September 10-15, 2017; Lisbon, Portugal; Day #4 Highlights – Draft

Executive Highlights

Greetings from Lisbon, where EASD day #4 is a wrap. On the therapy side, the day started off strong with presentation of full inTandem3 results on Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. We’re nonplussed by Dr. David Nathan’s editorial on this data in NEJM. We bring you our thoughts, in addition to all the key data, below. We also heard UBC’s Dr. James Johnson question how close we really are to generating true beta cells from human embryonic stem cells (and how close we can get in the near future) and a fascinating analysis on diabetes outcomes trends in the US. On the tech side, we were truly moved by a poster that demonstrated dramatic improvements in hospitalization and work absenteeism in Belgium following national reimbursement of CGM, and the exhibit hall provided a slew of updates.

If you missed our previous installments of EASD highlights, you’ll find days #1-2 here (EXCSEL’s pragmatic design, within-class differences of GLP-1 agonists) and day #3 here (VERTIS SU, new EMPA-REG OUTCOME analysis). And if you’re more the forward-looking type, see our preview here. We know the full EXCSEL results presentation (4:15 PM local time in the massive Roma Hall) is at the top of many of your agendas … it certainly tops ours : >, as is AZ’s SGLT-2 dapa data being shown at 8:30 am.

Diabetes Therapy

1. The indisputable highlight on Wednesday was Professor Melanie Davies’ presentation of full inTandem3 results on Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin for type 1 diabetes. The paper was simultaneously published in NEJM, alongside what we perceived as an overly negative editorial by Dr. David Nathan. The class is a breakthrough for type 1s who are used to very complicated insulin dosing – the DKA risks are manageable (though far more education is needed in our view) and we thought ending the piece with “beware!” was over the top. Indeed, regardless of regulatory decisions, type 1 patients will take the class, so they may as well be safe rather than forbidden to take it.

2. Steno Diabetes Center’s Dr. Jens Øllgaard shared new post-hoc findings from the Steno-2 study, showing that multifactorial intervention (glucose-lowering, blood pressure-lowering, and lipid-lowering simultaneously) significantly reduces risk for heart failure vs. standard of care. Over the course of the 21-year trial, the relative risk reduction for heart failure hospitalization was a whopping 70% in favor of multifactorial treatment (HR=0.30, p=0.002).

3. A morning symposium was dedicated to the TOSCA.IT study, a large (n=3,028) multicenter CVOT conducted across Italy to compare TZD pioglitazone head-to-head with sulfonylureas, including glimepiride, glibenclamide, and gliclazide. The primary endpoint (non-fatal MI, non-fatal stroke, all-cause death, or urgent coronary revascularization) showed no significant difference for pioglitazone vs. SUs (HR=0.96, 95% CI: 0.74-1.26, p=0.79), but the great Dr. Stefano Del Prato presented positive glycemic data.

4. Alpha-glucosidase inhibitor acarbose (Bayer’s Glucobay) did not meet any of its CV endpoints in the Acarbose Cardiovascular Evaluation (ACE) CVOT, but did, very excitingly, show an 18% risk reduction vs. placebo for the secondary endpoint of new-onset type 2 diabetes (HR=0.82, 95% CI: 0.71-0.94, p=0.005) in a Chinese population with prediabetes and a previous history of CV events (n=6,526). Full results were simultaneously published in the Lancet.

5. UBC’s Dr. James Johnson (Site Head for the new Novo Nordisk Research Centre Oxford), while impressed by how far the field has come, is “not really sure when we’ll get” to converting human embryonic cells to true beta cells, pessimistically wondering whether we’ll get there this century. [His conclusion slide did say that “we are on the right track towards making mature beta cells”.]

6. University of Pennsylvania’s Dr. Michael Rickels presented compelling data (n=15) demonstrating that 150 ug of Xeris’ soluble mini-dose glucagon (G-Pen mini) prevents exercise-induced hypoglycemia more effectively than a basal rate reduction and with less hyperglycemia than seen with a big dose of glucose tablets (40 grams).

7. EASD’s scientific sessions opened on Tuesday morning with the prestigious Claude Bernard award and lecture, which this year went to Dr. Bernard Thorens of the University of Lausanne in Switzerland.

Diabetes Technology

1. A very compelling poster shared 12-month outcomes from a national Belgian reimbursement of CGM (n=515; RESCUE). The hospitalization and work absenteeism outcomes were quite compelling: the percentage of patients experiencing each event declined 64%-75%. A tremendous win for CGM and a study we look to see replicated in large databases.

