American Diabetes Association 77th Scientific Sessions

June 9-13, 2017; San Diego, CA; Full Report – Type 1 Diabetes Cures, Adjunct Therapies, and Pathophysiology – Draft

Executive Highlights

This document contains our coverage of Type 1 Diabetes Cures, Adjunct Therapies, and Pathophysiology at ADA 2017. Immediately below, we enclose our themes on the category, followed by detailed discussion and commentary. Talk titles highlighted in yellow were among our favorites from ADA 2017; those highlighted in blue are new full report additions from our daily coverage.

For comprehensiveness, we have included some talks in this report that also overlap with our ADA 2017 GLP-1 Agonist, Insulin Therapy, SGLT-2 Inhibitor, Policy and Reimbursement, and Epidemiology, Education, and Additional Topics reports.

Table of Contents 

Themes

Progress on Adjunct Therapies for Type 1 Diabetes

  • ADA 2017 featured substantial forward momentum on adjunct therapies for type 1 diabetes. Particularly notable were the suite of results for Lexicon/Sanofi’s SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. Across two oral presentations and two posters, Lexicon shared full data from the phase 3 inTandem1 and inTandem2 trials, as well as the phase 2 inTandem4 dose-ranging study and a JDRF-partnered phase 2 study in young adults with poorly-managed type 1 diabetes. inTandem1, a double-blinded trial that randomized 793 patients to either placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg, impressively met its primary endpoint on top of optimized insulin therapy by producing a mean placebo-adjusted A1c reduction of 0.35% in the 200 mg arm (baseline A1c post-optimization=7.6%; p<0.001) and 0.41% in the 400 mg arm (baseline A1c post-optimization=7.6%; p<0.001) at 24 weeks. More than twice as many patients achieved net benefit (defined as the percentage of patients with A1c <7% at 24 weeks and no episodes of severe hypoglycemia or DKA during the study period) on sotagliflozin 400 mg compared to placebo: 44% and 34% of participants in the 400 mg and 200 mg arms respectively achieved net benefit at week 24, compared to just 22% of those in the placebo arm (p<0.001). Patients taking sotagliflozin further experienced a 1.6 kg (3.5 lbs) and a 2.7 kg (6 lbs) weight reduction at 24 weeks with the 200 mg and 400 mg doses, respectively – this compares to a mean weight gain of 0.8 kg (1.8 lbs) in the placebo group (p<0.001). The similarly-designed inTandem2 study demonstrated significant A1c reductions of 0.36% (200 mg dose) and 0.35% (400 mg dose) with sotagliflozin vs. placebo (p<0.001) in patients with type 1 diabetes on optimized insulin regimens (baseline A1c = 7.7-7.8% after insulin optimization). In addition to this primary endpoint, 32% of patients in both sotagliflozin groups achieved the secondary endpoint of “net benefit”. The phase 2 inTandem4 study demonstrated statistically significant improvements in A1c and key primary endpoints such as secondary urinary glucose excretion, postprandial glucose, body weight, fasting plasma glucose (non-inferior), and blood pressure for sotagliflozin over placebo. Very notably, Lexicon shared data on beta-hydroxybutyrate (BHB) levels at baseline and at week 12 – as a measure of ketogenesis, BHB measurements are very helpful as we consider the potential DKA risk of sotagliflozin. Notably, the mean increase in blood BHB at week 12 was only 0.1 mmol/l, which is the lowest value detectable by a point of care BHB meter. Dr. Paul Strumph, Lexicon VP of Clinical Development, noted that this level of BHB increase is lower than what is typically seen with selective-SGLT-2 inhibitors – a promising nod toward a potentially better safety profile for SGLT-1/2 dual inhibitors like sotagliflozin in type 1 diabetes. Across these trials, there were fairly balanced adverse event rates across all three arms, somewhat higher rates of DKA with sotagliflozin, and somewhat lower rates of severe hypoglycemia. While there is some concern in some quarters about type 1 patients taking this class, there is no way to stop it so we advocate better education – as well, it may be valuable to look at gaps in therapy for type 1s in order to better understand patients taking SGLT-2 inhibitors off label. We applaud Lexicon for collecting so many outcomes and hope that these will be standardized soon.
    • A JDRF-partnered study of sotagliflozin in young adults with poorly controlled type 1 diabetes failed to demonstrate significant A1c reductions vs. placebo but showed promising improvements in other clinically relevant endpoints.  The trial enrolled 87 patients age 18-30 with type 1 diabetes and an A1c ≥9% and topline results were announced in December. Sotagliflozin produced placebo-adjusted A1c reductions of 0.35% (baseline = 9.7-9.9%) and the difference between groups was not statistically significant (p=0.10). However, sotagliflozin did appear to produce improvements vs. placebo on postprandial glucose, body weight, time in range, and A1c in patients with a baseline A1c of 9-10%. In addition, approximately 8 times as many patients in the sotagliflozin group achieved the “net benefit” endpoint of A1c <7% at 12 weeks with no severe hypoglycemia or DKA compared to the placebo group, though the absolute percentage of responders was low in both groups (16% vs. 2%). We were especially impressed by the CGM data from the study – sotagliflozin therapy produced a one-third increase in time spent in range of 70 mg/dl-180 mg/dl – mean proportion of time-in-range was 44% on sotagliglozin, compared to 33% at baseline. This study is a good example of the limitations of using A1c as the sole metric of efficacy for diabetes drugs, as other parameters like time in range and weight loss are likely more relevant for many patients.
  • On the GLP-1 agonist front, the highly-anticipated Lira Pump Trial demonstrated significant improvements in A1c, body weight, and time-in-range with liraglutide as an addition to insulin pump treatment in people with type 1 diabetes. People with type 1 diabetes using CSII and with overweight (n=44) were randomized to receive liraglutide 1.8 mg or placebo in addition to regular insulin pump therapy for 26 weeks. Compared to placebo, liraglutide as an add-on to insulin pump treatment produced significant improvements in A1c (-0.6% vs. +0.2%; p<0.001) and striking weight loss (-7.3 kg [16.1 lbs] vs. -0.6 kg [1.3 lbs]; p<0.001) results without increasing the time spent in hypoglycemia (3.2 vs. 3.5 events; p=0.77). While the A1c reduction may be perceived as fairly modest by some for a GLP-1 agonist, we’re especially impressed given the low A1c baseline, by the substantial weight loss, and by what increased time in ranges were. Excitingly, liraglutide as an add-on to insulin pump therapy gave participants significantly more time spent in the normoglycemic range (57% vs. 45%) – a crucial outcome for patient quality of life and perceived therapeutic and personal success. Currently approved for type 2 diabetes (under the trade name Victoza) and obesity (under the trade name Saxenda), these results underscore the potential of liraglutide for type 1 diabetes as well. We do remain confused that insulin use did not go down overall.
  • In terms of novel therapies, Dr. Jeremy Pettus presented exciting phase 1 data on the last day of the conference demonstrating that a single dose of the human glucagon receptor (GCGR) antibody REMD-477 can produce substantial and long-lasting (weeks!) reductions in insulin requirements and improvements in glycemia and time-in-range in people with type 1 diabetes, without increasing hypoglycemia. In a double-blind study, people with type 1 diabetes (n=21) were randomized to receive a single subcutaneous injection of either 70 mg REMD-477 or placebo. One day following the injection, participants who received REMD-477 experienced a significant 26% reduction (12 units) by the second day after the injection (p=0.02). Furthermore, REMD-477 produced substantial reductions in average daily blood glucose concentration not days but weeks after the injection. For people in the treatment arm, average glucose fell 27 mg/dl in the first week post-injection (p<0.0010), -31 mg/dl in the second week (p=0.05), and -20 mg/dl in the third week (p=0.05). REMD-477 further produced substantial increases in time-in-range. In the week following the injection, participants on REMD-477 spent 71% of their time in normoglycemia (70-180 mg/dl), versus 56% for those on placebo (p=0.0001), and the effect persisted into the second week post-injection (70% time-in-range with REMD-477, versus 57%; p<0.05). We are very moved by the sheer timescale of REMD-477’s powerful actions and eager to learn more about the upcoming phase 2 study, which according to Dr. Pettus will examine the effect of multiple weekly doses of the peptide drug. For good reason Dr. Pettus’ presentation was certainly one of the most highly-anticipated highlights of the President’s Oral Sessions – the very final event of ADA, highlighting particularly notable late-breaking abstracts – and we will be watching the progress of this work very closely. Although this work is clearly in its earliest stages, REMD-477 is a perfect exemplification of a patient-friendly diabetes therapy that optimizes important outcomes beyond A1c – namely time-in-range and a vastly reduced injection burden.
  • On the less positive side, ADA 2017 also featured disappointing results for metformin therapy in type 1 diabetes, in one of the largest studies to-date of this popular medication in this patient population. The JDRF-sponsored REMOVAL study failed to meet its primary endpoint of improvement in mean carotid intima media thickness (cIMT), a common surrogate marker for CV risk. What’s more, the glycemic endpoint findings from REMOVAL were modest at best. While metformin adjunct therapy products statistically significant differences in A1c compared to placebo, the clinical significance of the reduction is somewhat debatable. From a baseline of 8%, patients on metformin experienced a mean A1c decline 0.24% greater than patients on placebo after three months (p<0.0001). This reduction seemed to attenuate over time – after 36 months, this treatment difference was 0.13% in favor of metformin (p=0.006), though A1c had risen above baseline for both groups. Further, the reduction of insulin dose in the metformin group was extremely modest (a 1.9 unit/day difference at the end of three years, p=0.0018) and the hazard ratios for minor and severe hypoglycemia actually had a point estimate favoring placebo (though the finding was not statistically significant). All in all, the authors of the study conclude that REMOVAL results do not support the assertion in current treatment guidelines that metformin causes a clinically-meaningful improvement in glycemic control for people with type 1 diabetes. Regarding the whole of the data, including the CV findings, independent commentator characterized the findings as “suggestive, but not conclusive.” Metformin is arguably one of the most commonly-used off-label adjunct therapies for type 1 diabetes currently and, thus, the results from this long-term study are particularly disappointing. We look to sotagliflozin and other SGLT-2 inhibitors, GLP-1 agonists, and other therapies yet on the horizon as being more promising for this population of high unmet need. Additionally, we also note that some of the “headlines” around this study were deceptive – we want to make sure patients get the real story on the value of metformin in type 1 based on this trial.

Disappointing to Mixed results on T1D Cures and Prevention

  • It was a bleak meeting overall for type 1 cures and prevention, as readouts from numerous studies were disappointing at worst, and mixed at best.
    • The primary endpoint for TrialNet’s highly-anticipated Oral Insulin study – time from intervention to diagnosis in the primary stratum – was negative, but researchers saw an interesting signal in one of the secondary strata. The two cohorts are almost identical (mIAA and ICA antibodies or both GAD65 and ICA512 antibodies), but members of the primary stratum had first phase insulin response above threshold, while those in the secondary stratum had first phase insulin response below threshold. This seemingly small difference in disease stage had a huge impact on the efficacy of 7.5 mg oral insulin daily: Those in the primary stratum receiving oral insulin progressed to diabetes diagnosis at the same rate as those in the placebo group, while diabetes diagnosis in members of the secondary stratum receiving oral insulin was delayed by an average of 31 months (2.5 years!) vs. the placebo group. These results suggest to us that, perhaps, had people in the primary stratum not been treated until they had impaired first phase insulin responses, then they may have also benefited from the therapy. In a press conference the day prior, study PI Dr. Carla Greenbaum said that she was “flabbergasted” by this finding. Stanford’s Dr. David Maahs pointed out that the study was not a home run, but a 31-month delay to diagnosis in a specific cohort of patients is surely an incremental victory – for a young child, that delay could mean over 6,000 fingersticks not performed, and 930 nights during which a parent can sleep through the night without having severe hypoglycemia on the mind. None of the presenting experts had anything more than a hand-wavy mechanistic explanation for these surprising results: Dr. Greenbaum called attention to the fact that the participants in the second stratum who do progress to diabetes do so much faster, regardless of treatment group, than those in the other three groups. She suggested that there may be a “flare up” of the disease, as seen in MS and Crohn’s, during which immune intervention can prove beneficial. Meanwhile, Dr. Desmond Schatz hypothesized that some beta cell destruction (determined by impaired first phase insulin response) begets an enhanced immune response, which oral insulin can blunt. There’s obviously a lot of mechanistic research to be done, but we’re definitely intrigued by this specific cohort.
    • The DiAPREV-IT trial of Alum-GAD in children with multiple IAAs but no diabetes showed that the therapy was safe, but ineffective in delaying or preventing progression to diabetes. Given GAD-induced immune tolerance’s storied history, many had high hopes that this trial would deliver results, but the intervention demonstrated no tangible benefit. In addition, regardless of stratum (two antibodies, three to six antibodies) or baseline glucose tolerance, the absence of delayed progression held. That said, the study had a small sample (n=25 Alum-GAD; n=25 placebo) and was therefore not powered for these subanalyses – it may be worthwhile to conduct larger trials in attempts to unearth subgroups of responders.
    • Lastly, a JDRF-backed phase 2 study of Gleevec (Imatinib) in adults recently diagnosed with type 1 diabetes showed faint signals of beta cell protection. Over the year, the primary outcome, C-peptide AUC during a mixed meal tolerance test, declined steadily in the placebo group, while the group that received Gleevec followed the same trajectory for the first few months, before diverging and ending up with a statistically significant increase by month 12. While the findings are nowhere near definitive, highly regarded investigator Dr. Stephen Gitelman told us that the purpose of the study was to demonstrate feasibility to support future studies in pediatric patients, where he thinks the drug can have much more pronounced effects.
  • It’s been a long time since we’ve seen a very positive biological study in type 1 diabetes – in fact our associates haven’t even been in diabetes long enough to see one. The above studies serve as a reminder as to how difficult it is to nail down a therapy as protective against diabetes. Assuming an efficacious compound is under investigation, zeroing in on effective dosing regimen, time and frequency of administration, and responding subpopulations is no easy feat. Boston Children’s Hospital’s Dr. Joseph Wolfsdorf put it beautifully: “Imagine in the 1930s,” he began, “when penicillin was discovered. It kills bacteria in a petri dish, so they started a trial with penicillin to kill streptococcal pharyngitis in the throat, 5 mg/day. What if the dose had been in the completely wrong universe? Are we struggling to make headway here because we don’t know how to dose the therapy?” It’s anyone’s guess, but at this point, we’ve sadly gotten accustomed to seeing late-stage failures, such as anti-CD3 therapies in the Protégé and DEFEND trials. When will the tide turn?
  • As alluded to earlier, we were a little put off by somewhat misleading headlines in press releases announcing these trial results. For REMOVAL, the title read “Long-Term Metformin Treatment Found to Reduce Risk of Heart Disease in Adults with Type 1 Diabetes” – REMOVAL was not a cardiovascular outcomes trial, it failed its primary endpoint, and the main content of the ADA press release only mentions secondary/tertiary endpoints, which was very surprising. The DiAPREV-IT headline read “Autoantigen GAD-Vaccine is Safe for Children at High Risk for Developing Type 1 Diabetes” – while this is true and reflects the primary outcome of the study, it doesn’t disclose the more pertinent finding, that the vaccine did not prevent or delay the development of diabetes. So many people in our field our so busy and may not have the time to delve deeply into every email and press release that passes through their inboxes, so it is absolutely critical that the media is as transparent and accurate as possible. Further, we recently heard from healthcare journalists at the Spotlight Health conference that the proliferation of low-quality health news in the mainstream media is due in part to newer and less-trained journalists who rely heavily on press releases, rather than investigating the primary results themselves through journal publications, etc. We so appreciate the enormous support the ADA provides for press during its annual meeting each year – as we understand it, over 200 press correspondents were registered for the 2017 Scientific Sessions – and we hope to see greater attention paid to press release headlines in the future, given the immense responsibility entrusted to this organization.

