you see is consistency on hypoglycemia wherever you look for it. In the degludec experience, the titration phase was problematic. The meta-analysis often times showed that there was excess hypoglycemia during titration, and then it flipped. However what you see with U300 glargine is consistency in the hypoglycemia benefit no matter when in the trial you are. The extension study on EDITION I will report relatively soon. Studies will deliver as planned. 2013 is the year when all of the studies will be released.

Q: Can you say you have not seen any CV event signals with U300 thus far? What’s your level of confidence that the FDA won’t make you do a CVOT prior to approval? Can you remind us what you’re thinking in terms of timing for biosimilar Lantus in the US and Europe?

A: The molecular entity is identical. What changes between U300 and Lantus is the volume. The volume delivers a different PK/PD. However the patient exposure – how much insulin present in blood stream of the patient – is very similar to Lantus. What U300 does is redistribute the presence of insulin in the blood stream so you have a super flat profile. Honestly it’s hard to think of a rational for a CV study. In discussing and hearing reactions to the presentation EDITION I at ADA from KOLs, no one considered that as a likely request. One company has been announcing they are developing biosimilar glargine – Lilly. Based on information we have, we could expect Lilly to be in position to launch in the US and in Europe by 2015.

Q: So you have not seen any CV signals with U300?

A: EDITION I is only one study, and it shows an absolute balance.

Q: The level of severe hypoglycemia was 5% with U300 vs. 5.7% for Lantus in EDITION I; that was roughly 12% reduction. Is that meaningful? Especially against Tresiba, which showed a bit less than 20% reduction? Do you think this may become a claim of superiority for marketing purposes?

A: From a statistical point of view, this is inappropriate. Studies should have a pre-specified hypothesis being tested. In this case, the relative risk for nocturnal hypoglycemia had a decrease of 21% in EDITION I and a 15% decrease in the degludec study. I think all we can do when we do studies is formulate hypothesis and test them. If, afterwards, we initiate a post-hoc analysis, we obviously always find something. So what I would like to say to you is that the assessment of severe hypoglycemia needs to come from a meta-analysis of all studies. What we’ve seen here today is rarely seen with degludec – the consistency of information with hypoglycemia. Although we only mention topline data for EDITION II, we were pleased to see the same consistency.

Q: One question on the EDITION program: it looks like Lilly is running a blinded trial for its novel basal while your EDITION is entirely open label. What conversations did you have with regulators? Does that matter? Additionally, on the price of Lyxumia – you’ve shown volume share in Germany, what does that mean in terms of value share and Lyxumia pricing?

A: When preparing the phase 3 study, it was done in consultation with regulatory agencies. So the characteristics of the study were ostensibly discussed. What creates a barrier to blinding in this case is the device. So the possibility of carrying on the study was limited to having in unblinded, and this was obviously part of our submitted dossier. On Lyxumia price, we can clearly say we don’t want that to be a barrier to market access. It is priced roughly at parity to Byetta across markets, which is similar to about 1.2 mg Victoza.

Q: Following up on the favorable PK/PD profile – can you give commentary on the timing and flexibility of dosing vs. Lantus? Especially in the extreme dosing interval of eight to 40 hours vs. Lantus’ more rigorous 24-hour dosing plan.

A: Today what we have is what we’ve presented at ADA. We see the PK/PD in multiple doses suggest a longer duration of action. We will explore how this translates into flexibility. Today we are limited to the information we have, which is what you just saw. The tail of the glucose infusion rate appears to be significantly longer with U300 when compared to Lantus.

Q: U300 is the same molecule as Lantus, so I guess it will be considered under an sNDA. So am I correct in assuming you will have a six-month review by the FDA? Can you comment on the risk of having an advisory committee meeting? On prices, apparently you have set the precedent not to look for too high of a premium. Why not go for a high premium if you have some good data like this confirmed in the next studies?

A: I can’t comment from the point of view of the regulators, but what I can tell you is that we’re planning to submit the dossier in 2014. FDA has had an evolving approach to the requirement for advisory committee meetings, so it would be purely speculative to give any answer. On pricing strategy, we consider that this would be a new generation of insulin that really brings an added value for patients eligible to insulin. On the other hand, we don’t want price to be barrier to broad expansion. So I am indicating that we would have a price in the same range as Lantus, but potentially at a slight premium. It has nothing to do with the value profile of the product that we are building, but we just don’t want price to be a barrier to growth and expansion to this new solution for people living with diabetes.

 

Additional Topics

Oral Sessions: Epidemiology of Diabetes Complications and Mortality

Cancer Outcomes in Patients with Dysglycemia on Basal Insulin: results of the ORIGIN Trial (281-OR)

Louise Bordelau, MD (McMaster University, Hamilton, ON)

Dr. Louise Bordeleau presented results from a sub-analysis of the ORIGIN trial that examined cancer outcomes. As a reminder, the ORIGIN trial was a multicenter, randomized 2x2 factorial trial that examined the effect of insulin glargine treatment vs. standard care and omega 3 fatty acid treatment vs. placebo on cardiovascular outcomes in patients at risk for CV disease who had either impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes. Results from the trial presented at least year’s ADA demonstrated no increased risk of cardiovascular outcomes or cancer with glargine treatment. This subanalysis further examined cancer outcomes in the ORIGIN trial. Data on cancer deaths and cancer-related hospitalizations was collected from the date of randomization at every visit, while cancers not requiring hospitalizations and any other cancer events since the date of randomization were ascertained starting in January 2010. 953 patients (7.6% of all patients) developed cancer during the trial, and cancer incidence was 1.32/ 100 person-years. There was no significant difference in cancer death rates or adjusted incidence of cancer between the study’s glargine vs. standard care arms. There was also no significant difference in the incidence rate of common subtypes of cancer (lung, colorectal, breast, prostate) between the study’s two arms. Finally, use of metformin and dose of metformin at baseline or post-randomization did not impact the risk of developing cancer. These results underscore the strong message delivered at last year’s ADA about glargine’s neutral effects on cancer – we continue to see this as a big win for the drug.

