April 1-4, 2016; Boston, MA; Full Report – Draft

Executive Highlights

This report features our full coverage from the Endocrine Society’s 98th Annual Meeting (ENDO 2015) held in Boston, MA from April 1-4 along with our coverage of pre-conference events (Endocrine Fellows Series, Diabetes Management Workshop, Obesity Management Workshop) that occupied the three days prior to the official start of ENDO. This year’s meeting was quite a bit busier than last year’s – 9,300 attendees was the final count vs. 8,500 in 2015 – and inched back toward the record of 10,150 attendees seen in 2014 … and for good reason. After all, was it just us or was there more new news (big announcements and clinical data) at this ENDO than there usually is? From BU’s Dr. Ed Damiano disclosing plans to commercialize the Bionic Pancreas via a new public benefit corporation to the first full phase 3 data for semaglutide to the debut of phase 2 data on Novo Nordisk’s oral GLP-1 program, these were big revelations that we would normally have expected to take place at ADA. We presume this was partly the result of ENDO’s new timing - this year’s meeting shifted back a month after moving from June to March between 2014 and 2015. If it means more exciting news earlier in the year, we certainly won’t complain : > … We’ll see if the trend continues next year April 1-4 in Orlando. FL.

Our report below includes a synthesis of some of the meeting’s overarching themes, followed by full coverage of ENDO presentations organized into the four events we attended: (i) ENDO 2016; (ii) the Endocrine Fellows Series; (iii) the Diabetes Diagnosis and Management Workshop; and (iv) the Obesity Management Workshop. Please note that talks that we found notable are highlighted in yellow and those that were not included in our daily reports (days #1-2 highlights report here and days #3-4 highlights report here) are highlighted in blue.

Themes

Diabetes Drugs

• Our sense was that basal insulins received more attention than their rapid-acting counterparts at this year’s ENDO – overall, this is not that surprising since basal insulin is so much easier to prescribe and is growing more quickly. Dr. Chantal Mathieu’s (KU Leuven, Belgium) presentation on new insulins was almost entirely focused on the basal insulin side, dealing mostly with the advantages of Sanofi’s Toujeo (insulin glargine U300) and Novo Nordisk’s Tresiba (insulin degludec) over Sanofi’s Lantus (insulin glargine). Basal insulins also stole the spotlight in the exhibit hall, where Novo Nordisk’s booth was entirely dedicated to Tresiba and Sanofi’s booth devoted about half its space to Toujeo. We did see results from a PK/PD study of Novo Nordisk’s faster-acting insulin aspart showing an onset of appearance roughly twice as fast compared to regular aspart – these data should help support the drug’s value proposition and complement the phase 3 data demonstrating superior postprandial control with the faster-acting formulation compared to regular aspart. The relatively greater focus on basal insulin likely reflects the growing popularity of SGLT-2 inhibitors and GLP-1 agonists as options to control postprandial glucose – in the company’s 3Q15 update, Lilly Diabetes head Mr. Enrique Conterno cited this trend as a key factor behind the recent slower growth in the mealtime insulin market. We see this shift as a net positive due to the advantages of SGLT-2 inhibitors and GLP-1 agonists on hypoglycemia, weight, and CV effects (at least in some cases), though we do expect that many patients will eventually still need to move to prandial insulin later in the course of the disease.
  
  • Concentrated insulins also received a significant amount of attention – likely a reflection of rising insulin resistance rates as obesity has increased. Lilly’s exhibit hall booth prominently featured the recently approved Humulin U500 KwikPen, which Lilly has said it developed in response to significantly increased demand for concentrated insulin in recent years. Indeed, at a product theater for Humulin U500, Dr. Robert Hood (Endocrine Clinic of Southeast Texas, Beaumont, TX) noted that providers have been “bugging Lilly for years” to produce a dedicated delivery system for Humulin U500. Dr. Wendy Lane (Mountain Diabetes and Endocrine Center, Asheville, NC) also led a dedicated session on U500 and other concentrated insulins, centered around her own personal high-dose insulin algorithm.
• Pioglitazone has been gaining traction as a potential treatment option once again, after demonstrating reductions in stroke and MI risk in the IRIS trial. Throughout the meeting, we heard multiple speakers point to the benefits of the drug, specifically noting potential combinations or clinical guidance around its use. Dr. Zach Bloomgarden (Icahn School of Medicine at Mount Sinai, New York, NY) suggested the potential of pioglitazone in low doses to help prevent the drug’s undesirable side effects; meanwhile, Dr. Daniel Einhorn (Scripps Health, La Jolla, CA) emphasized how clinical studies have largely cleared the drug’s possible cancer risk and the positive access implications of pioglitazone’s generic status and low cost. Both Dr. Einhorn and Dr. Silvio Inzucchi (Yale University, New Haven, CT) also expressed enthusiasm for combinations with pioglitazone, particularly with GLP-1 agonists and SGLT-2 inhibitors, with Dr. Inzucchi specifically pointing to the promise of a pioglitazone/empagliflozin combination. The IRIS trial has certainly elevated pioglitazone’s profile in recent months and we agree that the public health implications of a low-cost, generic drug can be extremely beneficial if the appropriate next steps are taken to further understand the drug’s risk/benefit profile and to incorporate this into guidelines.
• In addition, several talks delved into the underlying mechanisms of GLP-1 agonists, with particular emphasis on their effects on the brain. Dr. Olivia Farr (Beth Israel Deaconess Medical Center, Boston, MA) presented results from a study showing that GLP-1 agonists diminish activation in certain key brain areas in response to fatty and calorie-dense foods. Another study presented by Dr. Gianluca Iacobellis (University of Miami, FL) demonstrated that Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) dramatically reduces metabolically harmful epicardial fat – a particularly intriguing finding in light of the recent positive topline results from the LEADER CVOT. Dr. Karolina Skibicka (University of Gothenburg, Sweden) discussed several key brain areas involved in reward circuitry that express GLP-1 receptors and noted that GLP-1 agonists may even have utility for the treatment of alcoholism and other addictions. Neural mechanisms appear to be an important component of GLP-1 agonists’ effects on weight in particular, and we see this as one of the most intriguing areas of current obesity research.

Diabetes Technology

• ENDO 2016 saw a huge focus on the Bionic Pancreas with standout presentations from both BU’s Dr. Ed Damiano and MGH’s Dr. Steven Russell. Dr. Damiano kicked off the meeting with a PACKED opening plenary that that disclosed plans to commercialize the Bionic Pancreas via a new public benefit corporation Beta Bionics. The company holds the exclusive rights to all the intellectual property previously owned by Boston University, including patents on the algorithm, the iLet device, and custom infusion set. During his talk, Dr. Damiano also unveiled the third generation fully integrated iLet dual-chamber pump, which Beta Bionics plans to test in a four-site bridging study in 4Q16 and a pivotal study in 2Q17 (with insulin-only and insulin+glucagon arms). Highlights from Dr. Russell’s presentation included news that: (i) the iLet will pair with a still-to-be-named Bluetooth-connected BGM; and (ii) will be powered by AAA batteries. This is the first we had heard of either detail. We think both are smart moves, since linking the meter to the iLet will reducing patient burden and eliminate manual calibration errors (e.g.. incorrectly inputting a glucose value), while using AAA batteries should keep the device cost down (no need for a fancy lithium rechargeable battery). Dr. Russell also shared that he has submitted an NIH grant to test the iLet in type 2 diabetes (currently under review). The application comes on the heels of a small pilot of the iLet device in this population that Dr. Russell noted “has worked well.” He speculated that such an application would roughly “double” the US closed-loop market size – a bigger market is important for the viability of any small closed-loop company like Beta Bionics, and we hope rigorous trials can document the benefits. Along similar lines, Dr. Russell hinted that the team is planning pilot studies of the glucagon-only system in patients with post-bariatric hypoglycemia (patients that have an excess of endogenously produced insulin) and those with congenital hyperinsulinism that do not respond to pharmacotherapy [granted, a very small population but pretty neat]. Ultimately, we are thrilled to see progress in bringing the Bionic Pancreas from the academic setting to patients – for more on Beta Bionics, see our detailed coverage here.

Obesity

• The minimal presence of obesity at ENDO pointed to growing research into the role of the brain as well as disappointment of the obesity pharmacotherapy market. Leading obesity researcher Dr. Michael Schwartz (University of Washington, Seattle) presented data and insights on the involvement of the injury of hypothalamic neurons and associated glial responses while numerous young researchers at the meeting also focused on how neurotensin, leptin, and ghrelin in the brain affect weight management. In addition, Dr. Daniel Bessesen (University of Colorado, Denver, CO) delivered a very well-attended “Year in Obesity” session, as he touched on the latest obesity research (microbiome, genetics, meal timing) and criticized Orexigen’s actions around its CVOT Light Study, noting how the obesity drug market has been slow and received significant bad press. The exhibit hall surprised us with Eisai’s presence with Belviq (lorcaserin), but nonetheless, other than Belviq and Novo Nordisk’s Saxenda (liraglutide 3.0 mg), the representation of obesity drugs still remained disappointingly low.

 

Detailed Discussion and Commentary

ENDO 2016

Presidential Plenary: Technology and Delivery Breakthroughs in Diabetes

Outpatient Studies Testing Automated Glycemic Control with a Bionic Pancreas

Ed Damiano, PhD (Boston University, MA)

During a captivating and packed morning plenary, Dr. Ed Damiano disclosed plans to commercialize the Bionic Pancreas via a new public benefit corporation, Beta Bionics. He also unveiled the third generation fully integrated iLet dual-chamber pump, which Beta Bionics plans to test in a four-site bridging study in 4Q16 and a pivotal study in 2Q17. See Beta Bionics’ website here and our detailed coverage from Friday here. The updated iLet device is 17 mm thin (and ~33% smaller than the first-gen prototype), with a sleek aluminum exterior and glass capacitive touchscreen to improve the user experience. Beta Bionics holds the exclusive rights to the iLet device, as well as all additional Bionic Pancreas intellectual property previously owned by Boston University. Dr. Damiano demonstrated the easy iLet setup process for the audience, which simply requires body weight entry (no prior insulin or glucose data – this adaptation has long been a hallmark of the Bionic Pancreas algorithm and is unique in the field). The setup screen also includes functions to start and calibrate the CGM, place an infusion set, and load the insulin or glucagon cartridges. We appreciated the review of the intuitive Tidepool-developed user interface, which we first saw at FFL 2015 and heard about again at last November’s DiabetesMine event.

• Dr. Damiano asserted that the Bionic Pancreas simultaneously solves the four greatest concerns in type 1 diabetes management: (i) it reduces mean blood glucose to lower the risk of long-term complications; (ii) it “profoundly curtails” hypoglycemia, and will likely eliminate severe hypoglycemia; (iii) it automates blood glucose control, unburdening people of the daily hassles of managing type 1; and (iv) it unburdens people with type 1 and their families of the emotional hardship and fear of hypoglycemia and long-term complications. Said Dr. Damiano. “A technology that could address any one of these concerns would be a breakthrough; a device that simultaneously solves all four is truly gamechanging and paradigm shifting.” We wholeheartedly agree and are thrilled to see progress to bring the system from the academic setting to patients – the automated insulin delivery competitive landscape gets more packed by the day, and it’s good to see many systems coming to compete with Medtronic’s MiniMed 670G (FDA submission before the end of June).
• Dr. Damiano also reviewed previous clinical data from several prior Bionic Pancreas studies (The Bionic Pancreas Multicenter Study in 2014-2015, and the Summer Camp Studies in 2013 and 2014), remarking on the reduction in mean glucose and less time spent <60 mg/dl and >180 mg/dl in study participants vs. standard care. He emphasized the huge variability in daily insulin requirements in people with type 1 diabetes, noting that the Bionic Pancreas can adapt to these needs and “comply with the patient” rather than the other way around – “Do you want to follow your insulin, or do you want your insulin to follow you?” It is of course ludicrous to expect flat glycemia every day with the manual, static insulin dosing protocols used today in type 1 diabetes; we love that automated insulin delivery can adapt to that variability seamlessly with less patient burden.

Making Human Pancreatic Beta Cells for the Study and Treatment of Diabetes

Doug Melton, PhD (Harvard Stem Cell Institute, Cambridge, MA)

Dr. Doug Melton discussed upcoming steps for his stem cell-derived beta cell replacement therapy for type 1 diabetes. He first reviewed the research that went into developing the widely heralded differentiation protocol and the results showing functional capacity comparable to that of islet cells from cadaveric donors. He also noted that his team has applied the protocol to iPS cells in addition to embryonic stem cells and that those cells have also demonstrated glucose-responsive insulin secretion and the ability to reverse diabetes in a mouse model. Dr. Melton then listed several challenges his team aims to address in the near future. He explained that while his differentiated cells are functionally indistinguishable from donor islet cells when transplanted into animal models, there are still some small discrepancies in glucose-responsive insulin secretion, particularly at lower glucose levels, when the cells are analyzed individually ex vivo. As mentioned at last year’s ADA, his lab is also working on modifying the differentiation protocol to produce complete (or near-complete) islets with multiple cell types. To that end, they have done RNA sequencing on every cell from four donor islets to get a complete picture of the gene expression profile they are aiming for. They have successfully modified the differentiation protocol to produce alpha and delta cells in addition to beta cells (albeit less efficiently) and are working on producing cells that secrete ghrelin and pancreatic polypeptide. In addition to these incremental changes, Dr. Melton acknowledged that the big challenge will be finding a way to protect the cells from immune attack, either through encapsulation or biological protection. His group has already made significant progress toward this goal, recently publishing positive preclinical results with the cells using an alginate microencapsulation device developed by Dr. Dan Anderson (MIT, Cambridge, MA).

President's Opening Remarks and Award Presentations

Lisa Fish, MD (Hennepin County Medical Center, Minneapolis, MN)

In this year’s presidential opening remarks, Endocrine Society President Dr. Lisa Fish announced the upcoming launch of the society’s first open-access journal, the Journal of the Endocrine Society. The journal is expected to launch in fall 2016 and will publish in basic, translational, and clinical endocrinology; past Society President Dr. Larry Jameson (Perelman School of Medicine, Philadelphia, PA) will serve as the journal’s first editor-in-chief. Additionally, Dr. Fish emphasized that the journal’s mission, through its open access, is to “bring greater equity to science and medicine through broad communication” – we applaud the Society for providing more venues to make the scientific field and the public smarter about endocrinology.

• Dr. Fish also shared that EndoCares, the society’s “giving back” campaign, has partnered with the Diabetes Education and Camping Association. Not only would this work help young people with diabetes form valuable communities, the partnership also aims to bring together providers in new avenues. We love this interdisciplinary collaboration as it helps integrate different areas of expertise and brings the bigger patient perspective closer to the provider and scientific research at large.

Plenary

KO1-K/O Rounds: Why Endocrine Science Matters – in 3 Minutes

Hilary Woodworth (Michigan State University, East Lansing, MI) and Juliette Brown (Michigan State University, East Lansing, MI)

A new fast-paced, “knockout round” session on Saturday featured a focus on the brain’s role in obesity, with novel insights on neurotensin and the neural circuitry between leptin and ghrelin. Ms. Hilary Woodworth discussed the interplay between dopamine neurons and the neuropeptide neurotensin, as she demonstrated that knocking out neurotensin-responsive dopamine neurons in the rodent model is associated with a phenotype that protects obesity. Specifically, these knockout mice remained slim despite consumption of a high-fat diet and engaged in significantly greater physical activity. In addition, Ms. Juliette Brown  highlighted the complexity of the neuronal circuitry involving the hormones leptin (which contributes to weight loss) and ghrelin (which promotes feeding). She focused on the lateral hypothalamic area within the rodent model’s brain, demonstrating that disruption of the ability to respond to leptin here not only disrupts the response to leptin, but the response of ghrelin as well, leading to obesity. While much of this research is in the early stage, the excitement around how the central nervous system drives obesity is clearly becoming a growing area of interest. On a separate note, we loved the fun and fast-paced dynamics of this “knockout round,” in which these young researchers competed on the basis of their concise and engaging presentation skills with only three minutes and one PowerPoint slide – an increasingly important skillset as attention spans decrease in this day and age!

Oral Presentations: Novel Treatment for Diabetes – Focusing on GLP-1 and SGLT2

Dapagliflozin Induces Ketosis in Patients with Type 1 Diabetes

Husam Ghanim, PhD (University of Buffalo, Buffalo, NY)

With a title like “Dapagliflozin Induces Ketosis in Patients with Type 1 Diabetes,” it was clear that the presenters of this oral presentation were not messing around. The study (n=30) provided one of the best datasets yet on the risk of DKA and mechanistic underpinning of ketosis seen with the use of SGLT-2 inhibitors in type 1 diabetes. This study was unique in that it administered an SGLT-2 inhibitor – AZ’s Farxiga (dapagliflozin) – in addition to not just insulin, but also the GLP-1 agonist liraglutide. A GLP-1 agonist would be expected to protect against DKA by blunting glucagon secretion, so the fact that both ketosis and diagnosed DKA occurred is particularly worrisome (unless the GLP-1 agonist therapy led to a large reduction in insulin dose, in which case it might not be protective). Before going to DKA, presenter Dr. Husam Ghanim noted that dapagliflozin had real benefits, like additional weight loss, no additional hypo, and what looked to be a modest A1c improvement. Dr. Ghanim’s group did a beautiful job demonstrating the mechanism at play behind the ketosis, by showing statistically significant increases in glucagon secretion (~35% increase), plasma free fatty acids (~70% increase), and hormone sensitive lipase (~25% increase) – the sequence of steps towards ketosis – along with the ketones acetoacetate (~50% increase) and beta-hydroxybutyrate (>200% increase). The risk appears real, though we still believe it is very manageable if appropriate patient and provider education occur optimally (contact Richard.wood@d-qa.com for more details on this front).

• Dr. Ghanim shared details on both the cases of DKA that occurred in the trial. Both cases occurred shortly after the escalation from the 5 mg dapagliflozin dose to the 10 mg dose.
  
  • The first had euglycemic DKA, with a glucose concentration of <160 mg/dl. Her total daily insulin dose had fallen from 33 units to 26 units, which for her was only 0.35 U/kg.
  • The second case had hyperglycemic DKA. Her insulin dose had changed
• A pressing action item for the diabetology community is to design and disseminate a protocol for mitigating the risk of DKA for type 1 diabetes patients taking SGLT-2 inhibitors. By all accounts there is a lot of consensus on the important points, namely: (i) starting and probably staying on the lowest dose available; (ii) capping the insulin dose reduction at 10%-20%; and (iii) keeping the absolute insulin dose from falling below 0.5 U/kg. Dr. Anne Peters (USC, Los Angeles, CA), who was one of the first to speak out about the euglycemic DKA story, shared her personal protocol for off-label use of SGLT-2 inhibitors in type 1 diabetes at last year’s EASD. Effectively educating stakeholders – especially patients and the hospitalists that may be the first line for confronting euglycemic DKA cases when they occur – will be critical to ensuring that SGLT-2 inhibitors have a future in type 1 diabetes care.   
• Dr. Ghanim gave us a sneak peak at data from the original study investigating liraglutide in type 1 diabetes – these are to be published shortly in Diabetes Care. The benefit was apparent but modest, following the precedent of the larger LIRA-1 trial that was presented at ADA last year. The small size of the Buffalo study came through at a few points, such as when the liraglutide 1.2 mg group achieved a substantially larger placebo-adjusted A1c reduction from baseline (~0.5%, p<0.05) than the 1.8 mg group (~0.15%; p=NS). Liraglutide’s effect was more pronounced when it came to reductions in postprandial glucose AUC and glucagon, which were dose dependent and statistically significant across the board.

Questions and Answers

Q: In a recent study by Bob Henry with canagliflozin, they showed not only DKA, but also an increased risk of hypoglycemia. You said you did not see that here, but it looked like you had three episodes of hypo, with one being severe, with dapa, and just one with placebo. I do not think it is fair to say that there was not increase in hypoglycemia.

A: The difference in numbers was not statistically significant. The study also randomized two-to-one, so there were more patients on the drug than on placebo.

Efficacy and Safety of Once-Weekly Semaglutide Monotherapy Versus Placebo in Subjects with Type 2 Diabetes (SUSTAIN 1)

Christopher Sorli, MD (Billings Clinic Research Center, Billings, MT)

This presentation – in front of a packed house – featured the first results from the phase 3 program for Novo Nordisk’s once-weekly GLP-1 agonist candidate semaglutide. We already knew that the placebo-adjusted glucose lowering (~1.5% A1c reduction from a baseline of ~8%) and weight loss (~3 kg / ~7 lbs) results were fairly strong, as those topline results were released last year. As perhaps the best indicator of this product’s potential, both semaglutide doses helped three-fourths of patients achieve a final A1c below 7% without any weight gain or severe or BG-confirmed symptomatic hypoglycemia (vs. 19% of the placebo group). In addition, 59%-60% of the patients on semaglutide reached an A1c of 6.5% or lower. GLP-1 agonists, along with SGLT-2 inhibitors, tend to do especially well with these composite endpoints. We have seen unusually high rates of nausea elsewhere in the semaglutide clinical development program, but in SUSTAIN 1 nausea was reported in only 20%-24% of patients taking the drug, and the vast majority of cases were both mild and temporary. There were a couple imbalances in the safety analysis, namely a pair of four-to-zero imbalances vs. placebo with both malignancies and gallstones. Mitigating factors for the malignancies include: (i) there were two times as many patients in the trial taking semaglutide as placebo; and (ii) the cancer cases were not all of one type, raising the odds that the imbalance was due to chance.