Advances in More Patient- and Caregiver-Friendly Glucagon for Hypoglycemia

  • Zealand and Xeris highlighted their continued progress on the liquid-stable glucagon autoinjector front at ADA 2017. In a poster, Zealand detailed phase 2 results from a PK/PD study of its liquid-stable glucagon analog dasiglucagon in people with type 1 diabetes (n=58), demonstrating that dasiglucagon, like native glucagon, can rapidly and effectively increase blood glucose concentration following a controlled, insulin-induced hypoglycemia event in which blood glucose fell to 55 mg/dl. On the pharmacodynamic front, the three highest dasiglucagon doses used in the study (0.3 mg, 0.6 mg, and 1.0 mg) each took a median of six minutes to raise plasma glucose levels to above 70 mg/dl, versus 6 and 7 minutes for the 0.5 mg and 1.0 mg doses of native glucagon, respectively. Notably, the increase in plasma glucose was longer-lasting and more pronounced with dasiglucagon; this larger glucose excursion profile promisingly suggests that dasiglucagon may be superior to native glucagon at preventing recurrent hypoglycemia. The FDA is expected to provide guidance on dasiglucagon’s development imminently. The candidate is currently in phase 2 development both as a single-dose rescue pen (phase 3 to begin as soon as 3Q17) and as a multi-dose component of a dual hormone artificial pancreas system. We were also pleased to get a glimpse at promising efficacy/safety results for Xeris’ G-Pen Mini mini-dose glucagon for both non-severe hypoglycemia events (1068-P) and for exercise-induced hypoglycemia (67-LB). All in all, we are very pleased to see this progress toward a more patient-friendly and feasible alternative to the current very complex, error-prone native glucagon kits – a longstanding area for improvement in diabetes care. This area is certainly heating up!
  • We also heart exciting updates on the nasal glucagon front from Lilly. Dr. Elizabeth Seaquist presented positive real-world data on Lilly’s phase 3 nasal glucagon, showing that 96% of patients experiencing hypoglycemia recovered within 30 minutes following treatment and that most of the caregivers were highly satisfied with the device. The study enrolled 129 adults with type 1 diabetes, and 69 of these participants experienced a total of 157 symptomatic moderate or severe hypoglycemia events (a blood glucose of approximately <60 mg/dl or requiring assistance) during the course of the study. For 151 of these episodes (96%), a 3 mg dose of nasally-delivered glucagon met its primary endpoint of “awakening or returning to normal status” within 30 minutes, as determined by a caregiver. For five of the remaining six events, caregivers noted recovery within 45 minutes, and in four of these instances, the patient’s blood glucose was ≥70 mg/dl 30 minutes after administering nasal glucagon. A majority of caregivers, 70%, were able to deliver nasal glucagon to a patient experiencing hypoglycemia within 30 seconds, while 98% were able to do so in <2 minutes – what an exciting and much-needed improvement to the lengthy reconstitution process of existing glucagon options. The health and healtheconomic burden of hypoglycemia remains far too high, and we’re hopeful that advances like Lilly’s nasal glucagon will bring us leaps and bounds ahead in our ability to treat the complication.

Award Lectures

  • In this year’s inspiring Banting Medal for Scientific Achievement lecture, Columbia’s Dr. Domenico Accili presented his vision of a revamped toolkit for diabetes care in 2021, 100 years after the discovery of insulin: Prevention of beta cell de-differentiation, a gut-targeted Foxo1 inhibitor to coax gut cells into producing insulin in a glucose-dependent manner, and selective insulin sensitizers. The meat of his talk focused on dispelling the perception that beta cell failure is a consequence of beta cell death; rather, his data suggest that beta cell dedifferentiation is to blame. Dr. Accili sees a big opportunity here: If beta cells are not dead, but just quiescent as dedifferentiated of converted cells, then there’s a chance to restore beta cell health even after the onset of hyperglycemia. For type 1 diabetes, Dr. Accili’s lab has set sights on coaxing gut cells into producing insulin in a glucose-dependent fashion, and for type 2 diabetes, Dr. Accili explained that it is possible to modulate critical nodes of insulin signaling to dial up/down individual bio-responses, enabling selective reversal of insulin resistance. With a portfolio this lengthy and deep, we can’t think of anyone more deserving of this award than Dr. Accili – our only hope is that he sticks with it and delivers 2021: A Diabetes Odyssey.

Detailed Discussion and Commentary

Symposium: Type 1 Diabetes Immune Intervention Trials

Type 1 Diabetes TrialNet Oral Insulin Trial – Introduction and Background

Jay Skyler, MD (University of Miami, FL)

Miami’s Dr. Jay Skyler explained how the TrialNet study came out of the DPT-1 oral insulin trial, which began in 1994. In DPT-1, oral insulin didn’t delay the development of type 1 diabetes. However, in this study, the inclusion criteria was initially confined to autoantibodies five standard deviations above the mean, but due to lagging enrollment, the team reduced the criteria to three standard deviations above the mean. In a post-hoc sub-analysis of only the patients who started with autoantibody concentration of at least five standard deviations above the mean, an extrapolation suggests that oral insulin delayed development by ~five years! Since this finding was purely hypothesis-generating, the TrialNet developed the current oral insulin study.

Type 1 Diabetes TrialNet Oral Insulin Trial – Results and Conclusions

Desmond Schatz, MD (University of Florida, Gainesville, FL)

Dr. Desmond Schatz presented mixed results from the TrialNet Oral Insulin study investigating the efficacy of oral insulin in delaying or preventing the onset of diabetes in relatives (mean age 8.6 years old) at risk for type 1 diabetes: The primary outcome, time from intervention to diagnosis in the primary stratum (participants with mIAA and ICA antibodies or both GAD65 and ICA512 antibodies and first phase insulin response [FPIR] above threshold), was negative – patients who received 7.5 mg oral insulin daily (n=198) progressed to diabetes at the same rate as those in the placebo group (n=184). The survival curves (below) are almost identical (HR=0.87, 95% CI: O.61-1.24, p=0.42), and on an annualized basis, rate of diabetes was 8.8% in the oral insulin group (58 individuals over six years) and 10.2% in the placebo group (62 individuals). However, it wasn’t all bad news for the hopeful audience. The TrialNet team pre-specified three secondary strata in which to explore the preventive effects of oral insulin. Two of them– (i) participants with mIAA and either GAD65 or ICA512 antibodies, FPIR above threshold (n=114) and (ii) participants with mIAA and either GAD65 or ICA512 antibodies, FPIR below threshold (n=2) – exhibited no difference in time to progression, just as the primary stratum did. But researchers saw an interesting signal in one of the secondary strata, participants with mIAA and ICA or both GAD65 and ICA512 antibodies, FPIR below threshold (same as primary stratum apart from FPIR level): Time to type 1 diagnosis was delayed in the oral insulin group (n=27) by an average of 31 months (2.5 years!) vs. the placebo group (n=27). Annualized rate of diabetes, per the survival curve below, was nearly cut in half, from 34.1% (19 progressions to diabetes in six years) to 18.1% (13 progressions) by the treatment (HR=0.45, 95% CI: 022-0.91, p=0.01). All of the four stratum and outcomes are shown in an excellent summary figure made by Stanford’s Dr. David Maahs. When all of the strata are collapsed and analyzed together, there was no difference in progression (annualized rate of 8.7% in oral insulin group, 10.4% in placebo; p=0.08). From a safety perspective, the therapy was well-tolerated – in 560 patients, there were no severe adverse events, and zero participants had a grade five adverse event (there was one instance of a grade four). This was truly a mammoth study, and our hats go off to the remarkable clinicians and staff at 87 locations who screened nearly 140,000 relatives to enroll 560 participants and gave this trial their utmost attention for 10 years.

  • Dr. Schatz concluded his presentation of the results with one emphatic, make-no-mistake-about-it slide that simply read: “Monotherapy unlikely to prevent or delay type 1 diabetes.” Indeed, it’s seeming more and more clear that a cocktail of medications will be necessary to address the multiple sources of immune attack, ER stress, and other pathologies that trigger the onset of type 1 diabetes. See our notes from Dr. Jay Skyler’s ENDO 2017 talk for a list of type 1 prevention and intervention trials, many of which are combinatory in nature. Our type 1 diabetes cure and prevention competitive landscape also contains an overview of several ongoing efforts.
  • We were hoping to hear a mechanistic speculation on what might be the driving the heterogeneity of results among patients with the same antibody background and differing only in FPIR, but it sounds like there is a lot to parse out – TrialNet PI Dr. Carla Greenbaum said in a press conference the day prior that she and her team were “flabbergasted” upon seeing an effect in the one secondary stratum. There was a working group meeting this morning to analyze future options. Dr. Greenbaum called attention to the fact that the participants in the second stratum who do progress to diabetes do so much faster, regardless of treatment group, than those in the other three groups. She suggested that there may be a “flare up” of the disease, as seen in MS and Crohn’s, during which immune intervention can prove beneficial. There’s obviously a lot of work to be done, but we’re definitely intrigued by this specific cohort.

Type 1 Diabetes TrialNet Oral Insulin Trial – An Oral Insulin Mechanistic Study

Peter Gottlieb, MD (University of Colorado, Aurora, CO)

In addition to the TrialNet study, Dr. Peter Gottlieb is conducting a trial with higher doses of oral insulin at the Barbara Davis Center. Participants are randomized to either 67.5 mg of oral insulin daily (n=45) or 500 mg bi-weekly (n=47) for six months, followed by six months of monitoring. The rationale is that the TrialNet study tested 7.5 mg (30/mg/m2), while the most effective dose in NOD mice was 300 mg/m2. The Pre-POINT study suggested an immune signal at 67.5 mg daily (the human equivalent of the effective dose). The rationale for bi-weekly dosing was that the most effective regimen in mice was to give them the human equivalent of 600 mg/m2 twice a week, not daily. Dr. Gottlieb speculates that activation of Treg cells may be more likely occur with intermittent dosing. Thus far, preliminary analyses on the first subjects in the trial suggest an increase in mIAA and reduction in GAA in those in the 67.5 mg/day group. Further analyses are underway. Dosing is one of the many banes of trials, especially in prevention – how is one to know how much and when to give an agent that could have a very small therapeutic efficacy window?

Type 1 Diabetes TrialNet Oral Insulin Trial – Independent Commentary

David Maahs, MD (Stanford University, Palo Alto, CA)

Dr. David Maahs’ independent commentary was largely positive – he pointed out that while the study was not the homerun that we had all hoped for, a pre-specified secondary hypothesis was met, and a 31-month delay to diagnosis could be viewed as a victory. He urged the audience to re-educate ourselves to accept incremental advances and to consider the perspectives of people living with diabetes – 31 months is two-and-a-half years without the burden of living with diabetes. For a young child, that could mean over 6,000 fingersticks not performed, and 930 nights during which a parent can sleep through the night without having severe hypoglycemia on the mind. Given that there was an observable effect in a portion of the participants, Dr. Maahs wondered if the cost of oral insulin is low enough to warrant further studies – the results demonstrate a step in the right direction, but is result significant enough to pour many more millions of dollars into the question? If yes, there is clearly a need for further hypothesis-driven mechanistic studies enriched for the responder stratum to better understand the pathophysiology. Another expensive, but we would argue worthwhile, effort would be to follow the participants who didn’t develop type 1 diabetes during the trial – how long does the protective effect last? And for those in the oral insulin group who did develop type 1 diabetes – will they have better outcomes vs. those in the placebo group? Dr. Maahs also explicated the need for better and cheaper assay techniques to make it more feasible to screen for antibodies and risk on a population-level, and also to lower the barriers of time and cost for these long-term prevention trials.

Questions and Answers

Q: I wonder if the delay observed in the stratum may have to do with timing – once you’re actually damaging the beta cells, you may be able to activate the immune system more?

Dr. Schatz: This gives us an opportunity to really study the mechanism. We’ve lumped all stages of type 1 diabetes together in the past – it was surprising to see the effect in the secondary stratum. They already lost FPIR. Is the immune response different at different stages of the disease? I think there’s evidence for that, but we have not conclusively shown there’s a difference. The hypothesis is you need some beta cell destruction, enhanced immune response, and you get a slight delay.

Dr. Yogish Kudva (Mayo Clinic, Rochester, MN): The SS1 cohort in the intervention group seems to be conflatable to clinical practice – what are the barriers? In an a priori designed study, this looks like a good effect?

Dr. Schatz: The primary stratum showed no effect in the population as a whole…Dr. Maahs talks about screening, and should oral insulin be used in a certain population. I think, if it’s safe and cheap and does no harm, there will be some people, who we need to figure out their responses. I personally think if it’s safe, we’ll use combo therapy in the future, but this study showed it couldn’t be used in primary stratum. That study was negative. We need to understand more about the secondary stratum. And those in the primary stratum who had no benefit, who are now in the secondary stratum – would they benefit?

Q: Have to come back and say, is this question of heterogeneity? How are those patients in the second stratum different? It might be something other than timing, and we don’t want to miss that.

Dr. Schatz: These are obviously post-hoc analyses. What we got to do as a group is to define responders and do personalized medicine in the future, but these are hypothesis-generating. We need to take a look at how we do studies.