2. We visited 14 diabetes tech booths in the exhibit hall, with some notable updates: (i) mySugr launched its US bundle for $39.99/month with unlimited strips, an Accu-Chek Guide BGM, and CDE coaching; (ii) One Drop shared plans to launch direct Chrome BGM-to-Apple Watch transmission in 4Q17; and (iii) Cellnovo reported an FDA review delay. Much more below!

3. Dr. William Polonsky, Prof. Richard O’Brien, and Prof. Eduard Montanya discussed real- world challenges in type 2 diabetes, identifying adherence as the primary driver for the gap between outcomes observed in clinical trials vs. the real world, and suggesting strategies to improve it.

4. At the end of Ascensia’s symposium on behavioral change, CEO Mr. Michael Kloss announced a global innovation competition, the Ascensia Diabetes Challenge. €200,000 in cash prizes are available for digital solutions that improve the lives of people with type 2 diabetes. The goal is to surface novel ideas, smart as Ascensia aims to move beyond a BGM company. Judges include members of the Ascensia team, Dr. Bill Polonsky, and others.

5. Dr. Osama Hamdy gave an overview of Healthimation’s virtual weight management program (using animation, gaming, and leveraging Joslin’s Why WAIT program), sharing that the platform now integrates with devices for passive data upload. The slide showed a connected scale, a smartwatch, and Ascensia meters. We heard about this “healthcare animation studio” last December and remain intrigued, though there is much to prove.

Big Picture

1. CDC’s respected Dr. Edward Gregg shared some fascinating insights on the changing character of the US diabetes epidemic: A diversification of complications and maintained cumulative incidence and secondary events. 

Diabetes Therapy Highlights

1. inTandem3 Full Results: More People on Sotagliflozin vs. Placebo Achieve A1c <7% without Severe Hypo or DKA; DKA Controversy Continues in Dr. Nathan Editorial

The indisputable highlight on Wednesday was Professor Melanie Davies’ presentation of full inTandem3 results on Sanofi/Lexicon’s SGLT-1/2 dual inhibitor sotagliflozin for type 1 diabetes. This was a 24-week trial (n=1,402) investigating 400 mg sotagliflozin vs. placebo on a primary endpoint of the proportion of patients achieving target A1c <7% with no severe hypoglycemia or DKA. Of note, this was a global trial (whereas inTandem1 took place in the US/Canada and inTandem2 took place in Europe/Israel) without an insulin optimization period, making it closer to “real life.” The primary endpoint was met by 29% of people in the sotagliflozin arm vs. 15% in the placebo arm (p<0.001). Mean A1c reduction was 0.8% with sotagliflozin vs. 0.3% with placebo, culminating in a treatment difference of 0.5% (p<0.001). Notably, A1c was blinded throughout the 24 weeks, which may have led to less aggressive insulin adjustment. Sotagliflozin was associated with ~5 lbs weight loss vs. ~2 lbs weight gain for participants on placebo, for a treatment difference of ~7 lbs (p<0.001). These weight effects were particularly positive, as >70% of study participants had a BMI >25 kg/m² at baseline. In patients with systolic blood pressure ≥130 mm Hg at baseline, sotagliflozin gave a treatment difference of 3.5 mmHg (p<0.002 vs. placebo) at 16 weeks. Treatment differences for total, basal, and bolus insulin doses were -5, -3, and -3 units/day, respectively (p<0.002 for all comparisons). There were four DKA events (0.6%) in the placebo group vs. 21 (3%) in the 400 mg sotagliflozin group, leading to 11 treatment discontinuations in the latter arm. In the sotagliflozin group, DKA was adjudicated in 4% of pump users and 2% of patients on MDI. In an NEJM editorial published alongside the inTandem3 paper, Dr. David Nathan gives a lot of weight to this DKA signal, arguing that this risk persisted despite trial protocol offering extensive patient education around DKA. We’re very curious to learn more about the nature of this education, but we also point out that there’s a lack of consensus in the field about best practices for managing DKA risk – we’ve heard many clinicians say that they “are sure” type 1 patients are well-educated but dQ&A data suggests many patients are not familiar with ketone meters even when they have been given meters for the trial. We continue to believe this risk can indeed be managed, even if education/monitoring strategies haven’t been widely discussed yet or standardized in the field. We do note that identifying and responding to DKA can be very non-intuitive and we believe education may need to be more extensive than some doctors or even clinical trialists imagine. Still, we don’t think coming to a consensus would be too challenging (but we don’t think it’s been done yet, at least not that we’ve seen).