• As a test of semaglutide in treatment-naïve patients, SUSTAIN 1 is valuable for regulatory purposes but is not very clinically relevant given that GLP-1 agonists are not prescribed first-line. The double-blind trial randomized 388 type 2 diabetes patients on no baseline glucose-lowering therapy 1:1:1 to semaglutide 1.0mg, semaglutide 0.5 mg, and placebo for 30 weeks. The doses were escalated upwards over 4-8 weeks.
• Notably, both semaglutide doses performed comparably when it came to glucose lowering efficacy, lowering A1c by 1.5% (0.5 mg) and 1.6% (1.0 mg) from a mean baseline of 8.1%. There was no mean A1c change from baseline in the placebo group. Presenter Dr. Sorli suggested during Q&A that in this trial, mean baseline A1c was low enough that even the lower semaglutide dose took patients to ~6.5%, and the higher dose had no more room to lower glucose further given that GLP-1 agonists only stimulate glucose lowering when glucose levels are high. We’d buy it, as we’ve seen greater magnitude A1c reductions out of semaglutide in other trials – including in the oral semaglutide abstract presented in this same session. Seven-point SMBG profiles showed clear reductions in both fasting glucose and postprandial glucose excursions.
  
  • Body weight fell by a placebo-adjusted 3.5 kg (~8 lbs) with semaglutide 1.0 mg and 2.7 kg (~6 lbs) with semaglutide 0.5 mg.
• GI tolerability results were relatively good in this trial, but there were a few minor blips in the safety and adverse event profile. Rates of nausea (20%-24% of patients taking semaglutide) were comparable with those for other GLP-1 agonists, and better than we have seen from other semaglutide trials. The vast majority of nausea cases on both doses were categorized as mild, and especially for the lower dose, most resolved by week 15. Still, a not-insignificant proportion of patients started on semaglutide discontinued treatment due to adverse events (6.3% in the 0.5 mg group and 5.4 in the 1.0 mg group vs. 2.3% on placebo). Many patients will tolerate some amount of transient nausea if a drug’s glucose lowering efficacy – and especially its weight loss effects – are strong, but the higher rates of nausea seen elsewhere in the clinical development program for semaglutide make GI tolerability an item to watch as more phase 3 results comes out.
  
  • There was a slight imbalance in serious adverse events, with 5.4%-5.5% with semaglutide and 3.9% with placebo. Interestingly, there were four-to-zero imbalances in both gallstones and malignant neoplasms not in favor of semaglutide. The cancer cases were distributed across cancer types, and it is worth remembering that there were twice as many patients on semaglutide as on placebo in the trial. Gallstones are a risk factor for acute pancreatitis, but no cases of pancreatitis were reported in the trial. There was, however, the usual increase in pancreatic enzymes seen with most GLP-1 agonists. We wouldn’t ring any alarm bells yet, but we will be looking closely at the malignancy and gallstone numbers for other SUSTAIN trials.
• What do the positive topline results from LEADER, the cardiovascular outcomes trial for semaglutide’s predecessor Victoza (liraglutide), mean for semaglutide? In terms of efficacy and weight loss, semaglutide appears to be delivering on its next-gen potential, with the caveat that there have not been head-to-head trials vs. Victoza. However, in Victoza’s favor, it is hard to beat demonstrated cardioprotection as a selling point. Interestingly, while Novo Nordisk ran LEADER as a fairly long and robust CVOT with the potential to demonstrate cardioprotection, SUSTAIN 6 (the CVOT for semaglutide) is remarkably short, with a registered start-to-finish more than two years shorter than LEADER’s – SUSTAIN 6 was actually completed earlier this year, and results may not follow too far behind those from LEADER. Since SUSTAIN 6 may not be long enough to demonstrate cardioprotection, Victoza may have a perpetual upper hand on the cardiovascular outcomes portion of its label. Such a scenario (especially if oral semaglutide becomes available) could slightly diminish injectable semaglutide’s relative appeal to payers, patients, and providers, though we still believe that those who take a look at the data will see semaglutide as the most effective agent out of Novo Nordisk’s GLP-1 agonist portfolio.

Questions and Answers

Q: So do you think there will be no cardiovascular outcomes benefit with this agent, unlike what we have with liraglutide?

A: Time will tell.

Q: Can you comment on what looked to be a minimal dose response between the two semaglutide doses?

A: It is probably multifactorial, and this is obviously speculative, but it may just be this specific population of patients. With the efficacy of this drug, and the fact that it turns itself off when glucose levels are normal, we may be getting patients down to an A1c level where there is not a lot of buffer to go lower. The SUSTAIN program is comprehensive, with different populations being studied, and future trials may show more of a dose response.

Q: How does the decrease in A1c compare with that for other GLP-1 agonists?

A: That would be comparing apples and oranges. This was a robust reduction in this patient population, but we don't yet have data on any direct comparisons.

Q: Could you discuss the four cases of malignancy seen in the semaglutide arm?

A: Yes, there were two in each semaglutide group, with no consistency across organ systems.

Q: Could you discuss injection site reactions and blood pressure data?

A: There were no statistically significant differences in either systolic or diastolic blood pressure. Injection site reactions were extremely rare, but I do not recall the specific numbers.

Q: Isn’t the lack of reduction in blood pressure different than what we see with other agents in the class?

A: There was a trend towards lower blood pressure, but it was not statistically significant in this study.

Robust Dose-Dependent Glucose Lowering and Body Weight (BW) Reductions with the Novel Oral Formulation of Semaglutide in Patients with Early Type 2 Diabetes (T2D)

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center at Medical City and University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock gave us a first look at full phase 2 data on Novo Nordisk’s oral GLP-1 agonist program, which was advanced into phase 3 last summer; topline results from the phase 2 program were released a little over a year ago. Phase 2 tested a wide range of daily oral semaglutide doses, from 2.5 mg through 40 mg, along with a placebo group and a 1 mg injectable semaglutide group. Glucose lowering, weight loss, and GI tolerability data were dose responsive across the range of doses tested, with the maximum oral dose looking fairly similar in almost all respects to the 1 mg subcutaneous dose. Dr. Rosenstock mentioned during Q&A that this is the first time that a peptide has been administered orally with such great effects, a fact that merits recognition. Given that rates of discontinuation treatment – ostensibly due in large part to high rates of nausea – were above 25% for the higher doses, we believe Novo Nordisk was wise to only move lower doses (3 mg – 14 mg) forward into phase 3. In the data tabulated below, it is evident that efficacy was good even at the 10 mg and 20 mg doses, while there was a large step-up in nausea and discontinuations in that same range. Especially with oral GLP-1 agonists possibly positioned as a first-line add-on to metformin, acceptable tolerability is an important priority for oral semaglutide. Plus, lower doses are much more realistic to manufacture, given that even a 14 mg daily oral dose is ~100x more drug molecule than the 1 mg weekly subcutaneous dose.

• Adverse event profile:
  
  • The overall rate of hypoglycemia was low, with only two cases of severe hypoglycemia reported: one with injectable semaglutide and one with oral semaglutide 40 mg
  • There were three confirmed cases of pancreatitis in the trial: one with subcutaneous semaglutide, and two with oral semaglutide. All were mild to moderate, with none classified as serious adverse events.
  • There were no irregularities in the incidence of neoplasms or cardiovascular adverse events.
• In this study – and, it seems, moving forward – tablets were administered in the fasting state. Subjects abstained from food and fluid intake for at least 30 minutes after tablet ingestion. We imagine dose timing such as first thing in the morning or the very end of the day would make this acceptable for most patients, but Novo Nordisk will need to study what happens to the drug’s efficacy and safety if patients do not adhere to those instructions. Variable absorption is one of the biggest challenges with oral delivery of peptide drugs.   
• Even though the 40 mg oral dose is not being carried forward to phase 3, data on a faster and slower dose escalation protocol for that dose was enlightening. The group with the slow uptitration experienced fewer reported adverse events and around half the incidence of treatment discontinuations as the accelerated uptitration group. Dr. Rosenstock indicated that more data comparing the fast and slow protocols will be presented at a later point in time. We have not yet seen specifics on the uptitration protocol being used in phase 3, but we imagine from these early results that there may be advantages to making the slow uptitration standard.

Table: Summary of Results from Phase 2 on Oral Semaglutide

	Placebo	2.5 mg	5 mg	10 mg	20 mg	40 mg	SC (1 mg)
Number of patients	71	70	70	69	70	71	69
A1c change	-0.3%	-0.7%	-1.2%	-1.5%	-1.7%	-1.9%	-1.9%
FPG change (mg/dl)	-1.1	-17.3	-27.8	-42.1	-41.9	-51.2	-56.3
% achieving A1c < 7%	28%	44%	81%	84%	86%	88%	93%
Body weight change (kg)	-1.2	-2.1	-2.7	-4.8	-6.1	-6.9	-6.4
% achieving >5% weight loss	13%	21%	21%	56%	64%	71%	66%
Adverse events	68%	67%	63%	75%	81%	79%	81%
Nausea incidence	1.4%	12.9%	14.3%	33.3%	34.3%	33.8%	31.9%
Treatment discontinuations	1.4%	8.6%	5.7%	11.6%	27.1%	22.5%	14.5%

Questions and Answers

Q: Have oral administration of insulin been tried?

A: Oral insulin is much tougher. Companies, including Novo Nordisk, are trying. It is much harder since you want insulin to go into the portal circulation, and you need different titratable dosages. Here, with GLP-1, you have specific dosages. But there is still potential with insulin, and companies have been working on it for many years, and will probably continue working on it for many years.

Q: One of the challenges with oral peptide development is the effect of food. You dealt with this by asking patients not to eat for 30 minutes after dose administration in the fasting state. In the real world, my impression is that patients would not always comply with that. What effect would a patient eating 20-30 minutes before or after dosing have on bioavailability?

A: Novo Nordisk did sophisticated studies looking at timing of administration to estimate post-dosing fasting intervals, from two hours down to 30 minutes, and they came up that the best way is 30 minutes. Probably there may be a slight advantage to one hour, but between one hour and 30 minutes there are no major changes. We think 30 minutes is doable.

Q: The slide showed that the drug absorption is happening in the stomach, not the small intestine. Isn’t that unusual?

A: Well this is an unusual presentation: it is the first time ever that a peptide is being administered orally with such impressive results. 

Q: At around six months, adverse GI events seemed to dissipate. Does the weight loss dissipate as well?

A: The PIONEER phase 3 program will study oral semaglutide for more than one year, and there is also a longer cardiovascular outcomes trial. This was a shorter trial.

Consistent HbA1c Changes with Empagliflozin/Linagliptin Irrespective of Body Mass Index, Renal Function, or Gender

Kamlesh Khunti, MD, PhD (University of Leicester, UK)

A new analysis of data from Lilly/BI’s Glyxambi (empagliflozin/linagliptin) phase 3 trials showed that the combination achieves consistent A1c changes irrespective of BMI, renal function, or gender. As a reminder, the phase 3 trials of Glyxambi (presented at ADA 2014) found that at 24 weeks, the high-dose combination (empagliflozin 25 mg/linagliptin 5 mg) achieved A1c reductions of 1.1% and 1.2% (from baseline A1c of ~8%) as initial therapy and add-on to metformin, respectively. The analysis first cut the data by baseline BMI <25 kg/m² vs. ≥25 kg/m² – these results found consistent A1c reductions with the high-dose combination in both the initial therapy (A1c reductions of 1.13% [lower BMI] and 1.08% [higher BMI]) and add-on to metformin studies (A1c reductions of 1.21% [lower BMI] and 1.19% [higher BMI]). Similarly, there was a consistent effect regardless of baseline eGFR (60 to <90 ml/min/1.73 m² vs. ≥90 ml/min/1.73 m²), with all arms achieving ~1% A1c reductions at the high dose of Glyxambi (1.08% and 1.06% in the low and high eGFRs, respectively, in the initial therapy study). As for gender, the effect also remained relatively consistent (in the add-on to metformin study, females and males achieved A1c reductions of 1.16% and 1.22%, respectively), except that females in the initial therapy study demonstrated a somewhat lower response compared to males (A1c reductions of 0.87% vs. 1.28%). Overall, these data supported the use of Glyxambi across a broad range of patients with type 2 diabetes, although it was noted in Q&A that it is important to take note of the lower response of females when prescribing therapy in this patient population. This first-in-class SGLT-2/DPP-4 inhibitor combination has certainly been a highly anticipated approach and the consistency found across the board in this analysis is encouraging in terms of incorporating this combination into future therapies, such as the triple-therapy tablet of empagliflozin, linagliptin, and metformin Dr. Ralph DeFronzo (University of Texas Health Science Center, San Antonio, TX) referred to at EASD – see our coverage of his presentation of Glyxambi’s 52-week results for more.

The Glucagon Receptor Antagonist LGD-6972 Reduces Fasting and Postprandial Glucose in a Multiple-Dose Clinical Trial

Eric Vajda, PhD (Ligand Pharmaceuticals, La Jolla, CA)

Dr. Eric Vajda presented positive phase 1b data of Ligand’s glucagon receptor antagonist LGD-6972, demonstrating that the candidate substantially improves glycemic control and is well tolerated. This randomized, double-blinded, placebo-controlled study (n=48) was a multiple ascending dose trial in normal healthy volunteers and individuals with type 2 diabetes. Over 14 days, normal healthy volunteers were administered a once-daily 15 mg dose of LGD-6972 while type 2 diabetes participants were randomized to either 5 mg, 10 mg, or 15 mg doses per day. The findings demonstrated that LGD-6972 reduced fasting plasma glucose in normal healthy volunteers (from ~97 mg/dl to ~86 mg/dl). In type 2 diabetes participants, the results found dose dependent decreases in fasting plasma glucose, with reductions of ~37 mg/dl, ~50 mg/dl, and ~53 mg/dl for the 5 mg, 10 mg, and 15 mg doses, respectively (from a baseline of ~160 mg/dl-200 mg/dl). From these findings, Dr. Vajda estimated an A1c reduction of ~1.5% at steady state with the highest dose. Notably, he also highlighted that these glucose reductions were observed in both fasting and postprandial states throughout the day. In addition, the study’s oral glucose tolerance test showed that LGD-6972 increased the insulin excursion and decreased glucagon excursion after an oral glucose load. Regarding the candidate’s safety and pharmacokinetic profile, the study had no serious adverse events (nausea and headache being the most common adverse events, mild to moderate in nature) and the candidate was well tolerated with no clinically significant changes in hematology, clinical chemistry, urinalysis, ECG, or vital signs. Dr. Vajda also pointed out that LGD-6972 was well absorbed with a long half-life (~50 hours) and that the drug’s steady state was achieved in a relatively short amount of time (within seven to 10 days). While this study’s duration is short, the data are promising for further clinical development. But as a small company, it may be challenging for Ligand to differentiate itself in the type 2 diabetes drug arena with the market’s increasing high bar, although LGD-6972 can be an appealing candidate to partner. For the company’s latest and more of our thoughts, please see our coverage of Ligand’s 4Q15 update.

GLP-1 Receptors Exist in the Parietal Cortex, Hypothalamus, and Medulla of Human Brains and the GLP-1 Analog Liraglutide Administered in the Context of a Cross-over, Randomized, Placebo-Controlled Trial Alters Brain Activity in Response to Highly Desirable Food Cues in Individuals with Diabetes

Olivia Farr, PhD (Beth Israel Deaconess Medical Center, Boston, MA)

This study demonstrated the distribution of GLP-1 receptors in the brain (this was apparently a first), and showed that GLP-1 agonists diminish activation in certain key brain areas in response to fatty and calorie-dense foods. Dr. Olivia Farr’s group first used immunohistochemistry on human brain samples and found GLP-1 receptors in the hypothalamus (which deals with homeostatic “body-maintaining” functions), the medulla (the “ancient” or “reptilian” brain), and parietal cortex (which performs higher-level conscious thought). To explore the functional effect of GLP-1 receptor activation in the brain, Dr. Farr’s group used fMRI brain scans while displaying study participants with a succession of images of highly desirable fatty and/or calorie rich foods, less desirable foods (we thought some of the salad pictures in this category looked quite good), and non-food objects. Specifically in response to the highly desirable food cues, liraglutide led to less activation in brain areas related to attention and processing. In other words, liraglutide seems to make fatty and calorie-dense foods less desirable to patients. With GLP-1 agonists increasingly relevant as therapies for obesity – an application for which higher doses are use to specifically target the brain – it will be interesting to “look under the hood” and figure out what neural circuits GLP-1 agonists are modulating.    

Questions and Answers

Q: What else do you think could be affected by the changes in parietal function?

A: It seems like patients were attending less to those highly desirable food cues, inducing weight loss. In this study, participants had not yet begun losing weight, so presumably it is the changes in neural activation that are leading to the weight loss.

Q: What do you think is more important, the hypothalamic activation, or parietal activation?

A: In humans, control of eating is very complicated. It’s not just the homeostatic system in the hypothalamus. People eat for reasons other than being hungry. I think it’s the cortical systems that are most interesting, because that’s where attention and control circuitry is.

Q: Did you assess baseline preferences for foods before doing the MRI scans? Vegetarians may not perceive high fat foods like burgers as desirable.

A: We excluded vegetarians and people with strict dietary regulations. We also had a panel rate the food images for desirability.

Q: Were these obese people you were testing – people who may have made bad life choices?

A: I don’t impose a moral judgment. It’s not necessarily that they have been making bad choices, but instead that their brain is simply wired in a different way. And by giving them therapeutics like GLP-1 agonists, we may be able to treat the underlying cause of obesity.

Oral Presentations: Cardiometabolic Risk – Salt, Fat and Sex

Liraglutide Induces a Rapid and Large Epicardial Fat and Left Ventricular Mass Reduction Beyond Weight Loss and Glycemic Control

Gianluca Iacobellis, MD (University of Miami, FL)

Dr. Gianluca Iacobellis presented data from a randomized clinical trial demonstrating that Novo Nordisk’s GLP-1 agonist Victoza (liraglutide) dramatically reduces metabolically harmful epicardial fat – fat stored between the myocardium (heart muscle) and epicardium (the membrane that surrounds the heart). Of course, such results are of even greater interest now that we know that Novo Nordisk’s LEADER trial for Victoza demonstrated statistically significant cardioprotection vs. placebo. In Dr. Iacobellis’ group’s six-month study, 100 fairly well controlled type 2 diabetes patients randomized to add liraglutide to their baseline metformin therapy experienced a statistically significant 42% reduction from baseline in epicardial fat, as assessed by ultrasound; the comparator group on metformin alone saw essentially no change from baseline. This change far outstripped the magnitude of liraglutide’s beneficial effect on A1c or BMI. The reduction in epicardial fat was associated with improvements in left ventricular mass, a marker of cardiovascular health. Dr. Iacobellis hypothesized that GLP-1 receptor agonism in epicardial fat promotes the activation of brown adipose tissue, leading to an improvement in insulin sensitivity. In his conclusion, Dr. Iacobellis suggested that pharmacologic and/or genetic therapies targeting epicardial fat could reduce its metabolically harmful effects in diabetes and perhaps even transform it into a protective role.

• Why single out epicardial fat? Dr. Iacobellis suggested the epicardial fat is the “visceral fat depot of the heart,” in that it is an active endocrine organ with gene activation associated with inflammation, immune activity, and apoptosis. Increased epicardial fat is associated with abdominal fat, insulin resistance, and hyperglycemia. In contrast, some drugs with known cardiovascular benefits (including statins) have been shown to reduce epicardial fat. GLP-1 agonists appear to induce reductions in both visceral and subcutaneous fat, giving Dr. Iacobellis’ group good reason to investigate its effects on epicardial fat.

Questions and Answers

Q: Do you have plans to duplicate this study, but with SGLT-2 inhibitors?

A: It is a good question, and our group is working on that. I do not have results for that yet, but it looks like the osmotic diuretic effect may give you an indirect reduction in epicardial fat, though it probably is not as direct an effect as with GLP-1 agonists. We are in the preliminary phase on those studies and we hope we can give you results in 2017.

Q: Did you see any association with changes in visceral fat?

A: Yes of course, we published before that epicardial fat correlates with other fat deposits.

Inter-Relationships Between the Severity of Metabolic Syndrome, Insulin and Adiponectin and Their Relationship to Future Diabetes and Cardiovascular Disease: The Princeton Lipid Research Study

Mark DeBoer, MD (University of Virginia, Charlottesville, VA)

Dr. Mark DeBoer presented data supporting the use of a metabolic syndrome (MetS) severity score as a continuous measure of an individual’s metabolic and cardiovascular risk. He explained that classical diagnostic criteria for metabolic syndrome likely miss some patients who may be at risk because they are binary and based on population values that may not apply to certain gender or racial/ethnic subgroups. Using NHANES data, Dr. DeBoer’s group developed a formula that multiplies values for clinical parameters (BMI, glucose, lipids, etc.) by standardized coefficients based on how heavily that parameter influences MetS in a particular demographic subgroup. The resulting “severity score” was shown to correlate with surrogate markers of MetS, providing some validation that it is accurately measuring risk. In their most recent research, Dr. DeBoer’s group aimed to examine the relationship between this score and insulin and adiponectin. Using data from the Princeton Lipid Research Cohort, they found that MetS severity was significantly correlated with insulin and adiponectin levels cross-sectionally and between childhood and adulthood. A multivariate analysis found that the MetS score and insulin levels (but not adiponectin levels) were both independent risk factors for type 2 diabetes in this cohort; only the MetS score was an independent risk factor for cardiovascular disease. Dr. DeBoer believes this severity score has great potential as a tool to identify high-risk patients and follow changes in people’s status over time; it could also be very useful as an outcome for research.

