June 10-14, 2016; New Orleans, LA; Day #2 Highlights – Draft

Executive Highlights

Hola from NOLA, where the second day of ADA 2016 has wrapped up at the New Orleans Ernest Morial Convention Center. In tech, we joined the throng of bright-eyed, eager attendees who couldn’t wait to get their hands on the latest Medtronic 670G artificial pancreas pivotal trial data (-0.5% A1c, -44% hypoglycemia risk) and results from Abbott’s IMPACT study (compelling 38% reduction in time spent in hypoglycemia, 74 minutes fewer per day <70 mg/dl). On the drug side, we saw microvascular outcomes data from EMPA-REG OUTCOME and late-breaker full results from the SWITCH 1 and 2 trials for demonstrating a hypoglycemia benefit for Novo Nordisk’s Tresiba (insulin degludec). Elsewhere, we heard NIDDK’s Dr. Judith Fradkin thoughts on precision medicine and ooh’d and ahh’d at the dazzling exhibit hall. See below for our top five diabetes technology highlights, top five diabetes drug highlights, and five honorable mentions, followed by detailed discussion and commentary. Want to see our other key takeaways from the conference thus far? Check out our Day #1 highlights! Want a crystal ball into the future? Take a peek at what the next few days of ADA holds with our preview and our ADA resource hub – let the good times roll!

Diabetes Technology Top Five Highlights

1. Medtronic presented its three-month pivotal study of the MiniMed 670G/Enlite 3 hybrid closed loop system (n=123). The topline data compared to a two-week open-loop run-in period was excellent: (i) an impressive 0.5% reduction in A1c (!) from a low study baseline of 7.4%; time <70 mg/dl declined 44% (from 6% to 3%); and time <50 mg/dl declined 40% (1% to 0.6%). The glucose profiles really put into perspective how much this shrinks variability.

2. Abbott shared long-awaited positive topline results from FreeStyle Libre IMPACT study, comparing Abbott’s FreeStyle Libre to SMBG in type 1 patients in good control (baseline A1c: 6.7 %). The study met its primary endpoint at six months – relative to the control group, patients using FreeStyle Libre spent ~74 minutes fewer per day <70 mg/dl (a 38% reduction; p<0.001).

3. Dr. Hood Thabit presented brand new, exciting data from the Cambridge team’s automated insulin delivery system in inpatient type 2 diabetes – the first of this kind of closed-loop study ever done. The study shared striking improvements in efficacy and safety vs. the truly grim standard of care achieved with open-loop in the hospital.

4. Dexcom’s Dr. David Price shared a retrospective database evaluation from six months of G4 Share users, showing no differences in mean glucose, estimated A1c, or glucose variability between pump (n=939) or MDI (n=648) users.

5. Abbott’s Exhibit Hall shared a slew of updates and headlines our coverage of the technology-focused booths: (i) the US debut of FreeStyle Libre Pro on an Exhibit Hall floor (still under FDA review); (ii) confirmation that the consumer version has not been submitted to FDA; (iii) an updated timeline on LibreLink – multiple EU launches slated for this month; (iv) the debut of Abbott’s new LibreView data management software; (v) news that LibreLink will soon sync with LibreView; and (vi) confirmation that the company is working hard on LibreLink Apple compatibility and further discussion about the possibility of an iPhone adapter to power the NFC-reading capability.

Diabetes Drug Top Five Highlights

1. Lilly/BI presented positive microvascular outcomes data from the EMPA-REG OUTCOME trial for Jardiance (empagliflozin) in a poster (1086-P). Results showed that Jardiance led to a significant 38% risk reduction for the composite microvascular endpoint (HR = 0.62, 95% CI: 0.54-0.70; p<0.001) compared to placebo.

2. Novo Nordisk presented data from the phase 3b SWITCH trials in two late-breaking posters (87-LB and 90-LB) demonstrating significant reductions in overall, nocturnal, and severe hypoglycemia with Tresiba (insulin degludec) vs. Sanofi’s Lantus (insulin glargine).

3. AZ presented a poster (1014-P) demonstrating significant improvements in glycemic variability with Bydureon (exenatide once weekly) vs. placebo. We were very excited to see CGM used in this study and look forward to much more on this front.

4. Dr. Ele Ferrannini (University of Pisa, Italy) hypothesized that a shift toward ketone body metabolism could have been responsible for the cardioprotective effect in EMPA-REG OUTCOME.

5. The diabetes manufacturers brought their A-game for the exhibit hall at ADA, where we learned a great deal about new and existing therapies ...

Very Honorable Mentions

• Dr. Ed Damiano, CEO of Beta Bionics, revealed that Zealand’s liquid stable glucagon analog will be tested in clinical trials with the fully integrated iLet bionic pancreas in the 2H16.
• Dr. Christopher Sorli (Billings Clinic, Billing, MT) introduced a series of visual aids to help clinicians appropriately identify the optimal patient population for each diabetes medication.
• Dr. Judith Fradkin (NIDDK, Bethesda, MD) discussed the NIH’s plans for rolling out the Precision Medicine Initiative (PMI) Cohort Program, sharing ambitious benchmarks slated for completion by the end of 2016.
• Dr. Ildiko Lingvay (University of Texas Southwestern, Dallas, TX) advocated for a “treat to success” paradigm involving a combination of an SGLT-2 inhibitor and an incretin as the second-line therapy after metformin.
• Earning a standing ovation, Dr. Margaret Powers (ADA, Alexandria, VA) made a forceful argument for the value of and need for increased access to diabetes self-management education (DSME) in her President, Health Care, & Education Address.

Diabetes Technology Highlights

1. Medtronic 670G Shines in Pivotal: 0.5% reduction in A1c, 44% Decline in Hypoglycemia, Compelling Glucose Profiles

Medtronic presented a late-breaking poster on its single-arm, non-randomized, three-month pivotal study of the MiniMed 670G/Enlite 3 hybrid closed loop system in 124 participants (n=94 adults, 30 adolescents). The topline data compared to a two-week open-loop run-in period was excellent: (i) an impressive 0.5% reduction in A1c (!) from a low study baseline of 7.4%; time <70 mg/dl declined 44% (from 6% to 3%); and time <50 mg/dl declined 40% (1% to 0.6%). Wow! – it was highly impressive to see the impact on A1c, given the strong reduction in hypoglycemia and the very well-controlled population of pumpers. Notably, those with a baseline A1c >7.5% actually saw a 1% reduction after three months on the 670G. Time-in-range (71-180 mg/dl) improved from 67% during the baseline run-in to 72% during the study, with time >180 declining moderately (27% to 25%). While that improvement does not sound significant, it is clear from the compelling glucose profiles (see below) that the MiniMed 670G (in pink) moderated extreme highs (e.g., 300 mg/dl) (e.g., 200 mg/dl), which didn’t show up as improvement in time in 70-180 mg/dl. The profiles are really worth looking at – they show how the MiniMed 670G tightened the range of glucose values throughout the entire day in both populations, with particularly strong efficacy overnight. Total daily dose increased ~7% from baseline (48 u to 51 u; p<0.001), though a smaller proportion of insulin was given as basal insulin (we unpack this below). Surprisingly, both adolescents and adults gained a bit of weight on the MiniMed 670G: +3 lbs (1.4 kg) in adults and +2 lbs (1.0 kg) in adolescents. While weight gain is never a positive, this does not strike us as big concern for the 670G or other hybrid closed loop systems, given potential for less hypoglycemia-induced weight gain. Hybrid closed loop was used for an impressive 87% of the three-month study period (median), with slightly higher usage in adults (88%) than adolescents (76%). The new Enlite 3 sensor showed a solid improvement, with an overall MARD of 10.3% vs. reference (i-STAT) over a 24-hour measurement period (part of the study’s six-day hotel phase). This was consistent with data shown at ATTD, though only 2% of points were in hypoglycemia. Lots more analysis of the results and study background are in the detailed discussion section.

• Overall, we see these pivotal data as compelling and outstanding for the entire field of automated insulin delivery. This study was clearly designed for speed and to prove safety to the FDA, so it’s hard to read too much into the efficacy results, where were not pre-specified endpoints. Still, reducing A1c 0.5% at the same time hypoglycemia declined 44% is a huge win – and the results were consistent in adolescents and adults. This was also a very real-world study in current pump users, some of whom were on CGM prior to study start. It’s clear that automated insulin delivery will make a difference even with first-gen hybrid closed loop products, and even in well-controlled patients. Of course, the hope is it can really improve outcomes for those with an A1c >10% or at high risk of severe hypoglycemia, groups that were both excluded from this study. We also hope to hear more on usability of the system as well as user-friendliness.
• In talking to investigators, the patient reactions they’ve heard from trials have been even more impactful than the data. Said Dr. Rich Bergenstal, “This is a definite step forward. Beyond what the numbers say, the true benefit is in the stories of sleeping at night, peace of mind. I’m happy to get a little help from technology.” With an FDA submission planned before the end of this month, and 80% of pivotal study patients using this device as part of the FDA’s continued access program, some of the other pump companies may be nervous as the first AP-like system hits the market – we assume that the entire market will expand as well. Of course, the first AP system will push all of them to move faster and differentiate their offerings – the more user-friendly the systems become, the faster the market will expand.

2. Abbott’s Big IMPACT – a Compelling 38% Reduction in Time Spent in hypoglycemia, 74 minutes Fewer Per Day <70 mg/dl

Abbott shared long-awaited topline results from FreeStyle Libre IMPACT study, comparing Abbott’s FreeStyle Libre to SMBG in type 1 patients in good control (baseline A1c: 6.7 %). The study met its primary endpoint at six months – relative to the control group, patients using FreeStyle Libre spent ~74 minutes fewer per day <70 mg/dl (a 38% reduction; p<0.001). There was not a significant difference in A1c between the groups, though both saw a 0.15% increase by the end of the study – unsurprising given the very low A1c to start. Clearly the higher A1c is a “healthier” A1c given far less hypoglycemia. Pre-specified secondary endpoints were particularly compelling – patients using Libre spent ~49 minutes fewer per day <55 mg/dl (a 50% reduction; p<0.0001) and ~33 minutes fewer per day <45 mg/dl (a 60% reduction; p<0.0001). Now that is a meaningful reduction in a very dangerous zone! Measures of nocturnal hypoglycemia were also significantly lower with FreeStyle Libre as patients spent ~28 minutes fewer per night (a 40% reduction; p<0.0001) in hypoglycemia. Patients using Libre spent ~22 minutes fewer per day in extreme hyperglycemia > 240 mg/dl (p=0.02) and spent ~60 minutes greater/day between 70-180 mg/dl (p=0.0006). FreeStyle Libre pretty much completely replaced fingerstick testing, suggesting a high level of confidence in the factory-calibrated sensor: SMBG frequency with FreeStyle Libre fell from a mean of ~5.5 tests/day at baseline to 0.5 tests/day (one every two days) at six months, a testament to the real-world accuracy in patients on insulin therapy. This is very good news as it seeks FDA approval, with now two large RCTs backing up this finding. Quality of life data was significantly in favor of FreeStyle Libre too. Overall, patients reported significantly improved satisfaction, convenience, and flexibility associated with Libre, and reported significantly greater satisfaction with their understanding of diabetes. They were significantly more likely to recommend Libre and to be satisfied continuing Libre use. There were no device-related serious adverse events and 13 instances of minimal adverse events (e.g., infection, allergy) reported by 10 subjects.

• The positive results of IMPACT are not a surprise after REPLACE, and highlight the tremendous and scary amount of hypoglycemia type 1 patients on insulin therapy are experiencing every day: all patients at baseline were spending ~200 minutes per day <70 mg/dl! The hypoglycemia data discussed above is very clinically meaningful (-74 minutes per day) – notably, there is still significant room to improve therapeutic approaches, since patients on Libre were still spending two hours (!) <70 mg/dl per day at six months, presumably driven by overtreating hyperglycemia and the typical intensively managed patients used to too much hypoglycemia. Meanwhile, standard of care saw patients were still spending over three hours <70 mg/dl per day. In that sense, the results tell us as much about Libre as they do about the real-world dangers of insulin therapy, particularly in these “well controlled” patients skating close to the edge. Avoiding hypoglycemia on insulin therapy is truly difficult as A1c gets below 7%, and we’re not sure that delicate balance is appreciated enough. Libre can certainly help and changing therapy to improve safety certainly strikes us as an underappreciated priority.
• Notably, these data underscore the limitations in using A1c as an endpoint for diabetes technology (this study did not have A1c as the primary outcome, unlike REPLACE). Both groups saw a 0.15% increase in A1c in this study (6.7% to 6.9%), though the “quality of A1c” improved markedly in the FreeStyle Libre group – 74 fewer minutes per day <70 mg/dl (a 38% reduction), and 33 fewer minutes per day <45 mg/dl (a 60% reduction in time spent at a highly dangerous level). Meanwhile, the control group was still spending three hours per day in hypoglycemia with an A1c 6.9%! Do payers appreciate the gravity of that change? How could that change impact short and long-term costs? Overall, we think further A1c reduction in this study would have been unlikely from such a low base: the population was already in what is typically viewed as excellent control (6.7%), there was no mandatory per-protocol insulin adjustment, and the baseline hypoglycemia was simply too high to drive things down further. While we do not suggest comparing results since the technologies were not used head-to-head, some will note that the MiniMed 670G pivotal reduced A1c 0.5% from a higher 7.4% baseline and drove a 40% reduction in hypoglycemia – that Medtronic study did not have a control group, and time spent in hypoglycemia was 1.4 hours per day during the 670G baseline compared to 3.4 hours per day in this study. Overall, it’s terrific to see multiple technologies focused on creating greater safety and higher-quality A1cs for patients – patients will choose technologies based on cost, convenience, etc.