• As a reminder, the ORIGIN trial was a multicenter, randomized 2x2 factorial trial that examined the effect of glargine treatment vs. standard care and omega 3 fatty acid treatment vs. placebo on cardiovascular outcomes. It enrolled 12,537 people with impaired fasting glucose, impaired glucose tolerance, or early type 2 diabetes mellitus who were at high risk of CV events; participants could not have active cancer. Participants were randomized to glargine or standard of care, and omega 3 or placebo. Patients were followed for a median of 6.2 years (IQR 5.8 – 6.6 years). Data from the trial presented at least year’s ADA showed that glargine treatment was not an increased risk of cardiovascular outcomes or cancer. For more details on the trial, see our ADA 2012 ORIGIN coverage.
• This subanalysis examined cancer outcomes in the ORIGIN trial. Data on cancer deaths and cancer-related hospitalizations was collected from the date of randomization at every visit. Cancers not requiring hospitalization and any other cancer events since the date of randomization were also ascertained starting in January 2010. Cancers were classified by their primary anatomic site, status (new or recurrent), clinical consequence (death/hospitalization), certainty (definite probable or possible; definite or probable were included in analyses). 12,537 patients (35% female) with a median age of 63.5 years were included in the analysis. 82% had prior diabetes, with a mean diabetes duration of 5.4 years. Overall, 953 patients (7.6%) of patients developed cancer during the trial. Cancer incidence was 1.32/ 100 person years.
• There was no significant difference in cancer death rate or adjusted incidence of cancer between the study’s glargine vs. standard care arms. There was also no significant difference in the incidence rate of common subtypes of cancer (lung, colorectal, breast, prostate, etc.) between the study’s two arms. Analyses of baseline data suggested that those who developed cancer were older, had higher alcohol intakes, had higher rates of CV events, and were more likely to smoke. Additionally, patients with new diabetes were more likely to develop cancer. Metformin use was similar between those who did and did not develop a cancer event.
• Use of metformin and dose of metformin at baseline and post-randomization did not impact the risk of developing cancer. It also didn’t impact the hazard ratio of cancer due to glargine. Similarly, use of metformin in combination with an SFU, A1c, and weight had neutral effects. Use of metformin and metformin dose also did not have an effect on development of breast cancer in women participants. Use of metformin with a sulfonylurea, A1c, and weight post-randomization similarly had no effect on this outcome.
•  

Questions and Answers

Q: Why didn’t you look at the effect of insulin dose on cancer outcomes the way you looked at metformin dose?

A: The insulin dose was fairly low. We did not set the trial up to do an analysis with insulin doses, so it’s not something that could be done down the road.

Q: On one of the slides you showed that there were more people with no cancers among those taking SFUs. The difference was statistically significant. Yet afterwards, you analyzed SFU use along with metformin. Are SFUs protective for cancer?

A: We haven’t looked at SFU use alone, but when you add metformin, it doesn’t have an effect.

Q: But SFU use seems to be overrepresented in the ones without cancer.

A: These are baseline characteristics at the time of randomization. It is hard to make a causal relationship from the baseline characteristics. What is important is exposure during the trial. When we included this variable in the model, it didn’t make a difference.

Q: Can you comment on the cases of pancreatic cancer?

A: This is a rare cancer. We didn’t see a significant difference between the treatment arms.

 

Oral Sessions: Hypoglycemia – Mechanisms and Clinical Aspects

Tackling Intractable Problematic Hypoglycemia in Type 1 Diabetes: The Dafne-Hart Pilot Study (255-OR)

Stephanie Amiel, MD (King’s College London, London, UK)

Dr. Stephanie Amiel presented results of the DAFNE-HART pilot study, which aimed to develop an intervention to address motivational and psychosocial factors underlying persistent impaired hypoglycemia awareness. This pilot study enrolled 24 adults with type 1 diabetes that had a median 16 episodes of moderate hypoglycemia in the six weeks prior to study start and mean patient-reported severe hypoglycemia of 3.5 events over the last year (mean baseline A1c was 7.8%). The intervention delivered included motivational interviewing and cognitive behavioral therapy to educate and alter patients’ thoughts and behaviors around hypoglycemia. The program identified and addressed three “thinking traps:” 1) that one can “soldier on” through hypoglycemia; 2) there are no adverse outcomes to impaired hypoglycemia awareness; and 3) overestimation of the risks associated with hyperglycemia. Three months after engaging in the six-week course, patients’ average A1c remained the same, and annualized severe hypoglycemia event rate fell from 3.5 to zero. In addition, the median number of moderate hypoglycemia events in the last six weeks fell to one. Patients wore a CGM for five days before and after the intervention, which revealed that the change in hypoglycemia was driven by a reduction in duration of daytime hypoglycemia. Measures of psychological distress improved – there was a significant change in worrying about hypoglycemia avoidance and a significant change in behaviors around low blood glucose. Audience members seemed very impressed with Dr. Amiel’s results during Q&A; notably, Kaiser Permanente’s Dr. Jim Dudl asked if the curriculum would be available for Kaiser or others to engage with.

Questions and Answers

Q: My question is about using CGM. To what extent do you think the technology made available to these people with alarms and whistles played a role in helping them avoid severe hypoglycemia?

A: The data I showed you were from blinded CGMs they couldn’t see. A very small number of patients were already using real time CGM. We didn’t give patients any new technology. What was interesting in subsequent follow-ups that will confound follow-up for this study is that – several patients have now engaged with new technology, including patients who had previously not expressed interest in doing so. So we’re not just changing their hypoglycemia experience, but we’re also changing their understanding of the severity of the problem.

Q: How did you ascertain these patients that are so refractory to treatment? Did these patients’ families insist? Where did their readiness for change come from?

A: That has been looked at quite closely. We found these patients through educators. People were referred to our program for refractory hypoglycemia. These people don’t not engage with services, they just don’t engage with avoiding hypoglycemia.

Dr. Jim Dudl (Kaiser Permanente): We’ve published similar results with a behavioral approach for people with A1cs over 9%. It’s very attractive. I wonder if your curriculum is propriety or could it be reviewed for us or others to build the same sort of model for hypoglycemia?

A: The curriculum is being modified according to input from patients and educators. There’s still some tinkering to do, and we believe we’ll have to do an RCT for it. We’ll have to prove for our payers that it works with more sustained benefit than three months. We’d be delighted, particularly, to look at collaborating over an early roll out. We think the publication of this curriculum is one of the outcomes that we will be telling the National Institute of Health Research (NIHR), our funders in the UK, we can provide.

Q: Do you think recurrent hypoglycemia determines personality phenotype or the other way around?

A: Relatives often say to me that the person with hypoglycemia unawareness is prone to recurrent behaviors they know to be unhealthy, even outside of diabetes, and can’t stop. There are data suggesting may be a genetic predisposition to hypoglycemia unawareness. We need to see if we can reverse it fully as this would make an inherited risk less likely.