Imatinib (Gleevec) in New-Onset Type 1 Diabetes—Background and Results

Stephen Gitelman, MD (UCSF, San Francisco, CA)

Opening with the question “What can we do to make beta cells great again?” UCSF’s Dr. Stephen Gitelman presented results from a JDRF-backed phase 2 study of Gleevec (Imatinib) in adults recently diagnosed with type 1 diabetes (n=67). Gleevec is a tyrosine kinase inhibitor commonly used to treat leukemia and other cancers – several case reports and other studies have suggested a possible type 1 diabetes benefit in patients being treated for cancer, which has been substantiated in NOD mouse models. Participants received either 400 mg of Gleevec (n=45) or placebo (n=21) for six months, followed by six months of follow-up – over the year, the primary outcome, C-peptide AUC during a mixed meal tolerance test, declined steadily in the placebo group, while the group that received Gleevec followed the same trajectory for the first few months, before diverging and ending up with a statistically significant increase by month 12 (~0.6 nmol/l vs. ~0.5 nmol/l; p=0.05). Insulin use increased steadily over time in both groups, but to a greater degree in the placebo group (+~0.15 units/kg/day vs. +~0.02 units/kg/day; p=0.049). Interestingly, dose initially dipped in the treatment group, but then climbed more or less in parallel with the placebo group, indicating there might be a short window where Gleevec turns the clock back on insulin dependence. There was no difference in A1c over the course of the trial (everyone was treated to a target of <7%), and likewise no difference in the distribution of adverse events between Gleevec and placebo (though Gleevec did contribute to a marked increase in GI symptoms). In Q&A, Dr. Hans de Vries questioned why the statistical testing was all one-tailed, rather than two-tailed, as is commonly seen in a placebo-controlled study. Dr. Gitelman responded that his team wanted to get a sense of whether Gleevec would be beneficial in adults, before moving to kids (the ideal target, but FDA required evidence of prospective benefit in adults first), and had a limited budget. Significance is lost if the test is two-tailed, but we believe there is still enough of a signal here to warrant future research in pediatrics: The drug is relatively safe, and children would likely have a greater mass of beta cells that can be salvaged. Next up, Dr. Gitelman hopes to complete a per- protocol analysis, identify responders, and partition the effects of age in the 18-45 year-old study population (a greater effect in younger patients would suggest that Gleevec would be even more beneficial in children). He also wishes to conduct mechanistic studies and follow the subjects out to 24 months.  

  • We are highly intrigued by the fact that the beneficial effects of Gleevec appear to maintain, even augment, over the six months following the cessation of treatment. While we, nor Dr. Gitelman, don’t really know what is going on here, the lasting effect is certainly a clue as to how Gleevec is exerting its effect – epigenetic mechanisms? Immune re-training? Future mechanistic studies will be interesting to follow. Based on previous literature, we know that Gleevec could be working through mechanisms involving anti-inflammation, ER stress, and insulin sensitivity. In a brief interview, Dr. Gitelman proposed that it may have to do with dampening the unfolded protein response, which results in beta cell apoptosis. If this is the case, the way it translates to long-term protection (after dosing has stopped) is still a mystery, and we wonder about potential off-target effects.

DIAPREV-IT Trial with GAD-Vaccine—Results and Conclusions

Helena Larsson, MD, PhD (Lund University, Sweden)

Lund University’s Dr. Helena Elding Larsson shared the disappointing results of the DiAPREV-IT trial of Alum-GAD in children ages 4-18 with multiple IAAs but no diabetes (n=50): While the primary objective of safety was met, there was no significant effect on progression to diabetes in any of the groups included in the study. Children were randomized to receive two 20 ug doses of subcutaneous Alum-GAD (n=25) or placebo (n=25) 30 days apart. The survival curve shows that the intervention had no tangible impact on progression (HR=0.77; p=0.574). Overall, at inclusion, 26/50 had impaired glucose tolerance, and in the follow-up, 36% had been diagnosed with type 1 diabetes – fewer than expected. Further analyses showed that, regardless of stratum (two antibodies, three to six antibodies) or baseline glucose tolerance, the absence of delayed progression held. These are disappointing findings, but Dr. Larsson pointed out that the study was small and therefore not powered for subgroup analyses – future mechanistic studies will examine pathologic effects in cellular and humoral samples. On safety, there were no study related adverse events, increased risk of celiac or thyroid autoimmunity, signs of accelerated progression to type 1 diabetes, and while GADA titres increased in children treated with Alum-GAD, there was no effect on other IAAs. Despite a negative result, the successful safety outcomes shown here could prove useful in future studies investigating alternative dosages or combinational approaches.

  • Despite its storied and promising history, GAD-induced immune tolerance has not delivered at this point. Boston Children’s Hospital’s Dr. Joseph Wolfsdorf asked whether we should continue to investigate it as a therapeutic option. While he doesn’t know the answer, it clearly keeps him up at night. “Imagine in the 1930s,” he began, “when penicillin was discovered. It kills bacteria in a petri dish, so they started a trial with penicillin to kill streptococcal pharyngitis in the throat, 5 mg/day. What if the dose had been in the completely wrong universe? Are we struggling to make headway here because we don’t know how to dose the therapy?” It’s anyone’s guess at this point…

Symposium: Results of the JDRF Reducing with Metformin Vascular Adverse Lesions in Type 1 Diabetes (REMOVAL) International Multicenter Trial

Introduction, Study Rationale, and Design

Helen Colhoun, MD (University of Edinburg, UK)

The REMOVAL trial was published online in Lancet Diabetes & Endocrinology just as this symposium began, and Dr. Helen Colhoun opened by outlining motivations for the trial and reviewing study design. She highlighted a lingering and concerning problem in type 1 diabetes care – patients face a 2.5-4x risk for CV disease compared to a background population, without adequate adjunct therapies to address it. Metformin is prescribed for some type 1 patients and is recommended in ADA and other treatment guidelines. However there have only ever been nine small studies, the largest of which studied was in 100 participants followed for one year (a total randomized follow-up in all studies of 192.8 patient years).  The evidence summarized in a meta-analysis published in 201o by Dr Colhoun and Dr Petrie demonstrated insulin-sparing effects, weight loss benefits, and possible A1c-lowering efficacy. There was a slight impact on LDL in one previous study in which few patients were treated with statins.  DCCT/EDIC, is the only study that has showed a long-term benefit on macrovascular complications in type 1, stemming from intensive glucose-lowering, but risk factors other than glycemia are correlated with CV outcomes, so metformin might lower frequency of CV events by impacting other risk factors or by other pleiotropic effects as in type 2 diabetes.  Ambiguity surrounding metformin’s mechanism of action means that much remains unknown about the molecule’s specific effects on different physiological systems. All of this possibility led the REMOVAL research team to select this well-known generic drug for a CV study. The group decided to look at an intermediate marker of CV risk, carotid intima media thickness (cIMT), as a proxy for potential long-term cardioprotection. Adults ≥40 years-old with type 1 diabetes (n=428) were randomized to twice-daily metformin at a 1,000 mg dose (n=219) or to placebo (n=209), both on top of standard of care (which included insulin titration/adjustments). Treatment and data collection continued for three years, following an initial three-month run-in period of insulin optimization. The primary outcome was rate of progression of mean far wall cIMT at baseline, 12 months, 24 months, and 36 months. Secondary outcomes included A1c, LDL cholesterol, albuminuria, weight loss, insulin dose, and endothelial function. Rate of progression to maximal cIMT was a pre-specified tertiary endpoint.

Study Population

Alicia Jenkins, MD (University of Sydney, Australia)

REMOVAL studied 428 middle-aged adults with long-standing type 1 diabetes at high risk of cardiovascular disease, as defined by three or more risk factors (including BMI >27 kg/m3, A1c >8%, known cardiovascular or peripheral vascular disease, current smoker, high blood pressure, high cholesterol or triglycerides, strong family history of cardiovascular disease, or diabetes duration >20 years). Baseline characteristics were well-balanced between the metformin and placebo-treated arms in terms of age (55 and 56 years), diabetes duration (33 and 34 years), BMI (28 kg/m3), A1c (8.1% and 8.0%), total daily insulin dose (0.63 and 0.68 units/day), frequency of prior cardiovascular disease (14% and 11%), blood pressure (systolic: 130 and 129 mmHg; diastolic: 73 and 72 mmHg), and cholesterol (LDL=85 mg/dl and HDL=62 mg/dl for both groups). Notably the study population had high rates of retinopathy: only 12% of participants in the metformin arm and 8% of participants in the placebo arm had no form baseline retinopathy, with the rest of the population showing high incidence of non-proliferative diabetic retinopathy (64% and 63%), inactive proliferative diabetic retinopathy (16% and 19%), and proliferative diabetic retinopathy (7% and 9%). On the renal front, the majority of participants in the metformin and placebo arms alike had normal eGFR (58% and 62%), though there was some incidence of stage 1 CKD (11% in both groups), stage 2 CKD (27% vs. 23%), and stage 3a CKD (3% and 4%). Furthermore, the study population had high usage of statins (82%), antihypertensives (73%), and anti-platelet drugs (39%).

Glycemia

Irene Hramiak, MD (St. Joseph’s Healthcare, Ontario, Canada)

Dr. Irene Hramiak took the stage to discuss the impact of metformin on A1c and insulin dose in the three-year REMOVAL trial. From a baseline of 8%, patients on metformin experienced a mean A1c decline 0.24% greater than patients on placebo after three months (p<0.0001). After 36 months, this treatment difference was 0.13% in favor of metformin (p=0.006), though A1c had risen above baseline for both groups. Dr. Hramiak characterized this effect as “small, but highly statistically significant,” calling attention to the steep slope of glucose-lowering in the first three months, even though the benefit appeared to dissipate with follow-up.

  • Average daily insulin dose grew for participants in the placebo arm but decreased for participants in the metformin arm over three years, culminating in a “modest” treatment difference of 1.9 units/day (p=0.0018). Of note, a majority of patients enrolled in REMOVAL (58%) were on a background of basal bolus therapy, while 33% were on an insulin pump, 3% were on twice-daily basal insulin, and 5% were on some other insulin regimen.
  • The hazard ratios for minor and severe hypoglycemia were 1.12 and 1.23 in favor of placebo at the 36-month mark, but neither of these reached statistical significance (p=0.259 and 0.442, respectively), leading Dr. Hramiak to conclude that metformin did not increase risk for hypoglycemia. While this is important data to report from a safety perspective, one of the reasons we’re pushing for better adjunct therapies in type 1 diabetes is that we want to lower a patient’s insulin dose and thereby reduce hypoglycemia – a point estimate in the “wrong direction” is somewhat disappointing in this context. We might’ve hoped for a significant hypoglycemia benefit in REMOVAL, but we recognize that insulin dose wasn’t drastically decreased with the addition of metformin by any means (Dr. Julio Rosenstock argued during Q&A, a change of ~two units per day is “absolutely nothing”). All in all, these glycemia results were disappointingly neutral. We’re hesitant to give up on metformin’s role in type 1 diabetes care and treatment algorithms (see the Q&A section below for a deeper dive on this topic), but as acknowledged by the REMOVAL investigators, and contrary to current guidelines, metformin did not offer a clinically-meaningful benefit to A1c on top of insulin therapy.

Primary Endpoint

Nishi Chaturvedi, MD (University College London, UK)

REMOVAL’s primary endpoint was mean carotid intima media thickness (cIMT), a commonly-used surrogate marker for cardiovascular risk. cIMT essentially reflects the thickness of the inner two layers of the carotid arteries (atherosclerosis) and can be measured by careful and quality assured noninvasive ultrasound techniques. Over the course of the three-year study, mean cIMT increased at a rate of 0.006 mm/year in the metformin-treated group vs. a faster 0.010 mm/year rate of increase in the placebo group, though this trend did not reach statistical significance (p=0.1664). However, the related tertiary outcome of maximal cIMT increased at a significantly slower pace in the metformin-treated group (0.012 mm/year) than the placebo group (0.25 mm/year; p=0.0093).  In biological terms, mean cIMT reflects overall thickening of the wall of the artery, while maximal cIMT, favored by the DCCT-EDIC investigators, includes areas of plaque and focal thickening.

Clinical and Metabolic Outcomes

John Petrie, MD (University of Glasgow, Scotland)

Dr. John Petrie, primary author of the study, presented secondary endpoint data. From a baseline 84 kg (185 lbs), body weight decreased for patients on metformin and increased for patients on placebo, leading to a treatment difference of 1.2 kg (2.6 lbs) sustained over three years (p<0.0001). Metformin also demonstrated positive effects on LDL, which fell 5 mg/dl in the treatment group but remained flat in the placebo group at year three (p=0.0117) and on eGFR – this measure of renal function rose sharply for people on metformin in the first three months, and after 36 months showed a treatment difference of 4 ml/min/1.73m2 in favor of metformin (p<0.0001). In less positive news, metformin was not associated with a statistically significant benefit to retinopathy or to endothelial function.

  • The signals for weight loss and lipid-lowering efficacy support metformin’s current niche in type 1 diabetes care, in that many HCPs prescribe the generic drug to their type 1 patients to mitigate insulin-induced weight gain in those with overweight or obesity. During Q&A, Dr. Partha Karr shared that these findings provide some reassurance on how he runs his practice and when he turns to metformin for type 1, which is most often for a patient who also wants to lose weight or improve cholesterol. Looking at REMOVAL through this lens, the results still spotlight metformin’s value and utility in type 1 diabetes management, although they don’t bring to light any new benefits to CV biomarkers or glycemia.

Safety

Martijn Brouwers, MD (Maastricht University Medical Center, Maastricht, Netherlands)

Dr. Martijn Brouwers stepped up next to discuss additional safety outcomes of interest. Treatment discontinuation was significantly higher among participants treated with metformin (41 cases, amounting to 27%) than placebo (19 cases, amounting to 12%; p=0.0002), and accordingly total adverse events occurred significantly more frequently in the metformin-treated group (27% vs. 12%; p<0.001). As expected with metformin, gastrointestinal issues were the most commonly reported adverse events, occurring in 16% of metformin-treated patients versus 3% of those in the placebo group (p<0.001). Additionally, vitamin B12 deficiency occurred significantly more frequently in the metformin-treated group (12%) than the placebo group (5%), translating to a significant elevation in vitamin B12 deficiency risk (HR=2.76; p=0.0094). Dr. Brouwers noted that vitamin B12 deficiency is a known side effect of metformin; the long-term effects of this kind of vitamin B12 deficiency are unclear but if undetected may include aggravation of sensory neuropathy. The REMOVAL data add to a body of evidence that Vitamin B12 should be monitored  during long term metformin therapy: this is rarely done in routine clinical practice.  Finally, there was no increase in hypoglycemia between either treatment arm, and serious adverse events were equivalent between the metformin group (16%) and placebo group (15%).