Oral Presentations: Fresh Thoughts on Diabetes Treatment

Higher Early Insulin Exposure and Greater Early Glucose-Lowering Effect with Faster-Acting Insulin Aspart vs Insulin Aspart Across a Clinically Relevant Dose Range

Tim Heise, MD (Profil, Neuss, Germany)

Insulin expert Dr. Tim Heise presented the results of a randomized, single-center, double-blind, single-dose clamp study examining the precise PK/PD properties of Novo Nordisk’s faster-acting insulin aspart formulation in 46 adult type 1 diabetes patients. Pharmacokinetically, faster aspart had a ~3-4x greater insulin area under the curve in the first 15 minutes, with the difference greatest at higher doses. This was in the context of comparable total exposure over the full five hour clamp study. The onset of appearance for faster aspart was roughly twice as fast as regular aspart, with a time to half-maximal concentration and time to peak concentration arriving around 30% quicker and 10% quicker, respectively. This PK profile translated to statistically significant pharmacodynamic differences, namely a 20%-26% (5-6 minute) faster onset of pharmacodynamic action. Time to peak glucose-lowering action (50% GIRmax) was 22%-25% (9-12 minutes) faster, while the time to max glucose-lowering action was 8%-22% (10-30 minutes) faster depending on the dose. These data did a great job of supporting faster aspart’s value proposition, and complement the non-clamp phase 3 clinical trial data we’ve seen demonstrating __________.

Oral Presentations: Mechanisms and Treatment of Diabetic Complications

Dapagliflozin: Metabolic and Molecular Mechanisms of Increased Plasma Ketones

Carolina Solis-Herrera, MD (University of Texas Health Science Center, San Antonio, TX)

A small, mechanistically oriented study from the team at University of Texas Health Science Center in San Antonio attempted to shed more light on the connection between SGLT-2 inhibitors and ketoacidosis, but whereas much of the controversy has focused on type 1 diabetes, this study examined ketoacidosis in type 2 diabetes patients. A total of 21 patients (average age of 52-55 years, average A1c = 8.6%) were randomized to dapagliflozin 10 mg or placebo for two weeks, with an insulin clamp performed at the beginning and end. As expected, dapagliflozin improved fasting glucose levels (161 mg/dl at baseline to 126 mg/dl after two weeks) and insulin sensitivity. However, as we’ve seen in other studies, there was an 20% increase in fasting plasma glucagon and a 50% reduction in plasma insulin, which appears to have pushed the body to increasingly use fat as an energy source instead of glucose – the mechanism underlying ketosis. Accordingly, plasma ketones rose from 0.05 to 0.19 mM (the threshold for ketosis is 0.5 mM). Though SGLT-2 inhibitor induced ketoacidosis is fairly uncommon in type 2 diabetes, it does occur, especially in patients with minimal residual insulin secretory capacity or during periods of stress like surgeries. These data also match the general findings of a study presented at ENDO on dapagliflozin and ketosis in type 1 diabetes – the picture on so-called euglycemic DKA is slowly, finally getting clearer.

Oral Presentations: Bedside to Bench: Clinical and Genetic Regulation of Lipid Metabolism

Liraglutide 3.0 Mg Reduces Body Weight and Improves Cardiometabolic Risk Factors in Adults with Obesity or Overweight and Prediabetes: The SCALE Obesity and Prediabetes Randomized, Double-Blind, Placebo-Controlled 3-Year Trial

Ken Fujioka, MD (Scripps Health, San Diego, CA)

Dr. Ken Fujioka presented new data from the SCALE Obesity and Prediabetes three-year extension trial, showing that treatment with Novo Nordisk’s Saxenda (liraglutide 3.0 mg) improves cardiometabolic risk factors – blood pressure and cholesterol – compared to placebo. At 160 weeks, the Saxenda intervention group experienced greater reductions in systolic blood pressure (-2.8 mmHg, p<0.0001), triglycerides (-6%, p=0.0003), total cholesterol levels (-2%, p=0.03), and high-sensitivity C-reactive protein (‑29%, p<0.0001) compared with those in the control group. The improvements are encouraging in the context of the positive topline results on weight loss and delayed onset of type 2 diabetes – see our previous coverage here. Of some concern, Dr. Fujioka shared that rates of gallbladder-related adverse events and confirmed acute pancreatitis were more frequent in those treated with Saxenda (2.9 events/100 patient-years of observation and 0.29/100 PYO) vs. placebo (1.2/100 PYO and 0.13/100, respectively). The imbalance led reports of overall serious adverse events to be slightly higher in the intervention group vs. placebo (15% vs. 13%). The need for chronic usage does raise the stakes for the drug’s long-term safety and we wonder what the data might look like stratified by Saxenda responders and non-responders – Are the difference in driven by weight loss or the drug itself?

• The abstract’s conclusion ties the positive findings to potential long-term cardiovascular benefits – no surprise given the recently announced topline results from LEADER (liraglutide 1.8 mg): “In individuals with prediabetes, [three] years of treatment with liraglutide 3.0 mg, as an adjunct to diet and exercise, was associated with delayed onset and reduced risk of [type 2 diabetes], weight loss and improvements in cardiometabolic risk factors, which if sustained in the long term may be associated with reduced CV risk.” It’s certainly conceivable that LEADER results could help Saxenda to some extent, and we can foresee patients/providers wanting to extrapolate the CVOT data down the road. Of course, there is a laundry list of caveats here (different patient populations, study durations, background medications, etc.), and if we learned anything from EMPA-REG OUTCOME, it is that clinical studies are unpredictable. Of course, we don’t see Novo Nordisk pursuing a Saxenda CVOT voluntarily (FDA didn’t require a separate CVOT for the drug) though it’s not hard to imagine that the question of whether we can connect the dots will emerge as a theme (at least among obesity circles) later this year.

Oral Presentations: Clinical – Late-Breaking

Weight Loss and Improvement in Hyperphagia-Related Behavior: Results from Bestpws, a Phase 3, Randomized, Placebo-Controlled, Clinical Trial of Beloranib, a Methionine Aminopeptidase 2 (MetAP2) Inhibitor, in Patients with Prader-Willi Syndrome

Merlin Butler, MD, PhD (University of Kansas, Kansas City, KS)

Zafgen presented new data from its phase 3 bestPWS study of beloranib in Prader-Willi syndrome (PWS), demonstrating improvements in cardiometabolic risk markers and a reduction in fat mass. As a reminder, the company recently announced that this six-month trial (n=107) achieved the co-primary efficacy endpoints, with statistically significant reductions in both body weight and hyperphagia-related behaviors. Dr. Merlin Butler expanded on this by presenting new findings on the secondary endpoints: beloranib was found to be associated with improvements in total cholesterol (-18 mg/dl and -17 mg/dl for 2.4 and 1.8 mg doses, respectively; baseline of 174 mg/dl) and LDL cholesterol (-18 mg/dl and -17 mg/dl; baseline of 101 mg/dl). In addition, the beloranib arms demonstrated reductions in leptin levels (-24 ug/l and -21 ug/l; baseline of 6.9 ug/l) and increases in adiponectin levels (+1.9 ug/l and +1.7 ug/l; baseline of 4.6 ug/l), consistent with altered fatty acid mobilization and lipid utilization. Dr. Butler also shared body composition findings (measured used DXA scans), showing a significant reduction in total body mass (-6% and -3%) and fat mass (-5% and -2.5%) at both doses, with minimal changes in lean body mass. Ultimately, the efficacy profile of beloranib continues to remain strong, although these data co-exist with the harsh safety signals of thromboembolism. Dr. Butler touched on this during Q&A, highlighting that Zafgen is working hard on understanding this signal and identifying if and how pulmonary embolism may be part of PWS’s natural history. We agree that this research will be critical for moving this treatment forward in PWS, but also for thinking about whether or not beloranib can eventually be indicated for general obesity – is this a safety signal only in the PWS patient population or in the broader populations as well? For more on Zafgen’s latest on a REMS program, please see our coverage of its 4Q15 update.

Clinical Session: Bionic Pancreas

Automating Glycemic Management in Diabetes Mellitus With a Bionic Pancreas

Steven Russell, MD, PhD (Massachusetts General Hospital, Boston, MA)

Dr. Steven Russell’s comprehensive overview of the Bionic Pancreas was headlined by new insight that the iLet will pair with a still-to-be-named Bluetooth-connected BGM. This is the first we have heard of this detail following Dr. Damiano’s big reveal of Beta Bionics’ commercialization plans on Friday. Dr. Russell did not name the meter or brand but did hint that it is “one of the most accurate” BGMs on the market. Based on Dr. Russell’s 2015 GTC Bio presentation that identified the Ascensia’s Contour Next Link (formerly Bayer), the OneTouch VerioIQ, and the Nova Biomedical STATstrip Express as the most accurate among 17 BGMs, we presume it is one of these. The goal in linking the meter to the iLet is twofold: (i) reducing patient burden; and (ii) eliminating manual calibration errors (e.g., incorrectly inputting a glucose value). Overall, we think it’s a smart move to stay competitive with Medtronic, who also uses Bayer meters in the MiniMed 640G and 670G (the 640G has the capability for remote bolusing from the meter – we don’t know if the iLet will do the same.) Dr. Russell also shared in Q&A that he has submitted an NIH R01 application for a type 2 trial of an insulin-only version of the Bionic Pancreas (currently under review) . The application comes on the heels of a small pilot of the iLet device in this population that Dr. Russell noted “has worked well.” He speculated that such an application would roughly “double” the US closed-loop market size: 21 million US patients with type 2 diabetes x 6% on complex insulin regimens = ~1.5 million type 2 patients. It’s early days for the type 2 project though a bigger market is important for the viability of any small closed-loop company like Beta Bionics – certainly the entire field is thinking longer-term about CGM, pumps, and automated insulin delivery in type 2, and we hope rigorous trials can document the benefits. See below for more thoughts on the unique prospect of commercialization a glucagon-only system in patients with post-bariatric hypoglycemia or congenital hyperinsulinism patients.

• Dr. Russell confirmed that the commercialized iLet will use AAA batteries – we had not heard this detail before. The team is not sure what battery life will look like in the real world, but the device will show a battery status icon like on an iPhone. We assume a battery life on the order of a few weeks would be reasonable. While the rechargeable vs. disposable battery debate is a tough one, using AAA batteries should keep the device cost down for Beta Bionics (no need for a fancy lithium rechargeable battery). 
• Dr. Russell shared the team’s glucagon-only home use study, first presented at AADE 2015; results continue to validate the addition of glucagon as effective and safe in minimizing hypoglycemia. In the randomized, placebo controlled, double blind trial, participants with hypoglycemia unawareness wore a pump with either glucagon or placebo every day while regulating their own insulin. Glucagon reduced overall hypoglycemia by 74% and nighttime hypoglycemia by 91% with no difference in reported nausea. In addition, the trial’s blinding was totally effective: patients correctly guessed they were on glucagon vs. placebo on only 42% of days (less than chance!). There were no adverse events associated with glucagon, and glucagon utilization was comparable (not greater) to use in dual-hormonal trials.
  
  • Dr. Russell pointed out that a system that could automatically correct with glucagon only does have real-world relevance. He pointed to patients with post-bariatric hypoglycemia (patients that have an excess of endogenously produced insulin) and those with congenital hyperinsulinism that do not respond to pharmacotherapy. Granted, these are small population though we liked Dr. Russell’s underlying message that these applications are not about profits – they are about helping patients. Yes! There are certainly populations that would benefit from glucagon-only closed-loop systems, and we were intrigued to hear that Dr. Russell is “planning pilot studies to test the Bionic Pancreas for both of these applications.”
• Dr. Russell’s presentation also featured a look at the group’s head-to-head data from an ongoing study comparing insulin-only and bihormonal versions of the bionic pancreas at different glycemic targets. We first saw these results at ATTD 2016. The Bionic Pancreas works reasonably well in insulin-only mode – mean blood glucose on the insulin-only system was 174 mg/dl and 161 mg/dl at set points of 145 mg/dl and 130 mg/dl, respectively. Rates of hypoglycemia were ≤ 1.0% in both cases – see the full data below. The team plans to test an even lower insulin-only set point (e.g., 110 mg/dl) to assess whether the insulin-only algorithm can bring further glucose reduction without increasing hypoglycemia. Refining this algorithm is paramount considering the plan remains to launch the Bionic Pancreas as an insulin-only system with glucagon to be added later.

Questions and Answers

Q: Is there any chance you will begin testing the Bionic Pancreas in type 2 patients soon?

A: I’ve actually submitted an RO1 application to do type 2 trials. We’ll see how the reviewers look at it. It’s an excellent question because I’ve had to educate myself more about type 2 diabetes in doing that grant. About 30% of patients take insulin and they have worst control of all people with type 2 diabetes. In fact, only 30% of type 2s on insulin meet their glycemic goals – the same percentage as in type 1s. This is way too low. Of course, you have to break it down further and look at the number of patients on complex insulin regimens that could gain benefit from the Bionic Pancreas. About 6% of people with type 2 are on complex regimens in the US; that’s about ~1.5 million people. We’ve done a small pilot and the system worked well in them. So, I hope the answer to your question is yes.

Ultimately, this could be very important for the viability of a tiny company. If you double the number of people that can use the product, that’s huge. Type 1 diabetes represents maybe 1.5 million patients in the US. It’s a pretty small market. It can be hard for companies to make it. We’ve seen pump companies go out of business because they can’t sustain themselves.

Q: Have you seen any irritation with glucagon? Have you seen any evidence of lipodystrophy, like we see with insulin?

A: I haven’t seen it but our trials have been pretty short. The majority of glucagon receptors are in the liver though so my hope is that there is a little biological effect locally where the glucagon is being administered. The hope is no, but only in longer trials will we be able to know for sure.

Q: Could you use the glucagon-only setup in patients with insulinomas? That would be a small group but could help them have a reasonable lifestyle.

A: It’s interesting that you ask but someone recently sent me an email about this. In patients that are not responding to drugs, there is the potential to use the glucagon-only Bionic Pancreas. That said, I would say that the dosing of the glucagon as it is currently set up is not intended for people who need massive doses. For that use, we’d have to recalibrate the algorithm.

Q: How does the Bionic Pancreas deal with a dropout in the CGM signal? How about during periods of CGM calibration? And what if there is a problem with the glucagon infusion?

A: Remember that the Bionic Pancreas doesn’t do basal insulin in the typical sense – it gives boluses every five minutes. Over time, it learns what is essentially a customized basal rate. If CGM data is unavailable for any reason, it defaults back to that “basal” rate. However, if you do input a blood glucose value manually, it does close the loop around that value. In theory, you could input a blood glucose value every five minutes and achieve the same control as you would achieve with CGM data. And in terms of glucagon, if there is a problem with the glucagon infusion, the system automatically defaults to insulin-only mode and raises the blood glucose set point.

Q: How confident are you in the accuracy of the sensor?

A: I agree that the sensor is the weak link in the chain. We’ve done work to assess accuracy, and we’ve found that Dexcom is the best. You’re still vulnerable to bad calibrations though. Since the burden on patients is decreased on closed-loop systems, we ideally want them to really focus on calibration and want sure their hands are clean, etc. For the iLet, we’re going to have our own meter that ships with the unit that links with Bluetooth. We picked one of the most the most accurate meter there, too, which has a MARD of 6%. Using a linked meter should reduce manual error from mistyping blood glucose into the device. All of that being said, we do not think we need to wait for more accurate CGM to close the loop because our studies have been real world and have taken the inaccuracy of the current Dexcom system into account.

Q: How long does the algorithm take to adapt to patients?

A: It can take the better part of a day for children or obese patients. In adults, it’s pretty good almost immediately.

Q: How will you go about speaking with insurance companies about covering the Bionic Pancreas?

A: Insurance is really a challenge. We’ve seen with Medicare that the government doesn’t want to pay for CGM. Beta Bionics will be working hard on that. We have a good case to make, and we have an argument that we’ll save payers money. However, they do not tend to think long term so I do think it’ll be a challenge.

Q: How do you know if the iLet battery is dead?

A: The iLet uses AAA batteries. We don’t know what battery life will be like in the real world but there will be a reminder bar like on an iPhone.

Q: How much will glucagon cost?

A: We’re hoping it’ll be about the same cost as insulin. The overall cost of the system will be higher since we’ll have both insulin and glucagon, but hopefully the cost of glucagon won’t be higher than insulin.

Clinical Session: U500 Insulin

When and How to Use U500 (or Other Concentrated) Insulin

Wendy Lane, MD (Mountain Diabetes and Endocrine Center, Asheville, NC)

The centerpiece of Dr. Wendy Lane’s presentation on concentrated insulin formulations was a home-cooked high dose insulin algorithm, but there was plenty of other wisdom on concentrated insulins as well. This clinical session was in line with the whole-conference theme of more focus on concentrated insulin, as rising prevalence of obesity and severe insulin resistance drive some patients to require insulin doses well above 100 units each day. She stated that Sanofi’s Lantus (insulin glargine) at its U100 concentration has diminishing additional efficacy per unit above 0.5 U/kg (this seemed like a surprisingly low threshold to us), explaining why some patients’ insulin needs seem to reach a point and skyrocket. She mentioned that U500 insulin can go into pumps, though the math is “complex.” As a reminder, Dr. Lane noted that instead of continuing to dial up the insulin dose, patients and providers can consider adding an insulin-sparing agent like a GLP-1 agonist.

• Dr. Lane ended by presenting her “High Dose Insulin Algorithm” – it finds a place for Novo Nordisk’s Tresiba U200 (insulin degludec), Sanofi’s Toujeo (insulin glargine U300), and Lilly’s Humulin U500 and Humalog (insulin lispro) U200. The starting point for the algorithm is whether a patient’s basal insulin dose is above or below 0.5 U/kg/day:
  
  • If below, and the patient’s daily total dose is less than 40 U/day, Dr. Lane recommends a U100 basal analog or Toujeo. If below 0.5 U/kg/day and the total dose is between 40 and 60 U/day, she recommends Toujeo or Tresiba U200.
  • If basal insulin dose is above 0.5 U/kg/day, she recommends Tresiba U200. We found it interesting that her algorithm recommends the less concentrated insulin (vs. Toujeo) as the total dose gets higher.
  • If bolus insulin is needed, the algorithm’s recommendation varies depending on whether the patient needs more or less than 320 total U/day:
    • Between 80 and 320 total U/day, the options are: (i) Tresiba U200 + Humalog U200 MDI; (ii) Humulin U500 MDI; or (iii) a concentrated rapid-acting analog or Humulin U500 by pump.
    • Above 320 total U/day: Humulin U500 MDI or by pump, with adjunct therapies considered
• For those not familiar with the world of concentrated insulin formulations, the benefits are real, and include: (i) improved absorption from smaller-volume insulin depots, leading to more predictable insulin action; (ii) fewer injections and/or lower volume per injection enhance patient comfort, potentially with a positive effect on compliance; and (iii) in some cases (such as insulin glargine), concentrating insulin can prolong its action profile.
• Dr. Lane stated that concentrated mealtime insulins could improve absorption and operability for pump users. They would be less of a game-changer, but still very helpful, for MDI patients, as they could allow small injection volumes and pens that last for more injections. The cast of characters that Dr. Lane mentioned here were (i) U200 insulin lispro; (ii) Lilly and Adocia’s U200 biochaperone insulin lispro candidate; (iii) U400 BIOD-531, which she mentioned was on hold; (iv) the well known Humulin U500 from Lilly; and (v) Flurolog from Thermalin, in development.

Questions and Answers

Q: Can you use U500 insulin in the V-Go?

A: I have mixed feelings. I think you should use U100 insulin there. There is a poster about it here, in fact. You can’t lower the basal rate at night on the V-Go, so if you want to get really good control, you need a real pump that lets you alter the basal rates.

Q: If I have patients on pumps with U100 and want to take them to U500, is it just a matter of diving by five?

A: Yes, above an A1c of 8% its simple division by five. Below 8%, use a 15%-20% reduction.

Q: Patients don’t get their pumps covered, in type 2.

A: When one of the patient cases I presented today aged into Medicare from her private insurance, I had to give her a pump I had in my office. We have a pump exchange program to provide old pumps to people. If people are upgrading pumps, ask them to donate the old pump to you.

Q: When switching people from U100 to U200 lispro, how do you counsel patients on what to expect?

A: They are bioequivalent, identical – it’s a beautiful thing. It’s not the case with all concentrated insulins, but it is when comparing U100 and U200 lispro.

Q: To what percent do you lower the insulin dose when you start an SGLT-2 inhibitor?

A: The only paper I know on that was presented at ADA two years ago, showing around a 9%-11% reduction in insulin when adding an SGLT-2 inhibitor. It’s just a modest reduction. SGLT-2 inhibitors do a lot to reduce glycemic variability, but it doesn’t reduce your insulin requirement as much as a GLP-1 agonist.

Q: I’m surprised that the glargine dose maxed out at 0.5 U/kg. In a 100 kilogram person that means you are maxing out at 50 units.

A: It’s true – you reach the point where you keep uptitrating and not getting further.

Clinical Session: Obesity

Year in Obesity

Daniel Bessesen, MD (University of Colorado, Denver, CO)

In Dr. Daniel Bessesen’s “Year in Obesity” lecture, he labeled the termination of the Light Study for Orexigen’s Contrave (naltrexone/bupropion extended-release) a “disaster,” and pointed to such safety trials as significant roadblocks for the obesity pharmacotherapy market. He criticized how this trial was “rolled out from a business standpoint,” noting the disappointment of gaining no new information from such a “huge investment” and the negative press that arose from the events. Dr. Bessesen acknowledged the many challenges of patient and provider uptake of obesity drugs, emphasizing the sad statistic that prescribing rates of these pharmacotherapies remain <3% of eligible patients. Notably, he pointed to the roadblock of safety trials for this market, specifically highlighting the press’ pessimism on Orexigen and Vivus, with their respective CVOT trials. As a reminder, Vivus’ revenues have been reaching historical lows for Qsymia (phentermine/topiramate extended-release), while the company has not yet begun its ACQLAIM CVOT – Vivus is currently discussing potential redesigns of the trial with the FDA. From our view, Orexigen will certainly similar challenges with Takeda’s recent departure from the partnership. While some obesity companies have pointed to the promise of positive CVOT results and the potential benefits these would bring to the market with regards to payers (we agree that this could possibly expand the market), obesity drugs have a long way to go before even reaching this possibility.