Intensification of Basal Insulin Therapy with Step-Wise Addition of Insulin Aspart Boluses vs. Basal-Bolus Therapy: The FullSTEP^tm Study (256-OR)

Helena Rodbard, MD (Endocrine and Metabolic Consultants, Rockville, MD)

Dr. Helena Rodbard presented the fairly intuitive findings that step-wise initiation of basal-bolus therapy provided non-inferior glycemic control compared to immediate initiation of a full basal-bolus regimen; meanwhile, the step-wise regimen was associated with a lower risk of hypoglycemia and better patient satisfaction. In addition, ~half of completers on the step-wise protocol required only one or two bolus injections/day at the end of the study, whereas all patients in the basal-bolus arm were on three bolus injections/day. Notably, about twice as many patients on the basal-bolus protocol dropped out of the study compared to the step-wise protocol.

• The FullSTEP study aimed to compare the efficacy and safety of incremental addition of bolus insulin aspart to basal insulin therapy against complete basal-bolus therapy (three boluses/day). People with type 2 diabetes (n=401) with mean baseline A1c of 7.9% participated in an eight-week run-in period with insulin detemir. They were then randomized to add step-wise insulin aspart (starting with one daily bolus injection and intensifying to two and three if A1c ≤7% was not achieved at 11 and 22 weeks, respectively) or full basal-bolus (insulin aspart three times/day). Treatment duration was 32 weeks.
• Mean A1c change from baseline to week 32 was similar between the two arms (0.9% vs. 1.1% reduction [n.s.] on step-wise vs. basal-bolus, respectively). Basal-bolus therapy initially provided superior A1c reductions at weeks 11 and 22, as might be expected, though by the end of the trial (week 32) the differences had abated. Mean fasting plasma glucose was similar between the two groups throughout the trial.
• Overall hypoglycemia was almost twice as frequent in the basal-bolus group compared to the step-wise group. When treatment-emergent hypoglycemic episodes were plotted by week, the step-wise group experienced fewer episodes of hypoglycemia every week.
• Only ~half of participants in the step-wise group who completed the trial required three bolus injections at the end of the trial. In the stepwise group, 17% required only one bolus injection/day; 27% required two bolus injections/day, and 40% required three after 32 weeks (14% dropped out). In contrast, 73% in the basal-bolus group were on three bolus injections (26% dropped out). Notably, nearly twice as many participants dropped out of the basal-bolus arm than the step-wise arm.
• The DiabMedSat patient satisfaction scale revealed that patients in the step-wise arm experienced greater treatment satisfaction. They scored more favorably on the burden, efficacy, and overall scores of this scale.

Questions and Answers

Q: At initiation, did you stop all OADs or maintain them?

A: They maintained background OADs at the same dose with no changes. There were about the same number of oral agents in both groups. The predominant oral agents were metformin or sulfonylurea. A few patients were on pioglitazone, and a few patients were on DPP-4 inhibitors.

Q: How did you monitor hypoglycemia?

A: It was depending on patient symptoms or using measurements. They were not on CGM. That would have been ideal, of course.

Q: How often did you see each patient to advise about dose adjustment? Was there any difference in weight gain between the groups?

A: There was no effect on weight gain. Both gained about 2 kg [4.4 lbs] at the end of the 32 weeks, but there was no difference between the groups. In terms of adjusting insulin doses, the basal insulin dose was adjusted weekly by the patients, depending on what the blood glucose levels had been over three consecutive days, using the 3-0-3 algorithm. Regarding the bolus insulin doses, they were adjusted on a daily basis by one unit. Patients were adjusting themselves going up or down one unit at a time.

Q: To clarify, you said step-wise had lesser hypoglycemia but more nocturnal hypoglycemia?

A: No, the step-wise group had fewer hypoglycemia episodes across the board, including less nocturnal hypoglycemia.

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

A Tribute to Dr. Richard R. Rubin

Barbara Anderson, PhD (Baylor College of Medicine, Houston, TX) and Mark Peyrot, PhD (Loyola University Maryland, Baltimore, MD)

Drs. Barbara Anderson and Mark Peyrot delivered heartwarming tributes to honor the late Dr. Richard Rubin as part of the Behavioral Science Contributions to Understanding Diabetes Symposium. As many already know, Dr. Rubin was a renowned psychologist whose contributions revolutionized our psychosocial understanding of diabetes. He served as an American Diabetes Association volunteer for more than 30 years, having been President, Health Care and Education in 2006-2007, chair of the Association’s Committee on Professional Councils, and chair of the Council on Behavioral Medicine and Psychology. He was also a professor of medicine and pediatrics at the Johns Hopkins University School of Medicine. It’s an understatement to simply count his long list of impressive achievements: over 100 publications and eight co-authored books, including three editions of Psyching Out Diabetes. Dr. Peyrot commemorated Dr. Rubin for his passion and ambition, and despite his accomplished career, Dr. Rubin never let his degree define who he was. Beyond his professional credentials, Dr. Rubin will always be remembered and celebrated for his tireless dedication to patient advocacy and education, especially in the critical realm of mental health. We thank him sincerely for his countless years of service and wisdom, as they continue to inspire the rest of us who are committed to the fight against diabetes.

 

Symposium: Primary Results of the Look AHEAD Randomized Controlled Trial of a Lifestyle Intervention in Overweight and Obese Individuals with Type 2 Diabetes

Introduction

Jeanne Clark, MD (Johns Hopkins University, Baltimore, MD)

Dr. Jeanne Clark opened the symposium with an overview of the design of the Look AHEAD trial, a single-blind, randomized, controlled trial that assigned participants to receive intensive lifestyle intervention (ILI) or diabetes support and education (DSE) (n=5,145). In the trial, 60% of participants were women, and 37% were minorities; participants had a mean age of 59 years, of whom 15% were on insulin and 14% had a history of cardiovascular disease. The study’s objective was to determine the long-term effects of intensive lifestyle intervention programs on cardiovascular morbidity and mortality in obese or overweight individuals with type 2 diabetes. The ILI was delivered in multiple phases over a median of 9.6 years, and consisted of multiple group sessions, individual sessions, phone calls, and intensive education on exercise and caloric intake. As a reminder, the study was terminated early for failure to show a difference in the primary endpoint between the two trial arms. For more information on the trial design, please visit the trials website: www.lookaheadtrial.org/public/LookAHEADProtocol.pdf.

Impact of a Lifestyle INtervention on Cardiovascular Events

Rena Wing, PhD (Brown University, Providence, RI)

Dr. Rena Wing presented on the impact of the intensive lifestyle intervention (ILI) on weight loss, cardiovascular risk factors, and cardiovascular events. The primary outcome of the study was the occurrence of a major cardiovascular event including nonfatal myocardial infarction, nonfatal stroke, death, or hospitalization for angina. ILI did not reduce the risk of cardiovascular morbidity and mortality, but participants in this arm did successfully achieve and maintain weight significant weight loss, improve their fitness, and see significant improvements in A1c, systolic blood pressure, and HDL.