• Last week, Lexicon released positive pooled CGM data from inTandem1 and inTandem2. At week 24, patients treated with 200 mg and 400 mg doses of sotagliflozin spent an additional 5% and 12% of the day in-range (70-180 mg/dl), respectively, compared to those taking placebo (p=0.026 and p<0.001, respectively). These percentages translate to an additional 1.3 and 2.8 hours in-range, respectively –we feel confident saying that this additional time-in-range would be an enormous win for anyone with diabetes. This is time not spent in hypo- or hyperglycemia, meaning that patients can feel well for nearly three more hours each day – and not have to spend time trying to get back into range. It’s unfortunate in our view that inTandem3 didn’t make use of CGM, given that time-in-range data may be a crux of the selling point for sotagliflozin, but we also note that FDA doesn’t accept CGM data.
• In our view, Dr. Nathan’s editorial in NEJM minimized the profound glycemic and weight loss benefits seen in this sotagliflozin study, while overemphasizing the DKA signal. One of his main points alludes to the training of inTandem3 participants on ketone monitoring, and he argues that if there was still an imbalance in DKA after patients received concerted education, this safety issue will surely persist in the real world. Dr. Buse provided a rebuttal, noting that DKA-related education in the trial was probably far from optimal, likely because there’s still a lack of consensus on what optimal DKA management should be. It would be a shame for a manageable safety issue to overshadow the glycemic and weight loss efficacy of sotagliflozin, and as Drs. Rosenstock and Buse clearly established, there is an unmistakable need for adjunct therapy in type 1 diabetes care. That sotagliflozin is an oral medication only adds to our excitement; AZ’s Symlin is an injectable adjunct type 1 treatment that has never quite taken off commercially – it’s far harder to take in our view though we are very eager for it to be reformulated by Adocia with rapid acting insulin. In Dr. Nathan’s closing paragraph, he suggests that automated insulin delivery (AID) will outpace pharmaceutical development for type 1, eventually making new, non-insulin drugs for this population unnecessary. To this, we respond that it’s a false reality to think AID will be affordable and accessible to everyone in the very near future – in the meantime, while the treatment options we have are just not good enough, sotagliflozin could be a significant stride. As a sidenote, we were surprised not to see any disclosures on AID since Mass General under Dr. Nathan’s direct care (through the very respected Dr. Steve Russell and team) has been involved in multiple bionic pancreas trials (about which we’re very positive).
• For even more on sotagliflozin and inTandem3, see our full write-up in detailed discussion and commentary down below. This includes insights from Drs. Clifford Bailey, Julio Rosenstock, and John Buse.

2. Steno-2 Finds 70% Fewer Heart Failure Hospitalizations with Intensive, Multifactorial Intervention vs. Standard Care

Steno Diabetes Center’s Dr. Jens Øllgaard shared new post-hoc findings from the Steno-2 study, showing that multifactorial intervention (glucose-lowering, blood pressure-lowering, and lipid-lowering simultaneously) significantly reduces risk for heart failure vs. standard of care. The 21-year trial randomized 160 people with type 2 diabetes to intensive, multifactorial treatment or to standard care for 7.8 years, after which point all participants were offered the multifactorial intervention for 13 more years of follow-up. The relative risk reduction for heart failure hospitalization was a whopping 70% in favor of multifactorial treatment (HR=0.30, p=0.002) – 10 patients in the intensive arm (13%) experienced this primary heart failure endpoint vs. 24 conventionally-treated patients (30%). For the composite endpoint of heart failure hospitalization/CV death, the relative risk reduction was 62% in favor of multifactorial treatment (HR=0.36, p=0.006), and for the composite endpoint of heart failure hospitalization/all-cause death, the relative risk reduction was 49% in favor of multifactorial treatment (HR=0.51, p=0.001). These are highly-significant and impressive results, highlighting another reason we should consider more aggressive early approaches to diabetes management: Intensive control of glycemia, blood pressure, and lipids targets three major risk factors for CV morbidity/mortality, and we hope payers and providers in the field are compelled by this outcomes data showing fewer heart failure hospitalizations (which, of course, are quite costly). Dr. Øllgaard also pointed out that there’s no strict requirement from the FDA to evaluate heart failure in diabetes CVOTs, but that this outcome should under no circumstances be ignored, given the frequency of this complication in diabetes. We’re glad to see this happening, with Lilly/BI and AZ going one step further to launch dedicated outcomes trials of their respective SGLT-2 inhibitor products (Jardiance and Farxiga) in heart failure (the EMPEROR HF and Dapa-HF clinical programs).