• Touching on more of the latest research in obesity, Dr. Bessesen shared that he doesn’t see genetics or microbiome research reaching “prime time” anytime soon, but highlighted that the work around meal timing is worth further exploring. On the genetics research in obesity, Dr. Besssen noted that we are making progress in this realm, identifying genes and understanding their mechanisms (pointing specifically to work on the FTO gene and its potential mechanisms through affecting food intake), but emphasized that genes’ small impact on body weight shows that “we have a long way to go.” Similarly, he shared that while he sees the microbiome as a very important area, he does not believe that its latest work is ready to be clinically applicable yet, with unanswered questions around the efficacy of fecal transplants and diet implications remaining. Notably, Dr. Bessesen pointed to meal timing as an area worth better understanding, stating that the timing of meals may have a more significant impact on weight loss than macronutrient composition can. Specifically, he presented recent research on how peripheral circadian clocks can mediate dietary restriction-dependent changes in lifespan and metabolism in the drosophila model, as the amplitude of clock genes are important in the lifespan benefits of dietary restriction. Meal timing research has certainly been a less discussed topic from what we’ve seen throughout the latest obesity talk. While this work remains early and very preclinical, we would agree that this area has substantial promise, as counseling patients on meal timing can be a cost-effective and simple intervention to add to the obesity treatment toolkit.

Clinical Session: Obesity – Prevention Strategies, Treatment Paradigms, and Research Needs for 2016 and Beyond

Obesity Research: Current Science and Path Forward

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

Pioneering obesity researcher Dr. Michael Schwartz hypothesized that the pathogenesis of diet-induced obesity involves injury of hypothalamic neurons, leading to associated glial responses and structural alteration within the brain. He introduced obesity as a disorder of energy homeostasis, characterized by an increase in the defended level of body fat mass, delving into the latest research around Agrp and CGRP neurons. Specifically, Dr. Schwartz highlighted that Agrp neurons (located in the arcuate nucleus) are “crucial” in the body’s adaptive response to caloric deficit, as these neurons are activated by leptin deficiency. Thus according to Dr. Schwartz, if this adiposity negative feedback system involving leptin becomes impaired, the enhanced activation of Agrp neurons can be predicted to favor the defense of elevated body fat stores, leading to obesity. Recent work by Drs. Carlos Campos and Richard Palmiter, in collaboration with Dr. Schwartz’s lab, shows that Agrp neuron activation also inhibits neurons involved in satiety and meal termination, such as CGRP neurons (located in the external lateral parabrachial nucleus), whose activation in the rodent model can promote sustained anorexia. Their ongoing work defining interactions between CGRP neurons Agrp neurons exemplifies recent progress in the identification of neuron subsets and circuits involved in energy homeostasis and how dysfunction of these circuits might predispose to obesity. An example of this dysfunction is the neuroprotective response activated in microglia and astrocytes that occurs in response to such neuronal damage, and is evident in the hypothalamus of rodents made obese by consuming a high fat diet. According to Dr. Schwartz, this sequence of events can then result in structural alteration of key brain areas for energy homeostasis. We can imagine this sequence prompting a vicious cycle of damage within the brain, helping to explain why obesity is so challenging to treat. That said,  the more we know about the pathophysiology of  obesity, the greater our ability to identify effective approaches to treatment. For more on Dr. Schwartz’ insights on what’s next for obesity research and treatment, please see our recent interview with him.

Clinical Session: Guidelines

ADA and AACE Guidelines for Individualized Diabetes Management

Silvio Inzucchi, MD (Yale University, New Haven, CT) & Lawrence Blonde, MD (Ochsner Medical Center, New Orleans, LA)

Drs. Silvio Inzucchi and Lawrence Blonde each presented summaries and rationales behind the individual guidelines that they were associated with – Dr. Inzucchi having helped with the ADA/EASD guidelines while Dr. Blonde represented AACE/ACE. Dr. Inzucchi included a mention of the recent outcomes trials that will likely impact prescribing behavior and, eventually guidelines, including EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin), LEADER for Novo Nordisk’s GLP-1 agonist Victoza (liraglutide), and IRIS for the venerable TZD pioglitazone. He did not comment much on either trial or drug beyond the headline findings of the trials, but in future versions of both guidelines we would not be surprised to see a big step up for GLP-1 agonists and SGLT-2 inhibitors, and perhaps a slight return to favor for pioglitazone now that it is generic and has been partially exonerated from a safety perspective (this one is harder to assess).

• Initial combination therapy remains at least somewhat controversial: during Q&A, there was some debate on the fact that the AACE/ACE algorithm recommends initial dual therapy in patients presenting with an A1c above 7.5%. At least one attendee expressed their belief that metformin and lifestyle intervention could take someone from a 7.6% down into the 6.5% range.

Clinical Session: CGM

Using CGM For Day-To-Day Insulin-Dosing Decisions

Steve Edelman, MD (UCSD, San Diego, CA)

“CGM has been the single most important advance for type 1 diabetes since the discovery of insulin.” Dr. Steve Edelman delivered a passionate presentation on the benefits of CGM in the day-to-day management of type 1 diabetes. He stressed that this positive view does not apply to blinded CGM, which he strongly believes is inappropriate in type 1 diabetes except in a research context. This was consistent with the view expressed by many participants at the recent AACE/ACE Consensus Conference on CGM, though a minority of attendees at that meeting argued that masked professional CGM has some value. It will be interesting to see how Abbott does with its blinded FreeStyle Libre Pro system in the US, which is expected to launch in mid-2016. Much of Dr. Edelman’s talk focused on the utility of real-time CGM to help patients make insulin-dosing decisions, particularly the significant adjustments patients make to bolus doses based on trend arrows (e.g., a BG of 220 mg/dl and two up arrows [take much more insulin] vs. two down arrows [take much less]). This work was first presented as a poster at ATTD 2014 and subsequently published in DT&T’s special CGM issue earlier this year. Dr. Edelman did not explicitly address adjunctive vs. non-adjunctive use of CGM, though he did briefly refer to a survey indicating 50% of patients would confirm a low CGM glucose value first before taking action, while the other 50% would treat right away. We assume more patients will begin using sensors to make treatment decisions once: (i) systems get insulin-dosing claims in the US (Dexcom expects it this year); (ii) accuracy and reliability continue to improve; and (iii) factory calibration arrives, putting fingersticks further in the background (Abbott’s FreeStyle Libre is “optimistically expected” by the end of 2016). Dr. Edelman repeatedly emphasized the benefits of CGM in eliminating the long-assumed tradeoff between tight control and severe hypoglycemia and took issue with the assumption that patients need to first be on a pump before beginning CGM – “I think that’s totally backwards.” We agree and look forward to data from the Dexcom’s Diamond study on this front at ADA 2016. Finally, Dr. Edelman half-jokingly noted that Medicare assumes his type 1 diabetes will disappear when he turns 65; while the bills to establish Medicare coverage of CGM are still in the works, we hope insulin-dosing claims and better cost-effectiveness data can convince CMS to reimburse the technology.

Clinical Session: Population-Specific

Type 2 Diabetes in the Older Patient

Graham McMahon, MD (Northwestern Memorial Hospital, Chicago, IL)

Dr. Graham McMahon’s comprehensive presentation on the care of type 2 diabetes in elderly individuals started with recognition of the “age-ism” that poses obstacles to effective treatment of this patient population. He also provided specific thoughts on glucose-lowering drugs as they pertain to older patients. In light of the cardioprotective finding from EMPA-REG OUTCOME, Dr. McMahon was positive on SGLT-2 inhibitors, characterizing them as “pretty gentle medicines” and praising their beneficial non-glycemic effects. He did point out that many older patients can’t afford SGLT-2 inhibitors. He suggested that most prescribers are not using GLP-1 agonists much in older patients – attendees, by a show of hands, agreed. Though Dr. McMahon acknowledged that GLP-1 agonists’ expense and injectable route of administration make them a challenge in this population, he noted that the data suggests that their efficacy is still pretty strong in older patients. While we have heard some renewed enthusiasm for the TZD pioglitazone in light of the new results from IRIS, there was none here: Dr. McMahon called it “a pretty nasty medicine” for older patients due to the risk of heart failure, fracture, and macular edema. 

Product Theaters

A Demanding Disease – Approaching the Challenge of Treating Patients with Diabetes who are Severely Insulin Resistant

Robert Hood, MD (Endocrine Clinic of Southeast Texas, Beaumont, TX)

This product theater introduced an audience of around 30-40 attendees to Lilly’s concentrated human insulin Humulin U500, which is now available in a KwikPen instead of only in vials. Humulin U500 has been a driver of Humulin franchise sales in recent years as increases in obesity and severe insulin resistance have increased the number of patients with daily insulin doses over 200 U (~3.7% of insulin-requiring patients are at that level). Dr. Hood noted that providers (himself included) have been “bugging Lilly for years” to produce a dedicated delivery system for Humulin U500, leading to the Humulin U500 KwikPen, which helps simplify translating dose volumes from U100 insulins.

• We’ve heard complaints from clinicians at conferences over recent years about price increases for Humulin U500 – Lilly did this to achieve per-unit parity with other insulins. However, a slide in Dr. Hood’s deck made the argument that Humulin U500 (via the KwikPen) is the “lowest-priced pen available” per unit of insulin. A chart pointed to a per-unit cost of 17 cents per unit with the Humulin U500 KwikPen vs. ~30 cents with analog mealtime pens and 25-30 cents per unit for analog basal pens. Of course, we’d prefer to see per-unit price comparisons vs. human insulins, but it’s good to see that Lilly is at least responding to the concerns voiced by clinicians and patients.

Symposium: Epigenetics in Diabetes – From Diagnosis to Complications

Epigenetic Changes in Patients with Type 2 Diabetes and Impact on Insulin Secretion and Action

Charlotte Ling, PhD (Lund University Diabetes Center, Malmö, Sweden)

We know that both genetics and environmental factors have a role to play in explaining a patient’s risk for developing type 2 diabetes. Few topics get at the intersection between the two better than  epigenetics, the modification of structures on or around a cell’s DNA without editing the core genetic information. Research on the epigenetics of diabetes risk is at a fairly early stage, but there exist intriguing signs that epigenetics plays a role in the pathophysiology of diabetes. DNA methylation, a form of epigenetic modification, is altered in islets taken from patients with diabetes. Presenter Dr. Charlotte Ling’s group has found 102 genes that are differentially methylated and regulated in type 2 diabetes. It is a little early to understand how the science of epigenetics could translate into therapies for diabetes; epigenetic-based screening and risk stratification tools are likely to arrive sooner. Even so, we’ll stay on the lookout, as epigenetics is a hot topic across the medical and scientific fields.

Symposium: The EATiology of Energy Balance: Neuronal Circuits That Regulate Appetite

Central Regulation of Feeding and Reward by GLP-1

Karolina Skibicka, PhD (University of Gothenburg, Gothenburg, Sweden)

We have learned a great deal about the mechanisms behind GLP-1 agonists’ activity on alpha and beta cells, but their effect in the brain is much more of a black box. Dr. Karolina Skibicka discussed a few key brain areas involved with reward circuitry that express GLP-1 receptors, such as the supramamillary nucleus. Preclinical data showed that GLP-1 conjugated with estrogen was able to target the GLP-1’s action to key brain areas involved in feeding behavior. We wonder whether this system of targeted delivery could deliver efficacy in brain areas that regulate feeding without the same degree of systemic side effects like nausea. 

• One of the most intriguing things we learned was that GLP-1 agonists may have utility for the treatment of alcoholism and other addictions. Both endogenous GLP-1 and the GLP-1 agonist exendin-4 demonstrated efficacy in reducing alcohol intake in preclinical studies, and Dr. Skibicka shared that clinical trials are getting underway.

Symposium: New Technologies in Type 1 Diabetes

New Insulins: Are They Getting Better?

Chantal Mathieu, MD, PhD (KU Leuven, Leuven, Belgium)

Dr. Chantal Mathieu focused on the unifying point that providers and patients must adapt their dosing practices for both basal and mealtime insulin when switching to the newer, longer-acting, more stable basal insulins. With the old generation of flagship insulins like Lantus (insulin glargine U100) and Levemir (insulin detemir) that may see slightly diminished efficacy by evening time, patients often used extra dinnertime bolus insulin to cover holes in basal coverage. With the new insulins that actually last 24+ hours like Tresiba (insulin degludec), Toujeo (insulin glargine U300), and Lilly’s shelved peglispro/BIL, providers need to think critically about which insulin doses a patient may need to increase, and which they may need to decrease, in order to avoid increases in hypoglycemia (the specific adjustments vary from product to product). To her, the clinical data specifically in type 1 suggests that Tresiba is a better insulin than Lantus, which is saying something because Lantus is already a very good basal insulin. On Toujeo, she thinks there is probably also a hypoglycemia benefit in type 1 vs. Lantus, although the specific study in type 1 was not powered to show it. She briefly expressed skepticism about weekly insulin for type 1, and more enthusiasm about oral insulin and smart insulin.

Questions and Answers

Q: I was surprised to see that you need less bolus insulin with insulin degludec. I would think that when you go from a variable profile to a flatter one, you would need more bolus insulin.

A: What we have done as clinicians is to cover holes in basal with bolus. To give an example, my friend Dr. Geremia Bolli in Italy sometimes recommends a fourth rapid-acting insulin injection between lunch and dinner, since they eat dinner so late.

Q: One thing you can do with Lantus is to reduce their morning dose by 10%-20% if they are going on a hike or doing some other prolonged physical activity. Can you do that with degludec?

A: Adapting a basal dosage the night before a hike is debatable, because then you will be hyperglycemic in the morning. That being said, when you have twice-daily glargine or detemir, you can play with the daytime basal analog. With degludec, glargine U300, and peglispro, you build up a plateau, and if you want to drop the insulin effect you need to drop the dose dramatically. There are studies in athletes to teach us how we should play with bolus doses and carbs to support these individuals with the longer acting basal insulins.

Corporate Symposium: Updates in Cardiovascular Risk Reduction in Type 2 Diabetes – New Insights and Outcomes in Treatment Options (Sponsored by Lilly/BI)

SGLT-2 Inhibitors: Cardiovascular Impact and Safety Concerns

Silvio Inzucchi, MD (Yale University, New Haven, CT)

Dr. Silvio Inzucchi discussed the discussion towards SGLT-2 inhibitors, which have received a lot of attention in the wake of EMPA-REG OUTCOME’s positive findings for Lilly/BI’s Jardiance (empagliflozin). Unsurprisingly, much of Dr. Inzucchi’s presentation focused on that trial, highlighting that it was the first trial in history to find a beneficial impact on cardiovascular events with a specific glucose lowering drug in high-CV-risk type 2 diabetes patients. He pointed to the early divergence of the event curves, suggesting that the benefic seen was probably not mediated by glucose reduction or through reduction in atherosclerosis (which takes time to develop). Switching topics, Dr. Inzucchi expressed real concern about the DKA being observed with use of SGLT-2 inhibitors in type 1 diabetes, and recommended strongly against that off-label application for the class until more is known. To conclude, Dr. Inzucchi emphasized how unprecedented it is to have drug classes in the treatment armamentarium that have proven cardiovascular benefits. He suggested that the findings from EMPA-REG OUTCOME, LEADER, and IRIS will need to have some impact on treatment guidelines, but did not go so far as to share specifics on how he would redesign them. 

• We appreciated Dr. Inzucchi’s update on pending analyses from EMPA-REG OUTCOME:
  
  • A paper is under review on the effect of empagliflozin on microvascular and renal outcomes. Dr. Inzucchi commented that much of the mystery of what this drug is doing may be in the kidney, pointing to a potentially fruitful area for future research.
  • An analysis is ongoing over the slight increase in the point estimate for non-fatal stroke with empagliflozin.
  • Also ongoing is a “mediation analysis” to explore predictors of the response seen in the trial.

Cardiovascular Effects of Medications for Glycemic Control: Evidence from Large Outcomes Trials

Hertzel Gerstein, MD (McMaster University, Hamilton, Canada) and Bernard Zinman, MD (University of Toronto, Ontario)

Drs. Hertzel Gerstein and Bernie Zinman described EMPA-REG OUTCOME as a perfect case in point for why large outcomes trials are extremely important. They both argued that claims (fairly widespread in the field in recent years) that large outcomes trials for diabetes drugs are not worth the money are groundless. As in past talks, Dr. Gerstein stressed that such trials are the only reliable way to ascertain a therapy’s effect on important outcomes. In particular, he noted that relying on a drug’s mechanism of action to predict its effects is clearly not sufficient. He also expressed skepticism about the use of large epidemiological studies in place of randomized trials, arguing that the results will always be confounded since it is impossible to adjust for confounders that researchers are not aware of or that were not measured appropriately. Dr. Zinman added that the CVOT requirements have enabled the diabetes community to learn a “huge” amount about cardiovascular risk. As he noted, the goal is to inform clinical practice and Dr. Zinman emphasized that these trials have done this in a major way. Ultimately, we agree that large, randomized outcomes trials are the gold standard of evidence. The main question facing the diabetes field is whether the information gained from such trials as they are currently designed is worth their substantial cost.

• The panel discussion and other Q&A sessions featured several nuggets of notable commentary from Drs. Inzucchi, Gerstein, and Zinman on the use of active comparators, SGLT-2s in type 1 diabetes, and much more – see below for some of our quotable quotes and see our detailed discussion and commentary section for a full transcript of the discussion:
  
  • “It is certainly important to design CVOTs with active comparators. Indeed, several such trials are ongoing.  Examples included the CAROLINA trial of  linagliptin vs. glimepiride, and the GRADE trial. Clearly, the trial design should be driven by the questions being asked. ” – Dr. Gerstein
  • “At this time, we should not routinely use SGLT-2s in type 1 diabetes. We are awaiting more data from larger on going trials.” – Dr. Zinman
  • “I would encourage everyone to resist the temptation to cut and paste what we learn from a high CV risk group to low-risk groups. That said, we do clinical trials to get better at what we do in our offices and clinics. If these positive trials don’t change guidelines, then why do we do these trials? I think the group that is charged with the next iteration of diabetes treatment guidelines will need to look at these data and think about where empagliflozin might best fit in.” – Dr. Inzucchi
  • “While I think the money is in the kidneys [regarding EMPA-REG’s cardioprotective mechanisms], I don’t think it’s simply because of reduction in renal disease progression. I think the effect on the heart may have to do with the drug’s diuretic and hemodynamic properties, all expressed through the kidney.” – Dr. Inzucchi
  • “Large outcomes RCTs are crucial and are the only reliable way to ascertain a therapy’s effect on important outcomes. The fact that we have seen results from such trials that were unexpected and unpredictable is evidence of this. If you knew  the results of your trial before starting it, it would not be worth doing it.”  – Dr. Gerstein
  • “There are two schools of thought on CVOTs. One school of thought is that CVOTs are fantastic. Not only do we get data on cardiovascular safety but we get data on other non-cardiovascular issues, such as pancreatitis , etc. I don’t agree with the group that says this money is being wasted and that we could do other things with it. For years, we’ve used diabetes drug without making a commitment to assess long term safety and other relevant outcomes..” – Dr. Zinman
  • “The FDA guidance has been a blessing to the diabetes community. Many people in the diabetes community have been involved in these trials. We’ve learned HUGE amounts about diabetesin the last 30 years and this has changed how we manage the disease. And there are still ongoing trials that are going to teach us more. No doubt … these have been a huge boon for the diabetes world.” – Dr. Gerstein

Panel Discussion

Hertzel Gerstein, MD (McMaster University, Hamilton, Ontario, Canada); Silvio Inzucchi, MD (Yale University, New Haven, CT); Bernard Zinman (Mount Sinai Hospital, University of Toronto, Ontario, Canada)

Dr. Bernie Zinman: Can you comment on the numerical increase in risk of stroke in EMPA-REG?

Dr. Silvio Inzucchi: It’s a modest signal. We were specifically looking at hemodynamic adverse events but didn’t see any differences between active therapy and placebo, even at higher doses. Actually, most of the imbalance in patients who experienced stroke in the empagliflozin groups appeared to suffer these adverse events after being off study drug. There doesn’t seem to be a rebound effect on blood pressure from stopping an SGLT-2, however. So we just cannot explain this finding. We are studying it further and are working on a paper specifically on stroke at this time. Just like how non-fatal MI was not significantly reduced, stroke risk was also not significantly increased. But it’s something we need to look at more carefully.

Dr. Zinman: Is SGLT-2 cardioprotection viewed as a class effect?

Dr. Inzucchi: We’ve been burned in this area before. What we’ve learned over time is that results from one drug’s trial cannot be generalized to an entire class. If the mechanism is the diuretic effect, then it could potentially be extended to other drugs. But let’s wait for these other trials before concluding anything.

Dr. Zinman: Could LEADER be a class effect?

This is a good example to look at – we know that lixisenatide had no benefit but LEADER’s public announcement says it’s positive. Here, it’s easier to explain because lixisenatide is a much shorter-acting compound and liraglutide lasts at least 24 hours, so there may be differences. Silvio and I can give you examples where it’s been a class effect but also where same-class drugs are different.