3. Cambridge team wows with fully-automated AID in inpatient type 2 diabetes. Open-Loop Hospital Glucose Control Is Terrible!

Dr. Hood Thabit presented brand new, exciting data from the Cambridge team’s automated insulin delivery system in inpatient type 2 diabetes – the first of this kind of closed-loop study ever done. The study shared striking improvements in efficacy and safety vs. the truly grim standard of care achieved with open-loop in the hospital. The parallel-arm study randomized 24 patients to receive either closed-loop therapy (n=12) or conventional subcutaneous insulin therapy per clinical guidelines with masked CGM (n=12) for a period of 72 hours. The data looked outstanding and terrifying at the same time – closed-loop control significantly improved time-in-target from 38% to 61% for the 100-180 mg/dl range (p<0.001). Mean glucose improved from 182 mg/dl to 161 mg/dl (p=0.065), though that signal was not significant. The study used unannounced meals, which made control much harder in the closed-loop arm. There was absolutely no difference in hypoglycemia in this type 2 population: time spent < 63 mg/dl = 0% [CL] vs. 0% [OL]. On safety, there were no severe hypoglycemia or adverse events associated with diabetes therapy and total daily insulin did not differ between the groups (63 units per day [CL] vs. 66 units per day [OL]). Ultimately, we were not sure what to expect coming into this oral, but the group’s impressive track record certainly delivered in another new setting. Ultimately, we left the presentation reminded yet again of the very negative state of current inpatient glucose management. Indeed, we were downright disheartened by the standard of care overnight (mean glucose = 202 mg/dl; see below), and the findings served as a striking reminder of: (i) the need for glucose management education in the hospital setting; and (ii) the great potential for inpatient technology to improve diabetes management and resulting outcomes. The tendency to accept hyperglycemia in inpatients is truly wrong.

• We were particularly impressed with data overnight Dr. Thabit shared – see Table 1 below. Closed-loop control doubled nocturnal time-in-target from 29% to 59% for the 100-180 mg/dl range (p<0.001), while mean glucose improved from 202 mg/dl to 161 mg/dl (p=0.065) with no hypoglycemia. There were zero episodes of glucose < 63 mg/dl on closed-loop vs. isolated incidents on open loop, making the hypoglycemia difference significant overnight too. We imagine nurses and other hospital-based HCPs would appreciate the chance to safely reduce blood glucose – many are very scared from what we know to have patients at “normal” blood glucose levels, given the risk (real or perceived) of hypoglcyemia. Many inpatients likely run “high” against their wishes.
• This trial did NOT use meal announcements, making this the first fully automated closed-loop Cambridge study. All the type 1 studies have used meal announcements, but Dr. Thabit stressed that a fully automated system is particularly practical in the inpatient type 2 setting where patients and nurses are less well educated – more on this below.

4. Dexcom Share Data Reveals No Difference in Mean Glucose, Estimated A1c Between Pump and MDI Users

Dexcom’s Dr. David Price shared a retrospective database evaluation from six months of G4 Share users, showing no differences in mean glucose, estimated A1c, or glucose variability between pump (n=939) or MDI (n=648) users. The de-identified data on glucose values were supplemented by customer info (age, insulin delivery) that Dexcom collects. The pump and MDI groups had identical average glucose values and variability across every age group (from 2-6 year-olds all the way to 65+ year olds), with just a single small exception: glucose variability was statistically significantly lower in adolescents (13-18 years) using injections. As would be expected, adult CGM users had better average glucose values vs. pediatric CGM users by ~30 mg/dl (see tables below estimated from the charts shown). This analysis also aligns with results from the T1D Exchange showing that in every age group, the same pattern holds – similar A1cs for CGM users on MDI or a pump. Could this provide a preview of what the randomized DIaMonD study will show tomorrow (Sunday, 4:30 pm) – that CGM is just as beneficial in injectors as pumpers? Presumably the answer is yes. Dr. Price noted that CGM use is increasing (now up to 16% in the T1D Exchange), and is overwhelmingly prescribed to pumpers: of all Exchange CGM users, 85% are on pumps vs. just 15% on MDI. Studies like this also underscore the inherent value in data streaming from devices to the cloud automatically – companies can use it to put data behind their arguments, drive study design, and inform marketing. Medtronic has written the book on this with CareLink, and we expect Dexcom will begin driving this too. We like the move toward greater safety no matter how type 1 patients are taking insulin.

5. Exhibit Hall – Technology: Abbott Shows FreeStyle Libre Pro on US Soil, Consumer Version Not Currently UNder FDA Review

Abbott’s Exhibit Hall shared a slew of updates and headlines our coverage of the technology-focused booths: (i) the US debut of FreeStyle Libre Pro on an Exhibit Hall floor (still under FDA review); (ii) confirmation that the consumer version has not been submitted to FDA; (iii) an updated timeline on LibreLink – multiple EU launches slated for this month; (iv) the debut of Abbott’s new LibreView data management software; (v) news that LibreLink will soon sync with LibreView; and (vi) confirmation that the company is working hard on LibreLink Apple compatibility and further discussion about the possibility of an iPhone adapter to power the NFC-reading capability. Lots of movement!

• See below for more details on all the above and coverage of our Exhibit Hall trips to BD, Dexcom, Insulet, J&J/Animas, J&J/LifeScan, MannKind, Medtronic, and Tandem.

Diabetes Drug Top Five Highlights

1. Positive Microvascular Outcomes Data for Lilly/BI's SGLT-2 Jardiance

Lilly/BI presented positive microvascular outcomes data from the EMPA-REG OUTCOME trial for Jardiance (empagliflozin) in a poster (1086-P). Results showed that Jardiance led to a significant 38% risk reduction for the composite microvascular endpoint (HR = 0.62, 95% CI: 0.54-0.70; p<0.001) compared to placebo. As with the results for cardiovascular outcomes, the curves began to separate very early (within ~3 months), and the benefit was sustained throughout the trial. The composite endpoint included quite a number of outcomes: time to first initiation of laser therapy for retinopathy, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy (defined as progression to macroalbuminuria, doubling of serum creatinine and eGFR ≤45 ml/min/1.73 m², initiation of renal replacement therapy, or death due to renal disease). The results for the composite endpoint appeared to be driven by nephropathy: Jardiance led to a significant 39% reduction in incident or worsening nephropathy (HR = 0.61; 95% CI: 0.53-0.70; p<0.001), but there was no significant difference between groups for the individual retinopathy endpoints. This data will add even more fuel to the debate around the mechanism of benefit in EMPA-REG OUTCOME; we see the results as consistent with either a diuretic effect (the closest thing to a consensus explanation at this point) or the novel ketone-related mechanisms proposed in two presentations today – see highlight #4 below for more. From a clinical perspective, we are absolutely thrilled at the prospect of a therapy that can improve renal outcomes, as chronic kidney disease remains one of the areas of greatest unmet need in diabetes.

2. Novo Nordisk's Basal Insulin Tresiba Beats Lantus on Hypoglycemia in SWITCH 1 and 2

Novo Nordisk presented data from the phase 3b SWITCH trials in two late-breaking posters (87-LB and 90-LB) demonstrating significant reductions in overall, nocturnal, and severe hypoglycemia with Tresiba (insulin degludec) vs. Sanofi’s Lantus (insulin glargine).  We saw topline results from both SWITCH 1 (type 1 diabetes) and SWITCH 2 (type 2 diabetes) in February. Novo Nordisk plans to submit the data to regulatory authorities in 3Q16 in the hopes of gaining some sort of label update, though we will keep our expectations in check given the FDA’s historically conservative approach in this area. While we were quite impressed with the data, we were also struck by how high the hypoglycemia rates were in both groups, particularly in the type 1 diabetes trial. To us this underscores the enormous complexity of managing diabetes with current insulin therapy and illustrates the need for as many tools as possible to help patients reduce their risk. We are also starting to see we need a different narrative for patients “in control” – currently, a patient’s “control” reflects their A1c, not their A1c combined with their time spent in hypoglcyemia, which seems like a limited way to assess success.

• SWITCH 1 demonstrated significant hypoglycemia reductions with Tresiba vs. Lantus in patients with type 1 diabetes at high risk for hypoglycemia. The double-blind trial randomized 501 patients to receive once-daily doses of Tresiba or Lantus for 32 weeks, followed by crossover to the other treatment for 32 weeks. Each 32-week period consisted of a 16-week titration period and a 16-week maintenance period, and both groups received injections of NovoLog (insulin aspart) at mealtime. Results showed a significant 11% reduction for the primary endpoint of severe or blood glucose-confirmed symptomatic hypoglycemia with Tresiba vs. Lantus during the maintenance period (event rates of 2,220.9 vs. 2,462.7 events/100 patient-years; p<0.0001). Tresiba also produced a significant 36% reduction in severe or blood glucose-confirmed nocturnal symptomatic hypoglycemia (event rates of 277.1 vs. 428.6 events/100 patient-years; p<0.0001) and a significant 35% reduction in severe hypoglycemia (event rates of 69.1 vs. 92.2 events/100 patient-years; p<0.05) in the maintenance period compared to Lantus. Results were similar for the full treatment period with significant reductions of 6%, 25%, and 26% with Tresiba vs. Lantus for the three respective endpoints. The results for other efficacy and safety parameters were comparable between groups; a post-hoc analysis found a 3% significantly lower total daily insulin dose in the Tresiba group.
• SWITCH 2 demonstrated significant hypoglycemia reductions with Tresiba vs. Lantus in patients with type 2 diabetes at high risk for hypoglycemia. The double-blind trial randomized 721 patients to receive once-daily doses of Tresiba or Lantus in addition to oral diabetes drugs (excluding sulfonylureas/meglitinides) for 32 weeks, followed by crossover to the other treatment for 32 weeks, with the same titration/maintenance periods as in SWITCH 1. Results showed a significant 30% reduction in severe or blood glucose-confirmed symptomatic hypoglycemia with Tresiba vs. Lantus during the maintenance period (event rates of 185.6 vs. 265.4 events/100 patient-years; p<0.0001). Tresiba also produced a significant 42% reduction in severe or blood glucose-confirmed nocturnal symptomatic hypoglycemia (event rates of 55.2 vs. 93.6 events/100 patient-years; p<0.0001). Rates of severe hypoglycemia were low in both groups and numerically but not significantly lower with Tresiba (event rates of 5.3 vs. 9.1 events/100 patient-years; p-value not given). Results were similar for the full treatment period with significant reductions of 23% and 25%, respectively, for the first two endpoints and a 51% reduction in severe hypoglycemia that just reached statistical significance (p=0.03). The results for other efficacy and safety parameters were comparable between groups; a post-hoc analysis found a 4% significantly lower insulin dose in the Tresiba group.

3. AZ's Bydureon Reduces Variability

AZ presented a poster (1014-P) demonstrating significant improvements in glycemic variability (“time in zone”) with GLP-1 Bydureon (exenatide once weekly) vs. placebo. The randomized, controlled, double blind study recruited 117 adult patients with type 2 diabetes using metformin (A1c 7-10%), who were randomized to open-label metformin XR (1500 or 2000mg daily) plus double-blinded Bydureon 2.0 mg (n=61) or placebo (n=56). Glucose concentration was measured via the Dexcom G4 CGM every 5 minutes during the last week before randomization (baseline), as well as during weeks 4 and 10. Compared to placebo, Bydureon provided significantly greater reductions in 24-h mean glucose on day six of week four (5.3 mg/dl vs. 26.0 mg/dl, respectively) and on day six of week 10 (3.0 mg/dl vs. 30.8 mg/dl, respectively). This is a major difference in our view and one that most patients would be excited to see. Similar results were observed for fasting plasma glucose (FPG), postprandial glucose (PPG), and mean amplitude of glycemic excursions (MAGE) (please see our detailed write-up below). Those on Bydureon experienced a significant increase in the time spent in euglycemia (70-180 mg/dl) from baseline to week four and week 10 (p<0.001 for both) – this was secondary to reductions in time spent in hyperglycemia (>180 mg/dl), with no increase in the time spent in hypoglycemia (<70 mg/dl); the finding was not observed in the placebo group. The authors concluded that Bydureon provides robust effects on measures of glycemic fluctuation at week four that persist to week 10. We applaud AZ for investing in a dedicated CGM trial, which we hope becomes a much more standard part of clinical development for new diabetes drugs. We wonder whether this study could lead to any sort of label update for Bydureon; if so, it could potentially help AZ differentiate the product within an increasingly competitive class – albeit a class that is set to grow significantly in 2016 and beyond in our view.

4. Could Increased Ketone Production With SGLT-2 Inhibitors Be Cardioprotective?

Dr. Ele Ferrannini (University of Pisa, Italy) hypothesized that a shift toward ketone body metabolism could have been responsible for the cardioprotective effect in EMPA-REG OUTCOME. This hypothesis was also outlined in a paper just published in Diabetes. Dr. Ferrannini explained that patients with type 2 diabetes have consistently higher lipid oxidation than people without diabetes, and the glucosuria produced by SGLT-2 inhibitors amplifies this effect by decreasing glucose and insulin levels and increasing glucagon levels. This effect has become a common point of discussion over the past year in the context of the potential increased risk of DKA, but Dr. Ferrannini suggested that it could produce positive effects as well. In his model, the increased availability of lipid substrates leads the liver to produce more ketone bodies, which are then taken up by the heart. Ketone bodies are very efficient fuel sources, meaning that at any given level of oxygen they generate more ATP compared to other substrates like glucose. Dr. Ferrannini noted that SGLT-2 inhibitors also lead to increased hematocrit (the ratio of oxygen-carrying red blood cells to total blood volume) and therefore could increase oxygen delivery to the heart. That combination of more oxygen and more efficient energy utilization could improve the heart’s contractile ability and lessen the strain on a failing heart. Dr. Ferrannini emphasized that this is only a hypothesis and that it should not preclude other more “conventional” explanations such as a diuretic effect, but it certainly adds an interesting new dimension to the discussion. At a BI/Lilly-sponsored corporate symposium later that evening, Dr. Lawrence Blonde (Ochsner Health System, Jefferson, LA) and Dr. Carol Wysham (Rockwood Clinic, Spokane, WA) both described this hypothesis as very compelling, and we are sure we have not heard the last of it.  