• In the Look AHEAD trial, the ILI group achieved greater weight loss and fitness compared to the diabetes support and education (DSE) group. Participants in the ILI arm had significantly greater weight loss than those in the DSE arm at all time points, with the greatest weight loss at one year (8.6%) and a differential loss across the trial of 4%. Additionally, the ILI group had significantly greater improvements in fitness at all time points.
• Additionally, ILI produced significantly greater improvements in cardiovascular risk factors compared to DSE. Specifically, ILI reduced participants’ A1c levels significantly more across the trial, with the greatest difference at one year. Systolic blood pressure improved significantly more in the ISI group, although diastolic blood pressure was similar in the two arms of the trial. Additionally, HDL cholesterol increased more in the ISI group. Although the DSE group showed significantly greater reductions in LDL cholesterol compared to the ISI group, both had reductions, and Dr. Wing pointed out that the use of statins across the trial was significantly higher in DSE.
• Dr. Wing reported that there was no significant difference in the primary outcome between the ILI and DSE groups at any point in the trial. The cumulative hazard ratio was o.95 (95% confidence interval = 0.83-1.09; p = 0.505). Dr. Wing proposed that a larger sustained weight loss may be needed to see a significant difference and that a greater use of statins and more intensive medical management in the DSE group may have reduced differences. She also suggested that early intervention before or within two years of diagnosis might be needed.
• Furthermore, Look AHEAD found no significant difference within three pre-specified subcategories: history of cardiovascular disease, gender, and race/ethnicity. The effect of intervention was similar across subgroups, and the confidence interval for every subgroup crossed 1.0, indicating no difference of the intervention between groups within each subcategory. However, Dr. Wing emphasized that, although non-significant (p=0.06), participants with no cardiovascular disease history had a lower event rate of primary outcomes on ILI compared to DSE. Participants with cardiovascular disease history had a much greater number of events during the trial, and the event rate for primary outcomes was non-significantly higher in ILI compared to DSE.

Impact of a Lifestyle Intervention on Health Care Costs and Utilization

Henry Glick, PhD (University of Pennsylvania, Philadelphia, PA)

Dr. Henry Glick discussed the long-term effects of intensive lifestyle intervention (ILI) on the use of medical services and cost of care, noting that the per-participant analyses were based on the intent-to-treat population. ILI significantly reduced the average number of medications per year compared to diabetes support and education (DSE), and specifically reduced the number of diabetes, lipid-lowering, and anti-hypertensive medications the participants took. ILI also reduced overall hospitalizations by 11.7% compared to DSE, and reduced cardiovascular hospitalizations by 12.5%. Participants in the ILI group had a significant average cost reduction per year of $602 versus DSE; these cost reductions were concentration in hospitalization (10.7% reduction) and medication costs (7.5% reduction). The ten-year cumulative medical costs of participants were also significantly lower in the ILI group ($71,746) compared to the DSE group ($77,124; p<0.0001). There were no significant differences in treatment effect on cost for age, BMI, gender, or race/ethnicity, although ILI only significantly reduced medication and total costs in patients with no history of cardiovascular disease and had no effect on these parameters in patients with cardiovascular history. They have not quantified DSE or ILI costs, although Dr. Glick indicated plans for evaluating the cost-effectiveness of ILI, and noted that the intervention could still be cost effective even with the failure to achieve the primary endpoint, because cost-effectiveness must take into account cost, survival, and quality of life as well.

Impact of a Lifestyle Intervention on Depression and Quality of Life

Lucy Faulconbridge, PhD (University of Pennsylvania, Philadelphia, PA)

Dr. Lucy Faulconbridge presented results on the impact on intensive lifestyle intervention (ILI) versus diabetes support and education (DSE) on the incidence of symptoms of depression. At baseline, participants had an average Beck Depression Inventory (BDI) score of 5.5 (≥11 qualifies as having mild symptoms of depression), 14% had BDI ≥11, and 17% took antidepressant medications. In addition, they had an average SF-36 Physical Component Summary (PCS; consists of general health perception, physical function, role limitations due to physical problems, and bodily pain) score of 48.1 and Mental Component Summary (MCS; consists of mental health, vitality, role limitations due to emotional problems, and social function) score of 53.9 (50 is the average). After eight years, ILI reduced the risk of progression to mild or more severe symptoms of depression by 20% versus DSE, as assessed by the BDI – the incidence of depression was 17.5% in the ILI group, versus 20.9% in the DSE group. Dr. Faulconbridge commented that this is the strongest evidence to date that ILI protected overweight and obese individuals from depression. However, there were no significant differences between ILI and DSE on the time to first use of antidepressant medications. In addition, there were no significant differences between the SF-36 Mental Component Summary (MCS) score between ILI and DSE, suggesting the protective mental health benefits of ILI were specific to depression.

 

Symposium: Nonprescription Therapies for Diabetes Mellitus

An Update on the ORIGIN Trial and What We Know About Omega-3 and Diabetes Mellitus

Aldo Maggioni, MD (ANMCO Research Center, Florence, Italy)

Dr. Aldo Maggioni summarized recent ancillary study results as well as updates on the highly anticipated ORIGIN trial, with a focus on the possible effects of daily 1 g supplementation of omega-3 polyunsaturated fatty acid (PUFA) on cardiovascular risk. In summary, these studies found no statistical difference of omega-3 supplementation versus placebo, and only marginal benefit in patients with diabetes. He also provided information on the most recent European clinical recommendations for omega-3 PUFA supplementation, which recommended moderate intake of omega-3. Dr. Maggioni concluded with an overview of the upcoming ASCEND trial, which compared aspirin against omega-3 supplementation in patients with diabetes with a primary endpoint of total cardiovascular complications.