Dr. Inzucchi: It’s important to note that the cohorts between ELIXA and LEADER were also different.

Dr. Zinman: Why did placebo rates go up at the end of the EMPA-REG trial?

Dr. Inzucchi: You have very few patients at the end of the trial. There were maybe 300-400 people left so the event curves get extremely labile.

Dr. Zinman: In EMPA-REG, were there differences in the arms as providers tried to avoid hypotension?

Dr. Inzucchi: There were modest differences. I believe about 10%-15% patients got another drug added to the regimen in the intervention arm. I don’t think this can explain the differences we found.

Dr. Zinman: Both empagliflozin and dapaglifozin are SGLT-2 specific; canagliflozin has SGLT-1 as well. Do you think this could contribute to differences in CV events?

Dr. Inzucchi: It’s hard to know. SGLT-2 is not expressed in cardiac myocytes to my knowledge, while SGLT-1 is. But we’re not sure what it’s doing in heart. It’s important to wait for these individual studies to understand the impact of each individual drug.

Dr. Zinman: Is the benefit of empagliflozin blunted in patients using diuretics?

Dr. Inzucchi: All subgroup analyses did not show statistical differences except for maybe those on mineralocorticoid antagonists. That group may have gotten less benefit, but the numbers are so small, it’s really hard to tell.

Dr. Zinman: Could SGLT-2 inhibitors be combined with GLP-1 agonists?

Dr. Inzucchi: In the latest ADA/EASD position statement, there is a specific absence of this combination. A lot of people wondered why this is since it seems logical to include this. Why leave it out? The reason is that the document was published in January 2015, and there was no study at that point using that specific combination. Thus, we as a professional organization could never advocate for a combination that had never been studied. Since that time, there have been reports of patients in CANVAS who are on that combination and the A1c and weight effects looks good. I believe that there are at least one, if not, two studies ongoing that are testing this combination and it’s potentially an important pairing. I would point out though that where I practice the combination of a GLP-1 agonist at the highest dose and an SGLT-2 inhibitor would run patients ~$1,000 a month. That’s a lot of money!

Dr. Zinman: What is your assessment of the increased fracture risk in SGLT-2s?

Dr. Inzucchi: There have been some inconsistent changes in calcium excretion and phosphate excretion. The fracture risk seems to be something seen thus far with canagliflozin,  Some have theorized that this may be due to falls driven by hemodynamic events. The number of events is very small. It’s something to keep an eye on but it’s hard to know if this has to do with effects on bone density or something else.

Dr. Zinman: What was the number needed to treat in EMPA-REG OUTCOME?

Dr. Inzucchi: It was in the same range of what you see in statin therapy.

Dr. Zinman: Yes, the number needed to treat was 39 over three years. That was remarkable because the patients were already on ACE inhibitors and statins in the background.

Dr. Zinman: If the standard of care is for A1c <7%, why was this not achieved in the EMPA-REG group?

Dr. Inzucchi: To some degree, these are real-world settings in busy diabetes and primary clinics. And this is what you see. Despite attempts, diabetes is a progressive disease. The results showed that A1c didn’t go up; it remained stable and those in cardiology might say that that A1c of patients with overt CV risk was actually quite acceptable.

Dr. Zinman: If you look at glycemic intensification, 60% of the placebo group had intensification. And half that number had that in both empagliflozin arms. The participating centers did their best to intensify glucose control. I’m sure that for patients who are older, it is more challenging. But they tried their best to lower A1c.

Dr. Zinman: Could cardioprotection in EMPA-REG OUTCOME be the result of reductions in renal disease?

Dr. Inzucchi: Possible. However, while I think the money is in the kidneys, I don’t think it’s simply because of reduction in renal disease progression. I think the effect on the heart may have to do with the drug’s diuretic and hemodynamic properties, all expressed through the kidney.  Further study is ongoing to determine this.

Dr. Zinman: Could the effect be through an arrhythmic effect?

Dr. Inzucchi: Unfortunately, we didn’t have holter monitors on these patients. One of the prominent reductions was in the sudden death subcategory of CV death, which we suspect was arrhythmic in origin.  This occurs commonly in heart failure, but remember that ninety percent of the EMPA-REG patients did not have heart failure at baseline. So, most of the imbalance in sudden death events were probably not just related to heart failure. We’re looking at this specific issue in more detail.

Dr. Zinman: Often, large trials don’t uncover clear explanations for mechanisms. What we have to do now is go back to the bench and study 20 to 30 patients intensely in a different way. It behooves us to try to understand this mechanism.

Dr. Zinman: Given these results, do you think the guidelines should be changed so that empagliflozin is first or near-first in the therapy of type 2 diabetes?

Dr. Inzucchi: I think we have to be cautious because most type 2 diabetes patients in our practices would not be eligible for EMPA-REG. Remember that these individuals had to have overt cardiovascular disease to be enrolled I would encourage everyone to resist the temptation to cut and paste what we learn from a high CV risk group to low-risk groups. That said, we do clinical trials to get better at what we do in our offices and clinics. If these positive trials don’t change guidelines, then why do we do these trials? I think the group that is charged with the next iteration of diabetes treatment guidelines will need to look at these data and think about where empagliflozin might best fit in.

Dr. Zinman: To give the Canadian perspective, our guidelines are evidence-based, like most are today. But the unique aspect is that the reviewers pay attention to the level of evidence. People who review are methodologists – they’ll look at the trial, endpoints, follow-up, etc. And they’ll say if the trial is great or not and use that to justify the recommendation. I think we should all practice evidence-based medicine. We can’t ignore this outcome. We think it’s a good study but we’ll let other methodologists look at it. If they think it’s good evidence, it has to play a role in how we use drugs.

Dr. Zinman: What about low-dose pioglitazone and empagliflozin together?

Dr. Inzucchi: We’ve been talking about this. The TZDs have had a rocky history over the past ten years. My personal view is that despite its ‘warts’, pioglitazone is the only drug for diabetes that has demonstrated a reduction in atherosclerosis events in high-risk patients. In contrast, empagliflozin worked primarily through non-atherosclerotic mechanisms. If pioglitazone, perhaps given at small doses to minimize side effects, prevents atherosclerosis from developing and then we treat concurrently with empaglifozin to reduce CV death, in those who do develop atherosclerosis. That could be a terrific combination.

Dr. Gerstein: I think the trial has to be done but it’s tough to do. It may never get done for a number of reasons. However, if we had a good surrogate of measures, I think it would be great to do.

Dr. Zinman: I’m a big believer that combination therapy early on is the way to go. We do that in cancer and HIV, but we don’t do it in diabetes. We’re stuck with one drug. However, this approach has to be tested rigorously. We’ve already heard of two combinations today. I think we’ve got a lot of work to do to figure out what’s the best initial combination. At the end of the day, I definitely don’t want hypoglycemia and I definitely don’t want weight gain. If a combination meets those requirements, I’m happy to test it.

Dr. Zinman: Would it be valuable to design CVOTs with active comparators? These are all placebo-controlled.

Dr. Gerstein: Absolutely. It’s being done in some trials. There’s linagliptin vs. glimepiride, which is the CAROLINA study. There’s the GRADE trial. It is appropriate to use active comparators. I think it depends on what the question is.

Dr. Zinman: Where are SGLT-2 and SGLT-1 in the rest of the body?

Dr. Inzucchi: SGLT-1 is in heart and SGLT-2 is not. Both SGLT-2 and -1 are in the kidney, but SGLT-2 appears to be more important there. SGLT-1 modulates glucose reabsorption in the GI tract.

Dr. Zinman: Should empagliflozin be viewed as a cardiology drug?

Dr. Inzucchi: Cardiologists are excited about this drug. I actually came to Boston from ACC in Chicago. Cardiologists are excited because the drug was reasonably well tolerated and because because therapy did not lead to hypoglycemia. So, they are wondering if it can be tested in patients with CVD who do not have diabetes?

Dr. Zinman: Have there been any trials of any kind looking at SGLT-2s in type 1?

Dr. Inzucchi: I think all three companies have studied this. It’s been shown that people lose weight and diabetes becomes easier to control. Insulin doses are reduced. But there’s a caveat – if insulin is reduced too much, you can augment DKA risk. I almost never use SGLT-2s in type 1.

Dr. Zinman: It’s really important to share here that these are not indicated for type 1 diabetes. We did a pilot trial – it was not controlled – but we had two cases of DKA. We’re used to looking at hypo as key marker for metabolic deterioration. You are safest not using it in type 1 diabetes until other trials have reported. If you think so for some reason due to the patient’s profile, you should use it, then you should definitely know that it’s off-label use. Give the patient blood ketone strips to measure regularly. Right now, I think we need to be very cautious. I think for sure, we shouldn’t use SGLT-2s in type 1 until we have more data.

Dr. Zinman: Since the SGLT-2 inhibitors were not included in GRADE trial, will they be included in another large comparative trial?

Dr. Inzucchi: There was some discussion about adding a fifth arm to the GRADE trial but statistically that would have been difficult to analyze. More importantly, TZDs were supposed to be included but the GRADE researchers felt that it might be difficult to recruit patients to go on TZDs with all the negative press they were receiving. And remember too, that the trial does not test combination therapy beyond metformin plus another drug.

Dr. Zinman: Someone in the audience says that in a small hospital, they’ve had two DKA cases in type 2 patients. One even had cardiac arrest.

My response to that is that it’s important to inform stopping medication during intercurrent disease. We have that in the Canadian guidelines specifically: if you’re ill, stop the drugs.

Dr. Zinman: What was the cost of EMPA-REG OUTCOME?

That’s above my pay grade. I don’t know the exact cost but it was in the hundreds of millions of dollars. That said, that’s nothing compared to a successful blockbuster drug, which could bring in ~$1 billion a year or more.

Dr. Gerstein: Many years ago, I asked folks at a pharmaceutical company “How do you decide how much to charge for a drug?” And the answer was:  “It’s what the market will bear.”

Dr. Zinman: So true. Remember that for some miraculous reason, drugs cost about a third in Canada relative to what they do in the US. And that’s not because the cost to manufacture is any different.

Corporate Symposium: New Complementary Insulin and GLP-1 Combinations to Achieve HbA1c Targets (Sponsored by Sanofi)

Current Standards of Diabetes Care

Daniel Einhorn, MD (Scripps Health, La Jolla, CA)

Dr. Daniel Einhorn shared a range of wisdom on the diabetes drug landscape, with Victoza (liraglutide), Jardiance (empagliflozin), Nesina (alogliptin), receiving the most positive mentions. Dr. Einhorn suggested that in today’s post-LEADER and EMPA-REG OUTCOME era, it would be “hard to justify not using these two classes of agents” (GLP-1 agonists and SGLT-2 inhibitors). Moreover, he specifically expressed preference for Victoza and Jardiance over competitors in their respective classes; he admitted that cardioprotection is most likely a class effect for both the GLP-1 agonists and SGLT-2 inhibitors, but that we cannot know for sure until we have data on the other drugs in those classes. He did, however, admit that formulary limitations are likely to be the primary determinant of choices between drugs in either class.

• Earlier in the same morning symposium, Dr. Einhorn emphatically suggested that the TZD pioglitazone deserves to make a comeback – the rationale being: (i) clinical studies have largely cleared pioglitazone’s reputation of carrying a risk for cancer or major adverse cardiovascular events; (ii) the effect on fluid retention is minimal at low doses and in combination with GLP-1 agonists or SGLT-2 inhibitors; (iii) the drug is now an inexpensive generic, making it accessible to many patients. Further to that, the IRIS trial recently demonstrated a reduced risk of stroke and MI by 24% (p=0.007) and new incidence diabetes by 52% (p<0.001) compared with placebo in patients with insulin resistance, potentially revitalizing pioglitazone. He also gave Takeda’s DPP-4 inhibitor Nesina (alogliptin) mention for being extremely cheap, a marker of how competitive the DPP-4 inhibitor class has become.

Corporate Symposium: The Truth of the Matter – An Evidence-Based Review of the Newer Antihyperglycemic Agents for T2DM (Sponsored by AZ)

Panel Discussion

Zach Bloomgarden, MD, FACE (Icahn School of Medicine at Mount Sinai, New York, NY), Derek LeRoith, MD (Icahn School of Medicine at Mount Sinai, New York, NY), James Gavin, MD, PhD (Emory School of Medicine, Atlanta, GA)

At an AZ-supported corporate symposium, Dr. Zach Bloomgarden shared a personalized approach to prescribing SGLT-2 inhibitors and GLP-1 agonists in high CV risk patients. When asked what class to prescribe for a patient with coronary artery disease, Dr. Bloomgarden emphasized first examining all of the patient’s characteristics. Specifically, he noted that if the patient was at high risk for heart failure (i.e. had prior heart failure), SGLT-2 inhibitors may be the ideal way to go, given the impressive reductions in heart failure risk seen in EMPA-REG. On the other hand, Dr. Bloomgarden “preferred the idea of GLP-1 agonists” in individuals with obesity or good heart function. Overall, the symposium held onto a theme of the importance of individualizing therapy and understanding the heterogeneity of diabetes through its presentations and commentary. With regards to using this approach in high CV risk patients in the context of all the recent CVOT data, seeing the full results of the LEADER trial for Novo Nordisk’s Victoza (liraglutide) (which has positive topline results) will hopefully provide more color on what patients would benefit the most from which class.

• On a somewhat similar note, Dr. Bloomgarden also suggested the potential of the TZD pioglitazone in lower doses. While the speakers (unsurprisingly) highlighted sulfonylureas as an inferior treatment choice, Dr. Bloomgarden noted that past studies of pioglitazone perhaps erred to the highest tolerable doses, which may have driven the well-known undesirable side effects such as weight gain and edema. However, he suggested that lowering the dose to 7.5 mg or 15 mg a day may maintain the drug’s benefits (i.e. risk reduction of stroke and MI as recently shown in the IRIS trial), while reducing the side effects. Dr. Derek LeRoith (Icahn School of Medicine at Mount Sinai, New York, NY) and Dr. James Gavin (Emory School of Medicine, Atlanta, GA) chimed in with support, expressing disappointment in “forgetting about insulin sensitization” and not using the “scientific concepts” the field “spent a lot of time developing.” With the positive results of the IRIS trial, pioglitazone has seemed to be picking up attention again – see our report on the findings for more of KOLs’ insights on TZDs.

Posters

Efficacy and Safety of Switching from Sitagliptin to Liraglutide in Subjects With Type 2 Diabetes: A Randomized, Double-Blind, Double-Dummy, Active-Controlled 26-Week Trial

Novo Nordisk presented a poster on the LIRA-SWITCH trial, which demonstrated that Victoza (liraglutide 1.8 mg) provided superior A1c reductions compared to continued treatment with Merck’s Januvia (sitagliptin). The trial’s findings showed that at 26 weeks, adults with type 2 diabetes who switched from Januvia (n=407) to Victoza achieved greater A1c reductions compared to those who continued Januvia treatment (n=204) (-1.1% vs. -0.5%; baseline A1c of 8.2%-83%). In addition, the Victoza arm experienced greater body weight reductions compared to the Januvia arm (-3.3 kg vs. -1.6 kg) (baseline weight of 89 kg-91 kg). Regarding safety, adverse events were more common with Victoza than with Januvia (69% vs. 57% of participants), with the most common adverse events being GI side effects in the Victoza arm. However overall, few serious adverse events were reported and no severe or confirmed nocturnal hypoglycemia was reported. While we would deem none of these findings as surprising, these head-to-head data further support the superior efficacy of the GLP-1 agonist class (but greater tolerability of DPP-4 inhibitors) and provide some additional guidance on potential next steps for patients uncontrolled on second-line therapy. See Novo Nordisk’s press release on the data for more.

XOMA 129, a Novel Insulin Receptor Negative Modulator, is Efficacious in Treating Insulin- and Glibenclamide-induced Hypoglycemia in Animals

XOMA presented a poster, demonstrating new positive preclinical data for its novel antibody fragment XOMA 129 (lead candidate of the XMetD program) for severe acute hypoglycemia. The poster’s data included findings from XOMA 129 in the preclinical models of both cell culture and animal pharmacology studies. The in vitro assays demonstrated that the candidate decreased the activity of insulin on mammalian cells over-expressing human, rat, and minipig insulin receptor (INSR) in a dose-dependent manner. As for the animal studies, the results showed that XOMA 129 was able to stabilize insulin or sulfonylurea-induced hypoglycemia in the rat model. Specifically, normal rats were administered insulin and the sulfonylurea glibenclamide to produce abnormally low glucose levels; intravenous administration of XOMA 129 at specific time points (when the drug-induced glucose levels were falling below normal levels) rapidly stabilized blood glucose levels and thus prevented hypoglycemia. In addition, the study also examined XOMA 129’s performance in the minipig model (to assess efficacy in mammals): in normal minipigs, intramuscular administration of XOMA 129 was found to achieve significant elevation of blood glucose lasting for several hours. These data support the further development of this antibody fragment and we can easily see the clinical applicability of this candidate in both type 1 and type 2 diabetes as a potential “emergency” hypoglycemia-prevention tool (similar to glucagon pens). As we heard in XOMA’s 4Q15 update, the company is “presently moving this asset forward toward clinical development” – for more on the company’s plans, please see our full 4Q15 report.

Exhibit Hall

AZ

Sporting a medium-sized booth on one of the front corners of the exhibit hall, AZ kept the messaging modest for its portfolio of products. Each product got one or two vertical static displays. Bydureon got the most valuable real estate at the front corner of the booth. AZ’s fixed-dose combinations received just as much attention as the standalone products – for example, one display featured Onglyza (saxagliptin) and Kombiglyze (saxagliptin/metformin) equally, while Farxiga (dapagliflozin) and Xigduo (dapagliflozin/metformin) each had a display. The most attention-grabbing part of the space was the massive Fit2Me food truck (Fit2Me is AZ’s free type 2 diabetes patient support program, launched in 2014). The quiche we tried was tasty!

Dexcom

Dexcom’s open booth occupied relatively prime real estate near the center of the exhibit hall and the location was paying off. We noticed a steady stream of foot traffic all afternoon and had a hard time finding time to chat with reps. When we did get to the front, the exhibit focused (as expected) on the Dexcom G5 mobile and paired iPhone and Apple Watch apps – a glass case sitting front and center of the booth showed the real things up close. Dexcom still expects to launch an Android version of G5 in 2016, supporting the major Android phone brands. The regulatory process here is more difficult than iOS, as there are so many Android phones to test. There were no updates on the progress of conversations with the FDA around the anticipated CGM insulin-dosing claim in 2H16 or on plans to launch a new touchscreen receiver, one-button insertion system, and smaller transmitter by the end of 2016.

Eisai

Eisai occupied a decent sized booth toward the front corner of the exhibit hall in its pink and blue color scheme, with a third of its booth dedicated to obesity drug Belviq (lorcaserin). The company featured large touch screens with the drug’s safety and efficacy data as well as a medical info booth. As we haven’t seen obesity drugs represented on major meetings’ exhibit floors in quite some time, we were slightly surprised to see Belviq at ENDO this year. As background, Arena/Eisai were not present at last year’s ENDO and its latest appearance to our knowledge was in the form of a small pop up booth at this past ADA. Similar to recent conferences, we did not see Orexigen/Takeda’s Contrave (naltrexone/bupropion extended-release) or Vivus’ Qsymia (phentermine/topiramate extended-release), indicative of the challenges these companies are facing.

Insulet

Insulet occupied a modest booth in the back corner of the exhibit hall. The majority of the exhibit was devoted to the OmniPod while a smaller section highlighted the recent data partnership with Glooko (announced in January). Reps confirmed that the company is working hard on the next-gen Bluetooth-enabled PDM and mobile app, which will display key real-time pump data on the phone AND integrate with Dexcom’s G5 app. Reps stressed that the company is prioritizing the app’s development, in line with recent commentary to strip down the PDM’s functionality and feature-up the app. No clearance timeline was given, but we assume the plan to submit it later this year (per 4Q15 call) still stands. It sounded like the regulatory challenges of patients dosing directly from the phone remain under discussion, though reps stressed that conversations are happening.

Intarcia

Carrying home field advantage in Boston, Intarcia had a modest-sized booth that nonetheless had prime position, on the front edge of the exhibit hall floor. On either side of a slick display case showcasing the ITCA-650 matchstick-sized osmotic mini-pump were two stations where representatives were demoing the insertion and removal procedures for the device. We can’t emphasize how easy the team at Intarcia has made the insertion: just sterilize the area, make a tiny half-centimeter incision in the skin, slide the insertion guide inside, and pull a trigger to leave the device inside. Read our report on the recent appointment of Dr. John Yee as VP, Head of Global Medical Affairs, Safety, and Operations for more on what is going on at Intarcia.

J&J/Animas

Friendly Animas reps gave us a quick rundown of the Vibe integrated with Dexcom’s G4 Platinum CGM. It was neat to see the attention this booth was getting, and we even overheard one attendee taking pictures so that he could compare the product with Tandem’s t:slim G4 – we’re not sure what his conclusion was though we thought Animas’ reps provided a very balanced overview of their device’s advantages (waterproof is the big one). Unfortunately, reps were unable to comment on progress with the Calibra Finesse bolus-only insulin delivery patch device (expected in 2Q15 to launch this year) or artificial pancreas project (pivotal study planning underway).

J&J/LifeScan

LifeScan reps did not share any updates on the company’s pipeline and did not appear too psyched to show off the Bluetooth-enabled OneTouch Verio Flex meter (the only product on display; see our take here). As expected, there were no comments on the exciting partnership with WellDoc to integrate BlueStar software into the OneTouch Verio Flex BGM and Reveal app. We see very high potential there to make glucose data more actionable for patients and give providers better tools to optimize therapy.

