ADA Postgraduate Course

March 4-6, 2016; San Francisco, CA; Full Report – Draft

Executive Highlights

The American Diabetes Association’s 2015 Postgraduate Course, which ran over the weekend in San Francisco, touched upon a range of the most clinically relevant issues in diabetes care today. These included insulin pricing, clinical data on SGLT-2 inhibitors, technology as a means to promote behavior change, and the benefits and limitations of the current CVOT paradigm. We were also glad to see the first-ever ADA postgrad presentation on the future of closing the loop (!). Included below is a quick list of five of our top highlights from the meeting, followed by our more in-depth coverage. We will have more detailed coverage in the next week.

1. Dr. Anne Peters (USC, Los Angeles, CA) characterized SGLT-2 inhibitors as a “wonderful class” – she expressed great enthusiasm for EMPA-REG and CVOTs and shared her comfort and clinical approach to prescribing the class in type 1 diabetes with regards to diabetic ketoacidosis risk.

2. Dr. Bruce Buckingham (Stanford University, Palo Alto, CA) summarized the current challenges, opportunities, and research in automated insulin delivery (AID), prompting applause from the audience when he stated, “you will be able to prescribe closed loop systems next year.”

3. In a passionate and engaging presentation, Dr. Irl Hirsch (University of Washington, Seattle, WA) tackled the challenging topic of skyrocketing insulin prices over the past decade – a “post script” to his talk at last year’s ADA Scientific Sessions. He noted that the field has “crossed a line” to the point where insulin has became unaffordable for many, particularly Medicare patients in the “donut hole”, those with high-deductible insurance plans, the uninsured, and those who simply can’t afford the high co-pays for insulin.

4. Dr. David Marrero (Indiana University, Indianapolis, IN) discussed the potential of technology to promote behavior change in diabetes. We thought this was among the most valuable talks we’ve heard on integrating more behavioral thinking into digital solutions – especially mobile applications – and it’s clear that Dr. Marrero (who has type 1) has a pulse on exactly what patients are thinking.

5. In a talk reminiscent of her Keystone presentation, Dr. Allison Goldfine (Joslin Diabetes Center, Boston, MA) addressed the benefits and limitations of the current CVOT paradigm for diabetes drugs and called for greater discussion among the scientific community about whether these trials are asking the most important clinical questions. She devoted a significant portion of the talk to explaining why many of these trials as currently designed are unlikely to demonstrate CV benefit.

Detailed Discussion and Commentary

General Session I

Cardiovascular Outcome Trials: Are They Really Needed?

Allison Goldfine, MD (Joslin Diabetes Center, Boston, MA)

In a talk reminiscent of her Keystone presentation, Dr. Allison Goldfine addressed the benefits and limitations of the current CVOT paradigm for diabetes drugs and called for greater discussion among the scientific community about whether these trials are asking the most important clinical questions. She devoted a significant portion of the talk to explaining why many of these trials as currently designed are unlikely to demonstrate CV benefit. She stressed that while they are well designed to evaluate the cardiovascular safety in high-risk patients, the trials would only be able to show superiority in the event of a direct non-glycemic effect that is strong enough to manifest within 1.5-3 years in the setting of standard therapy for diabetes, blood pressure, and lipids. Considering that no anti-diabetes drug evaluated under the 2008 FDA guidance have shown an increased risk for MACE, Dr. Goldfine encouraged greater discussion about whether the scientific community is satisfied with the information gained from CVOTs relative to their costs. Moving briefly to EMPA-REG, Dr. Goldfine provided an overview of the unexpectedly positive results along with her thoughts on driver of the benefit. She suggested that combined favorable effects on glucose, weight, blood pressure, and osmotic diuresis together are the most likely explanation though did not rule out the possibility of other mechanisms as well. She also touched on the DPP-4 inhibitor/heart failure controversy and suggested that a class effect, different drug-specific effects, or chance findings in some studies are all plausible explanations for the divergent results in the three DPP-4 inhibitor CVOTs. The issue remains unresolved though she noted that the reassuring results from TECOS (the largest and longest of the three trials) should largely rule out the hypothesis of a class effect.

  • Dr. Goldfine stressed that the jury is still out on the DPP-4 inhibitor/heart failure controversy. While the explanation remains unresolved, she suggested that the reassuring results from TECOS should largely rule out the hypothesis of a class effect. On the other hand, she also noted that there are no clear mechanisms to explain different drug-specific effects. Indeed, Dr. Goldfine suggested that the true story on heart failure likely cannot be extrapolated from existing trials because studies to date have not included enough heart failure patients to accumulate sufficient events for certainty. We’ll look forward to seeing whether future trials are able to (or unable to) replicate these results.

What’s New in the Standards of Medical Care in Diabetes – 2016?