• Dr. Maggioni summarized the results of the ORIGIN trial, which found no significant difference in cardiovascular complications in a placebo group versus a group taking once-daily 1 g omega-3 supplements. This study was composed of non-insulin dependent patients 50 years or older with impaired glucose tolerance (IGT), impared fasting glucose (IFG), or early type 2 diabetes patients that were also at high risk for cardiovascular complications. After 7 years of follow-up, the placebo patients and the patients on omega-3 supplements exhibited nearly identical rates of mortality by cardiovascular causes (p=0.72).
• An updated study conducted by Dr. Maggioni’s research group evaluated patients with a high risk of cardiovascular events with atherosclerosis. They investigated the potential effect of daily 1 g omega-3 supplementation and found no significant difference from the placebo arm after a median follow-up of 5 years (n=12,505). Using death or first hospitalization due to cardiovascular cause as the primary endpoint, there was no significant difference in outcomes between the placebo arm and the treatment arm of omega-3 supplementation (p=0.64). Even when accounting for diabetes and cardiovascular risk factors as interacting variables, the difference was not significant (p=0.68). Thus, based on ORIGIN and the follow-up ancillary studies, there was no significant benefit of omega-3 fatty acids in reducing the risk of death or hospitalization from cardiovascular causes.
• In conclusion, Dr. Maggioni summarized that the higher the risk status of the patient, the greater the benefit of omega-3 supplementation seems to be. He suggested that the European Society of Cardiology (ESC) guidelines on primary prevention, dyslipidemia, post-myocardial infarction prevention, and heart failure are all valid because of the marginal benefit the supplementation provides. The ESC recommends eating fish at least twice a week and also states that an omega-3 supplementation may be considered for patients treated with an ACE inhibitor, beta-blocker, and MRA/ARB. These guidelines are supported by a 2B level of proof, adding some amount of credibility to these suggestions.
• Dr. Maggioni indicated that the ASCEND trial, a 2x2 factorial study of aspirin versus omega-3 fatty acid supplementation, is expected to complete in December 2016 and will provide additional data for patients with diabetes. The study consists of 15,480 patients with diabetes without occlusive arterial disease. Its primary outcome measure is the combination of non-fatal myocardial infarction and non-fatal stroke or vascular death. Currently, this study has completed recruitment and should provide more comprehensive evidence on the potential effects of omega-3 fatty acid supplementation on cardiovascular health.

Questions and Answers

Q: Why did you use a dosage of 1 g omega-3 fatty acid in your studies instead of 3 g or 9 g, which are more conventionally used?

A: We started with the 1 g dose because the other trials conducted before were simply testing dietary advice. Previous trials showed benefit for the 1 g dosage. For this reason, we repeated the same scheme. When you use higher doses, you probably have better effects, but there are also some problems in patients who are under treatment with anticoagulants. In my opinion it is difficult to imagine a beneficial effect in patients with diabetes.

 

Symposium: Moving Toward a Cure in Type 1 Diabetes

Importance of Titrating Hope with Reality

Sandra Puczynski, PhD (Southern Illinois School of Medicine, Springfield, IL)

Dr. Sandra Puczynski, a parent of a child with type 1 diabetes, closed the session with a discussion of hope, her family’s experience with type 1 diabetes, a historical perspective on curing type 1 diabetes, and a brief outlook on the future. We appreciated her statement that “hope is essential…reality is the challenge.” She provided several literature reviews and her opinions on type 1 diabetes cure research – we especially agreed with her opinions that 1) research expenditures are not keeping up with the growth in diabetes (underscored by Dr. Judith Fradkin’s meet-the-expert talk on the first day of ADA 2013) and 2) conventional methods for designing and conducting clinical trials are not working. We have included some of our favorite quotes from her talk below.

• “For us, hypoglycemia was the most frightening experience. We probably kept our baby daughter too tightly controlled. It was the era of the DCCT and we lived in Pittsburgh at the time. Everyone was focused on tight control. It was not until the 1990s that we earned about the potential long-term consequences of hypoglycemia on the developing brain. Our daughter had several hypoglycemic seizures before grade school. No one at her school was prepared to deal with it.”
• “I just did a web search on the terms ‘Type 1 diabetes’ and ‘cure.’ I came across an article entitled, ‘Boston Children’s Hospital on the verge of a diabetes cure.’ The article said, ‘Last week, the hospital published information on new research that could allow diabetics to toss those shots for good” (Boston Magazine, June 13, 2013). Said Dr. Puczynski, “This is a bit misleading to say the least.”
• “The potential to cure type 1 diabetes is clearly within reach….approaches used in the past must be more aggressive, including combination approaches and novel interventions.” - Drs. Jay Skyler and Camillo Ricordi, Diabetes 2011
• “Either we have hope or we don’t; it is a dimension of the soul…an ability to work for something because it’s good, not just because it stands a chance to succeed. Hope is not the same thing as optimism. It is not the conviction that something will turn out well, but the certainty that something makes sense, regardless of how it turns out.” - Vaclav Havel, writer and former Czech President
•  “Insulin symbolized and stimulated our century’s commitments to medical research…it is considered one of the greatest discoveries in the history of medicine.” - Michael Bliss, The Discovery of Insulin, 1984

Update on Cellular Advances

Todd Brusko, PhD (University of Florida, Gainesville, FL)

Dr. Todd Brusko provided an overview of T regulatory (Treg) cell therapy for type 1 diabetes, arguing that Tregs could be a new paradigm for treating the disease. He reminded the audience that autoreactive effector T cells drive destruction of beta cells in type 1 diabetes and that people with diabetes may have subtle defects in Treg suppressor function. Thus, if we could deplete T cells or bolster Tregs, we could potentially alter autoimmunity. Dr. Brusko is largely focusing on the Treg cell side of the equation. For example, he and his team are working on expanding Tregs from umbilical cord blood, capitalizing on prior expansion technologies and safety data. The Tregs they have derived via their protocol express Treg markers, are quite pure post-expansion, and have suppressive capacity even after freezing and thawing. He is also working on engineering Tregs using lentiviral vectors to make them antigen specific (for example to an antigen like GAD) or to modulate their effector functions. Finally, he is exploring delivery of Tregs with nanoparticles bound to their surface. This would allow Tregs to carry their own “payload” of agents, such as the cytokine IL-2.

Questions and Answers

Q: Can you comment on the fluidity of the cells? Can they become effectors, especially those that have TCRs against islet antigens?

A: When you go through the stringent selection process we do, I think that minimizes some of the risk. T-reg plasticity has been shown in many systems in animal models, but I would challenge anyone to show where T-reg therapy has made autoimmunity worse. You don’t see effector cytokine expansion after T-reg production.

prevention Studies – Translating the Past into the Future

Srinath Sanda, MD (University of California at San Francisco, San Francisco, CA)

Dr. Srinath Sanda summarized ongoing prevention studies and areas of interest in the diabetes prevention field. He began by highlighting the TRIGR, Oral Insulin, Pre-Point, and INIT-II trials, as well as efforts with CTLA-4 Ig and anti-CD3. While TRIGR is a primary prevention study that utilizes a hydrolyzed cow’s milk formula, the Oral Insulin, Pre-Point, and INIT-II trials aim to induce immune tolerance via presentation of an antigen (insulin). Meanwhile, CTLA-4 Ig is a molecule that blocks T-cell activation by APCs and anti-CD3 is a monoclonal antibody against the CD3 molecule on T lymphocytes. Both have shown promise in phase 2 trials, and anti-CD3 has had positive results in subgroup analyses of phase 3 testing. Unfortunately, Dr. Sanda said, none of these approaches are directed at specific defects in the progression to type 1 diabetes. This is because we don’t yet know the mechanistic defect that leads to altered glucose metabolism. Both study of metabolomics signatures pre-diagnosis and statistical modeling of progression to disease in the DPP have yielded some new insights. Additionally, recent studies of T cells have suggested that T effector cells may be resistant to Treg mediated suppression in type 1 diabetes. Dr. Sanda concluded by stating that we still have many “gaps” to fill before we fully understand the immune perturbations that occur prior to clinical diagnosis. One of the first steps towards gaining a fuller understanding of this topic will be exploring why some therapies are only successful in the new onset period.