Conclusions

Peter Rossing, MD (Steno Diabetes Center, Copenhagen, Denmark)

Dr. Peter Rossing provided a helpful summary of the conclusions from each presentation that came before his. He emphasized that REMOVAL is the largest and longest trial of metformin in type 1 diabetes, and that it’s the first RCT to look at an intermediate variable for CV outcomes (this has to do with feasibility, since a traditional CVOT for metformin in type 1 is currently considered too large an investment for diabetes funding agencies). Despite an underwhelming result on the primary endpoint, Dr. Rossing positioned the statistically significant benefit to tertiary endpoint (maximal cIMT) as an exciting piece of data, perhaps one to explore further. He reiterated the significant benefits to metformin in terms of weight loss and (modestly) reduced insulin dose. REMOVAL results do not support the assertion in current treatment guidelines that metformin causes a clinically-meaningful improvement in glycemic control, Dr. Rossing explained, but they do suggest that metformin could have a broader role in CV risk management due to the weight loss, LDL-lowering, and slower progression to maximal cIMT. This latter point is a bold claim for clinical trial purists, since metformin did not show statistical significance on the primary endpoint of rate of progression to mean cIMT. That said, there have been no cardiovascular outcome trials to date in type 1 diabetes, so we agree with the Commentary in the Lancet Diabetes and Endocrinology that hope is still alive for metformin in better management of type 1 diabetes/CV complications.  For one, the generic drug is not going anywhere anytime soon, and it’s a widely-accessible therapy known to be effective in type 2 diabetes. In addition, we’d love to learn more about how elements of trial design could have skewed or muted efficacy findings. For example, a majority of participants were already well-treated with statins and blood pressure-lowering medications at baseline (which will be hard to avoid in selecting a real-world patient population), and this may have made it more difficult to demonstrate statistically significant benefit on a CV biomarker. Dr. Bill Tamborlane, who chaired the symposium, hinted during Q&A that cIMT may not be the ideal surrogate for CV outcomes, since it didn’t appear after six years of DCCT follow-up and thus may not be sufficiently “timely.” Another point raised during Q&A was that cIMT was already quite “favorable” at baseline, which may have made it more challenging to show an simprovement. These ideas are purely speculative right now, and we’ll leave it to the statisticians and other thought leaders to weigh in on REMOVAL at future meetings. Dr. Petrie announced that there will definitely be another symposium dedicated to this type 1 trial at EASD 2017 in Lisbon, Portugal.

Perspective

As commentator, Dr. Naveed Sattar set out to contextualize the REMOVAL results. He set the stage with a discussion of cardiovascular disease in type 1 diabetes. Recent data from a Swedish registry study demonstrates that individuals with type 1 diabetes and no CV risk factors have an 82% greater risk of a CV event than their counterparts in the general population – and yet there are no CV disease primary outcome studies in type 1 diabetes. Against the backdrop of this severe unmet need, the implications of the REMOVAL trial are frustratingly unclear. In Dr. Sattar’s view, a CV benefit is “suggestive but not conclusive” in REMOVAL, making it very unclear whether metformin should be recommended to people with type 1 diabetes to slow the progression of CV disease. On whether further trials are warranted to assess metformin for CV disease in type 1 diabetes, Dr. Sattar was torn. Though metformin is inexpensive and generally safe, making for relatively easy logistics, it seems as though other adjunct therapies (such as SGLT-2 inhibitors and GLP-1 agonists, which have demonstrated cardioprotective effects in type 2 diabetes) are better positioned for this large-scale investment of time and resources (though we’re less optimistic about the future of GLP-1 agonists in type 1 diabetes, given the safety signals in the ADJUNCT trials for liraglutide – though we believe some of this may have been due to trial design and dosing decisions). During Q&A, SGLT-2 inhibitors in particular were highlighted for their potential in type 1 diabetes and the chance that they may confer superior glycemic and CV benefits over metformin. We’re intrigued by this possibility, and we’re closely following Lilly/BI’s and AZ’s and Lexicon’s phase 3 programs for an SGLT-2 in type 1 and/or an SGLT-1/2. Despite REMOVAL’s somewhat underwhelming results, Dr. Sattar closed by reminding the audience of the significance of this undertaking as the single largest and longest randomized trial ever to examine a CV parameter of any sort in type 1 diabetes. We certainly hope it isn’t the last and to the point raised in Q&A, big funds are needed to invest in this (but that are a pittance compared to funds spent each year on avoidable complications).

Panel Discussion

Dr. Bill Tamborlane (Yale University, New Haven, CT): You talked a lot about LDL changing. I’d like to think about what wasn’t said. What happened to HDL?

Dr. Petrie: We saw very similar changes.

Q: One of the things that determines ability to see changes in cIMT is baseline cIMT. Your patients, I have to say, were extremely well-treated at baseline. To what extent do you think that messed up your power calculation? It’s hard to show improvement in endothelial function, as well, if at baseline you already have good endothelial function.

Dr. Hramiak: That’s a good point, that baseline cIMT was favorable. These patients were actually surprisingly well-treated on statins and blood pressure-lowering medications. Certainly, baseline values were lower than expected, and then rate of progression for mean cIMT was lower than anticipated from data from younger DCCT-EDIC patients and from other conditions.

Comment: Of course, because that’s where the lesion is. I recall another study that had low cIMT at baseline and the group made an incorrect negative conclusion about ezetimibe. You’re hurt by this in REMOVAL, I think.

Q: Are these participants a selected group of survivors? They have 32-33 years of T1D…what fraction of people would have already died of CVD before this time point?

Dr. Colhoun: By definition all cohorts are survivor cohorts, unless you begin the study from birth. If you’re asking if this was a population that was depleted of events – I don’t think so. A more interesting question is why in a population where event rates are fairly substantial do we not see substantially abnormal cIMT.

Q: cIMT is like tree rings, so the effect should persist. Will there be a data registry for these participants to see if the changes in cIMT we see at three years will become meaningful later?

Dr. Petrie: We have approval to follow these patients up in longer term. It will take a long time, but we certainly got that approval. As you say, they’re no longer on randomized treatment so we would be looking for a “metabolic memory” effect.

Dr. Julio Rosenstock (UT Southwest, Dallas, TX): I want to commend all the investigators. It takes a lot of work to do these kinds of studies, especially with a retinopathy component. There’s a real need for adjunct therapy in type 1 diabetes. But looking at the results of this trial, I basically see a negative study from all perspectives, not just the primary endpoint. You’re being generous on a potential reduction in CV events based entirely on a tertiary outcome. You’re using the word “modest” too much – two units is absolutely nothing in terms of reduced insulin dose. Yes, metformin is out there and it costs $2 at Walmart. But we need to raise the bar. This study would have been promising 10 years ago, when we didn’t have any other options, but now the SGLT-2 class has potential in type 1 diabetes. I take your word that a CVOT will one day be necessary for type 1. I hope this stimulates potential for a large outcomes trial of SGLT-2 inhibitors in type 1 diabetes, but metformin was totally negative in this trial.

Dr. Colhoun: Raise the bar? What we actually need to do is raise the money. There has never been a CVD outcomes study in the type 1 diabetes population for this reason.

Dr. Rosenstock: I agree with that, but metformin is not the drug. An SGLT-2 inhibitor or GLP-1 agonist would be the drug – certainly not metformin.

Dr. Colhoun: In our paper in Lancet we are certainly not claiming that this is a positive trial. We need a sustained and substantial effort to really drive forward a much higher standard and larger trials with CVD endpoints in type 1 diabetes. We spent a lot of time trying to raise the money to do a CVD outcomes trial with metformin, and it was extremely challenging. Let’s hope it happens someday. What we have done in this trial is create a very good network to show that trials  with a cardiovascular focus can be done in T1D, which is something people have been skeptical of.

Dr. Tamborlane: In the DCCT after six years of follow-up, cIMT differences were basically zero. This speaks to an issue about choice of surrogate outcome. Carotid thickening may not be timely enough to be able to show an effect.

Dr. Petrie: Ultimately, this is the study we designed after a lot of workshop with JDRF, and this is the outcome we chose. Treatment guidelines in the US and UK say you should use metformin for people who have type 1 diabetes and obesity to try and improve their glycemic control. One message from REMOVAL is that you should not – there’s not much of an effect on glucose control. It’s transient, though it’s statistically significant. So, REMOVAL changes our perspective on metformin for type 1 diabetes, pointing us to maybe investigate more cardiovascular effects.

Q: Did you look at sex differences within the groups? I ask because in the T1D Exchange study, the boys had an improvement but the girls did not (and the boys were more abnormal at baseline so maybe had more room to change).

Dr. Petrie: We haven’t looked into that, but we could do it easily.  We need to prioritize a few key post hoc questions so as not to over-interpret the subgroups -  this could be a good one.

Q: From a clinician’s perspective, why was metformin chosen and not an alpha-glucosidase inhibitor?

Dr. Petrie: As you know there is a large CVOT involving alpha-glucosidase inhibitors going on in China right now led by the Oxford group, with results expected reasonably soon. The study includes people with prediabetes.  In my view, there’s not enough data on alpha-glucosidase inhibitors in type 1 diabetes to justify this kind of trial. All these hypotheses are interesting and we’d love to see many trials for cardiovascular outcomes associated with different agents in type 1 diabetes – in fact we’d like to see any trial assessing this in type 1 diabetes – but if one trial is to be done it will likely be with an SGLT-2 inhibitor, if phase 3 data in type 1 diabetes is promising and shows adequate safety.  (Editor’s note – we’d love to see a CVOT with multiple therapies.)

Dr. Partha Kar (Portsmouth Hospitals, UK): Based on these results, as clinicians, would you prescribe metformin to your patients with type 1 diabetes at high CV risk?

Dr. Hramiak: Probably not. I’m more convinced that in adolescents who are more insulin-resistant and who have weight issues, we should prescribe metformin because they’ll see more benefit in terms of minimizing insulin dose. Hypoglycemia is a huge limiting factor of insulin, which is why we’re looking for adjunct therapies in the first place. Weight loss is also ideal. But to Dr. Rosenstock’s point: adjunct therapies in type 1 to-date have had trouble proving glycemic benefits beyond 0.2-0.3% A1c reductions, so we’re looking for something other than glycemic benefits. We have to combine outcomes as we did in this trial – it’s not just about glycemia, and it’s not just about CV disease.

Dr. Sattar: What would you do?

Dr. Kar: I already use metformin in the way you describe, so I don’t think REMOVAL will change my practice. Right now, I use metformin in type 1 patients who are overweight, so this just gives me more reassurance. I wasn’t expecting a huge CV benefit per se, and I think cIMT is an ambitious endpoint for a three-year study. But I won’t say this is a completely negative trial, because it confirms my use of metformin in the patients I’ve got.

Dr. Tamborlane: Metformin seems to have some effect, but its borderline. GLP-1 agonists are also being studied in type 1 diabetes. You really get substantial weight loss with these agents which may have an advantage that goes beyond just glycemic control. Another great hope is SGLT-2 inhibitors. It’s been a challenge to find drugs with cardioprotective effects for people with type 1 diabetes, but we’re still hoping that the holy grail is out there somewhere.

Dr. Chaturvedi: Is cIMT a poor outcome since it’s a surrogate? At the moment it is one of the best surrogates we have for cardiovascular endpoints that both predicts endpoints and can be employed easily in large clinical settings. We were not expecting an effect on cardiovascular risk through glycemia lowering alone, we were anticipating pleiotropic effects. Lastly, the effects we saw in the cIMT measures in this trial were actually greater than those shown in the DCCT trial. The DCCT trial saw modest effects on cIMT but quite striking reductions in cardiovascular outcomes ultimately. This is to say that it’s a bit unfair to criticize the endpoint we used. The effects on cIMT we saw here aren’t completely negligible.

Dr. Tamborlane: A lot of these patients were on statins, and a lot were on anti-hypertensive medications. We saw very little use of these agents in the DCCT. It’s hard to parse what the confounding effects of these other drugs may be. I would also suggest that another mistake is calling this study “REMOVAL,” because you didn’t remove anything. Maybe you should have called it the SLOW IT DOWN study.

Q: Did you compare the results between people who were obese vs. non-obese at baseline?

Dr. Petrie: These data are quite fresh, so we haven’t looked into that yet. This could be one to prioritize for post hoc analysis – we will present theses at EASD.

Dr. Calhoun: I take your point that DCCT-EDICT trial did in the end teach us about cardiovascular endpoints, but we can’t realistically wait 30 years to see if diabetes drugs have an impact on cardiovascular disease. The take-home message is that we’re trying to cut short answers to these big questions by doing small studies in type 1 diabetes with surrogate outcomes like cIMT. This will probably not resolve our clinical equipoise sufficiently, but it does tell us something. Perhaps Dr. Rosenstock is actually going to raise the money to do a large CVOT.

Q: The 1,000 mg dose of metformin isn’t particularly big, and it’s a lot less than what was used in DCCT and UKPDS. Is there any plan to do a protocol analysis on dose?

Dr. Petrie: I think we can do an analysis like that. We have an estimate of the dose of metformin taken by each participant over their time in the study based on tablets distributed and  returned. An important clinical message: when you give people 2,000 mg of metformin, you’re actually giving them less, because some patients will experience gastrointestinal adverse effects. We could look at subgroups of patients who tolerate metformin better. If you’re not experiencing side-effects (especially GI), and metformin might improve your CV risk profile and it might control your weight, why not take it?

Dr. Tamborlane: This has been a great discussion with terrific questions – one of the more enjoyable sessions I’ve been at.

Oral Presentations: GLP-1s and SGLT2s—To Do or Not to Do in Type 1 Diabetes Mellitus?

Twenty-Four-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem1)

John Buse, MD (UNC, Chapel Hill, NC)

UNC’s Dr. John Buse presented full data from the phase 3 inTandem1 trial, elucidating the benefit-risk profile of SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. inTandem1 was a double-blinded trial that randomized 793 patients to either placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg. The trial included a six-week insulin optimization period prior to randomization. As was reported in the topline results, even in the context of optimized insulin, the trial impressively met its primary endpoint by producing a mean placebo-adjusted A1c reduction of 0.35% in the 200 mg arm (baseline A1c post-optimization=7.6%; p<0.001) and 0.41% in the 400 mg arm (baseline A1c post-optimization=7.6%; p<0.001) at 24 weeks. inTandem1 employed a hierarchical statistical testing structure, in which secondary endpoints were assessed in the following order: (i) “net benefit” (defined as target A1c<7% with no severe hypoglycemia or DKA); (ii) weight; (iii) bolus insulin dose; (iv) fasting plasma glucose (FPG); and two measures of patient-reported outcomes – (v) the Diabetes Treatment Satisfaction Questionnaire status (DTSQ) score; and (vi) the two-item Diabetes Distress Screening Scale (DDS2) questionnaire score. We previously learned from a second release of topline data from inTandem1 that the 400 mg dose demonstrated superiority to placebo for all of these secondary endpoints, while the 200 mg dose only demonstrated superiority for A1c, net benefit, and weight. Dr. Buse very excitingly provided new detail on these secondary outcomes. More than twice as many patients achieved net benefit on sotagliflozin 400 mg compared to placebo: 44% of participants in the 400 mg arm achieved “net benefit” at week 24, compared to just 22% of those in the placebo arm (p<0.001). Those in the 200 mg arm also substantially more likely to achieve net benefit – 34% (p=0.002 vs. placebo). As was shared in the topline results, patients taking sotagliflozin experienced a 1.6 kg (3.5 lbs) and a 2.7 kg (6 lbs) weight reduction at 24 weeks with the 200 mg and 400 mg doses, respectively – this compares to a mean weight gain of 0.8 kg (1.8 lbs) in the placebo group (p<0.001). The results shared today revealed that the superiority of sotagliflozin 400 mg for the other secondary endpoints was similarly highly statistically significant (p<0.001). On the other hand, Dr. Buse noted that there was some heterogeneity between the impact of the two doses on bolus insulin dose – while sotagliflozin 400 mg was associated with a statistically significant decrease in bolus insulin (p<0.001; exact dosages not shared), there was no statistically significant difference in bolus insulin dose among those treated with sotagliflozin 200 mg and those in the placebo arm. On the other hand, the p-value for the difference between the 200 mg arm vs. placebo was below 0.05 for FPG (p=0.036), DTSQ score (p<0.001), and DDS2 score (p=0.002). That said, because of the hierarchical nature of the statistical testing, Dr. Buse emphasized that these findings may only be characterized as “descriptive” rather than significant. While some more conservative clinical trial purists may make a big deal about this, we’re very, very pleased to see consistency between the 400 mg and the 200 mg dose for these very critical endpoints. We’re especially excited about the quantification of the quality of life and patient satisfaction benefits of this drug – anecdotally, we’ve heard rave review from patients with type 1 diabetes taking selective SGLT-2 inhibitors and we’re glad to see this backed up with hard data. Safety data was as reported in the topline results, with fairly balanced adverse event rates across all three arms, somewhat higher rates of DKA with sotagliflozin, and somewhat lower rates of severe hypoglycemia. While there is some concern in some quarters about type 1 patients taking this class, we don’t think there is a way to stop it – it may be valuable to look at gaps in therapy for type 1s in order to better understand patients taking SGLT-2s off label. We applaud Lexicon for collecting so many outcomes and hope that these will be standardized soon. 