William Herman, MD (ADA, Alexandria, VA)

Dr. William Herman presented the ADA’s updated 2016 Standards of Medical Care in Diabetes, its annual set of evidence-based guidelines for healthcare providers on the diagnosis and treatment of patients with diabetes. Notable changes in the 2016 document include a greater focus on vulnerable populations, an expansion of the recommended population for prediabetes screening, an endorsement of continued access to pumps and CGM for patients over 65, and a dedicated section on obesity management. (The latter also includes a new table of currently approved medications for the long-term treatment of obesity – see below.) A new recommendation was also made to reflect evidence that adding ezetimibe to moderate-intensity statin provides additional cardiovascular benefits for select individuals with diabetes and should be considered. Dr. Herman speculated briefly on the promising role of SGLT-2 inhibitors in the treatment of type 2 diabetes as well though the official guidelines have not yet been updated in a substantial fashion – SGLT-2 inhibitors are still second-line therapy. Indeed, we continue to believe that more data (from coming trials) is needed before payers and government agencies change policy more broadly. To see the ADA’s full 2016 Standards of Medical Care, click here.

FDA-Approved Medications for the Long-Term Treatment of Obesity

The Microbiome and Diabetes: ADA/JDRF Research Symposium Summary

Robert Ratner, MD (ADA, Alexandria, VA)

In a talk reminiscent of his 2015 ADA Postgraduate Course presentation, Dr. Robert Ratner offered an overview of research into the gut microbiome. His remarks were optimistic – pointing to the potential of the sheer number and diversity of bacteria in the human gut and the strong association between changes in the microbiome and changes in the host’s metabolism – but also laid out a few major challenges for the field: (i) translating results from animal models to humans; (ii) a lack of large cohort studies; (iii) an incomplete understanding of what’s working and what’s not; and (ii) a lack of funding to understanding the basic mechanistic functioning of the immune system. Fortunately, this remains a very active area of research and Dr. Ratner shared a handful of learnings from the 2014 ADA/JDRF research symposium (see our coverage of Day #1, Day #2, and Day #3 for more details). Overall, we loved seeing his enthusiasm for the microbiome and it’s clear that the ADA believes the subject to be of the utmost relevance for both type 1 and type 2 diabetes. The organization has funded a good amount of microbiome research to date and it sounds like this will continue to be a priority in the future.

Concurrent General Session IIA

Progress in Closing the Loop

Bruce Buckingham, MD (Stanford University, Palo Alto, CA)

Dr. Bruce Buckingham summarized the current challenges, opportunities, and research in automated insulin delivery (AID), prompting applause from the audience when he stated, “you will be able to prescribe closed loop systems next year.” A major theme from his presentation was the fact that closed loop systems can provide impeccable nocturnal glycemic control – the “low hanging fruit” of AID – while performance during the day remains less impressive. Dr. Buckingham provided a slew of data supporting the efficacy of low glucose suspend, predictive low glucose suspend, and fully closed loop systems in preventing extreme hyper- and hypoglycemia at night. In terms of daytime AID, Dr. Buckingham identified many stumbling blocks affecting optimal control, including time delays, sensor accuracy, biologic variability (in insulin action and meal absorption), and physical activity. These challenges were reflected in a variety of data from Medtronic, UVA, Cambridge, and Boston AID systems that demonstrate less optimal glucose control during the day vs. night. Looking toward the future, Dr. Buckingham noted that infusion sets and sensors will continue to evolve, and that new insulin preparations such as Novo Nordisk’s fast aspart and Adocia/Lilly’s biochaperone lispro will improve postprandial control. Further, he stated that algorithms will continue to improve and adapt to individuals over time through the modification of basal rates, meal responses, and other patterns, ultimately evolving into a fully closed-loop system that does not require the user to carb count or deliver a premeal bolus – now that’s an exciting future!