• In his subsequent presentation, Dr. Sunder Mudaliar (UCSD, San Diego, CA) suggested that a similar hypothesis could apply to renal protective effects. He explained that the kidneys have very high energy needs and rely primarily on oxidative metabolism – their level of oxygen consumption is second only to that of the heart. The kidneys’ workload and oxygen requirements are even higher in diabetes due to abnormally high glucose reabsorption, and Dr. Mudaliar noted that the resultant renal hypoxia and oxidative stress are increasingly being recognized as independent pathways involved in the progression of chronic kidney disease. SGLT-2 inhibitors could relieve some of this stress by shifting renal metabolism toward ketone bodies (a more efficient energy source) instead of oxygen.

5. Diabetes Drug Exhibit Hall

The diabetes manufacturers brought their A-game for the exhibit hall at ADA. A year after its exhibit hall debut, Intarcia posted two fairly sizable booths instead of the single small booth we have seen at recent conferences. One eye-catching booth focused on the newly branded Medici delivery device with signage promising a “Renaissance in medicine delivery” and cheery seventies-themed décor. Another booth across the hall focused broadly on the need for a paradigm shift in type 2 diabetes treatment and featured a huge funnel hanging from the ceiling with words like “prevalence,” “hypo,” and “not to goal” going around and around in a downward spiral. We’re excited to see Intarcia intent on expanding GLP-1 therapy and look forward to seeing “in real life” how adherence improvements can affect patients’ lives. Elsewhere in the hall, Novo Nordisk continued to focus almost entirely on basal insulin Tresiba, with a few creative touches such as a large hanging parachute labeled “A1c” and a “virtual representative” of sorts (a webcam on a motorized roving base) circulating around the both. From the Lilly standalone and Lilly/BI booths, we got our first glimpse at the US branding and logo for biosimilar insulin glargine Basaglar – the minimalist design is a real treat for the eyes! We also saw stepped up marketing for Glyxambi (empagliflozin/linagliptin) featuring a Pixar-style cartoon dynamic duo representing the two components of the combination. Sanofi showed up with one of its largest and most elaborate booths in recent memory, which a heavy emphasis on Toujeo (U300 insulin glargine) and its accompanying patient support program. Janssen’s booth highlighted the recent expansion of Invokamet’s (canagliflozin/metformin) indication to include use as a first-line therapy, while AZ’s large, centrally located display included featured its entire diabetes portfolio and several interactive games for attendees.

Very Honorable Mentions

Honorable Mention: Beta Bionics to Use Zealand’s Phase 2 Glucagon, Insulin-Only Glycemic Target Studies Shows value of Glucagon

Dr. Ed Damiano, CEO of Beta Bionics, revealed that Zealand’s liquid stable glucagon analog will be tested in clinical trials with the fully integrated iLet bionic pancreas in the 2H16. The pivotal studies of the insulin-only iLet are still expected to start in 2Q17.  The bihormonal pivotal trial, which will begin after the start of the insulin-only pivotal trial, will require that a subset of the study cohort use the iLet for 12 months in order to gain chronic glucagon exposure for a new indication for use of glucagon in a bihormonal bionic pancreas. Zealand and Beta Bionics actually put out a joint press release yesterday announcing their collaboration, a big win for Dr. Damiano’s new public benefit corporation to commercialize their iLet bionic pancreas. Xeris has not moved particularly fast on its stable glucagon, and Zealand’s deep experience in protein chemistry will be a major asset in solving this problem. Dr. Steven Russell hinted at ATTD that Zealand’s phase 2 glucagon might be used, though today was the first confirmation it is the glucagon of choice going forward. Dr. Damiano did not comment on the submission timing, but we assume the plan is still an end of 2017 insulin-only PMA submission, with a potential PMA supplement to add glucagon in early 2019. Dr. Damiano’s actual oral presentation focused on the Bionic Pancreas 11-day multi-center home study (n=39), shared at several symposium presentations since GTCBio 2015 over a year ago.

• A separate oral from MGH’s Dr. Laya Ekhlaspour reiterated the insulin-only vs. bihormonal glycemic target studies first shared at ATTD. “Glucagon allows more subjects to have a mean glucose <154 mg/dl without increasing hypoglycemia.” We’ve reproduced the key findings below from the randomized, crossover study (n=20) comparing usual care to insulin-only and bihormonal versions of the Bionic Pancreas at different glycemic targets (insulin-only: 130 and 145 mg/dl; bihormonal: 100, 115, 130 mg/dl) over three-day experiments. The insulin-only and bihormonal systems were actually very similar with a glycemic target of 130 mg/dl: a mean glucose of 161 vs. 156 mg/dl and time <60 mg/dl of 0.8% vs. 0.5%. As the bihormonal target dropped to 115 and 110 mg/dl, mean glucose improved to 146 and 136 mg/dl without increasing hypoglycemia. The team is now exploring an insulin-only target of 110 mg/dl, as the use of 130 mg/dl was intentionally conservative. This time, the presentation added a compelling statistic: how many patients achieved a mean glucose <154 mg/dl (i.e., estimated A1c <7%)? This really showed the potential value of glucagon, though of course, an insulin-only system with a lower target might do better – though it would likely take longer to reach the lower targets and overall the system would not likely be as aggressive. 

• This study shows just how important glycemic target is to AID system performance, and echoes the takeaway from yesterday that closed-loop products should have adjustable target set points. [The MiniMed 670G does not have this; the algorithm targets 120 mg/dl and allows a temp target of 150 mg/dl for exercise.] The big question for glucagon, of course, is how much mean glucose, hypoglycemia, and user experience improves when the hormone is added to an insulin-only system.

Honorable Mention: “Clinical Density Plots” as Visual Aids for Therapy Individualization

Dr. Christopher Sorli (Billings Clinic, Billing, MT) introduced a notable series of visual aids to help clinicians appropriately identify the optimal patient population for each diabetes medication. These “clinical density plots” include a curve representing endogenous insulin secretion as a function of time and three curves representing insulin resistance level (for high, modest, and low insulin resistance). Patients that fall toward the bottom right section of the plot, representing those with a long duration of diabetes, low endogenous insulin secretion, and lower insulin resistance, should prioritize minimizing hypoglycemia risk. Patients that fall toward the top left of the graph, representing those with a shorter duration of diabetes, relatively preserved insulin secretion, and high insulin resistance, should prioritize treatments that have weight neutral or beneficial effects. Within this graph, shading of various sections indicates the patient population for which a particular treatment may be recommended, considered, or not recommended. Overall, Dr. Sorli most strongly recommended metformin, GLP-1 agonists, and SGLT-2 inhibitors for those who have relatively short diabetes duration and are concerned about weight gain. He recommended DPP-4 inhibitors and insulin for those with longer disease duration. Patients in the middle would do best with metformin, GLP-1 agonists, SGLT-2 inhibitors, and DPP-4 inhibitors in his view. We see these plots as a useful visual education tool for providers (especially primary care physicians) to help synthesize the benefits and risks of different drugs for individual patients in an understandable way. See our detailed discussion and commentary for pictures of the clinical density plots and accompanying thoughts for each major drug class.

Honorable Mention: Judith Fradkin on NIH’s Precision Medicine Initiative Plans

The highly respected Dr. Judith Fradkin (NIDDK, Bethesda, MD) discussed the NIH’s plans for rolling out the Precision Medicine Initiative (PMI) Cohort Program, sharing ambitious benchmarks slated for completion by the end of 2016. Notably, the NIH aims to have 79,000 participants fully consented and enrolled in the cohort, with biospecimens from at least 25,000 participants; the Institute expects to accomplish its final goal of enrolling one million participants by the end of 2019. Further, the NIH plans to launch a direct volunteer program and partnerships with five to seven major healthcare provider organizations to facilitate participant recruitment, and also expects that eight to ten studies using the cohort data will be underway by December 2016. The Institute will also launch the Sync4Science pilot program by the end of the year, which allows for standardized extraction of electronic health record (EHR) and insurance data from various records via a secure and functional platform. According to Dr. Fradkin, these goals will be accomplished with the FY16 NIH PMI appropriation of $200 million under the leadership of Mr. Eric Dishman, the recently selected Director of the PMI Cohort Program. The Cohort Program data itself will include self reported measures such as diet, substance use, disease, and symptoms, as well as baseline health data (vitals), structured clinical data from the EHR, select lab results, biospecimens (at least one blood sample), and mobile health data passively collected from smartphones and wearable sensors. In terms of data collection, analysis, and dissemination, Dr. Fradkin shared that the initial Core Data Set will be centrally collected and stored in a coordinating center; Mayo Clinic will serve as the “biobanking” site for the initiative. Researchers will have access to both data and biosamples, and data from their analyses will subsequently feed back to the central database where it will be released to participants, the general public, and other researchers for further analysis. It is very encouraging to see the government’s commitment to developing a strategic plan for the PMI implementation – we hope to see the momentum continue and ultimately bring more accurate diagnoses, improved disease prevention strategies, and better treatment selection for people with diabetes and other chronic diseases.

• According to Dr. Fradkin, diabetes will be one of the most highly-represented diseases in the PMI Cohort, with an estimated 135,658 cases at baseline. This will provide high power for identifying biological markers that signal increased or decreased risk of developing diabetes. Dr. Fradkin hopes this will lead to more precise delineation of diabetes types, and more targeted treatments as a result.
• Dr. Fradkin heavily emphasized the PMI’s focus on tackling health disparities through actively involving underrepresented groups in the Cohort Program. She noted that this will be especially important in diabetes, where disadvantaged populations are disproportionately impacted – we are very excited to hear this focus, as it is a key first step in addressing inequity issues and to also help us distinguish whether biology or social determinants are driving differences among various racial/ethnic groups.

Honorable Mention: SGLT-2 Inhibitor and Incretin Combination Therapy for “Treat to Success”

Dr. Ildiko Lingvay (University of Texas Southwestern, Dallas, TX) advocated for a “treat to success” paradigm involving a combination of an SGLT-2 inhibitor and an incretin as the second-line therapy after metformin. She argued that a “treat to success” paradigm (as opposed to the current “treat to fail” approach) involves treating early, treating intensively, and treating the underlying pathophysiology, while avoiding side effects as much as possible – what a positive approach! Dr. Lingvay argued that in the modern era of diabetes management, healthcare professionals can and should offer more than just glucose-lowering to their patients and should aim to maximize the non-glycemic benefits of diabetes medications. We’ve heard from several pharmaceutical leaders that the industry is certainly hearing the demand for “glucose-plus” therapies that offer cardiovascular or other benefits beyond A1c-lowering. In terms of specific combinations, Dr. Lingvay stated that the main advantage of a DPP-4 inhibitor/SGLT-2 inhibitor combination is that the two classes are available as a co-formulation, which could reduce treatment burden, improve adherence, and hopefully be available at a lower cost than the two separate agents. On the other hand, GLP-1 agonist/SGLT-2 inhibitor combinations are more efficacious in terms of A1c reduction and weight loss. Dr. Lingvay also highlighted the topline LEADER and SUSTAIN 6 cardiovascular outcome trial results for Novo Nordisk’s Victoza (liraglutide) and semaglutide, respectively – the prospect of combination therapy with two drug classes with demonstrated cardiovascular benefit is a very exciting one to us. Overall, Dr. Lingvay sees great promise in the use of the two drug classes together and even suggested that these combinations could eventually serve as an alternative to bariatric surgery.

Honorable Mention: “If DSME was a Pill, Would You Prescribe It?”

Earning a standing ovation, Dr. Margaret Powers (ADA, Alexandria, VA) made a forceful argument for the value of and need for increased access to diabetes self-management education (DSME) in her President, Health Care, & Education Address. Challenging the packed ballroom to think of DSME as a diabetes treatment in the same sense as a drug therapy (“If DSME was a pill, would you prescribe it?”), Dr. Powers demonstrated through the ADA/EASD position statement criteria that DSME is one of, if not, the best treatments available. Specifically, comparing DSME with metformin, she concluded that DSME was at least as effective, if not better, across all criteria. Dr. Powers noted that despite this powerful analysis, only 6.8% of individuals with private insurance receive DSME in the first year of their diagnosis, and only 5% of Medicare patients receive DSME. Pointing out that DSME additionally has psychosocial benefits that no drug intervention can replicate, Dr. Powers called for a paradigm shift in how we think about DSME, arguing that the default should be for DSME to be included as part of diabetes clinical decision support systems. We applaud the ADA for putting these issues in the spotlight at this meeting and we similarly hope to see greater efforts in incorporating DSME into guidelines but also in raising greater awareness of access to programs for the patients themselves.