Lilly

Lilly’s large main booth was front-and-center at the exhibit hall, with lots going on. The first thing we saw as we approached was a big new section on the new Humulin U500 KwikPen (previously Humulin U500 was only available in a vial). We’ve heard plenty at conferences over the past few years about the skyrocketing need for concentrated insulin formulations – following the rise in obesity and severe insulin resistance – and Humulin U500 fits the bill. Some other insulins are following this lead, such as Sanofi’s Toujeo (insulin glargine U300) and now Novo Nordisk’s Tresiba U200 (insulin degludec). Humulin U500 retains uniqueness for its higher concentration along with its action as somewhat of a hybrid between a basal and rapid-acting insulin. There was a product theater on the Humulin U500 KwikPen, and more generally this ENDO we heard even more than usual about the need for concentrated insulins. Elsewhere in the booth, the patient-friendly weekly GLP-1 agonist Trulicity (dulaglutide) carved out a solid section, with the same 1-2-3 messaging (“unmatched A1c reduction, weekly dosing, the Trulicity Pen”). BI-partnered Jardiance (empagliflozin) had a big board trumpeting that it has the most new patient starts in 2016 than any other drug in the class – we imagine its new status as a proven cardioprotective agent must be helping. The Tradjenta (linagliptin) section emphasized its dosing simplicity even in patients with limited renal function, while the Glyxambi (empagliflozin/linagliptin) section was modest in size and consistent with what we’ve seen at previous meetings.

• Lilly also had a satellite booth with screens asking the question “whose diabetes do you have?” It was largely a rest station, with no representatives present, and we assume the message has to do with solidarity with patients.

Medtronic

Medtronic’s booth featured both international and US sections that focused, respectively, on the MiniMed 640G with Enhanced Enlite and MiniMed Connect remote monitoring device (among other products). We were pleasantly surprised to see how busy the US side was – indeed, this was one of the more packed booths in the entire exhibit hall when we walked by (four rows deep). We picked up no new insight on the pipeline though had a good time playing with the MiniMed Connect app on iOS. Compatibility with Android continues to be a high priority, and we assume the 4Q15 timing to launch it before June 2016 still stands. We didn’t get any timeline update on the EU launch of the Guardian Connect standalone mobile CGM (a competitor to Dexcom’s G5), though we assume the previous timeline to launch ~May-July this year has not changed. As a reminder, this product was submitted to the FDA last month, putting it on track to hit the April 2017 launch timeline.

Merck

Merck arrived at ENDO with no surprises with its moderately sized booth (and typical froyo offerings), featuring its Januvia (sitagliptin) franchise. The usual booth items included five boards with Januvia’s efficacy data along with patient profiles, with specific focuses on the drug’s ability to be added to insulin or metformin and its use in patients with renal insufficiency. In addition, the booth featured two boards on its metformin/Januvia combination, Janumet. We don’t see Merck’s domination of the DPP-4 inhibitor class budging very much but see the company’s pursuit into the SGLT-2 inhibitor space with ertugliflozin as a smart move – see the company’s 4Q15 update for more.

Novo Nordisk

Not only did Novo Nordisk have a massive booth right at the entrance to the exhibit hall, but its messaging was all over the conference. Both presences were focused squarely on one product: the newly approved basal insulin Tresiba (insulin degludec), and especially the more concentrated U200 formulation. We are not kidding when we say that Tresiba U200 was everywhere, from the massive screen at the entrance to the convention center to the doors of our hotel elevator. We are not surprised, as this is the first major US endocrinology conference since the product’s US launch. The messaging focused on flexible dosing and its very long PK/PD profile (up to 42 hours). It was curious to us that Tresiba U200 got all the attention, but with a smaller injection volume per unit, comparable per-unit pricing, and the same FlexTouch pen, it arguably has the edge from a patient perspective. This, too, follows the conference-wide theme we noticed of insulins getting more concentrated as the average patient gets more obese and insulin resistant. We wonder if the choice to highlight the U200 insulin degludec formulation was influenced by the fact that Tresiba’s main competitor – Sanofi’s Toujeo (insulin glargine U300) – is a concentrated insulin. [Note: as opposed to insulin glargine U100 vs U300, higher concentrations of insulin degludec are  not expected to significantly alter PK/PD]. On the back side of the booth, Victoza (liraglutide) got a bit of space, but on the whole (unsurprisingly) this was Tresiba’s show.

Novo Nordisk – Saxenda

Novo Nordisk also had a separate booth focused on obesity drug Saxenda (liraglutide 3.0 mg) – a marketing setup that we’ve seen many times previously. Saxenda was brightly marketed in its purple color scheme as the “first and only GLP-1 FDA approved for chronic weight management,” as sales reps walked attendees through the safety and efficacy data and demoed the product with sample pens. Similar to what we have seen before, the marketing also centered around an image of a woman holding up a larger pair of jeans, with names of comorbidities written over them – likely focusing on the improvements of the secondary endpoints of the drug’s clinical data. We hope that one day, we can see “prediabetes” written here as well! See our coverage and insights on the glycemic improvements of Saxenda for more.

Novartis

At the Novartis booth, we were surprised to see zero marketing on DPP-4 inhibitor Galvus (vildagliptin), especially at an endocrine-focused meeting. Rather, the company dedicated the attention to its products for Cushing’s syndrome and growth hormone conditions. In our eyes, the absence of Galvus at its booth is a pretty significant confirmation of the company’s de-prioritization of diabetes. As a reminder, Galvus revenues fell 7% as reported YOY to $1.1 billion in 4Q15, with the drug receiving very little attention during the call, similar to many recent quarters’ calls – for more on Novartis, please see our 4Q15 update.

Sanofi

The basal insulin heavyweight had a relatively modest sized booth off to the side of the exhibit hall, though with a sleek white overhead banner it was easily visible. The first thing we noticed as we walked by (other than the usual six-feet Toujeo pen models) was that Afrezza still around. For background, in January Sanofi announced that it was ending its partnership with MannKind, though as per the agreement the marketing and commercialization rights for Afrezza would take 90-180 days to transfer. We expect this will be one of the last conferences for which we will see Afrezza in the Sanofi booth. About half of Sanofi’s booth was dedicated to the new flagship basal insulin Toujeo (insulin glargine U300), with examples of the pen on display. While some studies have shown what look to be hypoglycemia benefits with Toujeo over Lantus (insulin glargine U100), Toujeo’s current label restricts Sanofi’s marketing messaging to (mostly) statements of non-inferiority vs. Lantus.

Sanofi/Regeneron

Sanofi/Regeneron had a pop-up booth across from Sanofi’s main booth, promoting its PCSK9 inhibitor Praluent (alirocumab). The booth featured the product’s patient program MyPraluent and focused on the idea that Praluent’s dosing options can provide “more power if needed” and can be fit for a variety of patients. Amgen did not appear to be present with its PCSK9 competitor, Repatha (evolocumab), although from what we saw on the exhibit hall, attention toward the class was not significant overall. We believe results from CVOT trials will drive interest depending on results.

Tandem

Tandem’s characteristically modest booth showcased the company’s armamentarium of insulin pumps: the t:slim, t:slim G4, and t:flex. There were no new updates though reps did express huge enthusiasm for the “coming” pediatric approval on the t:slim – as a reminder, Tandem recently filed a 510(k) to expand the pediatric indication down to patients 6+ years old (it’s currently for 12+ year olds), with clearance expected in 2Q16. The lower age indication for the t:slim certainly expands the potential market size and is important to compete with the Animas Vibe, which is now approved down to age two. It did sound like a significant number of pediatric patients are already using the t:slim off-label – reps actually shared that the under-12 population is currently among Tandem’s most profitable demographics. No real surprise there, given the cool factor of the touchscreen interface.

Endocrine Fellows Series

Treating to Target: What Are the Goals in Pediatric and Adult Patients?

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

Dr. Irl Hirsch delivered a jam-packed presentation on a range of issues related to targets and outcomes in type 1 diabetes. On the subject of mortality (“the mother of all endpoints”), he noted that glycemic control appears to have a modest impact at best based on the available data. We would question whether enough and the right studies have been done in order to assess it accurately.He also expressed concern that acute complications (hypoglycemia and DKA) still account for a significant portion of deaths in people with type 1 diabetes – we agree this is absolutely unacceptable in an era with so many treatment options. The very narrow therapeutic range of insulin continues to be a major challenge.  Dr. Hirsch offered a more positive take on microvascular complications, citing the dramatically reduced rates in the post-DCCT era. He attributed the reductions in retinopathy in particular to greater use of mealtime insulin and emphasized that they have occurred without any significant change in average A1c. Dr. Hirsch also repeatedly emphasized that the risk for microvascular complications is quite low for patients who have not already developed them after 20-25 years of diabetes. We also wonder if this may be correlated with age when diagnosed. Because the risk of hypoglycemia increases dramatically for the same group of patients over time, he argued that stringent A1c targets may not be advisable or even ethical for that population. While this is certainly true for some people, we would argue that finding ways for those patients to achieve tight control without hypoglycemia should be the top priority. Along those lines, Dr. Hirsch praised CGM as an innovation even more meaningful than analog insulin in terms of reducing hypoglycemia and expressed dismay that the patients who could benefit most from it do not have access due to lack of Medicare coverage – from his mouth to Congress’ ears. He also provided his signature critique of A1c as the sole measure of blood glucose, noting that a long list of factors (from iron deficiency to aortic stenosis) can make it inaccurate for many patients. While the bulk of his talk focused on adults, Dr. Hirsch also touched briefly on the subject of pediatric A1c targets, noting that lower targets (7.5%) seem to be more effective than the higher targets of the past, but that the vast majority of patients are unable to reach these targets with current approaches.

Understanding Hypoglycemia in Type 1 Diabetes

Joseph Wolfsdorf, MB, BCh (Boston Children’s Hospital, Boston, MA)

Dr. Joseph Wolfsdorf delivered a passionate, comprehensive presentation on the importance of hypoglycemia in type 1 diabetes management. He repeatedly emphasized the stress that hypoglycemia causes for patients and families, particularly in his world of pediatric endocrinology – “people are living on the edge all the time.” He stressed that it is impossible to assign a single threshold for hypoglycemia and suggested that 70 mg/dl should be thought of as an alert value that draws attention to the potential of harm. Dr. Wolfsdorf noted that the frequency of nocturnal hypoglycemia in particular has been significantly underestimated in the past and that the potential to reduce this risk (and the fear that accompanies it) is one of the most attractive aspects of the closed loop. He expressed frustration about the variability and inaccuracy of many current blood glucose meters in the hypoglycemic range, noting that for a true blood glucose value of 60 mg/dl, a meter could report any value between 45 mg/dl and 75 mg/dl and still be considered sufficiently accurate by the ISO. He also noted that providers often cannot even select the most accurate device based on evidence due to insurance restrictions. Dr. Wolfsdorf then discussed some of the key risk factors for severe hypoglycemia, noting that long duration of diabetes is becoming an increasingly salient risk factor as people live longer but that tight control does not appear to raise the risk in and of itself as previously thought. In terms of prevention, Dr. Wolfsdorf emphasized the need for thorough education and the incorporation of hypoglycemia management into routine care; he also pointed to analog insulin, pumps, and CGM as important new tools that can help reduce risk. We are always glad to see greater focus on this issue, which we feel is too often downplayed by the FDA, guidelines committees, and others in our current A1c-centric world. We hope these messages can be used to push for greater access to the latest therapies and technologies, as the tools with the lowest risk of hypoglycemia are too often also the least affordable.

• During Q&A following the presentation, Dr. Irl Hirsch pointed to CMS’ competitive bidding program as an important part of the discussion of BGM accuracy. He explained that the program has allowed “offshore meters” primarily from Asian countries to enter the US without undergoing stringent quality control, leading to much worse accuracy that can be compounded when meters are used to calibrate CGM. Dr. Hirsch also referred to recently published data demonstrating increased mortality at competitive bidding test sites, presumably due to lack of access to meters in the first place. These results raise red flags for the already heavily scrutinized program and differ significantly from CMS’ 2012 report concluding that the program did not lead to any disruption of access or negative healthcare consequences.

Natural History/Pathogenesis/Immunopathology

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

Dr. Bruce Buckingham provided a rapid-fire overview of type 1 diabetes pathology, demonstrating the striking diversity of the disease’s distribution, etiology, and progression. He began by discussing the rising incidence of type 1 diabetes (+3-5% per year), noting that new cases are clustered in northern- and southern-most latitudes. Further, he noted that there is evidence of seasonal variation in type 1 diabetes incidence, with a greater number of new cases in colder months. Dr. Buckingham also highlighted several possible environmental triggers for type 1 diabetes, including cow’s milk, wheat protein, vitamin D, and exposure or lack of exposure to viral infections. Notably, the prevalence of parasitic disease and childhood diarrhea is concentrated in the equatorial region, contrary to the pattern of type 1 diabetes incidence closer to the poles – this supports the “hygiene hypothesis” that chronic disease is a result of lack of early exposure to pathogens. Dr. Buckingham also discussed the risk of complications, asserting that the amount of time before complications emerge seems to be similar regardless of age of onset and that children are not susceptible to microvascular complications due to the rapid turnover rate of collagen during this period; thus, most people with type 1 diabetes do not develop complications until after the onset of puberty. Despite the complex and poorly understood etiology of diabetes, Dr. Buckingham expressed optimism that the evolution of technological solutions like the closed loop will continue to improve diabetes management – while this is certainly true, the remaining uncertainty around disease pathophysiology underscores the difficulty of developing truly disease-modifying therapies.

• Dr. Buckingham highlighted the variation in type 1 diabetes distribution by latitude, season, demographic, and even birth month. Diabetes incidence is clustered in northern- and southern-most latitudes; these regions have also shown seasonal variation in type 1 diabetes incidence, with a greater number of new cases in colder months. Dr. Buckingham noted the interesting fact that Finland and Russia have similar latitudes and genetic makeups, but Finland has a drastically higher diabetes prevalence rate. Dr. Buckingham also shared data from a 2010 Diabetes Care study showing an association between type 1 diabetes and month of birth, with a greater number of cases occurring in people born in the summer months. The association was more prominent in northern US states than southern states. In addition, he noted that type 1 diabetes incidence is higher among Caucasians than among other ethnicities in the United States.
• Dr. Buckingham reviewed the physiological abnormalities of islet cells and the pancreas in type 1 diabetes, noting that they may reflect local rather than systemic inflammation. He noted that islets suffer from insulitis, loss of beta cells, and hyperexpression of class I MHC in type 1 diabetes, possibly causing beta-cell necrosis and diminished insulin production. He also reminded the audience that the pancreas itself changes in type 1 diabetes – it has a decreased overall weight, with atrophy of the dorsal region and lobular insulinitis.
  
  • Dr. Buckingham lauded MRI imaging of islet inflammation using Feraheme (a iron-containing compound) as a powerful non-invasive method for tracking changes in islet cell mass. He also discussed the utility of unmethylated insulin DNA in serum as a marker of islet cell death in the early stages of diabetes.
• Dr. Buckingham highlighted several possible environmental triggers for type 1 diabetes, focusing on studies of cow’s milk protein (beta-casein). He shared that intact cow’s milk has been shown to cause diabetes in rodents and has been associated with diabetes in humans in multiple countries. However, a large (n=2,160) randomized case control study published in JAMA (Knip et al, 2014) showed no significant difference in the number of autoantibodies in infants fed intact cow’s milk vs. casein hydrolysate (milk with degraded milk proteins).
• Dr. Buckingham displayed a set of images showing the geographic distribution of parasitic disease and childhood diarrhea – these were clustered in equatorial regions and roughly opposite to the distribution of type 1 diabetes. This supports the “hygiene hypothesis” that lack of early exposure to pathogens can lead to allergies and chronic disease; however, other data showed that enteroviruses are found in 75% of type 1 intestinal biopsies compared to 10% of controls. Dr. Buckingham also discussed results from several microbiome studies showing that children who develop type 1 diabetes tend to have a less diverse microbiome, and children with fully developed type 1 diabetes may have higher levels of butyrate-producing and mucin-degrading bacteria. The role of the microbiome in type 1 diabetes pathogenesis is one of the most fascinating areas of emerging research in our view – Dr. Alessio Fasano (Harvard University, Boston, MA) delivered an informative talk on this subject this month as part of the Commonwealth Club lecture series.
• In a particularly fascinating section of his presentation, Dr. Buckingham shared a series of studies demonstrating that the amount of time before complications emerge tends to be similar in people with type 1 diabetes regardless of age of onset. According to Dr. Buckingham, this phenomenon is explained by the fact that collagen controls the “metabolic memory” of glucose control through non-enzymatic glycosylation and advanced glycation end products; collagen also has a half life of 15 years in adults. Thus, most people with type 1 diabetes do not develop complications until after the onset of puberty.
• Dr. Buckingham concluded his presentation with an optimistic view on emergent closed loop systems, noting that the evolution of diabetes management technologies have dramatically improved the natural history of the disease. Ultimately, he believes these systems will decrease the burden of diabetes and improve outcomes. He spoke on a similar topic at ADA Postgrad 2016, where he stated that technology will continue to improve until it ultimately evolves into a fully closed-loop system that does not require the user to carb count or deliver a pre-meal bolus – now that’s an exciting future!

Depression and Diabetes

Jill Weissberg-Benchell, PhD (Northwestern University, Chicago, IL)

Dr. Jill Weissberg-Benchell, a leading authority on diabetes and mental health, discussed the complex issues of diabetes-related distress and depression. She explained that the risk of depression is elevated in youth with type 1 diabetes (prevalence of 15-33% vs. 2-7% in youth without diabetes) and in adults with type 1 (prevalence of 12-18% vs. 3-6%) and type 2 diabetes (prevalence of 9-18% vs. 3-6%). In both children and adults, depressive symptoms are correlated with worse outcomes (e.g., glycemic control, hospitalization, complications) and higher healthcare costs. The direction of those associations is often unclear, and at least in type 2 diabetes, evidence suggests that it is a bidirectional relationship. For youth with type 1 diabetes, particularly teenagers, Dr. Weissberg-Benchell emphasized that patients’ relationships with their parents are a major part of this equation. She explained that parents of children with diabetes are at higher risk for depression themselves, that depressed parents tend to misperceive their children’s behavior as overly pathological, and that parental engagement and a positive attitude are crucial to children’s mental health and successful diabetes management. She walked the audience through a case study of a depressed teenage patient and his overbearing mother to illustrate the need to appreciate patients’ and parents’ perspectives and address the interpersonal dynamics that can contribute to diabetes distress/depression. Dr. Weissberg-Benchell also lamented the inadequate access to mental health services for patients with diabetes (we were shocked to hear she is the only psychologist with a CDE in the entire state of Illinois) and advocated for the incorporation of depression screening into routine care. It is clear that the issues of diabetes distress and depression are being increasingly recognized by experts in the field – the challenge is translating that awareness into effective clinical practice in the broader medical community.

• During Q&A, Dr. Weissberg-Benchell noted that the label “diabetes distress” can be unintentionally insulting to some patients. In her experience, many patients have misheard the intended message from those like Dr. Larry Fisher (UCSF, San Francisco, CA) who have attempted to draw a distinction between diabetes distress and clinical depression – to them, it feels like their suffering is being downplayed. She argued that for a clinician, the important thing is to focus on the symptoms. If someone is experiencing distress about diabetes management, that is where to focus clinical care, whereas someone experiencing more general feelings of hopelessness or suicidal thoughts would require very different treatment. Ultimately, we still feel the distinction between diabetes distress and depression can be a useful one for clinicians and patients, but this was an important reminder of how easily messages can get lost in translation without effective two-way communication between providers and patients.

Questions and Answers

Q: In a situation like the case study, are you more likely to ask the parent to leave the room or speak to the parent and child together?

A: Both. There’s no way I will address this in one session. I need to spend time with Dan [the teenager] to get a sense of his joys, his goals, his friends, if he has a girlfriend. We heard last night about bringing in as many supports as possible. His mom right now is not capable of being his cheerleader, so I want to ask about that without the mom being there. I also definitely need to work with the mom alone to get a sense of her stressors and get support for her. I also want to work with them together. I’ll do all three over time.

Dr. Robert Eckel (University of Colorado, Aurora, CO): I recently heard Dr. Larry Fisher speak about this, and he really emphasized that rates of depression are not much different in people with diabetes. Diabetes distress was extremely common. How does a clinician distinguish between the two without questionnaires, or is that the next best step?

A: It’s a complicated answer. I’ve been in the audience for Dr. Fisher’s talks with people living with diabetes. Many adults with diabetes have misheard his intended message. They heard that “your suffering is not as bad as you think, it’s just diabetes distress.” I have heard that from a number of people. So you want to be really cautious about that conversation. From a clinician’s perspective, the bottom line is that people are hurting. No matter what the source is, you need to figure it out and help them. If you just look at the diagnosis for depression, people can have completely different sets of symptoms and still make the criteria. I don’t find that helpful as a provider. The symptoms of person A and person B can be so different, and my job is to figure out how to decrease their specific symptoms.

In some ways the diagnosis doesn’t matter. This is an esoteric conversation but you have to go to the symptoms. If someone is experiencing symptoms that are causing them enormous distress about the burden of the everyday slog of diabetes, that’s where to focus clinical care. If they’re feeling hopeless and thinking about ending their life, that’s where to focus care. In some ways it doesn’t matter whether it’s depression or distress. You have to figure out how to help them hurt less.