  • As we have heard from many in the field, Dr. Buckingham commented that infusion sets are the “weak link” in pump therapy, contributing to substantial site infection and inflammation. He cited data showing that scarring, erythematous nodules, erythema without nodules, and abscesses are all quite common occurrences in patients. He also showed findings from an infusion set wear study, which concluded that the duration of infusion set wear is specific to individuals and that lipohypertrophy, hyaluronidase, and insulin type do not make a difference. Certainly, we agree that major innovations in infusion sets is needed and are excited to see new products on the horizon. We wonder how the launch of BD/Medtronic’s FlowSmart Infusion set and Unomedical’s automatic inserter – both expected this year – may impact insulin pumping and improve the performance of automated insulin delivery systems going forward.
  • Dr. Buckingham expressed a high level of optimism for the role of AID in preventing nocturnal hypoglycemia, a huge benefit given the risk for people with type 1 diabetes. He cited results from the DCCT, which showed that 55% of severe hypoglycemia episodes occurred during the night. He also shared that while real-time CGM provides nocturnal alarms, patients do not respond 71% of the time.
    • Dr. Buckingham discussed three “game changing” AID methods for preventing nocturnal hypoglycemia (low glucose suspend, predictive low glucose suspend, and fully closed loop), citing data from various systems to support the benefit. He discussed the success of Medtronic’s predictive low glucose suspend function in particular, citing data from Maahs et al. that illustrated a significant reduction in the percent of nights <60 mg/dl for 120 minutes without an increase in the concentration of morning ketones. He did note that these systems are only effective 2-3 hours after going to sleep, since they can’t adjust for insulin from more recent boluses.
    • Dr. Buckingham also discussed overnight closed-loop camp studies of the Medtronic, DiAs, Cambridge, and MD-logic systems, citing impressive nocturnal results across the board. 
  • In terms of daytime AID, Dr. Buckingham identified time delays, sensor accuracy, biologic variability (in insulin action and meal absorption), and physical activity as the major stumbling blocks preventing optimal control. He discussed UVA’s DiAs, Medtronic 670G, Cambridge’s FlorenceD2A, and the Bionic Pancreas as promising closed loop systems that have shown reduced severe hyper- and hypoglycemia during the day. He acknowledged that all the systems tend to experience elevated postprandial glucose levels but that the peaks are sharp and fall rapidly back into range. As we’ve seen in all these studies, he stressed to the audience that the percent of time spent in hypoglycemia has been substantially reduced.
    • Though he did not share new data, Dr. Buckingham did provide a few quotes from the Medtronic 670G pivotal study highlighting the impressive patient satisfaction with the system. As a reminder, the 670G US pivotal study is will complete in the “next few weeks” (per Medtronic 4Q15) and an FDA PMA submission is targeted “before the end of June.”
  • Dr. Buckingham noted attendees that real-world CGM performance is significantly less accurate than research center CGM performance – “dirty hands” and comparisons to fingersticks meaningfully elevate MARD values. He shared similar commentary at the recent AACE/ACE Consensus Conference on CGM. For Dexcom’s G4 Platinum, he shared camp data indicating that MARD was 10.4% relative to YSI in the clinic vs. 17.5% relative to fingersticks at camp. For Medtronic’s original Enlite, MARD was 15% in the clinic vs. a dismal 19.2% at camp. For Medtronic’s next-gen Enlite 3, however, MARD was a consistent 10.8% relative to YSI at the clinic vs. 12% with fingersticks at camp. Enlite 3 is of course a much better sensor though study protocol also significantly improved real-world performance: organizers instructed campers to wipe off the first drop of blood and use the second. The risk of fingerstick calibration is an important consideration for CGM, especially as the field moves toward closing the loop and relying on CGM data for insulin dosing. We wonder if this could make Abbott’s case stronger at the FDA with FreeStyle Libre.

SGLT-2: Potential Benefits and Risks

Anne Peters, MD (USC, Los Angeles, CA)

In this presentation, the highly regarded Dr. Anne Peters characterized SGLT-2 inhibitors as a “wonderful” class, reviewing the benefits and risks of the drug class in both type 1 and type 2 diabetes. Regarding type 2 diabetes, she reviewed the cardioprotective benefits shown by EMPA-REG for Lilly/BI’s Jardiance (empagliflozin), expressing strong enthusiasm for the findings and the recent progress of CVOTs in diabetes. As for the risks behind the SGLT-2 inhibitor class, Dr. Peters pointed to hypoglycemia, genital mycotic infections, volume depletion/orthostatic changes, hypersensitivity, increased LDL, and bladder cancer. However, she stressed that, “the onus is on us” (especially with regards to the additional FDA warning on urinary tract infections), highlighting that providers have the ability to prepare patients to prevent such infections and other side effects with proper dosing techniques (starting low and gradually increasing). In addition, she noted that the fracture risk should not be dismissed, particularly in patients at risk for osteoporosis. Moving into type 1 diabetes, Dr. Peters addressed the diabetic ketoacidosis (DKA) issue, ultimately noting that she “oddly feels pretty comfortable with the risk” but emphasizing the need to use small doses (between 25 mg and 100 mg) and to employ a clear ketone monitoring protocol in this patient population. More specifically, Dr. Peters reviewed the data from Janssen’s phase 2 trial of Invokana (canagliflozin) in type 1 diabetes, highlighting the importance of identifying each patient’s baseline data around positive ketones and of managing periods of illness, insulin reduction, and physiological stress due to how often DKA cases are precipitated by such events. Additionally, Dr. Peters stressed that as many DKA cases can be euglycemic, first-line providers must be trained to recognize and treat this condition. This class has certainly had an eventful past year with both its ups and downs and in its recent aftermath, we applaud Dr. Peters for leading so many of these valuable insights and conclusions in both the clinical and research communities. Please see below for additional detail around her commentary.