inTandem1 Primary and Secondary Efficacy Endpoint Results

Endpoints

Sotagliflozin 200 mg (p-value vs. placebo)

Sotagliflozin 400 mg (p-value vs. placebo)

Placebo

A1c

-0.43% (p<0.001)                                 

-0.49% (p<0.001)

-0.08%

Net Benefit (proportion of patients with A1c<7% and no severe hypoglycemia or DKA)

34% (p=0.002)

44% (p<0.001)

22%

Weight

1.6 kg (3.5 lbs, p<0.001)

2.7 kg (6 lbs, p<0.001)

0.8 kg (1.8 lbs)

Bolus insulin

Undisclosed (p=0.10)

Undisclosed

Undisclosed

Fasting plasma glucose (FPG)

Undisclosed (p=0.036)

Undisclosed (p<0.001)

Undisclosed

Patient-reported Diabetes Treatment Satisfaction Questionnaire status (DTSQ) score

Undisclosed (p<0.001)

Undisclosed (p<0.001)

Undisclosed

Patient-reported Diabetes Distress Screening Scale (DDS2) score

Undisclosed (p=0.002)

Undisclosed (p<0.001)

Undisclosed

inTandem1 Safety Results

 

Sotagliflozin 200 mg

Sotagliflozin 400 mg

Placebo

Proportion of patients with ≥1 treatment-emergent adverse events

67%

71%

68%

% patients with diarrhea

7%

10%

7%

% patients with genital mycotic infection

6%

10%

3%

Number of patients with DKA

3 (1.1%)

8 (3.1%)

0

Number with severe hypoglycemia

11 (4.2%)

12 (4.6%)

  1. 6.7%)

A 12-Week Dose-Ranging Study of Sotagliflozin, a Dual SGLT-1 and SGLT-2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem4)

Paul Strumph, MD (Lexicon Pharmaceuticals, The Woodlands, TX)

Lexicon VP of Clinical Development Dr. Paul Strumph also took to the stage to discuss full results from the phase 2 dose-ranging inTandem4 study of sotagliflozin. The double-blinded, 12-week trial randomized 141 patients with type 1 diabetes to three doses of sotagliflozin (75 mg, 200 mg, or 400 mg), plus placebo. Unlike the phase 3 inTandem1 trial, inTandem4 only included a two-week placebo run-in period, rather than a six-week insulin optimization period.  The vast majority of the numeric data was already shared in the topline results, though Lexicon shared p-values for the first time, demonstrating that these results were highly statistically significant. The primary endpoint A1c results as well as the secondary urinary glucose excretion, postprandial glucose, body weight, fasting plasma glucose (non-inferior), and blood pressure results are summarized in the table below. Very notably, however, Lexicon shared data on beta-hydroxybutyrate (BHB) levels at baseline and at week 12 – as a measure of ketogenesis, BHB measurements are very helpful as we consider the potential DKA risk of sotagliflozin. Notably, the mean increase in blood BHB at week 12 was only 0.1 mmol/l, which is the lowest value detectable by a point of care BHB meter. Dr. Strumph also noted that this level of BHB increase is lower than what is typically seen with selective-SGLT-2 inhibitors. Overall incidence of DKA was very low this trial, with the only case of DKA in the entire trial occurred in the 400 mg arm – though, very notably, the patient who experienced DKA chose to continue the study after the event, demonstrating that the perceived benefits outweighed the DKA risk for this patient. Although just one case, this is unsurprising to us. The level of DKA observed in both inTandem4 and inTandem1 is somewhat lower in all arms than might be expected in a general type 1 diabetes population. Dr. Buse noted during Q&A following the inTandem1 presentation that all participants in the trial were very carefully and intensively educated on DKA risk management. Our sense is that this level of intensive education rarely happens in the “real-world,” and we hope that Lexicon will continue its leadership in pairing sotagliflozin with appropriate educational efforts when the product launches. Write Richard Wood of dQ&A for more on overall level of understanding by patients of DKA and DKA risk.

inTandem4 Primary and Secondary Efficacy Endpoint Results

Endpoints (placebo-adjusted for all efficacy endpoints)

Sotagliflozin 75 mg (p-value vs. placebo)

Sotagliflozin 200 mg (p-value vs. placebo)

Sotagliflozin 400 mg (p-value vs. placebo)

A1c

-0.25% (p=0.07)

-0.48% (p<0.001)

0.38% (p=0.006)

Urinary glucose excretion (g/day)

42 (p=0.006)

58 (p<0.001)

70 (p<0.001)

Change in 2-hour postprandial glucose reduction (mg/dl)

-20 (p=0.27)

-27 (p=0.15)

-49 (p=0.006)

Body weight

-1.3 kg (2.9 lbs; p=0.38)

-2.4 kg (5.3 lbs; p<0.001)

-2.8 kg (6.2 lbs; p<0.001)

Change in fasting plasma glucose (mg/dl)

-9 (p=0.51)

-9 (p=0.48)

-21 (p=0.10)

Change in systolic blood pressure (mmHg) in subgroup of patients with baseline ≥130 mmHg

-8.4 (p=0.26)

-6.8 (p=0.28)

-14.3 (p=0.013)

inTandem4 Safety Results

 

Sotagliflozin 75 mg

Sotagliflozin 200 mg

Sotagliflozin 400 mg

Placebo

Proportion of patients with ≥1 treatment-emergent adverse events

48.6%

28.6%

34.3%

50%

Number of patients with diarrhea

0

1

1

0

Number with genital mycotic infection

1

1

1

0

Number with DKA

0

0

1 (2.9%)

0

Number with severe hypoglycemia

1 (2.9%)

1 (2.9%)

1 (2.9%)

0

Efficacy and Safety of Liraglutide in Insulin-Pump-Treated People with Type 1 Diabetes: The Lira Pump Trial

Thomas Dejgaard, MD, PhD, Kirsten Nørgaard, MD, and Christian Frandsen, MD, PhD (Copenhagen University Hospital, Hvidovre, Denmark)

A team of researchers from Copenhagen University Hospital (Hvidovre, Denmark) presented the results of the highly-anticipated Lira Pump Trial demonstrating the clinical potential of the GLP-1 agonist liraglutide as an addition to insulin pump treatment in people with type 1 diabetes. People with type 1 diabetes using CSII and with overweight (n=44) were randomized to receive liraglutide 1.8 mg or placebo in addition to regular insulin pump therapy for 26 weeks. Dr. Thomas Dejgaard outlined the positive primary outcomes: compared to placebo, liraglutide as an add-on to insulin pump treatment produced significant improvements in A1c (-0.6% vs. +0.2%; p<0.001) and weight loss (-7.3 kg [16.1 lbs] vs. -0.6 kg [1.3 lbs]; p<0.001) without increasing the time spent in hypoglycemia (3.2 vs. 3.5 events; p=0.77). While the A1c reduction could be characterized as modest for a GLP-1 agonist, we’re especially impressed by the reduction from a presumably low baseline A1c combined with the substantial weight loss. As expected for a GLP-1 agonist, nausea was the most commonly reported adverse event for participants randomized to the liraglutide treatment arm; 64% of participants experienced this, though it was transient and disappeared over the first few weeks of the study (we’d love to better understand the experience and intensity of nausea since this percentage isn’t that helpful overall). Currently approved for type 2 diabetes (under the trade name Victoza) and obesity (under the trade name Saxenda), these results underscore the potential of liraglutide for type 1 diabetes as well.

  • Dr. Kirsten Nørgaard followed with a deeper dive into the impact of add-on liraglutide to insulin dosing and time-in-range. Excitingly, liraglutide as an add-on to insulin pump therapy gave participants significantly more time spent in the normoglycemic range (57% vs. 45%) – a crucial outcome for patient quality of life and perceived therapeutic and personal success. That said, there was no statistically significant difference in time spent in hypoglycemia (defined as <3.9 mmol/l [70 mg/dl]). Very surprisingly (shockingly), liraglutide also produced no change in total daily dose of insulin; it is less surprising that the distribution between basal and bolus insulin also wasn’t changed.
  • Dr. Christian Frandsen closed with a closer look at the effect of liraglutide on weight loss. In addition to producing significant reductions in the primary outcome of body weight, liraglutide also produced reductions in a number of more specific measures of body composition, including total fat, android fat, gynoid fat, and total lean mass. The mechanism of this effect is unclear but likely is not related to food preferences. As revealed by food preference surveys given throughout the study, liraglutide did not appreciably impact food preferences.

Questions and Answers

Q: Your group has already presented nice studies in obese and non-obese people with type 1 diabetes on MDI. What is different about this CSII population that the outcomes are so much better?

A: The A1c reduction in liraglutide treated patients were exactly the same (0.6%) between these trials. The major difference is that here we didn’t see an appreciable A1c change in the patients in the placebo arm, whereas we saw a -0.4% A1c reduction in the placebo arm in the other studies, leaving no significant difference between the treatment and control groups.

Q: Why the choice of a 1.8 mg dose of liraglutide? You showed very impressive weight loss – is this because people with type 1 are more sensitive to the drug? Did any participants need a reduction in dose?

A: I don’t think it’s true that people with type 1 diabetes are more sensitive to liraglutide. A few patients had to reduce to a 1.2 mg dose to minimize nausea side effects.

Q: Do you think these improvements you’re seeing are due to weight loss?

A: A large part of it could be the weight loss, that’s possible.

Oral Presentations: ADA Presidents Oral Session

REMD-477, a Human Glucagon Receptor (GCGR) Antibody, Reduces Daily Insulin Requirements and Improves Glycemic Control in People with Type 1 Diabetes (T1D)

Jeremy Pettus, MD (UCSD, San Diego, CA)

Dr. Jeremy Pettus presented exciting phase 1 data demonstrating that a single dose of the human glucagon receptor (GCGR) antibody REMD-477 can produce substantial and long-lasting (weeks!) reductions in insulin requirements and improvements in glycemia and time-in-range in people with type 1 diabetes, without increasing hypoglycemia. In a double-blind study, people with type 1 diabetes (n=21) were randomized to receive a single subcutaneous injection of either 70 mg REMD-477 or placebo. One day following the injection, participants who received REMD-477 experienced a significant 21% reduction (9 units) in daily insulin dose compared to those who received placebo (p=0.02); this intensified to a 26% reduction (12 units) by the second day after the injection (p=0.02).  Furthermore, REMD-477 produced substantial reductions in average daily blood glucose concentration not days but weeks after the injection. For people in the treatment arm, average glucose fell 27 mg/dl in the first week post-injection (p<0.0010), -31 mg/dl in the second week (p=0.05), and -20 mg/dl in the third week (p=0.05). REMD-477 further produced substantial increases in time-in-range. In the week following the injection, participants on REMD-477 spent 71% of their time in normoglycemia (70-180 mg/dl), versus 56% for those on placebo (p=0.0001), and the effect persisted into the second week post-injection (70% time-in-range with REMD-477, versus 57%; p<0.05). This increased time spent in normoglycemia with REMD-477 was driven by reductions in hyperglycemia; importantly, hypoglycemia did not increase with REMD-477. Although the mechanism of action of this candidate is not yet understood, Dr. Pettus presented evidence that a single dose of REMD-477 produces long lasting elevations in plasma glucagon and GLP-1 that don’t return to baseline until 57 post-injection. Adverse events were infrequent and minor (headache, oropharyngeal pain, etc.) and did not substantially differ between the REMT-477 and placebo groups (11 vs. 10 events), indicating a good safety profile for this candidate. We are very moved by the sheer timescale of REMD-477’s powerful actions and eager to learn more about the upcoming phase 2 study, which according to Dr. Pettus will examine the effect of multiple weekly doses of the peptide drug. For good reason Dr. Pettus’ presentation was certainly one of the most highly-anticipated highlights of the President’s Oral Sessions – the very final event of ADA, highlighting particularly notable late-breaking abstracts – and we will be watching the progress of this work very closely. Although this work is clearly in its earliest stages, REMD-477 is a perfect exemplification of a patient-friendly diabetes therapy that optimizes important outcomes beyond A1c – namely time-in-range and a vastly reduced injection burden.

Oral Presentations: New Insights into Prevention and Treatment of Hypoglycemia

Nasal Glucagon for the Treatment of Moderate-to-Severe Hypoglycemic Episodes in Real-World Settings in Adults with Type 1 Diabetes

Elizabeth Seaquist, MD (University of Minnesota, Minneapolis, MN)

Dr. Elizabeth Seaquist presented positive real-world data on Lilly’s phase 3 nasal glucagon, showing that 96% of patients experiencing hypoglycemia recovered within 30 minutes following treatment and that most of the caregivers were highly satisfied with the device. The study enrolled 129 adults with type 1 diabetes, and 69 of these participants experienced a total of 157 symptomatic moderate or severe hypoglycemia events (a blood glucose of approximately <60 mg/dl or requiring assistance) during the course of the study. For 151 of these episodes (96%), a 3 mg dose of nasally-delivered glucagon met its primary endpoint of “awakening or returning to normal status” within 30 minutes, as determined by a caregiver. For five of the remaining six events, caregivers noted recovery within 45 minutes, and in four of these instances, the patient’s blood glucose was ≥70 mg/dl 30 minutes after administering nasal glucagon. These are impressive results in a real-world setting, confirming what Locemia showed in phase 3 RCTs (Lilly acquired this pipeline product from Locemia in October 2015). A majority of caregivers, 70%, were able to deliver nasal glucagon to a patient experiencing hypoglycemia within 30 seconds, while 98% were able to do so in <2 minutes – what an exciting and much-needed improvement to the lengthy reconstitution process of existing glucagon options. Overall, 94% of caregivers were satisfied with nasal glucagon, including 56% giving it the highest “very satisfied” score. Dr. Seaquist emphasized that no calls to emergency services were made for any of the 157 hypoglycemia episodes, not even for 12 cases of severe hypoglycemia when patients were unconscious or experiencing convulsions or mental disorientation. Impressively, nasal glucagon met the study’s primary endpoint of recovery within 30 minutes in all 12 of these cases as well (experienced by seven participants), which supports the agent’s ability to rapidly raise dangerously low blood glucose in real-world settings. Though an FDA submission has taken longer than we expected since Lilly acquired the phase 3 product from Locemia (due to additional development work and establishing a manufacturing infrastructure), management shared in a separate interview with us that a filing is expected in 1H18, and the product will be submitted in other geographies shortly thereafter. The health and healtheconomic burden of hypoglycemia remains far too high, and we’re hopeful that advances like Lilly’s nasal glucagon will bring us leaps and bounds ahead in our ability to treat the complication. To that end, it’s extremely valuable to see real-world efficacy and feasibility data, since the immediate goal is to help patients/caregivers address hypoglycemia swiftly in everyday settings, avoiding an expensive hospital visit, emergency call, or need for a healthcare professional.