Detailed Discussion and Commentary

Posters

Pivotal Trial of a Hybrid Closed-Loop System in Type 1 Diabetes (99-LB)

R Bergenstal, B Buckingham, S Garg, S Weinzimer, R Brazg, J Ilany, B Bode, T Bailey, S Anderson, R Slover, J Shin, S Lee, F Kaufman

Medtronic presented a late-breaking poster on its single-arm, non-randomized, three-month pivotal study of the MiniMed 670G/Enlite 3 hybrid closed loop system in 124 participants (n=94 adults, 30 adolescents). The topline data compared to a two-week open-loop run-in period was excellent: (i) an impressive 0.5% reduction in A1c (!) from a low baseline (7.4%); time <70 mg/dl declined 44% (6% to 3%); and time <50 mg/dl declined 40% (1% to 0.6%). Wow! – it was highly impressive to see the impact on A1c, given the strong reduction in hypoglycemia and the very well-controlled population of pumpers. Notably, those with a baseline A1c >7.5% actually saw a 1% reduction after three months on the 670G. Time-in-range (71-180 mg/dl) improved from 67% during the baseline run-in to 72% during the study, with time >180 declining moderately (27% to 25%). While that improvement does not sound significant, it is clear from the compelling glucose profiles (see below) that the MiniMed 670G made extreme highs (e.g., 300 mg/dl) more moderate (e.g., 200 mg/dl), which didn’t show up as improvement in time in 70-180 mg/dl. The profiles are really worth looking at – they show how the MiniMed 670G tightened the range of glucose values throughout the entire day in both populations, with particularly strong efficacy overnight. Total daily dose increased ~7% from baseline (48 u to 51 u; p<0.001), though a smaller proportion of insulin was given as basal insulin (we unpack this below). Both adolescents and adults gained a bit of weight on the MiniMed 670G: +3 lbs (1.4 kg) in adults and +2 lbs (1.0 kg) in adolescents. While weight gain is never a positive, this does not strike us as big concern for the 670G or other hybrid closed loop systems, given potential for less hypoglycemia-induced weight gain. Hybrid closed loop was used for an impressive 87% of the three-month study period (median), with slightly higher usage in adults (88%) than adolescents (76%). The new Enlite 3 sensor showed a solid improvement, with an overall MARD of 10.3% vs. reference (i-STAT) over a 24-hour measurement period (part of the study’s six-day hotel phase). This was consistent with data shown at ATTD, though only 2% of points were in hypoglycemia.

• Overall, we see these pivotal data as compelling and outstanding for the entire field of automated insulin delivery. This study was clearly designed for speed and to prove safety to the FDA, so it’s hard to read too much into the efficacy results, where were not pre-specified endpoints. Still, reducing A1c 0.5% at the same time hypoglycemia declined 44% is a huge win – and the results were consistent in adolescents and adults. This was also a very real-world study in current pump users, some of whom were on CGM prior to study start. It’s clear that automated insulin delivery will make a difference even with first-gen hybrid closed loop products, and even in well-controlled patients. Of course, the hope is it can really improve outcomes for those with an A1c >10% or at high risk of severe hypoglycemia, groups that were both excluded from this study.
• In talking to investigators, the patient reactions they’ve heard have been even more impactful than the data. Said Dr. Rich Bergenstal, “This is a definite step forward. Beyond what the numbers say, the true benefit is in the stories of sleeping at night, peace of mind. I’m happy to get a little help from technology.” With an FDA submission planned before the end of this month, and 80% of pivotal study patients using this device as part of the FDA’s continued access program, we assume many of the other pump companies are nervous about these results. Of course, that will push all of them to move faster and differentiate their offerings.

RESULTS

• The MiniMed 670G drove an impressive 0.5% reduction in A1c from a low baseline (7.4%; p<0.001), including a 1% A1c reduction in patients with a baseline A1c >7.5%. Those with a baseline A1c of 7.0-7.5% saw a 0.3% reduction in A1c, while those with an A1c under 7% saw a 0.1% reduction in A1c. By the end of the study, 55% of trial participants had an A1c <7%, up from 31% at baseline.
  
  • The A1c improvement was consistent and highly significant across adults and adolescents: -0.5% in adults (baseline: 7.3%) and -0.6% in adolescents (baseline: 7.7%). Both were highly significant with p<0.001.
  • It is remarkable to see the impact on A1c, given the 44% reduction in hypoglycemia (see below) and the well-controlled population. We’re especially glad to see a strong 1% improvement in those with an A1c >7.5%, which brings hope this will be even more effective in those with an A1c >10% (who were excluded from the study).

• The MiniMed 670G tightened the range of glucose values throughout the entire day, particularly overnight. The modal day plots below show the median and interquartile range of sensor glucose values throughout the day and night in all patients (Panel A), adults (Panel B) and adolescents (Panel C). The gray band and dotted line shows the run-in phase, while the pink band and solid line show the study phase.
  
  • Consistent with pre-pivotal trials, the MiniMed 670G is most impactful overnight, driving patients down to ~140 mg/dl by early morning, tightening the range of overnight values, and eliminating hypoglycemia.
  • These modal plots really capture how much hybrid closed loop can make a difference at all times of day, even if it still requires manual boluses. Of course, systems are only going to get better with subsequent generations and faster insulin, and hybrid closed loop is a valuable first step.

Figure A: Modal Day – All Patients

Figure B: Modal Day – Adults

• The 670G narrowed the range of glucose values in well-controlled adults, though was slightly more conservative than open-loop therapy during the day. Note in the below that the black average line at most daytime points is higher than the dotted average line. This makes sense given the well controlled, early adopter study population and first-gen hybrid closed loop. Future generation products with more aggressive algorithms and faster insulins should drive further improvement during the day.

Figure C: Adolescents

• The 670G showed excellent efficacy in the tough adolescent population, improving hyper glycemia at all times of day, particularly extreme highs after breakfast and moderate highs in the evening. Average glucose levels were fairly consistent, with perhaps a slight edge to the 670G.

• Time-in-range (% of SG in 71-180 mg/dl) improved from 67% during the baseline run-in to 72% during the study, with time <70 mg/dl nearly halved (6% to 3%), time <50 mg/dl declining 40% (1% to 0.6%), and time >180 improving moderately (27% to 25%). All had p<0.001, and the improvements were pretty consistent between adults and adolescents. [Exceptions: adults saw more benefit on time <50 mg/dl, while adolescents saw more improvement in time >180 mg/dl.]
  
  • While the improvement in time-in-range does not sound significant, there are several critical factors to consider: (i) the reduction in hypoglycemia is very meaningful; (ii) patients were doing quite well during the run-in (67% in range); and (iii) based on the glucose profiles below, the MiniMed 670G clearly made extreme highs (e.g., 300 mg/dl) more moderate (e.g., 200 mg/dl), which didn’t show an improvement in time in 70-180 mg/dl, but still improved overall glycemia (see profiles below). The latter also explains why A1c improved at the same time hypoglycemia declined (which should raise A1c) and time >180 mg/dl didn’t change significantly.

* SG= Sensor Glucose

• The MiniMed 670G increased total daily dose ~7% from baseline (48 u to 51 u; p<0.001), though a smaller proportion of insulin was given as basal insulin. Since the MiniMed 670G only automates basal insulin delivery, the implication is patients were taking more manual boluses on hybrid closed loop (either in number or larger in size). Were they eating more or differently while on hybrid closed loop? If so, this could also explain the slight weight gain (see below)? The increase in insulin dose does not seem clinically significant, and many other studies have shown less or the same amount of insulin given.

• Both adolescents and adults gained a bit of weight on the MiniMed 670G: +3 lbs (1.4 kg) in adults and +2 lbs (1.0 kg) in adolescents. Oddly, these were both higher than the average weight gain for the overall study population reported on the poster (+1.5 lbs / 0.7 kg), so we’ve broken them out separately – we’re not sure what’s happening there but are following up with Medtronic.
  
  • While weight gain is never a positive, this does not strike us as a major concern for the 670G or other hybrid closed loop systems. We would not be surprised if further analyses reveal different eating behaviors while on hybrid closed loop. Keeping patients out of hypoglycemia could also help them lose weight, so the weight piece seems a bit difficult to interpret at this stage.

• Hybrid closed loop was used for an impressive 87% of the three-month study period (median), with slightly higher usage in adults (88%) than adolescents (76%). This was not further specified, but we see this usage as encouraging in a well-controlled population. Plus, >80% of pivotal study participants have continued using the system through the FDA’s continued access program, a good sign the benefits are worth it from a patient perspective. 

ENLITE ACCURACY

• The new Enlite 3 sensor showed a solid improvement, demonstrating an overall MARD of 10.3% vs. reference (i-STAT) over a 24-hour measurement period (part of the six-day hotel phase). There were very few points in hypoglycemia (2%) and hyperglycemia (25%), making it hard to compare this accuracy with other sensors. Still, the results are pretty consistent with what we’ve seen for Enlite 3 in other studies, including 11% in the pre-pivotal study presented at ATTD. Larger and more robust studies of Enlite 3, presented in four poster abstracts here at ADA 2016 (879-P, 897-P, 901-P, 916-P), suggest a similar ~10% MARD.
  
  • Medtronic still recommends 3-4 daily calibrations for Enlite 3, though the poster did not specify how many occurred in this study. We’re also not sure on what day of the sensor life this 24-hour CGM-reference accuracy comparison occurred.

STUDY STRENGTHS AND LIMITATIONS

STUDY BACKGROUND AND POPULATION

• This single-arm, non-randomized study enrolled pump users (≥6 months), with or without current use of CGM. Participants had to have type 1 diabetes for ≥2 years, an A1c <10%, and age 14-21 years old (adolescents) or 22-75 years old (adults).
  
  • Adolescent participants (n=30) had a mean age of 17 years, mean A1c of 7.7%, a mean BMI of 24 kg/m², and a total daily dose of 0.8 u/kg/day. The study enrolled 16 adolescents females and 14 adolescent males.
  • Adult participants (n=94) had a mean age of 45 years, mean A1c of 7.3%, a mean BMI of 27 kg/m², and a total daily dose of 0.6 u/kg/day. The study enrolled 53 adult females and 41 adult males.
• The MiniMed 670G/Enlite 3 was used in open-loop mode (with CGM) during a two-week run-in phase (baseline), then in closed-loop mode in a three-month study phase (unsupervised). The three-month phase included a six-day, five-night hotel stay for supervised activity and frequent venous blood glucose measurements (during one 24 hour period) with a reference instrument (i-STAT). This study was conducted at 10 sites in the US and Israel. 
• The 670G hybrid closed loop algorithm (ePID) automatically increases or decreases basal insulin, but all boluses require user input and confirmation (i.e., meal and correction boluses). Though not noted on the poster, here’s what we know about the algorithm: it targets 120 mg/dl, which can be raised to 150 mg/dl during exercise; it has a max limit on insulin delivery per hour and uses basal modulation to keep blood glucose in range (i.e., a hybrid closed loop that still requires meal boluses, and it cannot just correct a 350 mg/dl in one big correction bolus); it gives a new dose every five minutes; the 670G uses open-loop parameters to initialize hybrid closed loop (total daily insulin, basal, insulin:carb, insulin sensitivity factor); at the start of hybrid closed loop, there is a sensor accuracy check, along with a glycemic target adjustment for a smooth transition to closed-loop; the algorithm can adapt over time as things change; the 670G will revert to open loop if the sensor is inaccurate; and it will switch to safe mode or the pre-programmed basal rate in cases like sensor failure.
  
  • It’s worth noting that a missed meal bolus on the 670G hybrid closed loop could still mean several hours above range, as the higher basal rate will take a while to bring blood glucose back in zone. Still, the system is clearly much better than most patients are doing right now, and the hybrid closed loop is a great way to go until insulin gets faster and algorithms get even smarter.
  • Medtronic’s post-670G product will further close the loop by performing automatic correction boluses based on CGM values. Medtronic’s dinner tonight suggested it will enter a clinical study this month and be called the MiniMed 690G. This product will integrate the DreaMed MD-Logic algorithm to close the loop further – instead of only increasing basal insulin to gradually mitigate highs (670G) and bring blood glucose back to target, the next-gen algorithm will add automatic bolusing to correct highs. That should improve time-in-range much more and make the system more aggressive with missed meal boluses. The pre-ADA Analyst Meeting showed a picture of a smaller, touchscreen-looking, future-gen pump platform, but we’ve confirmed with Medtronic that is not the 690G.

Using Novel Flash Glucose-Sensing Technology Reduces Hypoglycemia in Individuals with Type 1 Diabetes (868-P)

Jan Bolinder, Ramiro Antuna, Nel Geelhoed-Duijvestijn, Stephan Matthaei, Raimund Weitgasser

In a poster presentation, Abbott shared long-awaited topline results from the FreeStyle Libre IMPACT study, a randomized six-month trial comparing Abbott’s FreeStyle Libre to SMBG in type 1 patients on MDI/pump therapy in very good control (baseline A1c: 6.7 %). The study randomized 241 type 1 patients 1:1 to use either capillary blood glucose testing (n=120; FreeStyle Lite) or real-time use of FreeStyle Libre (n=121). The data will be presented in full tomorrow (1 PM poster presentation; 7 PM symposium), but we wanted to bring you our analysis in a timely fashion following the poster’s appearance this morning.

After REPLACE, we were pleased to see that IMPACT’s primary endpoint was met at six months – relative to the control group, patients using FreeStyle Libre spent ~74 minutes fewer per day <70 mg/dl (a 38% reduction; p<0.001). There was not a significant difference in A1c between the groups by study end, though both saw a 0.15% increase from baseline to six months (6.7% to 6.9%). Certainly, the “quality” of A1c was improved immeasurably. Pre-specified secondary endpoints were particularly compelling – patients using Libre spent ~49 minutes fewer per day <55 mg/dl (a 50% reduction; p<0.0001) and ~33 minutes fewer per day <45 mg/dl (a 60% reduction; p<0.0001). These are remarkably important indicators since changes in a small number of minutes spent in that dangerously low range could mean many healthcare dollars saved annually; we have to imagine that that is one of the most compelling takeaways for Abbott and would form the crux of any reimbursement strategy. Measures of nocturnal hypoglycemia were also significantly lower with FreeStyle Libre as patients spent ~28 minutes fewer per night (a 40% reduction; p<0.0001) in hypoglycemia. The data here help counter the argument that the device’s lack of alarms poses a nighttime danger; we now have two sets of solid evidence that data from Libre can help patients and providers identify some nocturnal hypoglycemia and make change accordingly – good news for Abbott. Patients using Libre spent 22 minutes fewer per day in extreme hyperglycemia > 240 mg/dl (p=0.02) and spent ~60 minutes greater/day between 70-180 mg/dl (p=0.0006). FreeStyle Libre pretty much completely replaced fingerstick testing, suggesting a high level of confidence in the factory-calibrated sensor: SMBG frequency with FreeStyle Libre fell from a mean of ~5.5 tests/day at baseline to 0.5 tests/day (one every two days) at six months, a testament to the real-world accuracy in patients on insulin therapy. Quality of life data was significantly in favor of FreeStyle Libre. There were no device-related serious adverse events and 13 instances of minimal adverse events (e.g., infection, allergy) reported by 10 subjects.