  • Notably, Dr. Peters highlighted EMPA-REG’s finding of reduced risk in hospitalization due to heart failure, noting that this will be an important result to share with regards to cost savings implications. She noted that leveraging this piece of data at the local level helped her succeed in getting the drug class on Los Angeles County’s formulary, as she emphasized that cost savings are driven by reducing hospitalizations rather than preventing sudden death.
  • In discussing the EMPA-REG results, Dr. Peters also expressed excitement to “now have three trials show that diabetes drugs reduce cardiovascular risk.” (EMPA-REG, IRIS, and LEADER). She shared great enthusiasm that we can “now look cardiologists in the eye and say our drugs are helping in this holistic way.” While acknowledging that “it sounds odd,” Dr. Peters concluded that she is “glad that we did these CVOTs.Indeed, with the recent big news of both IRIS and LEADER, the framework and opinions around CVOT guidelines are likely to shift even more and we will be curious to see how the diabetes community and FDA continue to discuss these issues.
  • We also loved Dr. Peters’ incorporation of a patient testimonial video from her patient who participated in Janssen’s type 1 diabetes canagliflozin study. The patient, who was in the treatment arm, highlighted her experience of lower glycemic variability and reduction of insulin dosing and how these changes positively impacted her quality of life – an excellent example of bringing the patient perspective into the scientific community.
    • In addition, Dr. Peters shared that new subsets of data from this trial’s CGM, patient satisfaction, and variability findings will be presented at ADA.
  • We continue to believe that the DKA risk is manageable but that it is not completely straightforward. In light of the FDA’s update to the Warnings and Precautions of all approved SGLT-2 inhibitors to include the risk of DKA, we believe it is useful to learn more about patients’ experience with DKA and ketone testing. Indeed, the risk of DKA is considered to be manageable, but have patients talked to their doctors about the DKA and ketone testing? How confident are patients that they could recognize DKA? How important is the label update to patients and what do they plan on doing in response to it?
  • We had a conversation with the team at dQ&A, the diabetes research company, to get an answer to these questions. The team was particularly struck by the lack of preparedness for DKA among patients with type 2 diabetes, even those taking an SGLT-2: surprisingly, most patients had not talked to their doctor about it, and few own a ketone testing kit or were confident that they could recognize the symptoms of DKA. It is clear that there is much work that needs to be done to increase patient education about DKA and ketone testing and to increase access to ketone testing kits, but we remain optimistic that this is addressable. There’s more detail on dQ&A’s questions and answers about DKA and ketone testing here or you can reach out directly to Richard Wood at richard.wood@d-qa.com.

Questions and Answers:

Q: EMPA-REG had a specific population – patients who were older and high cardiovascular risk. Do you feel that we can generalize these findings or can we just use the class in that population?

A: I started using SGLT-2s commonly after metformin just because they seem to work. Knowing EMPA-REG now, I’m now doubly likely to use empagliflozin. I can’t say if it’s a class effect. I can’t tell if it helps for primary prevention. Given all the side effects and issues, I know they’re good agents. I use them as I did before but I’m more likely to give them to people with cardiovascular risk. Ultimately, we’ll have to wait for more data.

General Session IIB

Novel Technologies For Promoting behavior Change

David Marrero, PhD (Indiana University, Indianapolis, IN)

Dr. David Marrero discussed the potential of technology to promote behavior change in diabetes. We thought this was among the most valuable talks we’ve heard on integrating more behavioral thinking into digital solutions – especially mobile applications – and it’s clear that Dr. Marrero (who has type 1) has a pulse on exactly what patients are thinking. As we hear often, he began by stressing the potential for digital health solution to help patients manage the hundreds of decisions they have to make every day. However, he contrasted that promise with the fact that mobile apps to date have had a VERY short half-life – he cited recent data that the average dieting app is used for just two weeks before patients lose interest. Why is there this lack of stickiness? His remarks focused on what he believes are the two biggest hurdles to digital health uptake in diabetes: (i) “the paradigm of diabetes is negative reinforcement” – patients take action to avoid punishment as opposed to reaping rewards; and (ii) “what reinforces individuals is quite variable” – we can’t expect all patients to respond the same way to stimuli. Dr. Marrero suggested that future systems think more critically about ways to shape behavior through social groups (e.g., using activity trackers to reinforce health behavior) and collecting OBJECTIVE measures of behavior – he didn’t specify examples in his presentation though his emphasis on objectivity made us think of the difference between FreeStyle Libre (no alarms) vs. CGM. Ultimately, we felt Dr. Marrero delivered an appropriately nuanced take on the future of digital health solutions – there was clear enthusiasm for the future but also realism that these are early days and that real solutions need to reward vs. stigmatize patients in order to fit more sustainably into their lives.

  • The lack of positive and personalized reinforcement techniques in diabetes was a central theme of Dr. Marrero’s talk – “If I do everything perfectly in diabetes care, the best thing that can happen is nothing!” He also suggested that fear-based conditioning – e.g., you shouldn’t eat that doughnut because of the consequences 20 years down the line – is not a sustainable strategy either. His remarks cited a great deal of psychology research and the importance of tying behavior to immediate rewards. This is sorely missing in diabetes where the benefits of blood glucose control are only obtained several years down the line and are often not particularly concrete (e.g., reduced likelihood of complications vs. no chance of complications).
  • In addition, Dr. Marrero noted that many technologies that provide positive rewards overlook the fact that “what reinforces individuals is quite variable.” He spoke from personal experience suggesting that he finds sending his glucose data to caregivers to be quite intrusive to his management while others might find it helpful (e.g., a sense of accountability). We loved this idea of tailoring rewards – not just technologies – to patients and certainly believe that this is an important aspect of individualizing care that is often overlook - namely, how do patients WANT to be rewarded for their short-term decision making?

Meet-the-Expert Sessions

Weight Loss for Type 2 Diabetes Nice, but Necessary?