Questions and Answers

Q: What are the barriers to filling in the gaps you described?

A: The most important thing is for investigators from associated fields to become interested in type 1. We need new thinking – maybe from metabolomics, or beta cell biology. Folks who have worked on studying the immune system have to acknowledge that we need outside people who have different expertise. Additionally, maintaining organizations that are able to collect large cohorts of at risk individuals is very important.

 

Symposium: So Your Patient Has Diabetic Kidney Disease – Now What?

Diabetic Kidney Disease: Cardiovascular Risk Amplifier – What Works, What Doesn’t?

Maryam Afkarian, MD, PhD (University of Washington, Seattle, WA)

Dr. Maryam Afkarian gave a clear, evidence-based talk on managing cardiovascular risk in diabetic kidney disease. She explained that the two main markers of diabetic kidney disease (albuminuria and impaired glomerular filtration rate) are strongly, independently associated with cardiovascular mortality in both type 1 and type 2 diabetes (De Boer et al., Diabetes Care 2009; Ninomiya et al., J Am Soc Nephrol). In contrast, among patients with type 1 or type 2 diabetes whose kidney function is normal, mortality rates are similar to those for people without diabetes (Groop et al., Diabetologia 2009; Afkarian et al., J Am Soc Nephrol). Unfortunately, diabetic kidney disease is increasingly prevalent (De Boer et al., JAMA 2011), and data are limited on how these patients respond to different CV-protective therapies. Dr. Afkarian knows of no trials or post-hoc analyses about how glucose control affects CVD in diabetic kidney disease specifically, but she suggested that safety concerns are associated with A1c targets should be relaxed in type 2 diabetes patients who have kidney disease (as for other comorbidities and risk factors). She said that from the perspective of CV risk reduction in these patients, glycemic control appears less important than management of blood pressure and lipid levels. However, she clarified that glucose-lowering therapies are still important for preventing other complications.

Questions and Answers

Q: Among hypertension, hyperlipidemia, and hyperglycemia, which has the upper hand with regard to cardiovascular outcomes?

A: In the general population of people with type 2 diabetes, glycemic control seems not to do much for cardiovascular risk, up to 10 years. Lipid management seems to have some benefit, and antihypertensives show an undisputed benefit. But other organs besides the heart are affected by glycemic control, so that is still important.

 

Interest Group Discussions: Professional Section Interest Group Discussion on Complications

Comparing and Contrasting Outcome Studies of Intensive Therapy in Type 1 Vs. Type 2 Diabetes: Patient Characteristics and outcomes in the DCCT/EDIC Trial

David Brillon, MD (Weill Cornell Medical Center, New York, NY)

Dr. David Brillon discussed patient characteristics that were associated with benefits and risks of intensive glucose control in DCCT/EDIC. Several variables were associated with increased or decreased risk of developing micro- and macrovascular complications in the trial: people that had sustained C-peptide and lower advanced glycation end produce (AGE) formation were at lower risk for developing complications. However, people with a family history of type 2 diabetes, nephropathy, absent C-peptide, and increased AGE formation were at higher risk for complications. Several variables increased the risk of experiencing adverse events (AEs) in the intensive treatment group: prior hypoglycemia, absent C-peptide, family history of type 2 diabetes, and adolescence all predicted increased rates of AEs. Present C-peptide was associated with decreased rate of AEs.

Risks vs Benefits of Intensive Glycemic Control in Type 2 Diabetes Lessons from ACCORD, UKPDS, and ORIGIN

Matthew Riddle, MD (Oregon Health & Science University, Portland, OR)

In this thoughtful review, Dr. Matthew Riddle recommended glycemic control strategies for type 2 diabetes, based on three major randomized controlled trials (ACCORD, UKPDS, and ORIGIN). He urged clinicians to diagnose diabetes as soon as it occurs, and he suggested that A1c targets be stratified by risk (Riddle et al., Diabetes Care 2012). For people who have had diabetes for less than five years and who have few comorbidities, he targets A1c <7.0%; for people with disease duration longer than 10 years and multiple comorbidities, he targets A1c 7.0%-8.0%. For patients at intermediate risk, he targets A1c <7.0% but raises the goal if A1c does not drop by 0.5% within six months – this is because in ACCORD, a failure to respond to intensive therapy was associated with higher mortality. Dr. Riddle noted that we do not have enough data on patients whose A1c is persistently above 8.0% and who have other comorbidities (e.g., proliferative retinopathy, sustained proteinuria, severe hypoglycemia). However, he said that A1c targets of 8.0-9.0% are probably suitable for many of these people. He also noted the dearth of data on people with longstanding type 2 diabetes duration and low cardiovascular risk, since neither ACCORD, UKDPS, nor ORIGIN enrolled such patients. He concluded by optimistically suggesting that the future could bring “fewer hard decisions” and “more easy ones” – he proposed that if clinicians initiate intensive glucose control immediately after diagnosis, they will ultimately have fewer “really difficult” patients to manage (Riddle et al., Endocrinol Metab Clin NA 2012).

Questions and Answers

Q: Dr. Riddle, can the people who are slow to decrease their A1cs be discriminated in terms of CV risk factors?

Dr. Riddle: We haven’t done a detailed analysis of who they are. It should be done. My expectation is they will turn out to have a higher burden of complications at the outset. That hasn’t been shown quantitatively yet. I think an equally important point, that we actually did not collect data on, is the behavioral factors as well as the physiologic factors. A lesson for future trials is that we need to be collecting behavioral information to understand what it is that gets in the way.

Q: In ACCORD, there was a statistically significant increase in mortality among patients who were randomized to both intensive glucose control and intensive blood pressure control. Have you looked at whether hypoglycemia or other events influence this interaction?