• The positive results of IMPACT are not a surprise after REPLACE, and highlight the high and very unsettling degree of hypoglycemia type 1 patients on insulin therapy are experiencing every day. The hypoglycemia data discussed above is very clinically meaningful (-74 minutes per day) – notably, there is still much room to improve time spent in hypoglcyemia, given that patients on Libre were still spending two hours (!) <70 mg/dl per day at six months. Presumably when patients are receiving active advice from HCPs on how to change therapy (particularly to reduce hyperglycemia), this would improve further. Meanwhile, control group patients were still spending over three hours <70 mg/dl per day! In that sense, the results tell us as much about Libre as they do about the real-world dangers of insulin therapy, particularly in these well controlled, motivated patients who are clearly still skating close to the edge. Avoiding hypoglycemia on insulin therapy is truly, truly difficult as A1c gets below 7%, and we’re not sure that delicate balance is appreciated enough. The message here is to give patients and providers better tools to detect hypoglycemia patterns and titrate insulin therapy better, accordingly.
• These data also underscore the limitations in using A1c as an endpoint for diabetes technology (this study did not, unlike REPLACE). Both groups saw a 0.15% increase in A1c in this study (6.7% to 6.9%), though the quality of A1c improved markedly in the FreeStyle Libre group – 74 fewer minutes per day <70 mg/dl (a 38% reduction), and 33 fewer minutes per day <45 mg/dl (a 60% reduction in time spent at a highly dangerous level). Meanwhile, the control group was still spending three hours per day in hypoglycemia with an A1c 6.9%! Do payers appreciate the gravity of that change? How could that change impact short and long-term costs? Some may criticize that Libre did not improve A1c in this study, though we think it would have been unlikely: the population had a very low A1c to start (6.7%), there was no mandatory per-protocol insulin adjustment, and the baseline hypoglycemia was simply too high to drive things down further. While we do not suggest comparing results since the technologies were not used head-to-head, some will note that the MiniMed 670G pivotal reduced A1c 0.5% from a higher 7.4% baseline and drove a 40% reduction in hypoglycemia – that Medtronic study did not have a control group, and time spent in hypoglycemia was 1.4 hours per day during the 670G baseline compared to 3.4 hours per day in this study. Overall, it’s terrific to see multiple technologies focused on creating greater safety and higher-quality A1cs for patients – patients will choose technologies based on cost, convenience, etc.  
• Presumably, Abbott can secure some FreeStyle Libre reimbursement with these outcomes studies. Even nearer term, they could help secure FDA approval of the real-time version of FreeStyle Libre, with now two robust RCTs in the bank showing patients on Libre basically stop doing fingersticks.
• We highly commend Abbott for conducting these two long-term outcomes studies to put its glucose monitoring technology to the test in a real-world setting – REPLACE focused on reducing A1c in poorly controlled type 2s, and IMPACT focused on cutting hypoglycemia in well-controlled type 1s. Notably, neither study mandated insulin adjustment, leaving it up to clinicians and patients to make therapy changes as they saw fit. That ensured a real-world study, though perhaps left some efficacy on the table – it also reinforces in the “real world” how often patients are told they are in “good control” even with a significant amount of hypoglycemia.

Study Design

• IMPACT (ClinicalTrials.gov Identifier: NCT02232698) randomly assigned 241 type 1 patients 1:1 to use either capillary blood glucose testing (n=120; FreeStyle Lite) or sensor glucose data (n=121; FreeStyle Libre) for optimization of glucose levels. All patients entered the study as regular blood glucose testers (~5 fingersticks/day). During the study phase, patients in the intervention arm reviewed FreeStyle Libre Software summary reports (Ambulatory Glucose Profiles) with their clinician at regular intervals in order to make therapy adjustments, while those in the control arm reviewed diary readings with their clinician at similar intervals.
• Notably, insulin dose adjustments were made on an intention-to-treat basis. Providers were instructed to optimize therapy as they saw fit, but there were no A1c targets or previously mandated dose adjustments. This made it a very real-world study, and what we might expect from FreeStyle Libre in routine use.
• Patients at baseline had a mean age of 44 years, a mean A1c of 6.7%, a mean 22 year duration of diabetes, a mean BMI of 25 kg/m², and a mean self-reported blood glucose frequency of ~5.5 per day. Roughly 67% of patients (n=161) were on MDI. In short, this was a population with high potential to reduce hypoglycemia meaningfully if they were acting on data, but a challenging one in which to show an A1c benefit.

Results

• All measures of hypoglycemia were significantly lower following intervention with FreeStyle Libre vs. SMBG. Specifically, patients: (i) spent ~74 minutes fewer/day < 70 mg/dl (p<0.0001); spent ~49 minutes fewer/day < 55 mg/dl (p=0.001); (iii) spent ~33 minutes fewer/day <45 mg/dl (p<0.0001); and (iv) spent ~28 minutes fewer/night (p<0.0001). These are very important data given the costs associated with hypoglycemia, and the true dangers of spending any time at all <45 mg/dl.
  
  • Despite the encouraging trend above, we were struck by the prevalence of hypoglycemia at all levels. All patients at baseline experienced far-too-high ~200 minutes per day < 70 mg/dl, while patients on Libre experienced a still-far-too-high ~120 minutes per day < 70 mg/dl at six months.

Table: Hypoglycemia Data

• There was no significant difference in A1c between the groups, though both saw a slight numerical increase (0.15%). This was probably to be expected, given the incredibly low average and the ridiculous amount of hypoglycemia all patients saw at baseline.

Table: A1c Data

• Patients using Libre spent ~22 minutes fewer/day > 240 mg/dl (p=0.02) and spent ~60 minutes greater/day between 70-180 mg/dl (p=0.0006). We were glad to see time-in-range and time above range improve, suggesting the reduction in hypoglycemia was going to more quality time spent in an ideal glucose range. 

Table: Time-in-Range / Hyperglycemia Data

• As we saw in REPLACE, FreeStyle Libre pretty much completely replaced blood glucose testing, suggesting a high level of confidence in the factory-calibrated sensor. SMBG frequency with FreeStyle Libre fell from a mean of ~5.5 tests/day at baseline to 0.5 tests/day (one every two days) at six months. The trend is a testament to the real-world accuracy of FreeStyle Libre in patients on insulin therapy.

Figure: Number of FreeStyle Libre Scans and Blood Glucose Tests Per Day

• Patients in the FreeStyle Libre arm scanned for glucose 15.1 times per day, which is more than once every two waking hours. This is certainly more real-time glucose data than they were getting with SMBG! As a reminder, FreeStyle Libre’s label recommends confirmatory fingersticks in the EU: (i) during times of rapidly changing glucose; (ii) when hypoglycemia or impending hypoglycemia is reported by the system; or (iii) when symptoms do not match the system readings. However, these data continue to remind us that patients do not do fingersticks with FreeStyle Libre in the real world, something we’ve been hearing since the system launched.
  
  • The control group maintained their level of blood glucose testing through the study – baseline: ~5.5 test/day; six months: 5.6 tests/day.
• The poster also shared positive user experience data of FreeStyle Libre from the study. There was no background on how these questions were asked – we assume Yes/No – and we’re not how large the absolute improvements were on these scales. Overall, patients reported significantly improved satisfaction, convenience, and flexibility associated with Libre, and reported significantly greater satisfaction with their understanding of diabetes. They were significantly more likely to recommend Libre and to be satisfied continuing Libre use.
  
  • DQol satisfaction with treatment score and total worry score significantly improved with FreeStyle Libre vs. control (p<0.0001).
  • Perceived frequency of hyperglycemia was significantly improved with Libre vs. control (p<0.0001).
  • Diabetes Treatment Satisfaction Questionnaire showed increased treatment satisfaction with Libre vs. control (p<0.0001). We’ve broken down the DTSQ results below:
    • Patients reported significantly improved satisfaction with Libre than with their control baseline therapy (p<0.0001).
    • Patients reported significantly greater convenience with Libre than with their baseline therapy (p<0.0001).
    • Patients reported significantly greater flexibility with Libre than with their baseline therapy (p<0.0001).
    • Patients reported significantly greater satisfaction with their understanding of diabetes when using Libre than when using their baseline therapy (p<0.0018).
    • Patients were significantly more likely to recommend Libre therapy to someone else with diabetes than their baseline therapy (p=0.001).
    • Patients were significantly more likely to be satisfied continuing Libre treatment than they would be continuing their baseline therapy (p<0.0001).

Close Concerns’ Analysis

• The hypoglycemia improvement definitely lived up to our expectations. All measures of hypoglycemia (day+night and nocturnal) were significantly lower with FreeStyle Libre, and it’s quite evident that these results are meaningful – minutes of dangerous hypoglycemia saved daily could translate to ER visits avoided. The 50% reduction in time spent < 45 mg/dl is particularly striking.
  
  • Yikes, hypoglycemia is a real concern, and we finally have a tool to measure it. The results document not just the VERY high prevalence of hypoglycemia at baseline (> ~200 minutes per day < 70 mg/dl) but even after six months on Libre (~120 minutes per day < 70 mg/dl). Ultimately, the numbers speak to just how hard it is to dose insulin appropriately AND avoid hypoglycemia while getting A1c under control, a fact that is so often underappreciated. Looking at these numbers, we were reminded that devices do not improve diabetes management in isolation and – from a patient perspective – that accessible, smarter methods of insulin delivery are just as key.
  • IMPACT was designed with reimbursement in mind, and we wonder if payers will appreciate the value of the “higher quality” A1cs achieved here. This is a place where we believe patients can make a difference with advocacy, if they get organized. We’ve heard time and again that payers view A1c as the ultimate endpoint. We hope the time <45 mg/dl data is compelling for showing short-term cost savings. We also wonder if Abbott might be able to leverage its new data management platform LibreView to answer payer’s concerns. [See our detailed coverage of LibreView in Abbott’s exhibit hall write-up below.] Abbott’s long-term plan is to allow Libre glucose data to automatically populate LibreView upon scanning, and we imagine it would provide Abbott the ability to collect real-world personal uploads from Libre users in the same way that Medtronic and Dexcom collect personal uploads from CareLink and Clarity downloads. Medtronic has shown similar Big Data on cost reductions associated with the MiniMed 530G driving less hypoglycemia, and we imagine that Abbott could do the same. If the UHC/Medtronic deal shows one thing, it’s that payers need to be persuaded with data to reimburse technology.
  • Libre has seen impressive uptake, even out-of-pocket. What could these results add? Sales of Libre outside the US have driven four consecutive quarter of operational growth in the International business, though we do believe that reimbursement could be the key that will unlock the floodgates for Abbott. Could these results drive further uptake?
• All in all, we commend Abbott for breaking the mold in glucose monitoring by conducting now two long-term outcomes study of its device. There is certainly a wealth of evidence here that more frequent, actionable glucose data is beneficial for patients and that A1c in isolation just isn’t the best metric for clinical studies. As the evidence mounts, we hope that this will be reinforced.

Closing the Loop on Insulin Management—Are We There Yet?

Home Use of a Bihormonal Bionic Pancreas vs. Conventional Insulin Pump Therapy in Adults with Type 1 Diabetes—A Multicenter, Randomized Clinical Trial (77-oR)

Ed Damiano, PhD (CEO, Beta Bionics / Boston University, Boston, MA)

Beta Bionics’ CEO Dr. Ed Damiano revealed that Zealand’s phase 2 liquid stable glucagon analog will be tested in the 4Q16 bridging study of the fully integrated iLet Bionic Pancreas. The pivotal studies are still expected to start in 2Q17, and the bihormonal pivotal will last 12 months to gain chronic glucagon exposure data. Zealand actually put out a press release yesterday announcing the collaboration with Beta Bionics, a big win for Dr. Damiano’s new public benefit corporation to commercialize the Bionic Pancreas. Xeris has not moved particularly fast on its stable glucagon, and Zealand’s deep experience in protein chemistry will be a major asset on this intractable problem. Dr. Steven Russell hinted at ATTD that Zealand’s phase 2 glucagon might be used, though today was the first confirmation it is the glucagon of choice going forward. Dr. Damiano did not comment on the submission timing, but we assume the plan is still an end of 2017 insulin-only PMA submission, with a potential PMA supplement to add glucagon in early 2019.

• Dr. Damiano’s oral presentation focused on the Bionic Pancreas 11-day multi-center home study (n=39), shared at several symposium presentations since GTCBio 2015 over a year ago. As a reminder, the study was the team’s first true home-use study, comparing 11 days of Bionic Pancreas to 11 days of conventional pump therapy. Mean CGM glucose improved from 162 mg/dl on usual care to 141 mg/dl on the Bionic Pancreas, projecting an A1c improvement of 0.8% (baseline: 7.3%). Time <60 dropped by two-thirds (from 1.9% to 0.6%), while time >180 declined from 34% to 20%. Dr. Damiano emphasized the device’s ability to dramatically reduce inter-subject variability, to not deliver excess insulin (0.62 u/kg/day vs. 0.66 u/kg/day), and to adapt to patients based on using just body weight at initialization.