In this session, Ms. Jackie Boucher explored the role of weight loss in type 2 diabetes by discussing the evidence on lifestyle weight loss interventions, nutrition therapy interventions, and their health outcomes for the patient population. She shared that weight loss interventions in the general public typically result in 5% to 10% weight loss at six months but that plateaus and regain of weight loss often follow. Pointing to recent meta-analyses, Ms. Boucher highlighted that the literature does not support any one nutrition therapy approach and that 7%-8.5% weight loss, regular physical activity, and frequent contact with dieticians are associated with consistent weight loss intervention benefits. Similarly, studies examining the comparison of weight loss intervention with a variety of macronutrient compositions have demonstrated that calorie reduction rather than a specific macronutrient composition drives weight loss. In a similar vein, Ms. Boucher noted that a wide range of eating patterns is acceptable for diabetes management and decisions around eating patterns should instead focus on personal preferences. Importantly, Ms. Boucher emphasized that modest weight loss can bring about significant clinical benefits but that success is more likely if it occurs earlier in the type 2 diabetes disease progression. In patients with longer duration of diabetes, weight loss may or may not improve glycemic control due to greater insulin deficiency and insulin resistance. While it is disappointing to hear the diminished efficacy of weight loss in more advanced diabetes, this presentation very much emphasizes the need for prevention and early intervention, an area we need to better understand how to scale. For more on the role of weight loss, please see our coverage of a similar presentation from ADA.

General Session III

Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis

Jay Skyler, MD, MACP (University of Miami Miller School of Medicine, FL)

Dr. Jay Skyler addressed the complex topic of the staging and classification of diabetes, highlighting several key remaining research gaps. His commentary centered on topics raised at an October meeting sponsored by the ADA, EASD, JDRF, and AACE, which focused on genetic and environmental determinants of type 1 and type 2 diabetes, risk and progression, complications, and most importantly, how to determine appropriate individualized therapies. According to Dr. Skyler, the meeting emphasized individualization of care for both prevention and treatment of diabetes and identified three major needs: (i) gaining a better understanding of the pathophysiology of diabetes; (ii) identifying novel biomarkers; and (iii) developing novel therapeutic interventions. The need for novel markers is particularly acute in type 2 diabetes: Dr. Skyler discussed using antibody count as a staging system for type 1 diabetes (more on this below) but stated that the meeting did not determine a staging method for type 2 diabetes due to insufficient information on relevant markers.

  • To contextualize the complexity of the epidemic, Dr. Skyler provided a detailed summary on the genetic and environmental determinants of type 1 and type 2 diabetes. He referenced data showing that approximately 10-15% of patients with type 1 diabetes have an affected relative; interestingly, the lifetime risk of type 1 diabetes is higher for offspring of a diabetic father (6-9%) than for the offspring of a diabetic mother (1-4%). For type 2 diabetes, the lifetime risk is about 40% if one parent has type 2 diabetes, and even higher if the mother has the disease. Dr. Skyler noted that the strongest effect on type 2 diabetes risk is conferred by an intronic variant in the TCF7L2 gene (it encodes a transcription factor, though the mechanism is unclear). Dr. Skyler also provided a list of environmental factors affecting the development of both type 1 and type 2 diabetes: obesity, dietary factors, endocrine disruptors, autoimmunity, and gut microbiome composition. This long list of factors speaks to the wide-ranging and complicated nature of diabetes etiology; hopefully improved genomic testing and large-scale studies will help clarify their relative contributions to the development of diabetes.
  • Dr. Skyler provided a long list of research gaps in diabetes identified during the October meeting. The questions included: What determines the point at which beta cell dysfunction becomes irreversible? Why is the incidence of type 1 diabetes increasing? Why does the risk for type 2 diabetes increase dramatically with age? How do we develop inexpensive, specific and sensitive assays to identify beta-cell autoimmunity on a population-wide level? Can we identify features of single antibody positive patients associated with progression? Is atherosclerosis the same disease in type 1 and type 2 diabetes? Dr. Skyler stated that these research gaps are particularly urgent given the “explosive” prevalence of both type 1 and type 2 diabetes – we wholeheartedly agree, and will be curious to see how leading research institutions prioritize these questions given the currently limited resources for research.
  • Dr. Skyler suggested that antibody count could be a useful method of staging type 1 diabetes.  Evidence has shown that an increased number of autoantibodies is associated with an increased incidence of type 1 diabetes. According to Dr. Skyler, infants in particular have a high likelihood of progressing to type 1 diabetes if they develop autoantibodies. Such results on autoantibodies have informed the recently proposed ADA/JDRF staging system for type 1 diabetes: stage 1 = beta cell autoimmunity/normoglycemia/presymptomatic type 1 diabetes, stage 2 = beta cell autoimmunity/dysglycemia/presymptomatic type 1 diabetes, and stage 3 = symptomatic type 1 diabetes. During Q&A, Dr. Skyler shared that the meeting did not determine a staging method for type 2 diabetes due to the field’s limited understanding of the progression of the disease. This is a testament to the need to identify novel, measurable biomarkers to help better identify and diagnose stages of type 2 diabetes, as such staging systems can be invaluable for designing effective prevention trials and targeting therapies more precisely.
    • Dr. Skyler also noted that older age is associated with slower progression of diabetes. He displayed results showing that even after they develop diabetes, older people have a slower rate of decline in beta cell function (as demonstrated by the concentration of C-peptide over time). This has been one of the main points cited by proponents of using a different scientific/regulatory paradigm for type 1 diabetes in children vs. adults.

Questions and Answers:

Q: What did your meeting decide in terms of a staging for type 2 diabetes?