  • During a separate call with Dr. Seaquist and Lilly’s nasal glucagon team, we heard anecdotal evidence on caregiver responses to this innovative product: “it just makes so much sense to them.” Certainly, this intuitive ease of use is crucial for a product like glucagon, used often in high-stress emergency situations. Once nasal glucagon is available, we’ll be fascinated to see how the ease-of-use and satisfaction compares to upcoming auto-injectors in development (Xeris and Zealand, among others). 
  • According to Lilly management, the shelf life of this innovative product is anticipated to be comparable to current recombinant glucagon. We were happy to hear this, as it will be another pull for patients, providers, and payers. Cost is of course a big question with glucagon, and we so hope that this nasal glucagon is priced responsibly to maximize access to a superior, patient-friendly, cost-saving therapy. 
  • Locemia presented equally positive simulated usability data at EASD 2015, which also highlighted the simplicity of nasal delivery.

Effect of Ethanol Intoxication on the Antihypoglycemic Action of Glucagon

Laya Ekhlaspour, MD (Massachussets General Hospital, Boston, MA)

Dr. Laya Ekhlaspour, who at last year’s ADA discussed the merits of a bihormonal bionicpPancreas, now delves deeper into the practicality of micro-dosing with glucagon, presenting findings strongly suggesting that ethanol intoxication does not affect glucagon activity. In a random order crossover trial (n=15) using simultaneous hyperinsulinemic-normoglycemic and ethanol clamps, volunteers with type 1 diabetes were given two identical 50g injections of glucagon while sober and while intoxicated with a blood alcohol content of 0.1%, achieved by delivering the equivalent of 4 drinks in 20 minutes (we bet there are some pretty good stories!). Blood glucose rose following glucagon injection and then stabilized at 90 mg/dl for the duration of the study. Trends were similar in both arms of the study, indicating that ethanol intoxication does not alter glucagon activity and that micro-dosing with glucagon to reverse hypoglycemia is still a safe and effective option when a individual is intoxicated. However, Dr. Ekhlaspour did concede that liver glycogen levels were not recorded during the study, which, as one audience member pointed out, most likely contributed to the observed effect.  In the case of people with alcoholism (who are likely to be poorly nourished), reduced glycogen stores may limit the efficacy of glucagon to lower blood sugar. It should also be noted that with glucagon comes a huge additional cost and burden. Still, we take these results to be an encouraging step in the right direction regarding the pragmatism of a bihormonal bionic pancreas for everyday use.

Posters

Dasiglucagon, a Novel Soluble Glucagon Analog, Successfully Restores Blood Glucose Levels after Hypoglycemia in People with Type 1 Diabetes Mellitus (T1DM) (389-P)

T Heise, B Bysted, U Mouritzen, U Hovelmann, D Lamers, and D Moller

Zealand presented a poster detailing phase 2 results from a PK/PD study of its liquid-stable glucagon analog dasiglucagon. The trial compared four doses of dasiglucagon (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) to native glucagon (Novo Nordisk’s GlucaGen; 0.5 mg and 1.0 mg) in participants with type 1 diabetes (n=58), demonstrating that dasiglucagon, like native glucagon, was able to rapidly and effectively increase blood glucose concentration following a controlled, insulin-induced hypoglycemia event in which blood glucose fell to 55 mg/dl. On the pharmacodynamic front, the three highest dasiglucagon doses (0.3 mg, 0.6 mg, and 1.0 mg) each took a median of six minutes to raise plasma glucose levels to above 70 mg/dl, versus 6 and 7 minutes for the 0.5 mg and 1.0 mg doses of native glucagon, respectively (and 10 minutes for the 0.1 mg dasiglucagon dose). Dasiglucagon furthermore showed comparable performance to native glucagon in terms of the average time required to increase plasma glucose levels by 20 mg/dl; the four dasiglucagon doses (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) respectively took a median of 14, 10, 9, and 9 minutes to achieve this level of plasma glucose reduction, versus 10 minutes for both the 0.5 mg and 1.0 mg native glucagon doses. Notably, the increase in plasma glucose was longer-lasting and more pronounced with dasiglucagon: total plasma glucose excursions (as measured by area under the effect curve [AUE]) were significantly higher with 0.3 mg dasiglucagon versus 0.5 mg native glucagon (p<0.0001) and for both 0.6 mg (p=0.0043) and 1 mg (p<0.0001) dasiglucagon versus 1.0 mg native glucagon. This larger glucose excursion profile promisingly suggests that dasiglucagon may be superior to native glucagon at preventing recurrent hypoglycemia. On the pharmacokinetic front, dasiglucagon reached maximum exposure significantly later than native glucagon (~35 minutes; p<0.01), but demonstrated a significantly higher total exposure for all dose comparisons (p<0.001). In a separate conversation with Zealand, the company indicated that this could be suggestive of higher viability for dasiglucagon over native glucagon, meaning that dasiglucagon could achieve the same the same glucose increasing efficacy at lower doses – but of course this would need to be verified in future studies. Importantly, dasiglucagon was well-tolerated with a similar safety profile as native glucagon. For both dasiglucagon and native glucagon, the most commonly reported adverse events were nausea and vomiting (40 events with dasiglucagon, 35 events with native glucagon) and mild injection site reactions which disappeared within 30 minutes post-dosing (7 events with dasiglucagon, 5 events with native glucagon).

  • Following the release of these topline results in 3Q16, Zealand commented in its 4Q16 earnings update that the FDA is expected to provide guidance of dasiglucagon’s development in 1Q17. The candidate is currently in phase 2 development both as a single-dose rescue pen (phase 3 to begin as soon as 3Q17) and as a multi-dose component of a dual hormone artificial pancreas system. We are very pleased to see this progress toward a more patient-friendly and feasible alternative to the current very complex, error-prone native glucagon kits – a longstanding area for improvement in diabetes care. For more on the soluble glucagon arena more broadly, check out our soluble glucagon competitive landscape.

24-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT-1 and SGLT-2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes (inTandem2) (146-LB)

T Danne, B Cariou, P Banks, S Sawhney, P Strumph, and The Sotagliflozin inTandem2 Writing Group

The inTandem2 study demonstrated significant A1c reductions of 0.36% (200 mg dose) and 0.35% (400 mg dose) with sotagliflozin vs. placebo (p<0.001) in patients with type 1 diabetes on optimized insulin regimens (baseline A1c = 7.7-7.8% after insulin optimization). The company reported topline results from the study in December. The double-blind trial randomized 782 patients with type 2 diabetes to receive either placebo, 200 mg sotagliflozin, or 400 mg sotagliflozin for 24 weeks in addition to optimized insulin therapy. The study also included a double-blind long-term extension period of 24 weeks that is ongoing. In addition to the primary endpoint of A1c reduction at 24 weeks, investigators assessed a secondary endpoint of “net benefit”: the percentage of patients with A1c <7% at 24 weeks and no episodes of severe hypoglycemia or DKA during the study period. This endpoint was achieved by 32% of patients in both sotagliflozin groups vs. 15% of patients in the placebo group (p<0.001). While we appreciate seeing composite endpoints like these included in trials, as they are often more clinically relevant than A1c reductions alone, we understand from a regulatory perspective, there may need to be work standardizing them. In this case, while the significant difference vs. placebo is encouraging, the fact that less than a third of treated patients achieved the net benefit goal is somewhat disappointing. As for specific safety endpoints, rates of severe hypoglycemia were 3.8% with 200 mg sotagliflozin, 2.3% with 400 mg sotagliflozin, and 2.7% with placebo. DKA rates were 0.4% with 200 mg sotagliflozin, 1.1% with 400 mg sotagliflozin, and 0% with placebo.

Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes (67-LB)

M Rickels, S Dubose, H Wolpert, E Toschi, R Beck, M Cummins, BJ Newswanger, and MC Riddell

This phase 2 study compared Xeris’ G-Pen Mini glucagon vs. basal insulin reduction vs. glucose tabs as a way to avoid exercise-induced hypoglycemia, a persistent problem since the natural glucagon response is impaired in people with type 1 diabetes. Each trial participant (n=15) went through four conditions in a randomized crossover design: (i) control, (ii) 50% basal rate reduction five minutes prior to the start of exercise, (iii) oral glucose tabs (20 grams five minutes before start, and another 20 grams 30 minutes after start), and (iv) Xeris’ mini-dose glucagon injected subcutaneously into the abdomen five minutes prior to the start of exercise. The G-pen injection maintained plasma glucose levels between 125-175 mg/dl throughout the duration of exercise (45 minutes) and for 45 minutes after, while glucose tabs elevated blood sugar >225 mg/dl 45 minutes-post exercise. Basal insulin reduction was significantly less effective in avoiding hypoglycemia (p<0.001 vs. G-Pen), as mean plasma glucose dropped to ~75 mg/dl by the end of exercise and stayed low for 45 minutes after, which parallels almost exactly what happened on average in the control condition. In total, six people experienced hypoglycemia (defined by blood sugar <70 mg/dl) in the control condition, five in the basal rate reduction condition, and none in the mini-dose glucagon or oral tabs conditions. On the opposite end, five individuals experienced hyperglycemia (defined by blood sugar >250 mg/dl) in the oral tabs condition vs. only one in the mini-dose glucagon condition and none in the control or basal rate reduction conditions. These results show promising early efficacy for Xeris’ G-Pen Mini as a solution for exercise-induced hypoglycemia in type 1 diabetes – compared to control, basal insulin reduction, and oral glucose tabs, this mini-dose of glucagon minimized both hypoglycemia and hyperglycemia during and immediately after exercise. This study is particularly important since it also  shows how much more effective a small dose of glucagon is if given just before exercise, rather than waiting until hypoglycemia develops during exercise, the latter of which is repeatedly observed in duel hormone studies using glucagon in artificial pancreas  studies. The poster concludes that this phase 2 data supports a larger, longer-term study of Xeris’ G-Pen Mini, which we’d love to see. Xeris currently has one of the most advanced clinical programs for glucagon, and we’ll be watching eagerly for updates. See our glucagon competitive landscape for more information.

Efficacy and Safety of Mini-Dose Glucagon for Treatment of Nonsevere Hypoglycemia in Adults with Type 1 Diabetes (1068-P)

MW Haymond, S Dubose, MR Rickels, H Wolpert, VN Shah, JL Sherr, RS Weinstock, S Agarwal, AS Verdejo, MJ Cummins, B Newswanger, and RW Beck

Xeris’ G-Pen Mini was investigated in 17 adults with type 1 diabetes as a treatment for nonsevere hypoglycemia. In a randomized crossover design, participants spent three weeks with mini-dose glucagon and three weeks with oral glucose tabs to treat any cases of mild hypoglycemia. The primary endpoint of “success” was defined as blood glucose ≥50 mg/dl 15 minutes following treatment and blood glucose ≥70 mg/dl 30 minutes following treatment – 94% of patients in the mini-dose glucagon arm achieved success vs. 95% of patients in the glucose tabs arm. BGM and CGM data showed a similar profile for the G-Pen Mini vs. oral glucose tabs. In the first hour post-hypoglycemic event, people in the glucagon group spent 62% of time-in-range vs. 67% for people in the glucose tabs group (p=0.86). In the first two hours post-hypoglycemic event, participants in both groups spent a mean 79% of time-in-range (p=0.49). Time <70 mg/dl was a mean 35% for the glucagon group one hour post-hypoglycemia vs. 33% for the glucose tabs group (p=0.95). Two hours post-hypoglycemia, these values were 20% and 19%, respectively (p=0.63). The non-significant p-values indicate the G-Pen Mini’s non-inferiority vs. oral glucose tabs as a treatment for mild hypoglycemia, but the poster points out other distinct advantages to mini-dose glucagon: Namely, carbohydrates as a solution to nonsevere hypoglycemia lead to excess caloric intake and excess hyperglycemia, all of which could be avoided with Xeris’ G-Pen Mini. After six weeks of the study, participants were asked to choose between the two treatment options for an additional three weeks – ~50% opted to continue mini-dose glucagon. Injection discomfort and nausea were the primary reported adverse events associated with the G-Pen Mini, affecting 15 and three participants, respectively. Overall, these results support continued investigation of Xeris’ product for mild-to-moderate hypoglycemia, and we look forward to future data readouts. Xeris is an industry leader right now in the glucagon competitive landscape, and we’re very happy to see forward progress on the company’s various glucagon candidates.

Symposium: Preserving the Beta Cell Function

How Do We Protect the Beta Cell in Type 1 Diabetes?

Aaron Michels, MD (University of Colorado, Aurora, CO)

Dr. Aaron Michels from the University of Colorado Denver School of Medicine characterized type 1 diabetes as an immune-mediated disorder with beta cells actively contributing to disease pathogenesis. He discussed the stages of disease development, explaining that as of 2017, we are able to predict type 1 diabetes but we can’t effectively prevent it. Knowing what to target and monitor with immune therapies is critical. The study of human islet infiltrating immune cells provides disease-specific targets for immune therapies and suggests potential biomarkers for disease activity. Elucidating the immune-beta cell interface will help researchers devise strategies to protect beta cells. Dr. Michels highlighted that lobular beta cell destruction in the human pancreas, beta cells overexpressing HLA Class I, and blocked immune checkpoint inhibitors are all possible contenders leading to type 1 diabetes. The natural history of type 1 diabetes involves genetic risk, environmental triggers, beta cell injury, prediabetes, and diabetes. Attempts at beta cell preservation in people with type 1 diabetes have been minimally effective so far, but we are excited to continue following this important field.