Outpatient Glycemic Management in Type 1 Diabetes with Insulin-Only vs. Bihormonal Configurations of a Bionic Pancreas (79-OR)

Laya Ekhlaspour, MD (MGH, Boston, MA)

MGH’s Dr. Laya Ekhlaspour reiterated the insulin-only vs. bihormonal glycemic target studies first shared at ATTD. “Glucagon allows more subjects to have a mean glucose <154 mg/dl without increasing hypoglycemia.” We’ve reproduced the key findings below from the randomized, crossover study (n=20) comparing usual care to insulin-only and bihormonal versions of the Bionic Pancreas at different glycemic targets (insulin-only: 130 and 145 mg/dl; bihormonal: 100, 115, 130 mg/dl). The insulin-only and bihormonal systems were actually very similar with a glycemic target of 130 mg/dl: a mean glucose of 161 vs. 156 mg/dl and time <60 mg/dl of 0.8% vs. 0.5%. As the bihormonal target dropped to 115 and 110 mg/dl, mean glucose improved to 146 and 136 mg/dl without increasing hypoglycemia. The team is now exploring an insulin-only target of 110 mg/dl, as the use of 130 mg/dl was intentionally conservative.

• This study shows just how important glycemic target is to system performance, and echoes the takeaway from yesterday that closed-loop system should have adjustable target set points. The big question for glucagon, of course, is how much mean glucose, hypoglycemia, and user experience improves when the hormone is added to an insulin-only system.

Similar Estimated A1c Results Reported between Patients with Diabetes Using CGM whether on Multiple Daily Injection (MDI) or Continuous Subcutaneous Insulin Infusion (CSII) (81-OR)

David Price, MD (Dexcom, San Diego, CA)

Dexcom’s Dr. David Price shared a retrospective database evaluation from six months of G4 Share users, showing no differences in mean glucose, estimated A1c, or glucose variability between pump (n=939) or MDI (n=648) users. The de-identified data on glucose values were supplemented by customer info (age, insulin delivery) that Dexcom collects. The pump and MDI groups had identical average glucose values and variability across every age group (from 2-6 year-olds all the way to 65+ year olds), with just a single small exception: glucose variability was statistically significantly lower in adolescents (13-18 years) using injections. As would be expected, adult CGM users had better average glucose values vs. pediatric CGM users by ~30 mg/dl (see tables below estimated from the charts shown). This analysis also aligns with results from the T1D Exchange showing that in every age group, the same pattern holds – similar A1cs for CGM users on MDI or a pump. Could this provide a preview of what the randomized DIaMonD study will show tomorrow (Sunday, 4:30 pm) – that CGM is just as beneficial in injectors as pumpers? Dr. Price noted that CGM use is increasing (now up to 16% in the T1D Exchange), but is overwhelmingly prescribed to pumpers: of all Exchange CGM users, 85% are on pumps vs. just 15% on MDI. Studies like this also underscore the inherent value in data streaming from devices to the cloud automatically – companies can use it to put data behind their arguments, drive study design, and inform marketing. Medtronic has written the book on this with CareLink, and we expect Dexcom will begin driving this too. 

~ Estimated from Bar Graphs

~ Estimated from Bar Graphs

Posters

Effect of Exenatide Once Weekly on Glycemic Fluctuations in Patients with T2D

Juan Frias, MD (NRI, Los Angelas, CA), James Ruggles, Sergey Zhuplatov, Samer Nakhle, Eric Klein, Rong Zhou, Lei Shi, Poul Strange

Dr. Juan Frias (NRI, Los Angelas, CA), et al. conducted a randomized, controlled, double blind study investigating the effects of AZ’s Bydureon (exenatide once weekly) on glucose fluctuations in patients with type 2 diabetes. The study recruited 117 adult patients well-controlled on metformin (A1c 7-10%), who were randomized to open-label metformin XR (1500 or 2000mg daily) plus double-blinded Bydureon 2.0 mg (n=61) or placebo (n=56). Glucose concentration was measured via the Dexcom G4 CGM every 5 minutes during the last week before randomization (baseline), as well as during weeks 4 and 10. Compared to placebo, Bydureon provided significantly greater reductions in 24-h mean glucose on day six of week four (5.3 mg/dl vs. 26.0 mg/dl, respectively) and on day six of week 10 (3.0 mg/dl vs. 30.8 mg/dl, respectively).  Similar results were observed for fasting plasma glucose (FPG), postprandial glucose (PPG), and mean amplitude of glycemic excursions (MAGE) (please see table 1 below). Those on Bydureon experienced a significant increase in the time spent in euglycemia (70-180 mg/dl) from baseline to week four and week 10 (p<0.001 for both) – this was secondary to reductions in time spent in hyperglycemia (>180 mg/dl), with no increase in the time spent in hypoglycemia (<70 mg/dl); the finding was not observed in the placebo group. The authors concluded that Bydureon provides robust effects on measures of glycemic fluctuation at week four that persist to week 10.

• Both groups had eight patients withdraw from the study, leading to a retention rate of 87% in the exenatide group (53 patients analyzed) and of 86% in the placebo group (48 patients).
• Baseline characteristics were comparable between the two groups, with an average age of 55-56 years, percent male of 55-57%, similar race breakdown, duration of diabetes of 9-10 years, pre-trial metformin dose of 1,875-1,925 mg, body weight of 90-91 kg, BMI of 32, A1c of 8.0-8.2%, fasting plasma glucose of 168-178 mg/dl, 2-h mean post-prandial glucose of 221 mg/dl, 24-h mean glucose of 184-186 mg/dl, and MAGE of 90-91.
• Table 1: Effect of Bydureon vs. placebo on measures of glucose control and fluctuation

• Table 2: Effect of Bydureon vs. placebo on time spent in euglycemia and hyperglycemia

  Numeric data was not provided for time spent in the hypoglycemia range (<70 mg/dl)

  * p<0.001 for baseline vs. week 4 in the EQW group

  # p<0.001 for baseline vs. week 10 in the EQW group

• Serious adverse events were observed in four patients in the Bydureon group (one case each of acute pancreatitis, non-cardiac chest pain, chest pain, and nephrolithiasis), as well as in one patient in the placebo group (upper respiratory tract infection). The investigators considered these events to be unrelated to treatment.

Symposium: This Is How You Do It – Medication Options, Sequence, and Combinations for Optimal Management of Type 2 Diabetes

Bringing It All Together – What the Objective Clinician Should Do

Christopher Sorli, MD, PhD (Billings Clinic, MT)

Dr. Christopher Sorli introduced a series of valuable visual aids to help clinicians appropriately identify the optimal patient population for each diabetes medication. These “clinical density plots” include a trendline representing endogenous insulin secretion as a function of time and three trendlines representing insulin resistance level (for high, modest, and low insulin resistance). Patients that fall toward the bottom right section of the plot, representing those with a long duration of diabetes, low endogenous insulin secretion, and lower insulin resistance, should prioritize minimizing hypoglycemia risk. Patients that fall toward the top left of the graph, representing those with a shorter duration of diabetes, relatively preserved insulin secretion, and high insulin resistance, should prioritize treatments that have weight neutral or beneficial effects. Within this graph, shading of various sections of the graph indicates the patient population for which a particular treatment may be recommended, considered, or not recommended. Overall, Dr. Sorli most strongly recommended metformin, GLP-1 agonists, and SGLT-2 inhibitors for those who have relatively short diabetes duration and are concerned about weight gain. He recommended DPP-4 inhibitors and insulin for those with longer disease duration. Patients in the middle would do best with metformin, GLP-1 agonists, SGLT-2 inhibitors, and DPP-4 inhibitors in his view. We see these plots as a useful visual education tool for providers (especially primary care physicians) to help synthesize the benefits and risks of different drugs for individual patients in an understandable way. See below for pictures of the clinical density plots and accompanying thoughts for each major drug class.

• Metformin: Dr. Sorli generally supported the use of metformin as a first-line agent, but emphasized that it may not be the best medication for everyone. In particular, he noted that the drug has less efficacy in patients with longer disease duration and a lower insulin resistance level.

• Sulfonylureas: Not surprisingly, Dr. Sorli emphasized that sulfonylureas are only useful for patients with a degree of endogenous insulin production. Further, he pointed out that the use of the class could further stress the beta cells and reduce beta cell function, thus doing little to positively modify the course of the disease. Dr. Sorli also expressed concern about the weight gain associated with sulfonylureas. Ultimately, he asserted that the only real driver of sulfonylurea use is its cost and noted that he would only prescribe a patient a sulfonylurea if it were the only medication that they would be able to financially access.

• TZD Pioglitazone: While acknowledging that TZDs have largely fallen out of favor among patients and prescribers, Dr. Sorli argued that it’s not necessarily a “total nonstarter” to consider pioglitazone specifically in patients with very high insulin resistance. He also noted that pioglitazone may have beneficial effects on triglycerides, HDL cholesterol, and NASH and may even have a cardiovascular benefit. On the other hand, he acknowledged that weight gain and risks of congestive heart failure, edema, and fractures remain a concern.

• GLP-1 agonists: Dr. Sorli supported the use of GLP-1 agonists across a broad patient population from early- to late-stage disease in both those that are extremely insulin resistant and those that are relatively insulin sensitive. He especially highlighted the low risk of hypoglycemia and weight loss benefits, though he noted that the GI tolerability is a concern for some patients.

• DPP-4 inhibitors: Dr. Sorli classified this class as “exceptionally tolerable” agents. He particularly supports the use of DPP-4 inhibitors in geriatric patients. On the other hand, the lack of weight loss with DPP-4 inhibitors is a drawback when he considers their use in his highly insulin resistant patients. Overall, he stated that in his younger patients with insulin resistance, he tends to “twist their arms” to go on to a GLP-1 agonist instead.

• SGLT-2 inhibitors: The non-insulin dependent mechanism of the SGLT-2 inhibitor class led Dr. Sorli to suggest they are highly applicable across a broad range of patients. He praised the low hypoglycemia risk and weight benefit of the class, but noted that the medications have reduced efficacy in those with reduced kidney function and there may be issues with their use in patients already on other diuretic medications.

• Insulin: Dr. Sorli highlighted the titratable efficacy of insulin as a huge plus that allows its use in a broad range of patients across the insulin resistance spectrum. He also suggested that insulin may have disease modification properties when used early in the disease progression. Dr. Robert Ratner (ADA, Alexandria, VA) has similarly suggested that use of insulin in early-onset diabetes in the ORIGIN trial allowed patients to achieve consistent low A1cs. That said, Dr. Sorli noted that he does not see insulin as a first choice option after metformin but rather as an appealing part of a combination approach.

• GLP-1 agonist/basal insulin: Dr. Sorli sees GLP-1 agonist/basal insulin fixed-ratio combinations as an appropriate choice for a fairly broad patient population given the broad applicability of both classes. Despite his support for the use of insulin in combination with another agent following metformin, however, he expressed that he’d prefer to be able to titrate the two components separately in some cases.

Special Lecture: President, Health Care, & Education Address

Circles of Diabetes Care – From Complexity to Clarity

Margaret Powers, PhD (American Diabetes Association, Alexandria, VA)

Earning a standing ovation, Dr. Margaret Powers made a forceful argument for the value of and need for increased access to diabetes self-management education (DSME). Challenging the packed ballroom to think of DSME as a diabetes treatment in the same sense as a drug therapy (“If DSME was a pill, would you prescribe it?”), Dr. Powers demonstrated through the ADA/EASD position statement criteria that DSME is one of, if not, the best treatments available. Specifically, comparing DSME with metformin, she concluded that DSME was at least as effective, if not better, across all criteria. Dr. Powers noted that despite this powerful analysis, only 6.8% of individuals with private insurance receive DSME in the first year of their diagnosis, and only 5% of Medicare patients receive DSME. Pointing out that DSME additionally has psychosocial benefits that no drug intervention can replicate, Dr. Powers called for a paradigm shift in how we think about DSME, arguing that the default should be for DSME to be included as part of diabetes clinical decision support systems. We applaud the ADA for putting these issues in the spotlight at this meeting and we similarly hope to see greater efforts in incorporating DSME into guidelines but also in raising greater awareness of access to programs for the patients themselves.

• Dr. Powers argued that, if DSME were a medication, it would score highly in terms of efficacy, hypoglycemia risk, weight loss, side effects, and costs. She pointed to multiple studies that show high (>1%) A1c reduction with DSME, touted its near-total lack of hypoglycemia risk and side effects – even earning a round of applause when noting this – and noted at worst, a neutral (and quite possibly positive) effect on weight. She made it clear several times that reimbursement is, in fact, available for DSME from Medicare and most private insurers, meaning costs are also a wash when compared with medications like metformin – see our coverage of Medicare’s historic reimbursement of the Diabetes Prevention Program (DPP).
• In addition, Dr. Powers presented an even more powerful cost argument, demonstrating the potential of healthcare savings. While admitting that costs were the most difficult comparison (given the underrated availability of reimbursement), she pointed to one study that found that the average annual hospital charges for 33,000 patients who received any education was $6,244, which is 39% less than the $10,258 yearly average for those who received no education. As the evidence base around cost savings remains limited, it’s studies like these that we believe are so critical to bring into conversations with policymakers and payers.
• According to Dr. Powers, DSME carries psychosocial benefits that medications do not. These include reduction of diabetes distress and the often hidden emotional burdens that come with managing a demanding, progressive chronic disease like diabetes. Dr. Powers noted that DSME also improves quality of life, self-efficacy, healthy coping, knowledge, self-care behaviors, adherence to food plans, healthy food choices, and physical activity. As the field is paying greater attention to the emotional wellbeing and psychosocial aspects of diabetes, we hope that this particular point can prove to make the DSME value argument even more powerful.

Closing the Loop on Insulin Management – Are We There Yet?