A: The discussion was basically that we don’t have good information to specifically stage other than what we currently have with prediabetes and diabetes. We need good markers to tell how the disease is progressing and to identify which processes are going on. With type 1 fortunately we have antibodies we can measure.

Q: What can you tell us about other immune markers?

There is a subgroup of people that will develop celiac disease or thyroid disease, and you have to pay attention in those people for greater progression. We don’t know how this happens, and still need to fill in that gap.

Q: If a child is tested for antibodies, does that test need to be repeated later in life?

A: Up to the age of 10, there remains a 2-3% chance of converting each year. We ask people under the age of 10 to be rescreened on a daily basis.

Q: Can you provide more details on LADA and steps to treat it?

My bias is just that LADA is a type 1 diabetes process occurring more slowly as it does in older people. I think these days we have a lot of people having both type 1 and type 2 diabetes so they develop a component of each. People who are overweight with type 1 diabetes may need some of the type 2 diabetes treatments for the adipose components

Update on Incretin Therapy

Carol Wysham, MD (University of Washington, Seattle, WA)

Dr. Carol Wysham provided a comprehensive review on GLP-1 agonists and DPP-4 inhibitors, sharing her thoughts on the comparisons between the two classes. At a high level, she illustrated that incretin agents help address many of the “ominous octet’s” pathophysiological defects of type 2 diabetes. After reviewing much of the clinical data of incretins, Dr. Wysham concluded that compared to DPP-4 inhibitors, GLP-1 agonists have greater A1c reduction and weight loss but have higher risk for GI side effects. Regarding GLP-1 agonists, she highlighted that short-acting analogs lower post-prandial glucose while longer-acting analogs lower fasting blood glucose. She also presented the data on the greater benefits of adding GLP-1 analogs to basal insulin compared to prandial insulin, labeling this as a “new exciting area” of diabetes care. While Dr. Wysham did not provide much commentary around CV outcomes, she reviewed the neutrality of DPP-4 inhibitors’ CVOTs and pointed to the GLP-1 agonist class’ recent news of positive LEADER topline results for Novo Nordisk’s Victoza (liraglutide). On a separate note, she ended her presentation highlighting recent research demonstrating promising non-glycemic actions of GLP-1, including impacts on neuroprotection, appetite, and impact on liver fat with potential implications in Alzheimer’s disease, Parkinson’s disease, and NASH (a particularly important disease area as obesity prevalence rises). This class certainly has generated attention in not only diabetes – specifically, check out our coverage of a study examining Victoza in Alzheimer’s disease.

Changing Cost of Insulin Therapy in the US

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

In a passionate and engaging presentation, Dr. Irl Hirsch tackled the challenging topic of skyrocketing insulin prices over the past decade – a “post script” to his talk at last year’s ADA Scientific Sessions. He noted that the field has “crossed a line” to the point where insulin has became unaffordable for many, particularly Medicare patients in the “donut hole”, those with high-deductible insurance plans, the uninsured, and those who simply can’t afford the high co-pays for insulin. Dr. Hirsch cited staggering statistics on the growth of insulin prices over the past 13 years: a vial of insulin glargine increased in price by 593%, while a box of five insulin lispro pens increased 552% (compared to a total inflation of 8% and an overall medical inflation of 46% over the same period). That said, we assume these are increases in list prices for the products and do not factor in concurrently rising rebates. While Dr. Hirsch acknowledged the role of pharmaceutical companies in enabling the ballooning prices, he noted that pharmacy benefit managers (PBMs) appear to be responsible for much of the problem due to their lucrative and seemingly dishonest negotiations with insulin companies that include bribe-like “kickbacks” – one of the main points made in a recent NYT op-ed about the cost of insulin. As a short-term solution, Dr. Hirsch advocated for better training for new physicians on human insulin and considering using these more affordable insulins in some patients with type 2 diabetes (ReliOn, a WalMart brand of human insulin, is currently available for just ~$25 per vial). He also shared that, as he understands it, the ADA will take a leadership role in “trying to improve this entire situation.”  We applaud Dr. Hirsch for repeatedly taking on such a controversial, multifaceted topic. In the context of sky-high diabetes prevalence rates, the issue of insulin affordability is certainly an important one, and we look forward to seeing how the ADA will take action to help improve access.