Assessing Beta-Cell Function

Jerry Palmer, MD (VA Puget Sound Healthcare System, Seattle, WA)

Dr. Jerry Palmer reviewed multiple methods of assessing beta cell function in people with diabetes, or in those with prediabetes or presymptomatic type 1 diabetes. In this presentation, Dr. Palmer drew on data from both patients with type 1 and type 2 diabetes. He reviewed several different methods of assessing beta cell function, including measuring insulin secretion (particularly the amount and timing) and assessing proinsulin processing. He also acknowledged the statistical issues associated with measuring beta cell function. He closed by highlighting the Restoring Insulin Secretion (RISE) trial. While noting that it is still too early to draw conclusions from the trial, Dr. Palmer shared that the protocol of measuring beta cell function in the trial (via hyperglycemic clamps and oral glucose tolerance tests) is functioning well, based on the first few years of recruitment and early follow-up.

  • The delayed release of the C-peptide in response to oral insulin is an early indicator of risk for diabetes. The progression to diabetes is generally characterized by rising glucose levels accompanied by normal C-peptide levels at fasting glucose until about six months before the diagnosis. However, Dr. Palmer pointed to a study led by Jay Sosenko in the DPT-1 trial showed that when abnormalities in C-peptide response to oral glucose are measured, there is a delay in the response of those progressing toward a diagnosis compared to those who are not going at least as far back as 2 years (p<.01). 
  • Mixed meal tests (MMT) were found to be more reproducible and better tolerated than glucagon stimulation tests in two trials. When addressing the issues of statistical sensitivity, specific and reproducibility in assessing patients’ beta cell function, Dr. Palmer noted that both the TrialNet Study (n-148) and a European C-Peptide Trial (N=118) had conducted both these tests on the same recently-diagnosed patients and repeated them with in 3-10 days. There results showed that the MMT was more reproducible, better tolerated by patients with fewer adverse effects, and preferred. He stated the MMT was a stronger test and more sensitive to residual insulin secretion.

Questions and Answers

Q: If you had to choose which of the tests you demonstrated was the most highly sensitive for people, which would you use?

A: Firstly, it’s pretty well established that prior to diagnosis of type 1 we do glucose tolerance and then after do a mixed meal tolerance. I think what we need to do is model those two tests, maybe add some additional data points, such that we can get a measure of insulin sensitivity, so that whenever we talk about insulin secretion we do it in the context of how insulin sensitive patients are rather than absolute numbers.

Symposium: Technical Innovations in Islet Transplantation—Novel Approaches

Engineering Novel Encapsulation Platforms for Islets

Cherie Stabler, PhD (University of Florida, Gainesville, FL)

Dr. Cherie Stabler highlighted several novel beta cell encapsulation approaches that she views as particularly promising, including microencapsulation, nanoscale coatings, and new coatings created by covalent layer-by-layer encapsulation. She emphasized how these efforts can address several key considerations in the effort to fabricate nano-scale barriers to encapsulate pancreatic islets, such as ensuring a controllable thickness (through nanoscale control of capsule) and long-term mechanical stability (through covalently linking layers). According to Dr. Stabler, a “home run”  in encapsulation would involve resolving the immunological problem, the cell source problem, and the transplant problem. Islet encapsulation must solve issues of permeability, biocompatibility, and stability as well. The material must be permeable enough to allow nutrients such as glucose and oxygen to come into the islet and for insulin to leave the islet, while also being non-permeable to antibodies. Many materials degrade when put into the body, so the material must be stable enough to survive. In conventional microencapsulation, islets suffer from poor delivery of oxygen and nutrients, sluggish glucose response and insulin secretion, exacerbated by transplant site. ViaCyte has experienced some of these challenges firsthand in its phase 1/2 trial of PEC-Encap – due to the challenges with fibrosis and variable patient responses, the company has de-prioritized this effort to some extent and is instead focused on PEC-Direct, a direct vasculaization product that does not protect ViaCyte’s stem cell-derived islet progenitor cells from the immune system (requiring patients to take immunosuppressants. We’re so very glad that very smart people like Dr. Stabler are hard at work at creating next-generation encapsulation devices that can hopefully avoid some of the pitfalls of the first-generation efforts.

Bioengineering the Transplant Site―Application to Clinical Therapy

James Shapiro, MD, PhD (University of Alberta, Edmonton, Canada)

Dr. James Shapiro provided an overview of the current research to improve islet cell transplantation, concluding that bioengineering transplants is effective and that latest therapeutic cells are promising. He noted up front that while cadaveric islet cell transplantation via the Edmonton protocol (through the portal vein in the liver) are safe, simple, result in a predictable function of the C-peptide, and are therefore currently unmatched for efficacy. That said, he acknowledged that traditional transplantation through this method is not scalable, as it is not easy to procure donor cells, many cells are lost during the transplant (requiring multiple transfers), there is a risk of bleeding and clot, and retrieval is difficult. He highlighted several novel, alternative strategies, including: (i) bioengineering of the intra-abdominal endocrine pancreas; (ii) gastric submuscal transplantation of islets; (iii) device-less transplants; (iv) transplanted devices; (v) new cell products; (vi) cell product manipulation; and (vii) cell product co-transplantation. Dr. Shapiro concluded by cautioning that that vascularity and oxygen generation will need to improve in transplant sites outside of the portal vein before they become true alternatives, and that the “we may have to take a step back” from current portal efficacy as we improve these sites. ViaCyte in particular has experienced challenged with fibrosis and unpredictable, varied efficacy in its phase 1/2 trial of beta cell encapsulation product PEC-Encap. It’s clear that quite a few questions must be addressed before beta cell replacement and encapsulation become a viable type 1 diabetes cure therapy for the broader population.

  • Dr. Shaprio highlighted his research with ViaCyte’s stem cell-derived islet cell replacement therapies PEC-Encap and PEC-Direct , characterizing these efforts as some of the more promising cell therapies. PEC-Encap delivers beta cell progenitors through ViaCyte’s Encaptra device and showed some promise, though it the device was challenged by the body’s foreign body response. He is hopeful PEC-Direct, the new product from ViaCyte which allows for direct vascularization of implanted cells, will have better vascularization results and cell survival, though it will have to be taken with an immunosuppressant. PEC-Direct was recently approved for clinical trials by the FDA and Canada.
  • Dr. Shapiro also spoke briefly to new promising research in cell manipulation, specifically caspase inhibitors and apoptosis inhibitors. He expanded on the research he is doing with Conatus Pharmaceuticals into whether emricasan (IDN-6556) helps protect against allo- and autoimmunity of islet cell transplant recipients. Emricasan is also currently being developed by Conatus for NASH, in partnership with Novartis. Dr. Shapiro observed that in vitro manipulation of cells to confer protection can have a profound impact, and he is hopeful about where the research may go.
  • He also highlighted recent research in bioengineering the transplant site, citing the recent example of researchers utilizing the intraabdominal endocrine pancreas for a patient. In this case the single patient had 602,395 islet equivalents were combined with autologous plasma laproscopically layered onto the omentum. The patient came off insulin 17 days after her transplant, and continues to have stable glycemic control, though this was a recent procedure so long-term efficacy is not yet known.

Questions and Answers

Q: Very nice work and talk. In terms of bioengineering sites, you presented initial data but in terms of where this going when you move the data forward, any comment in terms of the end point you envision?

A: We move forward very slowly with this. Portal may be new for some but for us it’s established. We don’t want to expose patients to new approaches until we know there’s some promise, it doesn’t make sense to do this on 20 patients until we’ve seen it’s effective in a few. It is a tough balance between having a large base and not a large failure.

Symposium: Joint ADA/ISPAD Symposium—Current Status of Complications in Youth with Type 1 Diabetes

Update on Macrovascular Disease and Risk Factors—Time to be More Aggressive with Treatment?

David Maahs, MD (Stanford Children’s Health, Palo Alto, CA)

Cardiovascular disease (CVD) and the associated risk in patients with diabetes is an increasingly important topic and Dr. David Maahs made it clear that vigilance and aggressive steps are needed to rectify this association even in younger patients with diabetes. Dr. Maahs noted that although aggressive A1c control does not eliminate CV risk he would still like to see current progress on lowering A1c levels “move more quickly” as only 30% of pediatric patients are meeting A1c goals.  Citing data from the T1D Exchange that 69% of patients ages 6-13 and 62% of patients age 12-30 are not meeting LDL goals, Dr. Maahs reiterated that “we can do better” on cardiovascular outcomes in pediatric patients.  He contextualized this problem by stating that only 1% of pediatric patients is on lipid-lowering medication, giving us a sobering look at how urgent this problem could be in pediatric patients. Dr. Maahs did offer hope that artificial pancreas innovation would allow for better control of A1c levels and cited the SEARCH study that found that for every 1% change in A1c, there was a 4 mg/dl change in LDL levels. Dr. Maahs concluded with a look toward clinical trial data from a study with subjects taking atorvastatin for 6 months showing overall lower lipid levels and a “less atherogenic” cardiovascular profile. The AdDIT Study similarly showed that statins correct lipid abnormalities and show no adverse events. Dr. Maahs summarized by calling for improved screening, better treatment of risk factors to address CVD risk in adulthood, and more longitudinal studies of cardiovascular risk in pediatric patients.

Update on Retinopathy—Should We Screen or Not?

Kim Donoghue, MD (University of Sydney, Australia)

As part of a broader discussion on adolescent and youth complications in type 1 diabetes, Dr. Kim Donoghue provided a summary of the current, varied screening recommendations for diabetic retinopathy,  underscoring the need for quick diagnosis and subsequent intense treatment and metabolic control. Dr. Donoghue reviewed data from a number of studies that showed low to no prevalence of diabetic retinopathy in adolescents and contrasted this with a number of studies that did find higher rates. In a study conducted in the UK, Dr. Donoghue pointed out that 20% of individuals diagnosed with type 1 diabetes before age 2 had developped retinopathy by ages 12-13. This same study found that 9% of children with diabetes diagnosed at under 4 years of age had developed sight-threatening diabetic retinopathy by age 17-18. This was in contrast to studies done by the T1D Exchange, the University of Pennsylvania, and Yale University, which all found zero or very few pediatric patients with diabetic retinopathy. Dr. Donoghue attempted to explain this disconnect, pointing out that the investigations which found no prevalence of retinopathy featured larger proportions of younger adolescents, tracked subjects for shorter periods of time, and used tools that were not powerful to adequately detect retinopathy. Furthermore, recent data demonstrates higher hazard ratios for diabetic retinopathy patients with a longer duration of diabetes (1.6, 1.9, and 1.0 for diagnosis under age 4, between age 5-14, and age 15 or over, respectively). Taken together, these findings suggest that adolescents are at greater risk for diabetic retinopathy than we realize – especially if they have a long diabetes duration. Dr. Donoghue concluded by questioning whether our current recommendations for diabetic retinopathy screening are rigorous enough, asking what prevalence rate of diabetic retinopathy are we willing to accept and calling for increased research into the frequency of diabetic retinoapthy in children, using study cohorts that match the general population.

Symposium: Therapies to Preserve Beta Cells in Type 1 Diabetes (Supported by a grant from The Leona M. and Harry B. Helmsley Charitable Trust)

Therapy for Type 1 Diabetes – Short Treatment for Durable Benefit

Gerald Nepom, MD, PhD (Benaroya Research Institute, Seattle, WA)

Dr. Gerald Nepon discussed the potential role of short treatments with durable benefits in type 1 diabetes intervention. Overall, he noted that immunotherapies often have short-term efficacy, but lack durable and lasting outcomes. Previous therapies have been able to improve C-peptide outcomes temporarily for up to 18 months. However, cells will shortly resume decay after this time period at the original rate, resulting in a recurrence of disease. This transient effect of therapies on preserving beta-cell function is one of the largest challenges in creating therapy for type 1 diabetes. As a result, it may be beneficial to use a combination of therapeutic strategies that target T-cell memory. As an example of this, Dr. Nepom reviewed the findings from the phase 2 T1DAL study of anti-CD2 therapy alefacept, a drug that depletes effector memory lymphocytes. One-year and two-year results (presented at ADA 2013 and ADA 2015, respectively) observed that individuals taking alefacept experienced lower rates of hypoglycemiaduring and after the study, suggesting that the drug leads to durable effects and outcomes. That said, the study failed its primary endpoint of change in C-peptide AUC. Dr. Nepom concluded by emphasizing the importance of using multiple mechanism-informed strategies when creating therapeutic interventions. He further suggested that combination immunotherapy targeting T-cell memory is especially promising, due to T-cells’ ability to induce and stabilize remission and create transcriptional markers that stabilize phenotypes.

Questions and Answers

Q: Why did the incidence of hypoglycemic incidence decline?

A: The incidence of hypoglycemic incidence declined because the therapy cleared islet inflammation and allowed counter-inflammation to happen regularly.

Disease-Specific Therapy (Antigen-Specific Immunotherapy)

Carolin Daniel, PhD (Helmholtz Zentrum München, Munich, Germany)

Dr. Carolin Daniel began her talk by emphasizing the importance of immune tolerance restoration in type 1 diabetes. She presented an overview of an experiment that used humanized mice to see if regulatory FoxP3 T-cells (Tregs) could be generated in vivo. From the Tregs generated in humanized mice, methylation analyses of Foxp3 Treg-specific demethylated regions showed that the induced human Tregs from humanized mice were stable, functional, and prevented the development of type 1 diabetes. The implications of this finding are especially important for childhood type 1 diabetes, as higher frequencies of insulin Tregs may be linked to slower progression of the condition. Furthermore, there may be evidence suggesting that for children with islet autoimmunity, insulin-specific Treg cells may play an important role in the progression of type 1 diabetes. Dr. Daniel concluded by emphasizing the importance of future studies that increase our mechanistic understanding identified impairments in Treg induction and that better model islet autoimmunity in humanized mice.

  • Dr. Daniel described the process of in vivo human Treg induction in humanized mice. Tregs are induced in the mice through Greg conversion and subimmunogenic antigen stimulation. Greg conversion activated T-cells through agonist ligands, and human Tregs are induced through subimmunogenic stimulation. CD34+ cells are also developed, which are used to identify the incidence-specific T-cells. Induced Tregs are then observed and functionally characterized to test the mRNA abundance of Greg signature genes and T-cell effector genes. Analysis of the induced human Tregs indicated that higher frequencies of Tregs may be associated with slower onset of type 1 diabetes. 

Symposium: Bariatric Surgery in Special Populations

Bariatric Surgery in Type 1 Diabetes

Sangeeta Kashyap, MD (Cleveland Clinic, Cleveland, OH)

Dr. Sangeeta Kashyap presented data on the use of bariatric surgery in type 1 diabetes, concluding that surgery can lead to substantial weight loss and improved glycemic control in severely obese people with type 1 diabetes. Dr. Kashyap first presented a case series (n=10) of type 1 diabetes patients (mean baseline BMI of 42 kg/m2; mean diabetes duration of 22 years), with results showing that at a mean follow up of 36 months, “excess weight loss >60%” was achieved in all patients except in one case of adjustable gastric banding. In addition, mean A1c levels dropped by 1.1% (baseline of 10%, p=0.039) and insulin requirements dropped by 0.34 U/kg/day (baseline of 0.74 U/kg/day, p=0.004). Next, Dr. Kashyap presented results of a meta-analysis of 16 studies (n=106) published between 2013 and 2015, which similarly demonstrated significant BMI reductions (41.9 to 31 kg/m2), reduced insulin requirements, as well as reduced use of anti-hypertensive and lipid lowering agents. Notably, she stated that this patient population tended to experience profound glycemic changes (DKA, severe hypoglycemia) and GI dysmotility symptoms (prolonged ileus, acute gastric remnant dilation) in addition to the common postoperative complications of bariatric surgery. However, in conclusion, Dr. Kashyap noted that the favorable metabolic effects of bariatric surgery may facilitate medical management of type 1 diabetes in the setting of severe obesity.