Randomized Crossover Clinical Trial Comparing MPC and PID Control Algorithms for Artificial Pancreas (80-OR)

Frank Doyle, PhD (Harvard, Cambridge, MA)

Dr. Frank Doyle presented results from what he termed the “first, balanced, randomized study” comparing MPC and PID closed-loop control algorithms that came to two major conclusions: (i) that MPC outperformed PID on both the primary outcome and several secondary  clinical metrics; and (ii) that both algorithms provided safe and effective glycemic control. This is the first time we’ve seen results from this crossover study, which randomized 20 patients to each algorithm for a supervised 27.5-hour session that incorporated both announced and unannounced meal challenges. Broadly, findings very strongly favored the MPC algorithm – patients using MPC saw significantly greater time in range (70-180 mg/dl) throughout the study vs. those on PID (74% vs. 64%, p=0.02). Patients on MPC also seriously reduced their mean glucose both during the entire trial (138 vs. 160 mg/dl, p=0.012) and during the five-hour period after the unannounced meal (181 vs. 220 mg/dl, p=0.019). Dr. Doyle noted that there were no statistically significant differences in hypoglycemia (<70 mg/dl) though he did acknowledge that the frequency of hypoglycemic episodes was higher in the MPC group. Ultimately, we would point out that these were both relatively basic iterations of both control systems and that the results do not preclude the use of PID in the closed-loop setting or suggest that all MPC systems are superior to those leveraging PID. Instead, we felt Dr. Doyle made the case that the core of the MPC algorithm may be better suited to managing artificial pancreas (insulin delays and pump constraints), in addition to that fact that MPC is a more flexible platform for adding other functionality.

• For context, Dr. Doyle shared that standard and matched versions of both the MPC and PID algorithms were developed using well-known model-based methods. The algorithms had identical set-point control objectives (110 mg/dl) and had similar built-in features to prevent insulin stacking to ensure equitable testing conditions. Indeed, Dr. Doyle presented data from an in silico modeling experiment confirming that both algorithms performed very comparable in this controlled setting.
• Study design: Dr. Doyle explained that both algorithms were compared in two supervised 27.5-hour closed-loop sessions. Challenges in the study were designed to mimic the use of an artificial pancreas in the real world and to stress the algorithms. These challenges included no prior optimization of insulin pump parameters to initialize the system, overnight control after a 65 g carbohydrate (CHO) dinner, response to a 50 g CHO breakfast (both bolused at mealtime), and an unannounced 65 g CHO lunch to evaluate a missed meal bolus scenario.

Questions and Answers

Q: This may be an artifact of the short study but I noticed that your two algorithms were pretty convergent for first day and where you saw separation was in evening. Do you have differences between these algorithms overnight? Because that’s when you really see that separation occurring.

A: There was insulin-on-board vs. insulin feedback built into the MPC and PID algorithms, respectively, so it could have to do with that. I will say that the number of occurrences of pump suspension was higher for PID, so there’s an indication that MPC was more effectively using insulin in the presence of pump constraints (including IOB). 

Exhibit Hall

Abbott

A rotating, circular sign reading “FreeStyle Libre Pro” and accompanying a picture of the FreeStyle Libre Pro sensor and reader heralded BIG news in Abbott’s spacious booth … and the exhibit did not disappoint with a slew of updates: (i) the US debut of FreeStyle Libre Pro on an Exhibit Hall floor (still under FDA review); (ii) confirmation that the consumer version has not been submitted to FDA; (iii) an updated timeline on LibreLink – multiple EU launches slated for this month; (iv) the debut of Abbott’s new LibreView data management software; (v) news that LibreLink will soon sync with LibreView; and (vi) confirmation that the company is working hard on LibreLink Apple compatibility and further discussion about the possibility of an iPhone adapter to power the NFC-reading capability. See details on all the highlights below:

• Abbott has chosen ADA 2016 to debut its Libre Pro sensor at a US conference for the first time and came out with strong marketing intent. Among many gizmos and gadgets on hand, the booth featured a touchscreen display complete with videos that introduced attendees to Libre Pro’s features, seemingly omnipresent Libre Pro signage, and multiple demo sensors and readers on display. Reps and booth-goers alike shared huge enthusiasm for Libre Pro though the former were very quick to point out that the product remains at FDA with no timeline for approval. As a reminder, the product was most recently slated for a mid-2016 US launch (submitted in 2Q15), which would mean an approval would have to come soon to meet this timeline. It sounds like there are plans to launch Libre Pro in additional international territories in coming months (it’s currently available in India) though reps did not share any further details.
  
  • We happened to drop by the Abbott booth at the same time as a noted KOL, who asked an interesting question: Will providers have the option to give the Libre Pro reader to patients unblinded? The answer was a firm “No,” to which the KOL suggested that the professional version might see better uptake if this functionality was built in. He spoke to his positive experience giving Dexcom G4 CGMs to patients in a professional setting unblinded and the benefit of allowing them to see their data – he spoke in particular to the teachable moments unblinded CGM can create – e.g., connecting the dots between eating ice cream before bed and having a high morning fasting glucose. We, too, would love to see this functionality built in though can understand the counter-argument that the majority patients suitable for professional CGM/Libre might be overwhelmed if they were to go from intermittent BGM to continuous glucose data. We look forward to more discussion on this front.
• There were no updates on the US timing of the FreeStyle Libre consumer version, and management confirmed today that the system has yet to be submitted to the FDA. As a reminder, Abbott CEO Miles White said last year that the consumer version could be “optimistically” approved in time for an end of 2016 launch; that seems less likely at this point. 
• On the EU front, we learned an interesting new detail that FreeStyle Libre is available in readers that report in “mg/dl” or “mmol/l.” We had previously thought that only the latter was available. However, depending on the territory, management confirmed that there are Libre readers coded in both units, though individual readers do not allow patients to switch between mg/dl and mmol/l for safety purposes.
• Reps confirmed that LibreLink has seen a successful launch in Sweden and the Netherlands and remarked that the mobile app would come to other EU countries where FreeStyle Libre is available (Italy, Spain, Germany, France, and the UK) by the “end of the month.” See our coverage from earlier this week. We’re not sure if this was simply off-the-cuff commentary – especially given that Abbott said during Thursday’s official Sweden/Netherlands launch that only the German launch would come this month – but hints that Abbott is pushing strongly to get this to more patients as quickly as possible.
• Abbott continues to work “eagerly” on expanding LibreLink to Apple devices though reps reiterated ATTD commentary that the device may require an iPhone adapter to power the NFC-reading capability. As a reminder, the iPhone franchise (up to and including iPhone 5S) has not had NFC built-in and it sounds like this solution would work for both existing iPhones and the iPhone 6 (that, in fact, does support NFC but – according to the rep – does not have the ability to read data from Libre.) As we understand it, the adapter would be plugged into the headphone jack, would scan data from the sensor, and would then send the data straight to the app. We applaud management for identifying a workaround though it is a less-than-deal solution – requiring an adapter negates the seamlessness and patient convenience of scanning with just a phone alone.
• Abbott also unveiled its new LibreView cloud-based data management software – this is the first time we’ve seen the software on display in an exhibit hall. According to reps, the platform soft-launched in September 2015 but the company is still building up compatibility to support a full launch. The software allows patients to download data from both Abbott and other proprietary BGMs using an appropriate USB cable and can give healthcare professionals access to glucose data. We didn’t get the chance to explore the cloud-based software in depth, but it looks like the platform in its current form provides graphical displays with typical glucose trends and statistics – key for staying competitive with Medtronic CareLink and Dexcom Clarity. We did not see AGP graphs on any of the LibreView pictures, but assume this is part of the program.
  
  • We were told that LibreView will soon sync data from LibreLink, a logical step to keep FreeStyle Libre competitive on the connectivity and software fronts with Medtronic (Guardian and CareLink) and Dexcom (G5 and Clarity).

Amgen

Amgen brought a relatively large booth to the ADA floor, with all eyes on its PCSK9 inhibitor Repatha (evolocumab). Buzzwords and phrases on the product included “maximize efficacy from the start,” “intensive reduction,” and “predictable response.” We were very glad to see the Amgen booth and focus on PCSK-9 given the very high numbers of patients who need significant help on the cholesterol front. In a blue and white color scheme, several touch screens scattered throughout the booth showcased the product’s safety and prescribing information, while a video of PCSK9 inhibitors’ mechanisms of action played in the background. To illustrate “who Repatha is for,” the booth featured stacked blocks of “clinical ASCVD history,” “current statin use,” and “LDL-C levels.” Similar to last year, Amgen also incorporated an element of fun, with a hands-on game simulating PCSK9 inhibitors’ mechanism of action, as attendees threw stuffed LDL-C molecules onto Velcro-backed LDL receptors on two different walls, each representing either more functional (with fewer receptors available) or less functional PCSK9 (with more receptors available). In efforts to differentiate Repatha from Sanofi/Regeneron’s Praluent (alirocumab), Amgen also highlighted that Repatha is the only PCSK9 inhibitor with 30-day room temperature storage for patients, no dose titration, and one 140 mg/ml sub-Q dose every two weeks. The company seemed to come to ADA in full force, with scientific affairs and medical booths, a scheduled product theater, and of course, a popular espresso bar. As a reminder, Amgen’s recent calls have expressed strong enthusiasm for Repatha (first revenues released in 1Q16 at $16 million) and the company’s significant presence at ADA gives us the impression that Amgen has its eyes on diabetes once the product can gain the momentum to expand its indication – see our 1Q16 report for more.

AstraZeneca

AZ posted a large, centrally located booth that devoted essentially equal time to each of its diabetes products. Each featured drug – Farxiga (dapagliflozin), Xigduo (dapagliflozin/metformin), Bydureon (exenatide once weekly), Byetta (exenatide twice daily), Onglyza (saxagliptin), Kombiglyze (saxagliptin/metformin), and Symlin (pramlintide) – received its own block hanging from the ceiling, and most also had a small booth with a screen providing prescribing information. AZ’s booth was one of our more interactive experiences in the exhibit hall today; we tried our hand at the “mechanism of action challenge” for GLP-1 agonists and SGLT-2 inhibitors (we did pretty well but couldn’t beat the record time of nine seconds!) and built a personalized recipe collection at the station featuring the company’s Fit2Me patient support program.

BD

BD unveiled new branding in its spacious Exhibit Hall booth. The company has: (i) embraced a “lighter, brighter” look following the acquisition of CareFusion; (ii) updated its logo – see the new look below; and (iii) has updated its slogan from “Helping people live healthy lives” to “Advancing the World of Health.” Notably, the FlowSmart Infusion Set was not on display and reps did not share commentary on the most recent timeline (initial launch by September 2016, with full commercialization ~October-December 2016). We’ll be back with more tomorrow after testing the company’s “injection counseling virtual reality simulation.”

Dexcom

Dexcom’s booth in the center of the hall was flanked around by iPhones showing off G5 mobile in all its glory – including versions in mmol/l for attendees. Reps took us through the new Professional version of Dexcom Clarity, which will launch this summer and has some slight improvements to consolidate multiple patient accounts on one page. Oddly, providers can’t track their population of patients and easily identify those with dangerous glucose levels that need prioritization (like Glooko’s Population Tracker) – we hope this is added over time, since it makes so much sense and is where digital must take diabetes. Dexcom will also add standard deviation to Clarity this summer, along with a seven-day modal day overlay plot (the infamous CGM spaghetti chart, with each day appearing in a different color). We’ve heard that providers are asking for the spaghetti chart to be put back into Clarity, a surprise to us since they are so hard to make sense of. 

GSK

GSK’s booth was large but sparse, featuring a white theme with signature orange and purple accents. The booth’s colors were carried through to the treats of mango and acai berry sorbet on offer. The booth was focused entirely on the company’s sole approved diabetes drug: GLP-1 agonist Tanzeum (albiglutide). The marketing featured the slogan “Your experience may change theirs.” Our sense (based on the most recent sales and volume data) is that Tanzeum has struggled to break into the crowded GLP-1 agonist market – we believe the market will continue to expand and it will be interesting to see how it evolves. Tanzeum has a more modest efficacy compared to other agents, but we are surprised that the company’s strategy of competing on price has not paid off more in such a cost-conscious environment.

Insulet

The Insulet booth showed off the company’s snappy new branding, highlighted three major company goals: innovation (“commitment to pursue a hybrid closed loop artificial pancreas”), clinical benefits (72 continuous hours of insulin delivery), and quality of life (the tight-knit “podder community”). A corner of the booth showed off Insulet-branded Glooko, the data downloading product announced in January and now in over 1,000 clinics – wow! The company recently launched its new patient-facing app for reordering supplies, a precursor to its goal of viewing key pump data from the next-gen OmniPod on a smartphone app (FDA submission “later this year”). 

Intarcia

Intarcia wins the award for the most significant exhibit hall upgrade at this year’s ADA, posting two fairly sizable booths instead of the single small booth we have seen at recent conferences. One especially eye-catching booth focused on the newly branded Medici delivery device, with signage promising a “Renaissance in medicine delivery.” The décor had a bit of a seventies vibe, with neon lights hanging above the booth, bright blue plush carpeting, and walls covered with graphics of the Medici device with colorful flowers, smiley faces, etc. emerging from the end. The booth centered around two stations where reps demonstrated the insertion and removal procedures for the device – this has been the mainstay of Intarcia’s booth at previous conferences, though this time the reps went to great lengths to emphasize that they were promoting only the Medici device, not ITCA 650 (implantable exenatide mini-pump). Any questions about ITCA 650 were referred to the company’s second booth across the hall, labeled “Is T2D Spiraling Out of Control?” and featuring a huge funnel hanging from the ceiling with words like “prevalence,” “hypo,” and “not to goal” going around and around in a downward spiral. Even that booth featured little mention of ITCA 650 specifically, focusing instead on the need for a paradigm shift in how type 2 diabetes is treated. Intarcia is clearly making a concerted effort to broaden its focus beyond a single product, and we can’t wait to see what it has in store.