Dr. Riddle: That analysis was just completed and accepted. No, we have not looked at hypoglycemia as a predictor. Multivariate adjustments were done in some parts of study, but I don’t think it was looked at closely enough. Another possibility is that the blood pressure treatment caused unwanted effects that are as important or more important than hypoglycemia – for example, bradycardia with beta blockers. Currently we have more questions than answers.

Q: This is more of a comment – we are currently paid for performance, so there are criteria that you’re paid for based on how you achieve guidelines. The current A1c we’re supposed to achieve is <7%, so it seems like we’ll have to make some serious adjustments to that.

Dr. Riddle: Yes, this is very personal of you to share. I’m not speaking for ACCORD or anything else, but I think that’s a dangerous kind of general principle because it encourages health systems and doctors to take credit only for the easier to treat patients, and the difficult to treat patients are on their own. Having said that, I believe we’re moving pretty rapidly in all major guidelines and reimbursement structures toward the concept that one size doesn’t fit all and that excellent treatment for long duration patients probably includes A1c being maintained carefully in 7-8% range. I don’t think a one-size-fits-all <7% target will remain widely recommended by anybody.

Q: In addition to evaluating the frequency of hypoglycemia, did you look at the impact of baseline BMI and change in BMI during the period of observation, in terms of the risk of cardiovascular or other events?

Dr. Riddle: That is a very difficult analysis. Dr. Vivian Fonseca led a writing group that has completed a manuscript accepted for publication in Diabetes Care. In brief, the analysis was unable to determine whether weight gain in the trial was associated with increased cardiovascular rate or mortality risk. The data on weight gain were confounded by the weight loss that occurs in terminal illness and the weight gain that is a side effect of some diabetes therapies. Nothing conclusive has been found with regard to weight gain, to my knowledge.

Q: In my experiments people who do not respond to medication tend to have bad lifestyle. So my question is, how do you check the diet and exercise in those patients?

Dr. Riddle: I would say the research studies haven’t given us much direct guidance on this. Look AHEAD and DPP have generated a lot of evidence on that. In clinical practice, the translation of dietary and nutritional intervention studies into clinical practice is, as you suggest, a major goal. In our group we try very hard to identify people’s behavioral challenges and give the best guidance and support we can. At least where we live the reimbursement support for lots of time spent on this is not very good. For us, as for many people, it’s a barrier for getting the best lifestyle effort for many patients.

Q: In ACCORD, was there a difference in insulin dose among those who died?

Dr. Riddle: This was on our list of unanswered questions. A paper is being presented tomorrow by ACCORD group; I think it’s an oral. You will see the data there. We analyzed exposure to insulin, both for all insulins and for prandial vs. basal, with cardiovascular mortality as the endpoint. It’s very interesting data. I encourage you to go to that session.

Q: From the DCCT/EDIC study, we haven’t really seen the mortality data yet, if I remember correctly, then there was a numerical imbalance not favoring intensive therapy in the original DCCT trial. Will that mortality analysis be in the EDIC follow up analysis? Also, is there a possible influence of hypoglycemia?

Dr. Brillon: Because of the young age of the cohort in the DCCT/EDIC, there weren’t a lot of deaths in the cohort, so it took some years to have sufficient numbers to allow for proper statistical analysis between the two treatment groups. That event threshold has been reached. There is a manuscript being prepared. We got in mortality. It was mentioned in the Saturday session. There was no increased mortality seen with intensive treatment compared to conventional treatment. However, other aspects of that paper, including analyses we got on hypoglycemia, are obviously embargoed for publication, but there was no increase in mortality seen in DCCT/EDIC.

Q: Many studies prove that controlling A1c cannot make patients immune from complications. In the future, might we look for other biomarkers for complications?

Dr. Brillon: At this time we don’t have a lot of other biomarkers that we can use in terms of glucose effects. I alluded to AGE biopsies; many other studies have used serum or urine measures of AGE products. These tests appear to indicate predictive ability of these biomarkers with regard to microvascular complications. In some cases these appear to be independent of A1c. Also, enhanced formation of AGEs may help to identify people at increased risk of developing microvascular disease. This may explain why some individual patients have complications despite stringent glucose control, and others have high A1c but no complications. We have no ways to intervene based on AGE findings, but this is an area of some future importance.

Dr. Riddle: There is a longstanding hypothesis that glycemic variability contributes to the risk of complications, independently of A1c. Epidemiological data suggest that this may be the case. I know for sure of only one trial that is attacking this issue, because I am involved in it. Dr. Irl Hirsch and Dr. Jeff Probstfield are leading a randomized controlled trial in patients with type 2 diabetes. The comparison is between basal/bolus insulin and basal insulin with two-to-three injections of short-acting GLP-1 agonist per day. The thought is that the GLP-1 agonist might blunt postprandial glycemic variability. The study also includes holter-monitor measurements of cardiovascular health. For now, we still don’t know.

Q: What is the mechanism for the hypoglycemic preconditioning?

Dr. Riddle: Right now it’s an observation. As you know Philip Cryer and others have written extensively about physiologic changes that occur with blood sugar below 70 mg/dl. And included in what happens is a blunting of the ability to sense hypoglycemia (hypoglycemia unawareness). This is a diminution of the catecholamine secretory response and other physiologic changes too. What I believe right now is that part of this is nature’s adaptive response to falling glucose, which has some favorable parts to it: a newborn child or a very ill dying patient with a glucose level chronically below 50 mg/dl doesn’t have constant symptoms. That might be viewed as a favorable thing. But of course hypoglycemia unawareness allows glucose to gets to the level where the brain doesn’t function. That’s a very serious problem leading to traffic accidents, etc. A big problem is that a vulnerable patient with cardiovascular disease without prior hypoglycemia, if exposed to hypoglycemia, may have a surge of catecholamine response causing arrhythmias. Blunting of catecholamines in that setting may protect against death.

 

Interest Groups Discussions: Professional Section Interest Group Discussion on Clinical Endocrinology, Health Care Delivery, and Public Health

Easy to Say, Not So Easy to Do: Patient-Centered Care in the Era of Patient-Centered Guidelines

Jeffrey Gonzalez, PhD (Yeshiva University, Bronx, NY)

Dr. Jeffrey Gonzalez opened the discussion on patient-centered care by detailing the necessity of emotional distress evaluation. He presented studies in which 73% of adults with type 1 diabetes (n=34) and 49% of adults with type 2 diabetes (n=70) attributed their symptoms of depression, particularly reduced appetite and sleep disturbances, to diabetes (Tenenbaum and Gonzalez, Diabetes Educator 2012; Tanenbaum et al., J of Affective Disorders 2013). People’s explanatory statements tended to have three themes: 1) distress about diabetes; 2) overlapping symptoms; and 3) a bi-directional interaction between mood and blood glucose levels. Given the overlap between diabetes distress and depression, he pressed that HCPs must ask their patients why they are distressed, not just how much distress they are experiencing. Dr. Gonzalez recommended that HCPs use depression-screening instruments with their patients. He warned, however, that many have frequent false positives (up to 50% false positive rate), necessitating follow-up appointments on the topic of depression to evaluate the validity of a positive.