Questions and Answers

Q: Our experience with surgery in type 1 diabetes has not been positive. We’ve seen huge swings in glycemic control.

A: For the long term, these are difficult patients to manage. But even prior to surgery, it’s also difficult to control. I have patients on U500 drips and they’re really poorly controlled. There are going to be a few patients that will require something like this.

Q: I had a patient who had type 1 diabetes and RYGB and she suffered from severe hypoglycemia. What’s your experience with hypo?

A: We’ve had similar experiences. We’ve had to work very closely with nutritionists to tell them to eat more frequently, to use rapidly acting insulin, and to use insulin pumps. These are all things we need to individualize. The data for patients who had sleeve is far more encouraging. We don’t see those huge fluctuations with sleeve patients. Also our banded patients have been far easier to manage in terms of glucose excursions.

Symposium: Beta Cells Under Attack—Lessons from Transplantation for New-Onset Type 1 Diabetes

Addressing Cellular Immunity―Transplant Therapies Applied to New-Onset Type 1 Diabetes

Antoinette Moran, MD (University of Minnesota, Minneapolis, MN)

Dr. Antoinette Moran discussed lessons learned from transplant therapy immunosuppression that can be applied to treating new-onset type 1 diabetes. She underscored that manipulation of cellular immunity is key to preventing transplanted organ rejection. What’s more, alloimmune and autoimmune activation follow similar pathways and can be similarly blocked. Drugs that act at multiple points in the cellular activation pathway can also be used in type 1 diabetes, and combining multiple drugs is always required to prevent transplant allograft rejection – there is similar growing consensus in the diabetes that combination immune therapy will very likely be required for type 1 daibetes. In addition, two phases of immune therapy are generally required in transplant— an intensive induction phase followed by a less suppressive maintenance phase which is life-long. No therapy is one size fit all, as there is clinical heterogeneity in both disease manifestations and the response to immunotherapy. As a result, she emphasized that individual approaches likely need to be developed. In addition, she noted that children have a different disease course and response to immunotherapy compared to adults, including differences in pharmacokinetics of immunosuppressive drugs, length of exposure to immunosuppression, and possible interference with vaccinations. Children are also uniquely susceptible to toxicities related to growth, development, and cognitive function – thus it’s imperative that they are studied and considered separately from adults. We are excited that progress in immunosuppression therapy over the last 30 years has allowed long term success in organ transplantation and we’re pleased that some of the lessions from this experiment can be applied to the treatment of autoimmune conditions like type 1 diabetes.

Protecting the Beta Cell from Innate Immunity

Lorenzo Piemonti, MD (San Raffaele Scientific Institute, Milan, Italy)

Instead of the traditional beta cell transplantation strategy of increasing the potency of generalized immunosuppression regimes, Dr. Lorenzo Piemonti hopes to develop novel clinical protocols based on the use of drugs that more specifically target the immune response against transplanted beta cells. According to Dr. Piemonti, immediately after islet infusion, as much as 50% of the transplanted beta cells are lost in less than 24 hours thanks to the detrimental impact of the non-specific immune response and pre-existing and transplant-induced specific cellular immune responses against the beta cells. Dr. Piemonti’s work therefore focuses on identifying “master regulators” of the immune response and using techniques such as CXCR1/2 blockade and CCL2 blockade to quell inflammation. We certainly look forward to hearing how this work progresses; circumventing the immune response has remained the foremost challenge in beta cell transplantation work.

Beta-Cell Biomarkers―Assessing Islet Loss in Transplant and Type 1 Diabetes

Kevan Herold, MD (Yale University, New Haven, CT)

Dr. Kevan Herold gave a fascinating talk on the development of an assay to assess beta cell death and to better understand the natural history of beta cell loss. Beta cell death is a silent event and the timing and precipitants of it are largely unknown. Measuring beta cell function is one approach, but it can be affected by other environmental factors and thus inaccurate. To solve this problem the Herold lab developed an assay that can measure beta cell death through the release of insulin DNA with unmethylated CpG sites into the bloodstream by using droplet digital PCR. The first design of the assay used a nested PCR reaction to detect primers that amplified the CpG sites and then ran rtPCR detecting the difference between methylated and unmethylated sites. In a more sensitive and specific method of ddPCR, the lab can run tens of thousands of reactions in droplets to determine the methylation ratio. With the assay, the Herold lab found that there is high beta cell death and elevated unmethylated insulin DNA after total pancreatectomy with islet autotransplantion in young patients with congenital pancreatitis issues. It also found that much of the material is dead already in allogeneic islet transplantation. Other research groups have started using this technique, and have found a large increase in unmethylated DNA right after a transplant as well as higher levels in type 1 diabetes patients compared to those without diabetes. Another group put human islets into a mouse and looked at human islet cell death after transplant, seeing a huge increase in unmethylated rather than methylated DNA. In a study examining TrialNet Natural History subjects who were “at risk,” “high risk,” or had new onset type 1 diabetes, the “high risk” group had high unmethylated DNA levels, and they were significantly different in progressors, nonprogressors, and normal subgroups. This led to a new model of beta cell loss in type 1 diabetes where beta cell death takes place suddenly, rather than in a slow decline. The researchers also saw biomarker decline when patients were treated with anti-CD3 monoclonal antibody and not when treated with placebo (mirroring C-peptide). However, pitfalls to the assay remain in finding appropriate CpG sites to increase the specificity and sensitivity of the test and better understanding how beta cell stress may prevent methylation because of inflammation, epigenetic changes, and changes in function. Nevertheless, the assay is a valuable method of measuring beta cell killing in vivo, acting as a thermometer for beta cell health, and quantifying the loss of islets after transplantation or through autoimmune processes.

Questions and Answers

Q: There are a lot of different types of beta cell death, and macrophages may have different levels of efficacy in disposing of them. Does the type of death matter? Is there a difference in disposal?

A: That’s an extremely good question and we don’t know. We would need to model it in vitro to see the different types of death. It could be that apoptosis is completely silent in our assay.

Q: In the subpopulation of beta cells that are resistant to immune attack, I understand there is an upregulation of PDL1. Are all the beta cells expressing it?

A: They do increase expression of PDL1 and decrease beta cell antigens and seem to be resistant to killing. We’ve thought about this in checkpoint induced diabetes and we know of three tissues that do that in response to stress (your brain, your heart, and beta cells).

Lessons from Islet Physiology—Plasticity of Islet-Cell Function

Patrick MacDonald, PhD (University of Alberta, Edmonton, Canada)

Islet cell plasticity and heterogeneity has received increased interest in recent years, and while research has delved into cell identity phenotypes, there is still a knowledge gap in functional phenotypes of beta cells. At the Alberta Diabetes Institute IsletCore, Dr. Patrick MacDonald described the program to process organs for islet isolation, banking, and distribution and reviewed islet cell plasticity through the malleability of beta cell function in infants, the exocytotic capacity in beta cell compensation and failure, and function consequences of alpha cell to beta cell transdifferentiation. His presentation first focused on the malleability of beta cell function in infants, where islet isolations from infants expressing PDx1 and other islet markers start to lose these in culture over time and lose their phenotype. The islets did not function well and lost some functional proteins and had metabolic defects. This is not seen in adult islets because infant cells unlike adult cells cannot mount an exocytotic response to stress. When the lab ran infant cells through a ViaCyte like expansion and maturation protocol, they were able to reexpress proteins, demonstrating how the exocytotic response is plastic in infancy and occurs even in cells that retain insulin expression. The exocytotic capacity in beta cell compensation and failure is a functional measure of secretory granule available for release upon stimulation of an islet cell. Glucose exposure upregulates beta cell exocytotic capacity but these responses fail in type 2 diabetes. The loss of this pathway leads to impaired adaptation to a high fat diet in mice and contributes to a functional change to hyperinsulinemia and is dysfunctional in older people. Finally, Dr. MacDonald reviewed the functional consequences of alpha cell to beta cell transdifferentiation and the role of alpha cell dysfunction in diabetes. Functional changes in human type 2 diabetes alpha cells start to mimic exocytosis of beta cells, which can be recapitulated in high fat diet fed mice, including the hypersecretion of glucagon. In mouse models, deleting certain genes in alpha cells make them resemble beta cells in some phenotypes of glucose regulation of exocytosis, which is a fascinating and poorly misunderstood plasticity in “flipped” islet cells.

Symposium: The Future Face of Diabetes Care – Beta-Cell Replacement vs. Technology (Supported by a grant from The Leona M. and Harry B. Helmsley Charitable Trust

The Future of Diabetes Management Is Cell Replacement Therapy

Jeffrey Millman, PhD (Washington University in St. Louis, St. Louis, MO)

Dr. Jeffrey Millman, an alumnus of Harvard’s Dr. Doug Melton’s lab (and now of Washington University in St. Louis), offered a compelling overview of the current state of the stem cell-derived beta cell field, outlining the remaining challenges toward a viable beta cell replacement therapy. Dr. Millman highlighted two main ongoing challenges: (i) cell potency; and (ii) cell delivery. Of the two, he characterized cell potency as a largely solvable problem. He noted that, while current stem cell-derived beta cells are very similar to native, primary beta cells, there are still substantial differences in the expression levels of several important genes – this suggests that the stem cell-produced cells are not completely identical to human beta cells, which may have important functional implications. Notably, for instance, stem cell-derived beta cells have poorer insulin secretion than endogenous human beta cells. Dr. Millman showed data demonstrating the per-cell level of insulin secretion of the very best of stem cell-derived beta cells is comparable to the very worst of isolated human islets. That said, Dr. Millman emphasized that much progress has been made on this front and that the latest cells produced from his lab’s new, revised protocol appears to match the insulin secretion levels of human islets more consistently. On the other hand, Dr. Millman views cell delivery as the much larger limitation currently facing beta cell replacement therapy. As he put it, transplanted cells must be able to survive, which requires that they receive a steady stream of oxygen and nutrients while being protected from autoimmune attack. At the same time, the protection system must still allow for rapid diffusion of glucose to and away from the cells, or else there would be an unacceptable lag in the system, which could produce an unacceptable risk of hypoglycemia. Finally, concerns about the tumorigenic potential of these stem cell-derived products persist as well. Overall, given the novel nature of these cells, Dr. Millman emphasized the importance of being able to retrieve the cells for safety reasons – which rules out the gold standard Edmonton protocol that is currently used to transplant human islets. He highlighted a few of the ongoing efforts in beta cell encapsulation, including his work in collaboration with Dr. Dan Anderson’s lab at MIT to encapsulate cells in an immune-protective alginate device. We heard similar commentary on the limitations of beta cell replacement therapy from Dr. Doug Melton at Levine-Riggs 2017. While these challenges are to be reckoned with for sure, we’re encouraged that these greats don’t view them as insurmountable and we’re eager to see where this field goes in the next couple of years.

Professional Interest Group Session: Staging Presymptomatic Type 1 Diabetes – Is There Enough Evidence? (Supported by the Helmsley Charitable Trust)

Richard Insel, MD (Insel Consulting, New York, NY) and Dorothy Becker, MB (Children’s Hospital of Pittsburgh, PA)

In a “debate” that offered much more agreement than controversy, Drs. Richard Insel and Dorothy Becker provided a perspective on the rationale behind and remaining questions with regards to staging of presymptomatic type 1 diabetes. Dr. Insel emphasized the benefits of staging type 1 diabetes (and screening to identify patients at presymptomatic stages), including the opportunity to identify type 1 diabetes at an earlier time point (reducing the likelihood of diagnosis in DKA), potential to intervene earlier in type 1 diabetes with clinical trials for specific stages, and the chance to generate insights to refine the stages and optimize design of clinical trials for type 1 diabetes. Dr. Becker began her “counterargument” by stating that she’s actually in favor of the concept of staging presymptomatic type 1 diabetes. That said, she acknowledged several ongoing “hang-ups” in the field regarding this. She suggested one of the major issues is semantics – the term of presymptomatic type 1 diabetes has gone through several iterations, from “chemical diabetes” in 1972 to “prediabetes” in the 1980s to “presymptomatic T1D staging” in 2015. She highlighted the most recent term that has gained traction: Autoimmune Beta Cell Disorder (ABCD). She prefers this term to some degree, as it makes clear that type 1 diabetes is a disorder and not a disease (the latter term implies some sort of infection) and she emphasized that the development of autoantibodies is a marker of a potentially severe process, but not should be used to imply pathogenesis. We like the rationale behind this term, though it may be confused with the newly proposed “ABCD” term of obesity. Other potential issues with staging highlighted by Dr. Becker included heterogeneity in the rates of type 1 diabetes progression and the fact that there’s no treatment yet (though she pointed out that, ideally, treatments to delay or prevent type 1 diabetes could be developed for these presymptomatic stages). Overall, Dr. Becker emphasized the importance of refining the current stages of type 1 diabetes and cautioned against “throwing the baby out with the bathwater” by abandoning stages altogether. Hear hear!

Symposium: Biomarkers of Type 1 Diabetes

Biomarkers of Disease Progression and Efficacy/Treatment in Type 1 Diabetes

Massimo Pietropaolo, MD (Baylor College of Medicine, Houston, TX)

Dr. Massimo Pietropaolo highlighted the role of biomarkers in assessing type 1 diabetes progression, as well as the efficacy of potential therapies for type 1 diabetes. In particular, he discussed the TrialNet Pathway to Prevention program, which screens first-degree relatives of patients with type 1 diabetes for antibodies. Based on the number of antibodies at screening, TrialNet is able to predict risk of developing type 1 diabetes. Despite the advances made by TrialNet, Dr. Pietropaolo emphasized that, currently, the main biomarker of disease progression is the presence of antibodies – while this tells us that something is wrong, it won’t tell us what is wrong. Thus, Dr. Pietropaolo argued for the need for mechanistic biomarkers that correlate well with disease pathogenesis, as well as with the effects of potential therapies. To that end, he suggested looking for biomarkers in events that lead to autoinflammation, immunoregulation, beta cell function and beta cell stress/death, and islet-infiltrating T-cells.

 

-- by Melissa An, Adam Brown, Abigail Dove, John Erdman, Helen Gao, Brian Levine, Nancy Liu, Payal Marathe, Maeve Serino, Lisa Vance, Emily Yang, Yrenly Yuan, and Kelly Close