J&J/Animas

Animas’ booth occupied a small sliver of the J&J real estate. Excited reps eagerly provided us an overview of the Animas Vibe G4. They expressed great enthusiasm for the pumping accuracy of the product, suggesting that the solid foundation puts Animas at an advantage in the closed-loop game vs. Tandem (who also has its CGM-integrated t:slim G4). Reps also suggested that work on a G5-integrated pump is underway though did not provide any further specifics. Per J&J’s Medical Device Business review two weeks ago, the goal is be in a pivotal study of the hypoglycemia-hyperglycemia minimizer (HHM) before the end of this year, with a launch targeted by November 2017. Reps could not comment on other pipeline updates, such as the OneTouch Via on-demand mealtime insulin delivery device (previously Calibra’s Finesse). In the Medical Device Business review, a regulatory filing for the device is expected in 2H16, with an launch planned by May 2016.

J&J/LifeScan

LifesSan’s booth aimed to get booth-goers thinking about the biggest challenges they face on a daily basis (e.g., reimbursement, access) and create an opportunity for reps to explain how LifeScan’s portfolio solves these challenges – nice marketing! There were no major updates but we did notice that the OneTouch Verio Flex was on the floor, following the stateside launch in February 2016. Notably, the booth also featured a rep from WellDoc to talk about the companies’ recent partnership and it sounds like there is a lot of internal enthusiasm on this front as well as for the paired Reveal mobile app, which was also on display.

Janssen

As in the recent past, Janssen occupied the majority of J&J’s booth, with approximately equal real estate devoted to Invokana (canagliflozin) and Invokamet (canagliflozin/metformin). The booth had several prominent signs promoting the recent expansion of Invokamet’s indication to include use as a first-line therapy for type 2 diabetes. We see this as a major win for drug-naïve patients with a high A1c and believe it should spur greater use of Invokana in patients at earlier stages of the disease. The booth also had a substantial focus on ancillary programs for Invokana, including the CarePath patient support program and the Check Your Numbers Tracker App. We found it interesting that there seemed to be less of a focus on Invokana’s strong formulary positioning compared to previous exhibit halls – management acknowledged during the company’s 1Q16 update that Invokana has faced increased competition for formulary positioning this year but emphasized that it retains 80% preferred access in the combined commercial and Medicare Part D segments.

Lilly

Lilly’s classically red booth was set up in a circular labyrinth-like layout with sections promoting each of its diabetes products surrounding a quiet inner oasis with (sugar-free) artisanal espressos and café seating. We especially loved the wall that asked attendees to fill out magnetic tiles answering the question “Whose diabetes do you have?” as a show of support for loved ones with diabetes (answers were in the format “I have ___’s diabetes”). The center portion also featured screens that encouraged participants to explore Lilly’s extremely diverse product portfolio through the lens of the multi-organ pathophysiologies associated with type 2 diabetes – we previously saw this at the AACE 2016 exhibit hall. In terms of products, the booth devoted a sizable aqua-drenched section to its Humulin U500 KwikPen, the striking color scheme complementing the bright aqua body of the pen. We also got our first glimpse of Basaglar in a US exhibit hall – we love the minimalist logo that evokes A1c reduction with a single drop of a blood over a downward arrow. The screens for Basaglar drove home a single point: “Basaglar is coming December 15, 2016.” Clearly, Lilly/BI is already starting to build the excitement for the product. The booth also devoted floor space to Jardiance (empagliflozin), Glyxambi (empagliflozin/linagliptin), Tradjenta (linagliptin), Jentadueto (linagliptin/metformin), Trulicity (dulaglutide), and the Humalog and Humalog U200 KiwkPens.

Lilly/BI

Lilly/BI’s large, airy booth sported gray and teal accents against a predominantly white background – a contrast to the wood-paneled Scandinavian-modern-rustic look we’d become accustomed to. The booth’s star product was clearly Jardiance (empagliflozin) whose materials took up a full half of the display (along with those of its sister product Synjardy [empagliflozin/metformin]). Several touchscreens featured the memory game seen at the Lilly standalone booth – we counted at least four stations where attendees could try their hand at matching pictures of Jardiance-related info within 60 seconds. On the more old-school side, the Jardiance section also featured a croquet game in which attendees attempted to navigate through hoops such representing healthy lifestyle choices while avoiding obstacles such as “Mom’s Spaghetti” and “Desk Chair Dessert.” The other half of the Lilly/BI booth was evenly split among Glyxambi (empagliflozin/linagliptin), Tradjenta (linagliptin)/Jentadueto (linagliptin/metformin), and Basaglar (biosimilar insulin glargine). Lilly/BI has also stepped up its promotional materials for Glyxambi with a Pixar-style cartoon of a two-person cleaning crew (“Dual inhibition, ready for action”) to represent the dual empagliflozin and linagliptin components of the product. The exhibit even featured a photobooth area in which attendees would don props and pose with large statues of the two characters. We’re glad to see Glyxambi garner more attention within Lilly/BI’s marketing scheme – there have been high hopes for this product as the only incretin/SGLT-2 inhibitor fixed-dose combination on the market, but Lilly has been fairly quiet on its performance since its launch over a year ago.

MannKind

Our trip to the MannKind booth allowed us to experience the company’s nifty new spirometry solution for healthcare providers to test lung function before prescribing Afrezza. The small, relatively inexpensive device (~$400) pays for itself quickly, as providers can bill $50 for each test. It plugs directly into a desktop computer and is factory calibrated, saving time. It’s a massive improvement for endocrinologists that will now be able to do spirometry in-office, rather than sending patients to specialists. The MannKind team seemed enthusiastic and said they had “learned a lot” from the Sanofi partnership, and we look forward to seeing some commercial progress as MannKind takes over responsibility for the ultra-rapid inhaled insulin. We love seeing this new tool and think it will aid uptake significantly.

Medtronic

Medtronic’s expansive booth showed off its growing slew of products, including glass cases housing its MiniMed 670G/Enlite 3 (FDA submission by end of this month) and Bluetooth-enabled Guardian Connect mobile CGM (under FDA review, US launch expected by April 2017; EU launch this summer). We got a closer look at the next-gen CareLink report to optimize pump basal and bolus settings, which won’t be quite as specific as the Glooko/DreaMed vision. Instead of specific changes (I:C should be 1:12 in the morning), the CareLink report will share which time of day and direction pump settings should change (Increase basal rate from 8am – 12pm). Slides around the booth highlighted the growing list of partners, including IBM Watson (SugarWise app launching this summer with retrospective data analysis), Glooko (compatibility launching in July), and Nutrino (food app + CGM beta launched yesterday). Signs showed a larger presence in type 2 diabetes, highlighting the iPro 2 professional CGM and positive pump data from Opt2mise.

Merck

Merck and its DPP-4 inhibitor empire had a decently sized booth, with the majority of marketing unsurprisingly focused on the Januvia (sitagliptin) franchise. The green and white booth included six boards on Januvia and two on Janumet (sitagliptin/metformin), with emphasis on the drugs’ potential concomitant use with insulin, “strong” A1c reductions, and tolerability. The company also aimed to bring a patient-centric feel to the booth, with several large touch screens on images and stories of patients as well as a center to pick up patient education resources. In addition, Merck featured a yogurt parfait bar (which generated a decent amount of traffic) as well as a virtual reality experience on Januvia’s mechanisms of action – an increasingly popular entity in exhibit halls. Other non-diabetes drugs promoted at the booth included LDL-lowering drug Zetia (ezetimibe) and vaccine Pneumovax 23 (pneumococcal vaccine polyvalent). The TECOS results appeared to not be as heavily featured as we’ve seen in the past, likely due to the upstaging of the more recent CVOTs. Nonetheless, Merck continues to hold onto leadership of the DPP-4 inhibitor class, although the company has notably directed more attention to other classes recently, with the decision to drop once-weekly omarigliptin and greater attention to SGLT-2 inhibitor candidate ertugliflozin. For more on Merck’s latest, check out our 1Q16 update.

Novo Nordisk

Novo Nordisk’s bright, airy booth was hard to miss as one of the largest displays in the exhibit hall. In terms of products, the booth was focused almost entirely on Tresiba (insulin degludec), though there was a small amount of signage promoting Victoza (liraglutide) and NovoLog (insulin aspart). Promotional materials for Tresiba emphasized the product’s long duration of action and the potential for flexible dosing (“schedules change, dosing can too”). The Tresiba section also included a few creative touches such as a large hanging parachute labeled “A1c” and a “virtual representative” of sorts (a webcam on a motorized roving base) circulating around the booth. Aside from products, we were thrilled to see a sizable portion of the booth devoted to the company’s Cities Changing Diabetes program; when we stopped by, a presentation was in progress about the contribution of environmental sustainability initiatives to Novo Nordisk’s “triple bottom line.” As usual at ADA, Novo Nordisk’s booth also featured the popular A1c testing station, which was attracting a pretty substantial crowd.

Novo Nordisk (Saxenda)

Similar to recent meetings, Novo Nordisk had one booth focused exclusively on its obesity drug Saxenda (liraglutide 3.0 mg). In its typical purple color scheme, the promotional material emphasized Saxenda as the “first and only GLP-1 agonist” approved for chronic weight management, as reps walked attendees through clinical data and had demo pens on display. Imaging throughout the booth again featured a woman holding up a pair of old larger jeans inscribed with “excess weight,” “high cholesterol,” “large waistline,” and “high blood pressure” – highlighting the versatility of Saxenda. Next to a smoothie bar, a video also played in the background, stressing the “science of Saxenda,” with an emphasis on biology rather than willpower (we love this education piece for removing stigma). Not surprisingly, Novo Nordisk’s Saxenda booth was the only obesity drug representation on the floor, with no booths from Arena/Eisai, Vivus, or Orexigen – a stark contrast from ADA 2014, when the obesity drug market seemed to be at the height of its anticipation. We believe Saxenda sales would improve if the price were not based on the dose.

Sanofi

Sanofi’s large booth at the center of the exhibit hall was one of the largest and most elaborate Sanofi booths we’ve seen in recent memory. At the center of the booth, Sanofi created a COACH café, featuring dark wood floors, low-slung white sofas, and treats such as banana mint slushees and apple crisps. The café promoted Sanofi’s COACH patient support programs that offer live diabetes education and more to patients with a prescription for Toujeo (U300 insulin glargine). Toujeo itself occupied much of the square footage of the booth, which signage simply asserting “All Day. Every Day.” and characterizing Toujeo as “an insulin of today.” Sanofi’s other major insulin products, Lantus (insulin glargine) and Apidra (insulin glulisine), were also given sections of the massive booth. The giant SoloStar pens for Toujeo, Lantus, and Apidra returned to dominate a far corner of the booth. In a separate location, Sanofi’s unbranded Glycemic Explorer booth made a reappearance.

Sanofi-Regeneron

Sanofi-Regeneron, one of two PCSK9 inhibitor players on the ADA floor, had a decently sized booth focused on Praluent (alirocumab). The company marketed the product with an emphasis on its dosing flexibility, with repeated mentions of “power like never before…and more power if you need it,” with giant down arrows in a green and turquoise color scheme. Additionally, the booth stressed this flexibility as a key differentiator, with the message that Praluent is the only PCSK9 inhibitor that “offers two levels of efficacy.” Sanofi/Regeneron’s imaging also appeared to bring the patient to life, as several touch screens featured different patient types and walls showed images of patients with shirts exclaiming their lower LDL levels. In addition, we were glad to see the patient support program, MyPraluent, make up a wall of the booth, promoting information on how to help patients with coverage support, cost, and adherence. We have heard of the complex paperwork and processes involved in authorization for PCSK9 inhibitors for both patients and providers, so we would imagine that such patient support programs are critical for the product’s success – for more on this, see our 1Q16 update from Sanofi.

Takeda

Takeda took up a good amount of real estate toward the back of the exhibit hall, promoting Nesina (alogliptin), Kazano (alogliptin/metformin), and Oseni (alogliptin/pioglitazone). The marketing centered around the theme of a puzzle (“diabetes management is a puzzle” and “every piece counts”) while the booth included a few touch screens reviewing the products’ information and a “personality quiz” that tested attendees’ diabetes knowledge. Overall, the booth seemed to be lighter on promotional material, with approximately two-thirds of the booth’s space blocked off for a lounging area for international delegates – a nod to the fact that most of Takeda’s drugs are marketed ex-US. As expected, the booth had no mention of obesity drug Contrave (naltrexone/bupropion), as Takeda recently left the drug’s partnership with Orexigen – see our coverage of this news for more.

Tandem

In a surprise, Tandem’s booth showed pictures of its predictive low glucose suspend device and t:sport patch pump. The latter was the first image shown in a couple years, appearing as a 50% smaller pump worn on the body with a short infusion set (it looked just like Cellnovo’s pump), a “separate touchscreen controller or mobile app” (Tandem is presumably still in FDA discussions on this), waterproof, a rechargeable battery, and CGM integration. No timing was shared, but the 4Q15 call suggested an FDA submission would occur in 2017. The predictive low glucose suspend device looked just like the t:slim G4, but with a slightly updated interface to denote a suspend event (the color is really impactful). It is still expected to enter a feasibility study in summer 2016 and a pivotal study in late 2016. This product will be behind other AID systems that respond to hyperglycemia (MiniMed 670G, Animas Hypoglycemia-Hyperglycemia Minimizer, and many others), though perhaps the path to market is easier for PLGS. Signs on the top of the booth noted, “Having diabetes isn’t a choice. How you manage it should be.” The slogan was appropriate to describe Tandem’s portfolio of three pumps, and of course, even more apt to respond to the Medtronic/UHC agreement that excludes Tandem pumps.

--by Melissa An, Adam Brown, Helen Gao, Varun Iyengar, Nina Ran, Emily Regier, Ava Runge, Alasdair Wilkins, and Kelly Close