  • Dr. Hirsch described the striking discrepancy between the global share of insulin use and price in the US versus other countries. Notably, in 2013, insulin was a $21 billion global market with a compound annual growth rate of 15% for the previous five years. Of the global $21 billion, 52% came from North America, though only 7% of total insulin use came from this region. He attributed this discrepancy to the fact that the US has been willing to pay for “small incremental benefits in insulin” – especially related to improvements of hypoglycemia – that insulin analogs provide. While the US certainly pays higher insulin prices than other countries that have engaged in hardball negotiations with insulin manufacturers, the trade-off is more limited patient choice. In addition, characterizing the hypoglycemia benefits of analog insulins as “incremental” minimizes their substantial impact on the patient experience.
    • Further, Dr. Hirsch compared the prices of insulin around the world, demonstrating that prices in the US are higher than anywhere else in the world. For example, in February 2016, a vial of NPH was $2 in India and $11 in the UK; the same vial of insulin in the US was $136. For analog insulins, the difference was particularly marked: a vial of Humalog cost $12 in India, $20 in the UK, and $244 in the US. While it makes sense to adjust insulin prices to be appropriate for various markets, insulin prices in the US are exorbitantly high and do not reflect the needs and resources of patients with diabetes. 
  • Dr. Hirsch highlighted the concerning trend of insulin prices across manufacturers – when one company raises the price of insulin, a competitor matches this increase within 24 hours (“shadow pricing”). For example, on May 30, 2014, Sanofi increased the price of insulin glargine by 16%; the next day, Novo Nordisk increased the price of insulin by the same amount. He observed that in the past decade, this has happened a shocking 13 times.
  • Dr. Hirsch firmly stated that pharmacy benefit managers (PBMs) are responsible for much of the problem through their direct negotiations with insulin manufacturers. Dr. Hirsch cited a recent New York Times article by Kasia Lipska which stated that the rebates received by PBMs from insulin manufacturers look “suspiciously similar to kickbacks” and may “amount to as much as 50% of the list price of insulin.” According to Dr. Hirsch, drug channel companies, which include PBMs, chain pharmacies, and wholesalers, have higher revenues than pharmaceutical companies due to quadruple-counting of prescription revenues.
  • As an imperfect but necessary solution, Dr. Hirsch argued for better training for new physicians on using human insulin for type 2 diabetes. He did, however, stand more strongly by analog insulin for type 1 diabetes. This was similar to his take on the issue expressed at last year’s ADA Scientific Sessions. He noted that he prefers analogs due to decreased hypoglycemia risk, but cited a 2009 Cochrane Review and Diabetes Obesity Metabolism article demonstrating that there was no difference between NPH and analog insulin in terms of A1c and severe hypoglycemia. However, from Dr. Hirsch’s experience, many young residents have no experience with NPH or regular human insulin for type 2 diabetes, and specific training is necessary given the complex caveats of switching insulins.
    • He listed a series of other possible solutions, prefacing them by saying “for the record, I don’t particularly like any of them”: (i) developing insulin therapy guidelines that incorporate cost/benefit analysis; (ii) physician panels to recommend target prices based on magnitude of benefit; and (iii) allowing importation of drugs from abroad for personal use (though he conceded this is unlikely to be allowed). He also suggested that improved patient assistance programs (PAPs) may be helpful for patients, but highlighted the key criticisms that PAPS further add to the complexity of the healthcare system, charging that they enable drug makers to hike up drug prices and then make exceptions for those who can’t afford them.
  • During Q&A, ADA’s Dr. Robert Ratner shared that the ADA has been working on the issue of insulin pricing for a long time, and is trying to understand the incredibly complex system. He urged audience members to read the article on insulin pricing in the March issue of Diabetes Forecast, which includes a balanced view on the rising cost of insulin.
  • Digging deeper, Dr. Hirsch cited statistics on the price of insulin from 1960-2015 in the US, highlighting the skyrocketing price of insulin analogs. In 1960, regular (human insulin) was 0.2 cents per unit of insulin versus 14 cents per unit in 2015. Analog insulin was 4 cents/unit in 1996, and the price has grown to 26 cents/unit in 2015. He elaborated on this “sticker shock” by noting that as of January 2016, patients had a co-pay of $150/vial for insulin aspart, $185 for a box of five insulin glargine pens, and $40 for a vial of NPH insulin (after deductibles). Notably, Dr. Hirsch pointed out that ReliOn, a WalMart brand of human insulin, is currently available for just ~$25 per vial. 
  • Dr. Hirsch highlighted a few noteworthy anecdotes demonstrating the fragility of the situation for many patients with diabetes. For example, insurance only allows one vial of insulin to be dispensed at one time, meaning that patients can only pick up their next vial within 48 hours of running out of insulin, even if traveling. He also noted that he has seen many patients limit their carbohydrate intake so they would not need to take additional insulin. Furthermore, Dr. Hirsch explained that insulin has actually reached “black markets.” Medicaid patients who receive their insulin at a low cost will sell their insulin to Medicare patients in the “donut hole” who must pay for the full cost of their medications. According to Dr. Hirsch, this has been ongoing for years but has escalated recently.
  • Dr. Hirsch contextualized the issue by discussing the history of insulin production, highlighting the fact that Drs. Banting and Best altruistically sold their patent for $1 so insulin could be affordable to all. In 1924, the price of insulin in the UK was just 1 penny per day (in 2016 US currency). He noted how insulin prices stayed fairly low for decades before starting to climb in the 1990s and early 2000s. In his view, however, nobody could have predicted the tremendous rise in insulin prices that followed from 2005 to the present.

Questions and Answers:

Dr. Matt Orland (Missouri Baptist Medical Center, St. Louis, MO): Did you suspect the timing of Sanofi and Novo Nordisk’s price increases as leading up to the launch of Tresiba and Toujeo? This was before either Tresiba or Toujeo came out, almost as if it were in preparation for them.

A: Yes, that looks pretty obvious.

Dr. Orland: Also, when teaching people to use NPH and Regular, insulin is $25 but pens and syringes are $480 for a box.