3. TOSCA.IT Trial Pits Pioglitazone vs. SUs: Neutral CV Effects, but Pioglitazone Shows Distinct Hypoglycemia Benefit and Promising Durability of A1c-Lowering

A morning symposium was dedicated to the TOSCA.IT study, a large (n=3,028) multicenter CVOT conducted across Italy to compare TZD pioglitazone head-to-head with sulfonylureas, including glimepiride, glibenclamide, and gliclazide. The primary endpoint (non-fatal MI, non-fatal stroke, all-cause death, or urgent coronary revascularization) showed no significant difference for pioglitazone vs. SUs (HR=0.96, 95% CI: 0.74-1.26, p=0.79), but Dr. Stefano Del Prato presented positive glycemic data. A1c treatment difference after 60 months was 0.06% (p=0.01 for superiority). Dr. Del Prato emphasized that the trend is important here: sulfonylureas were associated with a greater initial drop in A1c, but based on rate-of-change data, the TZD pioglitazone demonstrated greater durability of glucose-lowering effect over time. Also on this point, on a very negative note, treatment failure (defined as A1c >8% at two consecutive clinician visits) was 37% more likely for SU-treated patients vs. pioglitazone-treated patients over 60 months (HR=0.63, 95% CI: 0.52-0.75, p<0.0001), underscoring durability of effect for pioglitazone. Dr. Del Prato remarked that these durability findings are consistent with past RCTs. Fewer patients in the TZD arm required new initiation of insulin therapy vs. the SU arm, at 11% and 16%, respectively (p<0.0001). Dr. Del Prato paused to mention the double whammy of a drug class that heightens hypoglycemia risk and also increases need for insulin, although he acknowledged the alternative possibility, that greater hypoglycemia rates seen for SU-treated patients in TOSCA.IT were perhaps driven by more insulin use. Severe hypoglycemia (blood glucose <60 mg/dl, requiring assistance) occurred in 2% of SU-treated patients and in <0.2% of pioglitazone patients (p<0.0001), while moderate hypoglycemia (blood glucose <60 mg/dl, not requiring assistance) occurred in 32% of the SU group and only 10% of the TZD group (p<0.0001). Notably, this trial was stopped early after a futility analysis indicated that it was unlikely the study population would reach the pre-specified 498 events (213 events were adjudicated and included in the CV analysis). On the whole, we found many reasons from this data why patient may well benefit from HCPs writing fewer SU prescriptions. These drugs showed high hypoglycemia risk and an attenuation of glycemic efficacy (in the real world, this might encourage providers to up-titrate, and higher doses of SUs may only exacerbate the hypoglycemia, weight gain, and beta cell burnout). Yes, sulfonylureas are cheap, but so are TZDs now that they’re generic. While the CV results were resoundingly neutral, the durability of A1c-lowering associated with pioglitazone in this study was intriguing, and we mention again the significantly lower risk of hypoglycemia; we can’t emphasize enough the importance of this outcome beyond A1c. Renowned cardiologist Dr. Robert Chilton, a well-respected voice in the field, said on Monday that he “can’t think of a better drug” in defense of pioglitazone, and we’d certainly be happy to see the generic diabetes market move away from sulfonylureas more toward pioglitazone – taking pioglitazone in low doses in particular may well be positive for many patients (this has not been studied enough in our view). For much more detail on TOSCA.IT, see our full coverage of the symposium below.

4. ACE CVOT Results: Bayer’s Glucobay Fails to Meet CV Endpoints, but Shows 18% Relative Risk Reduction for New-Onset Diabetes