Q: I see some patients with early-onset diabetes and many who developed diabetes in adulthood, and they’re so different. It strikes me, not in all patients but in some with early onset, almost as though diabetes was a form of child abuse. Since the age of five or nine they’ve been poked and prodded and told to do this and that and felt guilt and blame. Their lives have been altered by diabetes. I get the sense that it’s a bit like a form of post-traumatic stress when they get to me in their twenties. Some of them pull through in their twenties but sometimes a lot of bad behavior is ingrained. Adults who get it are like, “well this is interesting. What do I have to do?” They ramp up much quicker. They probably have more residual C-peptide too. But when you’re dealing with a post-adolescent, the transition is not just changing doctors, it’s changing attitudes and developing acceptance and ownership and the ability to manage. They just look like a deer in the headlights.

A: I agree. The challenge of the transition is that the metabolic rules are changing. In the middle of puberty, it doesn’t matter what you do because you’re so insulin insensitive. You can do everything right and struggle. Then you’re done growing at the same time someone says you’re officially grown up. It’s easier to manage the numbers when you’re not in hormonal craziness. The rules of diabetes change and the relationship between what you do and the numbers changes drastically. The neat thing once you’re over 22-23, or certainly over 25 when your frontal lobes are done developing, is you can connect behavior to outcomes. It makes more sense.

Dr. Linda Siminerio (University of Pittsburgh, PA): Would you agree that we should use other resources on our team? An educator has time to say this is distressing you, so let’s work on this thing first. A busy endocrinologist doesn’t have that extra hour. We have to start using our resources. We have such limited access and payment for mental health professionals.

A: I think most nurse educators are mental health professionals; they just don’t have the label. Yes, sitting down with people and digging into the barriers and overcoming them slowly can go a long way.

Dr. Siminerio: But an educator shouldn’t have to be able to figure out real depression.

A: No. Most PCPs have a good sense of good mental health clinicians in the community. Teaching them about diabetes might be a way to increase resources. Maybe they can take some patients because you know they’re good clinicians.

Clinical Trials: How to Interpret Study Findings

Roy Beck, MD, PhD (Jaeb Center for Health Research, Tampa, FL)

Dr. Roy Beck provided a statistician’s guide to clinical trial interpretation that was a sobering reminder of how easily the conclusions from these studies can be overstated or misrepresented. He cautioned against over-reliance on p-values, noting that they do not provide any information about the strength of associations and that confidence intervals are much more informative, though they are not even reported in many published papers. He explained that it is especially easy to over-interpret the many small pilot studies with positive point estimates and wide confidence intervals. Such studies can generate interesting hypotheses, but their promising results are typically not replicated in larger follow-up studies; he pointed to the studies examining metformin use in overweight adolescents as one example. Dr. Beck also emphasized the need to minimize confounding and bias in RCTs. He suggested that confounding can be addressed by stratifying patients during randomization, restricting eligibility criteria, or adjusting during analysis, though he acknowledged that the latter option can come across as “voodoo statistics” to the public. He noted that bias is a particular challenge in diabetes studies because so many factors are involved in glycemic control. His main solutions were simply to keep as many of these factors as possible constant between groups and pay close attention to how dropouts are handled. Finally, Dr. Beck sounded a strong note of caution about subgroup analyses, particularly in light of the current buzz around personalized medicine. He stressed that the more subgroups are analyzed, the greater the chance is of a false positive “significant” finding and that analyses of post-randomization factors like adherence are particularly suspect.

Many Roles in Type 1 Diabetes: Doctor and Patient; Parent and Spouse; Scientist and Advocate

Panelists: Irl Hirsch, MD (University of Washington, Seattle, WA), Robert Eckel, MD (University of Colorado, Aurora, CO), Margaret Scarborough Eckel, Clark Eckel, Jami Dinsmore Eckel

In an informal conversation moderated by the charismatic Dr. Irl Hirsch, Dr. Robert Eckel and his family shared their personal experiences living with type 1 diabetes. Dr. Eckel told the audience that he was diagnosed in 1953, and “can’t remember life without diabetes”. For the first three decades after his diagnosis, he relied on urine testing and boiling glass syringes to manage his blood glucose; years later, two of his sons were diagnosed with type 1 diabetes, including co-panelist Clark Eckel. During the hour-long panel, the family told a series of moving stories about the reality of type 1 diabetes, including a humorous experience with a diabetic cat and a surreal night spent reviving all three family members with simultaneous hypoglycemia. The importance of involving family in diabetes management emerged as a theme of the conversation – Clark’s wife Jami comes to many of his endocrinologist appointments, and views his CGM tracings on her smartphone throughout the day. At the same time, the family also stressed the value of independence and empowerment, emphasizing the importance of embracing diabetes and taking accountability for self-management. See below for some of our favorite quotes from this very human discussion.

• “If you were born in the 1950s with type 1 diabetes, there’s a 70% chance you’re dead. I’m a survivor.” – Robert Eckel
• “It’s hard to understand as a spouse who doesn’t have diabetes how you can do the exact same thing and get a different result.” – Jami Dinsmore Eckel
• “I don’t consider type 1 diabetes a disease. It’s a life. That doesn’t mean you dwell on it, it’s just a life.” – Robert Eckel
• “We’d sit in the waiting room with other parents who were terrified about this diagnosis…and we were basically the opposite. We said you’re going to live a normal life and that’s what we tried to do as much as possible.” – Margaret Scarborough Eckel
• “I think knowledge is power. You have to find a way to get people’s families engaged in some way.” – Jami Dinsmore Eckel
• “I think it’s so important that diabetics don’t sit around … it’s not a reason not to do something.” – Clark Eckel

“Hot Topics” Lunch Discussion

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

Dr. Irl Hirsch led an impromptu Q&A session during lunch on whatever “hot topics” were on fellows’ minds. The result was a freewheeling discussion touching on everything from frustration over rising insulin prices to the potential of GLP-1 agonists in type 1 diabetes. See below for notable excerpts from the discussion.

Dr. Irl. Hirsch (University of Washington, Seattle, WA): With the ACA, I have many patients with deductibles of $6,000 or more. In Washington we have choices on the exchange but I just found out that in Wyoming, the one choice on the exchange has an $11,000 deductible. Whether someone is admitted with new-onset type 1 diabetes or has to pay for insulin, they have to pay full retail price until they hit that. Even then the price may be unaffordable because they’re often paying a percentage of $300-$400 for a vial of insulin. This wasn’t an issue five years ago. Everyone could get insulin. That’s not necessarily the case anymore.

Dr. Jill Weissberg-Benchell (Northwestern University, Chicago, IL): Another issue is that for many individuals their medical coverage is completely separate form their mental health coverage. They might be able to see their endocrinologist or medical team at one facility, but the insurance company won’t let them to see the mental health practitioners there because they contract with a different group. It’s a crazy but true aspect of medical coverage.

Dr. Hirsch: I can beat that. We have it so they can see our providers but they can’t use our hospital if they get admitted. It’s absolutely crazy.

Q: I had a 23 year old white male with a BMI of 29-30 come in with a family history of diabetes and an A1c of 6.5-7. We got GAD antibodies on him and they were slightly elevated. We have been treating him as potential type 1 diabetic. What do you think about giving them GLP-1s or something else?

Dr. Carla Greenbaum (Benaroya Research Institute, Seattle, WA): I would want to get their glucose under control. What’s the easier way to do that? I think if there’s another agent that works, that’s fine. The mission is to make sure you’re making progress and not kidding yourself that you’re making progress. I don’t use GLP-1s a lot but they are very beneficial for some individuals. I’m not convinced the antibody status should tell you a diagnosis one way or another.

Dr. Hirsch: The way I generally do it is if someone is antibody-positive and clearly has type 1 diabetes, they go on insulin just to break whatever glucose toxicity is there. Then I tell them about TrialNet. If they come back and decided they didn’t want to participate, we have a discussion. I talk about the anecdotal evidence with new type 1 patients on insulin and my own handfuls of patients. I talk about the NOD mouse data showing that when they receive GLP-1, you see happy islets that get the GLP-1 infusion and very unhappy islets that don’t. Of course, we heard earlier that those NOD mouse studies can come back and bite you.

As of now, we don’t have appropriate RCTs on the impact of GLP-1 on newly diagnosed type 1 diabetes. The one we have the most experience with is liraglutide. Our experience has been amazing. It’s obviously patient-dependent and affected by how much beta cell function is still there. One patient was fortunate in that her insurance wouldn’t cover liraglutide but her father paid cash for it, and she had such a positive response I had to convince her to stay on insulin. She has A1cs in the low 5s. I’ve had others with great responses who usually stay on glargine and stop prandial insulin. But this is so anecdotal I’m almost embarrassed to share it. When I talk to people, especially in Europe, they see the same thing. It would also be interesting to think if we would use this therapy early in addition to one of Carla’s immune modulators.

Dr. Greenbaum: The challenge you suggested with NOD mouse models is that the scientific community is increasingly skeptical about animal models in terms of what’s going on with beta cells. There are lots of new studies on humans through cadaveric cells and nPOD. There is increasing thinking that the GLP-1 drugs will be most advantageous for supporting beta cells in the very young. That’s when you are having growth and remodeling. That poses a challenge – we are in the midst of discussing it. Do we test this therapy in the young population who is not yet at clinically overt stage 1 or stage 2 diabetes? There’s no safety data on this yet, but most people feel that that’s the population that has potential to stabilize beta cells.

Dr. Janet McGill (Washington University, St. Louis, MO): Type 1 diabetes in adults is such a spectrum. I had a patient who was 56 years old with an A1c of 6.4%, he was diagnosed and put on metformin and his BMI was 29. Would any of you measure anything? He’s doing fine except he has a history of Grave’s. It turns out his GAD was off the charts. I had another patient just like that with a BMI of 18 and an A1c of 6.1% on metformin who clearly had C-peptide. It’s such a spectrum. For us to treat them all the same doesn’t make great sense. This lady was on five units of Lantus and metformin and has been rock solid stable for four years at 6.1%. There’s no reason to do basal-bolus insulin. I put everyone on some insulin because I don’t want them falling off a cliff. Liraglutide is not a bad choice. But it’s such a spectrum, and it’s not appreciated until you measure these things. Some patients do very well with a little insulin and some other drugs.

Dr. Hirsch: That’s why we need to have the right kinds of randomized controlled trials. I’d ask the pediatricians – would you have any problem putting a five or six year old on a GLP-1 as part of a clinical trial?

Dr. Bruce Buckingham (Stanford University, Stanford, CA): Yes. You can do anything to adolescents. I’d start with them and then go down to the six-year-olds.

Dr. Greenbaum: I’m going to argue for the sake of arguing. The evidence keeps telling us that there’s something scientifically different between children, adolescents, and adults. We might be missing an opportunity to study children. There are definitely issues to wrestle with here. For example, there’s new data suggesting that more B cells infiltrate the pancreas in young people with diabetes compared to older people. We have a long way to go, but you might see a little bit more personalized medicine in that regard.

Case Presentation: Newly Diagnosed T1DM

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

Dr. Irl Hirsch used a series of case studies to illustrate the “chronic challenge” of classifying types of diabetes, emphasizing that many patients do not fit neatly into the classic type 1/type 2 phenotypes. In his practice, he typically divides adult autoantibody-positive patients into several buckets: classic type 1 diabetes, LADA, and “type 1.5 diabetes” (patients with obesity and preserved insulin secretion who lose beta cell function faster than typical patients with type 2 diabetes). In light of rising obesity rates, he has recently added a fourth bucket – “type 3 diabetes” – to this scheme to characterize adolescent patients diagnosed with type 1 diabetes before puberty who later develop obesity and insulin resistance. Dr. Hirsch pointed out that this diagnostic confusion can have broader impacts on clinical practice beyond the care of individual patients. For example, he noted that the curve from UKPDS showing progressive loss of beta cell function in type 2 diabetes is the “fundamental basis” of current treatment, yet that curve would likely be much less steep if the significant portion of patients with antibody positivity were excluded. His overall point was that the current classification scheme is fairly arbitrary and does not account for the significant overlap between patient populations. More nuanced, pathophysiology-based models like the recently proposed ADA/JDRF staging system for early type 1 diabetes should help to some extent – we hope to see similar efforts on the type 2 diabetes side in the future.

Strategies and Targets for Disease Modifying Therapies in T1D: A Look Into the Future of Endocrine Practice

Carla Greenbaum, MD (Benaroya Research Institute, Seattle, WA)

Dr. Carla Greenbaum reviewed the “why, who, what, and how” of disease-modifying therapies for type 1 diabetes, emphasizing the potential for lessons from other disease areas. She argued that there is a clear need for disease-modifying therapies in type 1 diabetes despite technological advances that allow better symptom management. She noted that many pediatric patients in particular have poor glycemic control, that hypoglycemia remains a significant problem, and that 10%-20% of patients still develop complications even with good control. Dr. Greenbaum then discussed the recently published ADA/JDRF staging system for early-stage type 1 diabetes; her group at the Benaroya Research Institute is currently working on graphics intended to convey that system to a lay audience (see below for one example). Her two key points were (i) type 1 diabetes begins once a patient has two autoantibodies, and (ii) the rate of progression from that point is highly age-dependent, with children progressing faster than adults. Dr. Greenbaum argued that there is a clear precedent for treating this sort of “silent disease,” pointing to hypertension as an example. She also stressed that it is crucial to set clear goals for disease-modifying treatments. This may involve moderating expectations – aiming to preserve a clinically relevant amount of C-peptide (which could be very small) rather than striving for complete insulin independence, or looking for a safe chronic therapy rather than trying to cure the disease with a single course of treatment. This presentation reinforced our sense that managing patient expectations may be one of the biggest challenges for the type 1 diabetes “cure” field going forward, as immune therapies, beta cell replacement therapies, and other approaches may be able to produce meaningful improvements for patients even if they fall short of a complete cure.

• Dr. Greenbaum offered several practical tips for endocrinology fellows sympathetic to the goal of disease-modifying therapies. Her main points of advice were (i) to become involved in clinical trials, through referring patients and/or as investigators and (ii) not to shy away from immunotherapy. She suggested that those in the diabetes field tend to be a bit wary of immunotherapy but emphasized that it is part of standard treatment for most other autoimmune diseases and is the only hope for disease-modifying treatments.

Current Strategies for DKA Management/Management of Hyperglyemic Crises

Guillermo Umpierrez, MD, CDE (Emory University, Atlanta, Georgia)

Dr. Guillermo Umpierrez provided a detailed discussion of the pathogenesis, diagnosis, and treatment of the two hyperglycemic crises in patients with diabetes: DKA and HHS (hyperosmolar hyperglycemic state). He mentioned that the main precipitating causes for both tend to be infection or failure to take insulin; while largely preventable, they are common, serious, and expensive complications of both type 1 and type 2 diabetes. He advocated for preventing these crises and their associated morbidity/mortality through patient education, strict blood glucose monitoring, and aggressive diabetes management. His presentation also touched upon euglycemic ketoacidosis as a potential complication of SGLT-2 inhibitor therapy, noting that ~10% of type 1 patients treated with SGLT-2 inhibitors develop ketosis. We agree that caution and full education is required for SGLT-2 inhibitor therapy, and continue to believe that many type 1 patients (as well as type 2 patients, for whom the risk is lower) know very little about ketone testing – ketone meters and test strips are also expensive and not well reimbursed at this stage. That said, we welcome more alternatives for type 1 patients, and believe that SGLT-2 inhibitors have the potential to profoundly improve patients’ quality of life and diabetes management. Ongoing phase 3 trials should provide a better sense of the class’ overall risk/benefit profile in type 1 diabetes and what can be done to minimize the risk of DKA – in the meantime, Dr. Anne Peters (USC, Los Angeles, CA) has developed her own personal protocol for off-label use that has so far been successful in avoiding DKA.

Breakout Session: Multiple Daily iNjection (MDI) Basics

David Maahs, MD (Barbara Davis Center, Aurora, CO)

This interactive workshop on the basics of MDI therapy led by Dr. David Maahs made clear that caring for patients with diabetes is more of an art than a science. On almost every question, from the choice of insulin to the pros and cons of inpatient vs. outpatient education after diagnosis to the best time to introduce technology, the consensus answer was “it depends.” Anecdotes from the pediatric endocrinologists in particular emphasized how overwhelming a diagnosis of type 1 diabetes can be for families who often feel bombarded with information and retain little of it. The wide-ranging discussion also provided insights into how some new therapies and technologies are used and perceived in current practice. Only two or three attendees indicated that they had used Novo Nordisk’s Tresiba (insulin degludec), though interestingly, one provider from New York noted that more insurers in his area (including Medicaid) seem to be switching to Tresiba from Sanofi’s Lantus (insulin glargine). The providers who had used Tresiba gave it positive reviews overall, noting that patients appreciate the lower required doses and more stable profile. CGM appeared to be an area of significant interest but fairly limited uptake. Most attendees reported that a few of their patients used CGM, but few used it routinely, and many expressed interest in learning more about how to interpret CGM data. Dr. Maahs stated that he believes the field is at an inflection point and that the reduced burden with new devices should help increase uptake. Of course, access remains an issue: one attendee noted that most of her patients are uninsured undocumented immigrants who simply don’t have access to the technology. We also heard an n=1 review of Abbott’s FreeStyle Libre from an endocrinologist in the UK: he stated that many of his patients love the device but that he himself has not been that impressed with the accuracy.

Continuous Subcutaneous Insulin Infusion (CSII) Basics

Timothy Bailey, MD (UCSD, San Diego, CA)

Dr. Timothy Bailey provided an instructive presentation on initiating and troubleshooting pump therapy in type 1 diabetes, cautioning that proper use of the technology is required to adequately balance the short-term and long-term burdens of diabetes. To optimize insulin dosing, he advocated for an iterative process that addresses various factors individually. Dr. Bailey stated that the first step to dose optimization is correcting frequent hypoglycemia through a 5-10% reduction in total daily dose (TDD). Subsequent steps involve setting and testing basal rates, carbohydrate ratios, and correction factors to control frequent hyperglycemia. In terms of pump design, Dr. Bailey surveyed the diverse range of pump types, cannula options, line disconnect mechanisms, and infusion set auto-inserters, highlighting the importance of working with patients to educate them on their options and determine the best fit. He also asserted that infusion sets are the “Achilles heel” of insulin pumping, as they can fail through a variety of mechanisms (occlusion, kinked cannula, leaking, hematoma, pullout) and present a risk of hyperglycemia and DKA. He shared a survey of 1,142 pumpers, which found that 54% reported an increase in blood glucose levels until they changed their infusion sites; 19% reported kinking, 12% had leakage, and 12% had air bubbles. Indeed, suboptimal infusion sets present a substantial stumbling block to adequate insulin pumping therapy, and we hope the launch of the new Medtronic/BD’s new MiniMed Pro-Set infusion set (expected in mid 2016) will offer a meaningful improvement for patients.

• Dr. Bailey also addressed other common problems of pumping, such as delayed boluses, inaccurate carb counting, too many basal rates, and lack of “meaningful monitoring” data (e.g. downloading and analyzing pump and meter/sensor data). To improve overall pumping performance, he advocated for using various mobile and web tools to download pump data, view insulin on-board, count carbs, and provide clinical decision support. He concluded by stating that connectivity is the next big wave in diabetes devices and care, with expanded smartphone integration promising to improve patient engagement.  With the growing development of integration platforms and closed loop systems, we agree that the future is bright for diabetes therapy, and look forward to hearing the latest later this week at ENDO 2016.

What I Wish I Was Told When I Left My Fellowship

Luisa Duran, MD (John Muir Health, San Ramon, CA)

Dr. Luisa Duran provided encouraging and candid advice for new fellows entering clinical practice, emphasizing the value of building trusting relationships with patients with type 1 diabetes. She shared her own experiences transitioning to private practice, noting her surprise that her new clinic did not have many of the resources and capabilities integral to her UW fellowship (pump/CGM/BGM downloads, CDEs, nutritionists, pharmacists, etc.). She also lamented the financial realities and time constraints of clinical practice – patient-contact hours bring in revenue, and thus employers often require doctors to squeeze in up to 20 patients per day. To save time, she recommended delegating billing, appointment follow-up, and paperwork tasks to office staff, and requesting that patients download their pump data at home before appointments. In terms of managing type 1 diabetes patients, Dr. Duran argued that CGM for endocrinologists should be analogous to EKGs for cardiologists: essential for uncovering subtle trends and helping patients manage their care. She also stressed the importance of ensuring preparation and training for all patients on pumps, noting that many of her patients with previously prescribed pumps had not received adequate education on carb counting and simply delivered “blind boluses.” To provide patients with optimal care, she urged attendees to remain dedicated to lifelong learning to stay abreast of the latest drugs and technologies. She also recommended putting effort into understanding insurance coverage to help make cost-effective decisions with patients – we hear again and again that insurance barriers represent some of the biggest hurdles for practicing physicians and wish this was emphasized more (or at all) during medical training. Despite the challenges and frustrations of clinical practice, Dr. Duran said the work is ultimately incredibly rewarding, especially as she continues to build strong long-term relationships with her patients. We applaud Dr. Duran for providing an honest perspective on the realities of endocrine care – it is certainly hard work, and we wonder how web and mobile tools and greater acceptance of team-based care might relieve providers’ administrative burden and time constraints in the future.