Dr. Linda Guadiani (Marin General Hospital, Greenbrae, CA): Why won’t the emergence of biosimilars have an effect on the price of insulin the way it will with statins? What are the forces in the market keeping it down?

A: I think it’s a complicated answer. It is more expensive to make a biosimilar because you are dealing with large insulin molecules. The question is, why is it just a little bit cheaper and not a lot cheaper? UW is able to purchase the insulin for pennies, while the university pharmacy then sells it back to the patient at dollars with a high profit margin. For those of you who don’t know about 340B pricing, it’s pricing that is set for hospitals or clinics that caters towards an indigent population. However, we were told last week that the 340B price, which has risen to $32/vial for Humalog and Novolog, is going up again next month. This creates more profit margin; this time for the pharmacy, not the insulin company or the PBM. Everyone wants their profit when they can get it! I know this pharmacy loses money on some things, so who can blame them? 

Dr. Jay Skyler (University of Miami, FL): Let me take a crack at analyzing one of your slides, where Humalog increases in both prescription and revenues. If the company wants to maintain their revenues per prescriptions one would think that that would be simple. But PBMs insist that there are kickbacks/bribes. If the company were paying these kinds of bribes to a distributor outside of US they would go to jail, but in US we have legalized this kickback scheme. A company like Lilly has to raise their price, because if they don’t, they don’t get a profit. This forces manufacturers to raise prices to give kickbacks, affecting the whole system. That is where the problem is.

Q: In your research, why can’t we get rid of these PBMs? Why isn’t the ADA taking a stronger stand? Isn’t this creating increasing health disparities, particularly among communities of color that have less ability to pay for this? There’s also black market in test strips – we don’t have decent test strips, lancets are being used over and over. This is worse and worse news.

A: I can’t answer why we can’t get rid of PBMs. I totally agree with your comments, I can’t speak to ADA, but Dr. Ratner can.

Dr. Ratner: The ADA has been working on this for a long time and we have been trying to deal with all the players so we can understand complexity that Irl showed you on the side. If you haven’t seen it, I urge you to get the March issue of Diabetes Forecast. It shows a balanced view of what’s going on in this market, and a simplified pathway of how insulin gets from the manufacturer to a person with diabetes. There are some specific points that the ADA has made. One, we serve people with diabetes and want to insure they have high quality, effective, safe medications that are affordable and accessible. Beyond that, we also understand that our current medications are not optimal. We need innovation and new products that make life better for people with diabetes – that takes R&D. One thing that is really true across the board is that we want transparency in where the money goes. We really wanted to know an answer to Dr. Skyler’s question of why the revenues are the same despite the marked increase in the pricing.

Bariatric Surgery for Obesity and Type 2 Diabetes

Sangeeta Kashyap, MD (Cleveland Clinic, OH)

Dr. Sangeeta Kashyap reviewed the efficacy and safety of bariatric surgery in type 2 diabetes, explored potential mechanisms of action, and discussed clinical and metabolic determinants of diabetes remission following surgery. Dr. Kashyap opened by illustrating the etiology of obesity and its relationship to type 2 diabetes, highlighting the complex regulation of food intake and the many downstream effects of insulin resistance on the muscle, liver, arteries, and others. She then reviewed the clinical data of bariatric surgery in type 2 diabetes, walking attendees through the results of the SOS and STAMPEDE studies as well as meta-analyses, emphasizing that surgery has been demonstrated to be more effective than intensive medical therapy in achieving glycemic control. Dr. Kashyap proposed mechanisms of this clinical outcome, suggesting that drivers can include negative caloric balance and weight loss, improvement in insulin sensitivity and “lipotoxicity,” or stimulation of the entero-insular axis and subsequent effects of beta-cell function. Notably, regarding predictors of diabetes remission, she illustrated that remitters tended to have greater increases in adiponectin levels compared to non-remitters; thus, Dr. Kashyap highlighted the promise of targeting additional weight or fat loss and adiponectin raising interventions for patients who relapse. Additionally, as we’ve heard before, she noted that diabetes remission characteristics of bariatric surgery appear linked to improvements in post-prandial glucose metabolism as other predictors of non-remitters include older age, longer diabetes duration, and poorer beta cell function. Ultimately, Dr. Kashyap emphasized that continuous surveillance for both micro- and macrovascular complications post-surgery is critical, as remission is not permanent. We agree that this perspective is incredibly important, as providers must set the appropriate expectations for patients that surgery is not a “cure,” but rather another intervention that requires continuous follow-up.

Questions and Answers:

Q: What is your strategy with all the new weight loss medications? Do you use these in patients who are not meeting weight loss goals with surgery?

A: A lot of weight regain is related to behavior and lifestyle. Those patients need to go back to the psychologist and dietician. Regarding medications, I have used appetite suppressants phentermine or phentermine/topiramate. I also use GLP-1 agonists in patients with residual hypo. I also use topiramate in low doses. Things related to reduction of appetite such as cravings for sweets can be helpful. You need to revisit behavioral and lifestyle issues and consider drugs that can help suppress appetite.

 

--by Melissa An, Helen Gao, Varun Iyengar, Emily Regier, Ava Runge, Kelly Close