• Dr. Gonzalez reminded attendees that it is difficult to adhere to diabetes treatment due the complexity of many regimens and the psychological challenges of the disease. These latter trials arise from 1) the disease “going on forever”; 2) people receiving inconsistent feedback (e.g., doing the same thing two days in a row with different glucose results); and 3) the reward for adhering to treatment is nothing happening twenty years later.
• According to Dr. Gonzalez, people’s descriptions of the link between their diabetes and feelings of depression tended to fall into three categories: 1) distress about diabetes, 2) overlapping symptoms of the two conditions, and 3) a bi-directional impact of glucose on mood and vice versa. Dr. Gonzalez provided examples quotes for each of these categories (detailed below).
  
  • Distress about diabetes
    • “I check my blood and it’s high and I check my blood and it’s low and I go back to eat something and it gets high again and it is just tiresome. Sometimes I get like, whatever, it just doesn't matter.” – 46 year-old male with type 1 diabetes.
    • “I’ve gained so much weight…I’ve never been this big in my life and part of the weight is due to the medication that I take. That really depresses me.” – 56-year-old female with type 2 diabetes.
  • Overlapping symptoms
    • “[I only forced myself to eat] when I was low and I had to eat something. So I guess, probably two or three times this week, I thought I really don't want to eat something but I have to.” – 24-year old female with type 1 diabetes.
    • “With the diabetes, I tend to go to the bathroom. So, it’s like three hours and then I’m up, then I’m back to sleep another two or three hours.” – 42-year old male with type 2 diabetes.
  • Mood ß à blood glucose levels
    • “Whatever goes on with me…one of my immediate responses in my head is ‘Oh my god…don't get nervous your sugar is gonna go high.” – 56-year old female with type 1 diabetes.
    • “My mood’s been up and down. One minute I’ll feel cold and the next minute I feel really…and then my sugars are out of control; they’re up and down. I’m hoping that I can get the diabetes under control.” – 57-year old female with type 2 diabetes.

Panel Discussion

Martha Funnell, MS, RN, CDE (University of Michigan, Ann Arbor, MI); Jeffrey Gonzalez, PhD (Yeshiva University, Bronx, NY); Chandra Osbourn, PhD, MPH (Vanderbilt University, Nashville, TN); William Polonsky, PhD (Behavioral Diabetes Institute, San Diego, CA); Tricia Tang, PhD (University of British Columbia, Vancouver, Canada)

Dr. Polonsky: I am very interested to meet anybody who thinks that patient-centered care is a bad idea. For me it is just about appreciating that people are not unmotivated to leave a happy long life. It is just that things get in the way. It is hard to know how to address this in our crazy business practices.

Ms. Funnell: With that said, I think we would like to start figuring out what is patient centered care in your minds. It is not just about numbers – it is not just numbers and EMRs (electronic medical records). Then what is patient centered care? My provider just told me we are patient centered care now. I asked him what they were doing differently. He said, well we changed the letterhead [laughter]. What we would like to hear from you is: what are your struggles with patient centered medical care, and what do you think is helpful for implementing this? What are your challenges?

Comment: I just had an idea. In our clinic we have just implemented another piece of paper that we give patients, which asks them “what is the purpose of your visit today?” You do not have to do it consistently, but every couple months ask patients “what are you distressed about today?” I think what we are all struggling with is that we only have 20 minutes with our patients. Having them fill this out in the waiting room might help streamline this.

Dr. Polonsky: The most useful question to ask is: “can you tell me one thing about living with diabetes that is driving you crazy?” You probably have a very busy practice, and their list is probably much longer than one thing. However, it is a good place to start, and it is better than asking what is the point of your visit today because the patient expects the HCP to answer that.

Ms. Funnell: Any other thoughts? We often ask our patients what they would like us to do. If you ask them what is distressing them, you have to address it.

Comment: I am in line with your thinking. You have to consider what the patient trusts, and what the patient expectations are. Rather than having the patient think that they are coming in for the physician to do his job, we need to have the patient consider what they are getting out of the visit to satisfy their distress; we need to go in their direction and not only our direction.

Comment: I find that patients are quite upset about finding out what that their next A1c is going to be and are distressed thinking that we are going to yell at them about it. That is not our job. I just cringe thinking about the person who preceded us and marked it in a red pen. I do not yell at patients. That is not my job. I need to empower them to reach the lifetime achievements.

Comment: When a patient comes into a new system, they are not used to telling anyone what they want. They are accustomed to hearing the physician’s side of the story and then agreeing or disagreeing with it – usually just agreeing with it. When I get a new patient, I tell them: tell me about yourself. What are your challenges with diabetes? What do you do as a hobby? What is new in your life? Then, the next time that I ask these questions, they tell me right away. Since I work in a large practice, some of my colleagues do not like that they now get an answer when they ask “how are you?” They are not used to hearing the answers. However, we have to open the door so patients can answer those questions honestly, and we have to educate colleagues to ask these questions. If we do not start with understanding what the patient wants from the physician, the visit is pretty much lost.

Dr. Polonsky: I think that one of the things that is implicitly crazy about how we treat diabetes in America is that when people come to see us, we unfortunately are not talking to them about “how can we help you get to somewhere safe and healthy with your disease.” The problem is we often have this implicit message of “how do we get you to behave?” Or “you need to behave.”

Comment: Working with minorities that are unlike myself, I work really hard to get to know a patient. As a physician, I have the eight minutes instead of the 30 minutes, so I really look to my team to build that relationship. Generally speaking, I have an idea of when I have a relationship with a patient and when I don’t, and I cannot move on until I have built that relationship.

Ms. Funnell: I liked your statement about patients being afraid of their A1c numbers. I think that diabetes is the one disease where instead of feeling like we need to treat the disease, we feel like we have a moral imperative to change the person. That needs to change. I ask people “tell me about this number.” This way we are not judging. The numbers should be about determining what the next step is. Our job is not to fix people.

Dr. Gonzalez: I agree with what you said, and I was just thinking we should move on to our next speaker. But let’s not leave this distress behind – we will have more time to discuss this.

 

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