T1DM and the Prevention and Treatment of Macrovascular Disease

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

Dr. Robert Eckel provided an in-depth survey of the literature on macrovascular disease in type 1 diabetes, concluding that more research is required to fully elucidate its relationship with glycemic control. He stated that there is substantial evidence supporting increased cardiovascular risk in type 1 diabetes, and CV death has been shown to correlate positively with A1c. As evidence, Dr. Eckel reviewed the cardiovascular results from the DCCT, which showed a lower cumulative incidence of any CV event with intensive vs. conventional treatment. Further, he noted that a large Swedish study (n~203,000) found that the risk of CV death increased with A1c, with the hazard ratio almost doubling between the A1c groups of 8.8-9.6% and ≥9.7%. Dr. Eckel also focused on the unique characteristics of CVD in type 1 diabetes compared to type 2; atherosclerotic plaque appears softer, more fibrous, more concentric, and more calcified in those with type 1 diabetes, with greater inflammation, fewer lesions, and less obstruction. Dr. Eckel also noted that LDL cholesterol is a modest risk factor for atherosclerotic cardiovascular disease (ASCVD) in type 1 diabetes but a major risk factor in type 2 diabetes. Patients with type 1 diabetes also have elevated HDL cholesterol levels, which impact the development of ASCVD to a greater degree in type 2 diabetes. This presentation powerfully illustrated the dearth of research on CVD in type 1 diabetes and reinforced our appreciation for the incredibly complex interactions that contribute to its development. Dr. Eckel and Dr. David Nathan (Harvard University, Boston, MA) led an informative workshop on this subject in 2014 that revealed similar themes of complexity and lack of evidence. We agree with Dr. Eckel that there are many unanswered questions in type 1 diabetes and macrovascular disease – when do patients with type 1 diabetes require statin intervention? How does the development of acute myocardial infarction in type 1 compare to type 2 and non-diabetic populations? How can the natural history of CVD in type 1 diabetes inform targeted diets to prevent atherosclerotic plaque development?

The Endocrinologist’s Role in Screening/Management of Microvascular Disease

Janet McGill, MD (Washington University, St. Louis, MO)

In a fascinating talk, Dr. Janet McGill emphasized the need for endocrinologists to be proactive about preventing and managing microvascular complications to a greater extent than is typical in current practice. On retinopathy, she strongly encouraged providers to perform basic eye exams at routine visits, to refer patients to a retinal specialist at the first sign of trouble, and to actively encourage them to keep up to date with vision care. In terms of therapies, she spoke positively about the two approved anti-VEGF agents (Bayer/Regeneron’s Eylea [aflibercept] and Roche/Genentech/Novartis’ Lucentis [ranibizumab]), noting that they are the only treatments that can improve vision rather than just preserving it. She acknowledged that these drugs are expensive (~$1,000 a month); our understanding is that this cost is a driver of significant off-label use of Genentech’s Avastin (bevacizumab) in DME, though this could change with the introduction of biosimilars in the future. Dr. McGill’s recommendations for diabetic nephropathy focused on the need to assess both albuminuria and eGFR, to track progression of the disease, and to make sure patients are monitored for parameters like calcium, PTH, and CV risk factors at later stages of the disease when many fall through the cracks. She expressed frustration at the lack of disease-modifying therapies in this area despite the long list of compounds investigated in the past and at present – see our most recent competitive landscape for an overview of the current pipeline. Therapies were not even mentioned in Dr. McGill’s discussion of neuropathy, which she described as possibly her least favorite complication due to the difficulty patients have managing pain. Despite the sobering subject matter, Dr. McGill ended on a fairly positive note, celebrating the improvements in diabetes care that have led to a larger and larger population of patients with longstanding disease – the challenge is doing more to ensure that these complex patients are receiving the best possible care.

Strategies for Diabetes management with Intense Physical Activity

Michael Riddell, PhD (York University, Ontario, Canada)

This “meet-the-professor” session led by Dr. Michael Riddell detailed the benefits, recommendations, and management strategies for physical activity in type 1 diabetes. Dr. Riddell began by discussing the guidelines for physical activity (150 minutes per week for adults, 60 minutes per day for children) and expressed dismay at the incredibly low adherence to them: 60% of adults in North America with type 1 diabetes are inactive (vs. 50% of the general population), and over two-thirds of youth with type 1 diabetes do not even achieve 30 minutes of exercise per day. According to Dr. Riddell, fear of hypoglycemia is a major barrier to engaging in regular exercise, along with lack of energy, poor body image, and diabetes-related embarrassment. The low rate of physical activity among people with type 1 diabetes is particularly troubling given the substantial benefits of exercise, including reduced postprandial excursions, lower LDL cholesterol, higher HDL cholesterol, and improved levels of apolipoproteins A and B. Further, Dr. Riddell shared results from a 2014 cross-sectional analysis of 4,655 Swedish patients showing a significant correlation between increased physical activity and lower A1c levels. That said, reaping the health benefits of exercise requires coordinating diabetes management to appropriately match the type, duration, and intensity of physical activity. For example, aerobic exercise tends to reduce glucose levels, so patients should ideally exercise with minimal insulin on board to avoid hypoglycemia, particularly nocturnal hypoglycemia. Conversely, intermittent, resistance, and anaerobic exercise can elevate glucose levels, a fact that should be taken into account when planning meals and insulin delivery to prevent hyperglycemia and/or DKA. We are always glad to see a greater focus on exercise in type 1 diabetes, which we feel is too often ignored in conference topics, patient education, and scientific research. Dr. Riddell has been incredibly instrumental in raising awareness and knowledge on the topic, and has also been an integral part of JDRF’s T1D Performance in Exercise and Knowledge (PEAK) program, a curriculum for managing physical activity with type 1 diabetes – we look forward to PEAK’s expected release later this year.

• To manage carbohydrate load before, during, and after exercise, Dr. Riddell recommended using tools such as “ExCarbs” as a starting point for prescribing carbohydrate quantities. ExCarbs offers algorithms based on body weight for various forms of exercise, such as vigorous aerobic exercise (1.0 grams per kg body mass per hour), moderate aerobic exercise (0.5 grams per kg body mass per out), and milder exercise (0.25 grams per kg body mass per hour).

Transition from Pediatric to Adult Care

Linda Siminerio, RN, PhD, CDE (University of Pittsburgh, PA)

Dr. Linda Siminerio discussed the transition from pediatric to adult care, reviewing the literature on the unique challenges and needs of the “emerging adult” age group (18-25 years). She explained that emerging adults with type 1 diabetes must simultaneously grapple with the daily demands of diabetes care, the complicated healthcare system, and the psychosocial challenges of adulthood. Not surprisingly, the emerging adult population is therefore at a high risk for premature morbidity and mortality, acute complications, alcohol/drug abuse, and mental illness. Compared to their peers without diabetes, emerging adults with diabetes choose similar life paths, and do not differ dramatically in alcohol use, sleep, smoking, depressive symptoms, loneliness, or disordered eating. They do, however, exhibit lower scores on measures of life purpose and satisfaction. Further, Dr. Siminerio stated that college students with diabetes typically report challenges to diabetes management such as time constraints, erratic schedules, dietary challenges, hypoglycemia concerns, and absence of social support. She noted that e only 61% of young adults attended an adult care program in the two years post transfer from pediatric care. To combat these difficulties, Dr. Siminerio advocated starting the process early (at least one year before the transition), assessing individual patients’ readiness for adult care, providing transition guides and resources, and maintaining communication between pediatric and adult physicians. This passionate and patient-centered talk reminded us that significant work remains in targeting this vulnerable age group, which requires a truly coordinated approach to facilitate a smooth transition process and optimize diabetes self-management, mental health, and overall wellbeing.

Diabetes Diagnosis & Management Workshop

T1DM Management in Children

Lori Laffel, MD (Joslin Diabetes Center, Boston, MA)

 “We can drop your A1c by 1.5% with one more blood glucose check and one more bolus.” Dr. Lori Laffel delivered a whirlwind, patient-centered presentation on type 1 diabetes management in youth, placing particular emphasis on the importance of family engagement. She presented two contrasting case studies of teenagers with similar durations of diabetes and therapeutic regimens but very different outcomes. One had uninvolved parents and suffered from depression and poor diabetes management, while the other had a very supportive family (that even built a gym in their basement and exercised together for up to 2.5 hours per day!) that helped her manage her disease very successfully. Dr. Laffel also emphasized the importance of using encouraging, understanding language to facilitate productive communication between providers, parents, and patients. For example, instead of automatically interrogating a teenager about what they ate in respond to a high blood glucose reading, she encouraged parents to react by (i) being grateful that their child remembered to check and shared the information with them and (ii) understanding that puberty increases insulin resistance, making diabetes management much more challenging. By the same token, it is much more effective for a provider to ask a patient when it is hardest for them to remember to bolus rather than asking “do you ever miss an insulin dose?” She stressed that even small changes in diabetes management can have profound effects on outcomes, noting that checking blood glucose once more per day is associated with an average A1c improvement of 0.5% and that adding one additional bolus every other day is associated with an average improvement of 1.0% based on evidence from observational studies. We appreciated Dr. Laffel’s down-to-earth, practical perspective on some of these intangible aspects of diabetes management– as evidenced by the candid discussion at last summer’s Friends for Life, navigating adolescence with type 1 diabetes can be extremely challenging for both patients and parents.

Assessment of Cardiovascular Risk in Diabetes: A Cardiologist’s Perspective

Jorge Plutzky, MD (Harvard University, Boston, MA)

Dr. Jorge Plutzky suggested that the recent positive results from CVOTs for diabetes drugs will likely impact cardiologists’ practice. The majority of his talk on CVD prevention in diabetes focused on screening and treatment of other risk factors like blood pressure and lipids for which there are safe, effective, and cheap therapies. However, he concluded with excitement about the opportunity to integrate new diabetes therapies into preventive care based on the results from EMPA-REG OUTCOME, LEADER, and IRIS. Interestingly, he even suggested that these therapies could be applicable in prediabetes, as he believes this may be the best stage for risk factor modification. As we see it, generalizability is the key question in this discussion, as FDA-mandated CVOTs of diabetes drugs (including EMPA-REG OUTCOME and LEADER) tend to enroll patients with longstanding type 2 diabetes and high CV risk – IRIS was an exception as an investigator-initiated study. As there are few incentives for companies to conduct additional expensive outcomes trials of these same drugs in a broader population, it will likely be left up to the medical community to estimate how generalizable the results are, in which case we assume there will be at least some increase in their use in lower-risk patients.

Legacy Effect, Timing, and Duration of Glycemic Control: What Can We Learn From the Long-Term Cardiovascular Trials?

Peter Reaven, MD (University of Arizona, Phoenix, AZ)

Dr. Peter Reaven reviewed the evidence supporting a subtle but real legacy effect of glycemic control on long-term outcomes. He reviewed the results from the pivotal trials in this area (DCCT, UKPDS, ACCORD, ADVANCE, VADT) and shared an intriguing DCCT analysis concluding that the strongest predictor of a patient’s risk of retinopathy progression at a given time was his or her A1c three to five years before – this was 2.5-fold more important than the patient’s current A1c value. On macrovascular disease, Dr. Reaven’s overall message was that there is some evidence of a benefit from glucose lowering but that it seems to require a significant A1c difference between groups and take several years to manifest. He argued that many of these trials, particularly those that enrolled patients with more advanced disease, may not have been long enough to reveal the full benefits of good glycemic control; this has been a common critique of many recent CVOTs for type 2 diabetes drugs as well. During Q&A, Dr. Reaven offered a few hypotheses on the underlying mechanisms of the legacy effect, citing changes in advanced glycation end-products (AGEs) and epigenetic changes due to hyperglycemia as two of the most exciting possibilities. He also acknowledged that since any effect of glucose lowering on CV outcomes appears to be modest, providers can likely get more bang for their buck with high-patients by focusing on other risk factors like blood pressure and LDL cholesterol.

Biology of Fetal Islet Beta-Cell Development and Feasibility of Stem Cell Therapy

Matthias von Herrath, PhD (La Jolla Institute for Allergy and Immunology, La Jolla, CA)

Dr. Matthias von Herrath outlined the challenges of immune therapy for type 1 diabetes and shared the broad strokes of what he believes could be a successful combination approach. The majority of his presentation focused on recent insights into type 1 diabetes pathogenesis made possible through nPOD research. These included findings of increased beta cell area and lack of insulitis during the prediabetic phase, upregulation of MHC class I antigens around the time of diagnosis, and some limited evidence of a role for viral infection and autoreactive T cells. Toward the end of the talk, he acknowledged the many challenges in the immunotherapy field, (half) joking that since “we don’t know what causes the disease, that makes for a bad start.” He emphasized that despite the history of frustration, it is clear that the immune system plays a considerable role in type 1 diabetes, and the challenge is finding therapies that can strike the right balance of efficacy and side effects. Dr. von Herrath feels strongly that the ultimate solution lies with combination therapy, which he believes should include one chronic maintenance component (like a GLP-1 agonist or an antigen-specific tolerogenic agent) and one short-term component to “reset” the immune system (like an anti-inflammatory agent or a therapy targeting T cells or B cells). Many other leaders in this field (including Dr. Jay Skyler, Dr. Carla Greenbaum, and several industry representatives) have agreed that combination therapy is the future of disease-modifying interventions for type 1 diabetes, though there is some difference of opinion on the specifics. Of course, the current poor understanding of disease etiology and the lack of approved drugs make designing programs to test the right combinations challenging.

Where Does Bariatric Surgery Fit in the Treatment and Cure of Diabetes?

Lee Kaplan, MD, PhD (Harvard University, Boston, MA)

Dr. Lee Kaplan advocated for greater incorporation of bariatric surgery into the type 2 diabetes treatment algorithm. He reviewed human and animal data demonstrating that bariatric surgery leads to profound physiological changes, metabolic improvements that are durable and independent of weight loss, and striking reductions in mortality, especially from type 2 diabetes. He also reviewed the results from the STAMPEDE trial showing greater type 2 diabetes remission with bariatric surgery vs. intensive medical therapy. Dr. Kaplan stressed that he does not believe bariatric surgery should be the primary therapy for type 2 diabetes due to its complications and costs, but he argued that it should be far more than an “outlier.” His ideal type 2 diabetes algorithm would begin with lifestyle intervention, move very rapidly to pharmacotherapy, and include surgery as an option for a subset of patients who are still doing poorly on intensive medical treatment, regardless of the patient’s obesity status. He also emphasized that surgery leads to diabetes remission in ~65% of cases and that use of a combination of surgery, lifestyle, and medications throughout a patient’s lifetime is the wave of the future. There appears to be somewhat of a growing consensus toward expanded use of bariatric surgery in patients with type 2 diabetes – as evidenced by last fall’s WCITT2D conference – but we anticipate that its use will grow only incrementally in the near future.

Obesity Management Workshop

Gut Hormones and Obesity: Etiology and Potential Drug Treatments

David D’Alessio, MD (Duke University, Durham, NC)

During a comprehensive presentation on gut hormones and obesity, Dr. David D’Alessio emphasized the efficacy of co-agonist therapies for the treatment of diabetes, highlighting the recent promising preclinical results for a GLP-1/GIP/glucagon receptor tri-agonist. He characterized the regulatory actions of several GI hormones, noting that few appear promising for the treatment of obesity due to the complexity of endocrine signaling. He asserted, however, that combining multiple satiety peptides appears to have a potent effect; for example, GLP-1 coupled with amylin can cause a greater reduction in food intake than either drug alone. Dr. D’Alessio also expressed enthusiasm for chimeric molecules, which can be engineered to bind multiple receptors (co-agonism) and enhance the satiety effect. He cited a series of results from animal models demonstrating the superiority of GLP-1/glucagon and GLP-1/GIP co-agonism compared to single agonism in lowering weight and glucose. Further, he noted that GLP/GIP/glucagon tri-agonism has been shown to magnify this effect due to the mixed mechanism of action targeting multiple systems. Although much more research is needed to determine whether these co-agonists will be a viable therapeutic option in humans, we believe this approach using combinations is one of the most promising ways to develop candidates that can meet the increasingly high bar for new type 2 diabetes drugs.

Weight Bias: Implications for Clinical Practice

Rebecca Puhl, PhD (University of Connecticut, Storrs, CT)

During a passionate presentation on weight bias, Dr. Rebecca Puhl discussed the vicious cycle of obesity and stigma, which ultimately leads to avoidance of healthcare, unhealthy behaviors, and poor outcomes. She highlighted the striking prevalence of reported weight discrimination, which impacts people of all ages, races, genders, and socioeconomic statuses. Multiple studies have shown that healthcare providers hold substantial biases toward patients with obesity, viewing them as less self-disciplined, less compliant, lazy, and annoying. This translates into poorer medical care for these patients, including shorter appointments, fewer interventions, and less relationship building. Even more troubling, there is evidence that patients who perceive negative provider attitudes avoid healthcare appointments due to feelings of embarrassment and fear of judgment. According to Dr. Puhl, this weight stigma and resulting healthcare avoidance lead to a cluster of detrimental health consequences – psychological distress, lack of physical activity, unhealthy eating behaviors, physiological stress responses – that ultimately exacerbate obesity. Indeed, evidence shows that adults who experienced weight stigmatization were three times more likely to binge eat than those without those experiences, and adolescents who reported weight-related victimization had an 80% greater likelihood of severe binge eating. To combat weight stigma in the healthcare setting, Dr. Puhl advocated for using person-first language (“people with obesity” vs. “obese people”), neutral terms for discussing weight (“unhealthy weight” or “high BMI”, not “fat” or “morbidly obese”), and establishing an appropriate environment with properly sized medical supplies, seating, and doorways. For more on this issue, please see our recent coverage of a Medscape survey, which similarly showed a significant need for greater provider education on obesity.

Update on Weight Loss Surgery

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

Dr. Philip Schauer provided an update on the safety and efficacy of bariatric surgery for weight loss and glycemic management, calling for international guidelines to include evidence-based recommendations for surgery to treat type 2 diabetes. He emphasized the increasing safety of bariatric weight loss procedures, sharing several studies demonstrating low rates of complications and mortality (~0.3%). Further, Dr. Schauer stressed the positive effect of surgery on long-term morbidity and mortality, citing data from the Swedish Obese Subjects (SOS) study that showed reductions in all-cause mortality, CV morbidity/mortality, cancer mortality, and microvascular complications with surgery vs. medical management. For type 2 diabetes specifically, he highlighted 11 RCTs since 2011 that compared bariatric surgery to medical treatment; ten of those studies found that surgery led to superior glycemic improvements and diabetes remission rates. He also shared data showing that bariatric surgery is cost-effective and potentially cost-saving, as it improves productivity and can potentially save thousands of dollars per patient in diabetes management costs. Despite all these data, Dr. Schauer noted that many prominent international diabetes organizations still exclude metabolic surgery from their guidelines for type 2 diabetes treatment. He strongly advocated for this to change, especially for those with a BMI of 35 kg/m² or greater. Indeed, we have been hearing a push for earlier intervention with surgery, with Drs. Lena Carlsson (University of Gothenburg, Sweden), Robert Eckel (University of Colorado, Aurora, CO), and Harold Lebovitz (State University of New York, Brooklyn, NY) even arguing for intervention as early as in prediabetes. While surgery may not be the scalable solution we are looking for in prediabetes or patients with BMI <35 kg/m², it is certainly encouraging to hear support for an additional treatment option for a patient population that currently has few effective choices available. To see some of the latest research on this, please check out our coverage of Dr. David Cummings’ (University of Washington, Seattle, WA) CROSSROADS trial, demonstrating type 2 diabetes remission at one year across BMI groups.

New Weight Loss “Devices”

Stacy Brethauer, MD (Cleveland Clinic, Cleveland, OH)

Dr. Stacy Brethauer surveyed three new FDA-approved endoscopic weight-loss devices, highlighting their potential to help bridge the “therapy gap” between medical (low risk, low efficacy) and surgical (high risk, high efficacy) therapies. He reviewed data supporting the safety and efficacy of the new devices, which include two intragastric balloon treatments (ReShape, Orbera) deployed temporarily in the stomach to limit food intake, and a vagal nerve blockage (EnteroMedics’ Maestro system) that blocks signaling in the vagus nerve to reduce hunger sensations. In addition, Dr. Brethauer showcased weight loss devices in the pipeline, including GI Dynamics’ EndoBarrier implant therapy, for which he expressed optimism (despite the US pivotal trial’s recent failure to meet its primary safety and efficacy endpoints) – we can imagine that the development of a clinical algorithm avoiding the hepatic abscess risk can be appealing to providers and patients due to the non-invasive nature of the device (see more on this from the German Diabetes Society statement). He also mentioned the AspireAssist Aspiration Therapy system, acknowledging its “yuck factor” but voicing enthusiasm for its potential to produce meaningful weight loss. Indeed, we agree prospects bode well for AspireAssist, with its unique mechanism of action of directly removing excess food from the stomach – although many may complain that it is not appetizing, the incredibly high number of patients who need therapy combined with the clear ROI on the device (as well as its positive patient preference data) may ease conversations with payers.

Mechanisms Underlying Weight Loss with Bariatric Surgery: Lessons from Animal Models

Randy Seeley, PhD (University of Michigan, Ann Arbor, MI)

Dr. Randy Seeley offered an intriguing look at the metabolic and weight benefits of bariatric surgery, suggesting that physiological mechanisms (altered GI signals to the brain and other tissues) rather than mechanical mechanisms (restriction and malabsorption) are responsible for these effects. Under this hypothesis, his team found that vertical sleeve gastrectomy (VSG) caused an elevation in serum bile acids (due to a decrease in liver bile acid reuptake), which act through binding to the farnesoid X nuclear receptor (FXR). In FXR knockout mice, there was no reduction in body weight, fat mass, or food intake and no improvement in glucose after surgery, indicating that the beneficial effects of VSG require FXR. Further, Dr. Seeley found that it is possible to recapitulate the effects of VSG in mice by diverting the bile acids to the lower intestine with a catheter, suggesting a potential avenue for a less invasive metabolic surgery in the future. He also noted during Q&A that FXR has been implicated in the microbiome, suggesting an opportunity for future studies on FXR-dependent changes to the microbiome following surgery.

 

-- by Melissa An, Adam Brown, Emily Regier, Lisa Rotenstein, Ava Runge, Manu Venkat, and Kelly Close