Alpha-glucosidase inhibitor acarbose (Bayer’s Glucobay) did not meet any of its CV endpoints in the Acarbose Cardiovascular Evaluation (ACE) CVOT, but did, very excitingly, show an 18% risk reduction vs. placebo for the secondary endpoint of new-onset type 2 diabetes (HR=0.82, 95% CI: 0.71-0.94, p=0.005) in a Chinese population with prediabetes and a previous history of CV events (n=6,526). In this multi-center, double-blind, secondary prevention CVOT, participants were randomized 1:1 to 150 mg acarbose vs. placebo after a five-week run-in period for optimization of background CV therapy, and were followed for a median of five years. University of Glasgow’s Dr. John McMurray outlined the ACE trial’s CV outcomes, showing no benefit for acarbose vs. placebo in this high-risk prediabetes population. There was definitively no relative risk reduction for the primary outcome of five-point MACE (CV death, non-fatal MI, non-fatal stroke, hospitalization for unstable angina, or hospitalization for heart failure; HR=0.98, 95% CI: 0.86-1.11, p=0.73) or for any of the secondary outcomes, including three-point MACE (HR=0.95 ,95% CI: 0.81-1.11, p=0.51), all-cause death (HR=0.95, 95% CI: 0.81-1.19, p=0.85), CV death (HR=0.89, 95% CI: 0.71-1.11, p=0.29), fatal or non-fatal MI (HR=1.12, 95% CI: 0.87-1.46, p=0.38), fatal or non-fatal stroke (HR=0.97, 95% CI: 0.70-1.33, p=0.83), hospitalization for unstable angina (HR=1.02, 95% CI: 0.82-1.26, p=0.87), and hospitalization for heart failure (HR=0.89, 95% CI: 0.63-1.24, p=0.48). On the bright side, acarbose appeared to reduce risk for new-onset type 2 diabetes by 18% (p=0.005 vs. placebo), and trial chairman Dr. Rury Holman (Oxford University, UK) revealed that this positive finding was accompanied by other beneficial metabolic outcomes, including a small but significant 0.07% reduction in mean A1c with acarbose vs. placebo (95% CI: -0.04 to -0.10, p<0.0001), a 0.24 mmol/L (~4 mg/dl) reduction in 2-hour postprandial glucose (95% CI: -0.16 to -0.32, p<0.0001), a 0.09 mmol/L (~2 mg/dl) reduction in triglycerides (95% CI: -0.07 to -0.12, p<0.0001), and 0.64 kg (~1.4 lbs) weight loss (95% CI: -0.53 to -0.75, p<0.0001). Full results were simultaneously published in the Lancet.

• Dr. Chantal Mathieu closed this symposium by providing an independent perspective on the ACE trial results, illustrating (literally) her opinion of the results with an image of a glass half full. Although acarbose did not achieve its primary endpoint on CV outcomes, Dr. Mathieu positioned the drug’s significant prevention of new-onset diabetes as an extremely important result – particularly given the rising tide of prediabetes globally, and especially in China where the trial was conducted. As Dr. Jean-Louis Chiasson (University of Montreal, Canada) contextualized earlier in the symposium, many expected this trial to meet its primary endpoint based on acarbose’s known beneficial effect on markers of CV risk and postprandial glucose (which is associated with worse CV endpoints), as well as the promising suggestion of cardioprotection for acarbose in a 2003 meta-analysis of the 1998 STOP-NIDDM trial, in which the drug was associated with a significant relative risk reduction in the incidence of MI (HR=0.09, 95% CI: 0.01-0.72, p=0.03) and all CV events (HR=0.51, 95% CI: 0.28-0.95, p=0.03) in comparison to placebo in a majority white population with prediabetes and no CV history. Given all this, to the question of why ACE did not reach superiority, Dr. Mathieu’s answer was a resounding “I have no clue.” However, she did propose a variety of potential hypotheses to explain this underwhelming result: (i) the 150 mg dose range used in the trial doesn’t impact CV outcomes; (ii) acarbose’s primary effect on postprandial glucose isn’t sufficient to make a difference on wider CV risk; and (iii) limited epidemiological understanding of the prediabetes population. She left us with an optimistic message: Prediabetes evolves to diabetes, and we now have extremely solid evidence for a drug that can prevent this. We agree with Dr. Mathieu that the drug’s ability to prevent the onset of diabetes in this high CV risk prediabetes population represents a major win. We can’t help but imagine what this could mean from a public health perspective if acarbose was used more widely for diabetes prevention. Even if this preventive effect is specific only to the very homogenous study population, the potential ROI for acarbose is massive given that an astonishing half of the adult population (500 million people) in China has prediabetes. To-date, acarbose (and alpha-glucosidase inhibitors in general) is most commonly prescribed in Asia, and we are curious whether the ACE trial’s impressive glycemic outcomes will spur greater use in North America and Europe, in the diabetes and prediabetes populations alike.

5. Will We Be Able to Generate True Beta Cells from Human Embryonic Stem Cells in the Near Future?

UBC’s Dr. James Johnson (Site Head for the new Novo Nordisk Research Centre Oxford), while impressed by how far the field has come, is “not really sure when we’ll get” to converting human embryonic cells to true beta cells. When displaying a timeline of progress in efforts to generate beta cells, he placed a question mark over the true beta cell where the year should go and commented “Notice I didn’t even put a century there, but that might just be me being pessimistic.” He later said that we’re on the right track towards making mature beta cells, but the question is when. He proceeded to outline a number of the barriers blocking progress, first calling on the field to reconsider experimental design and rigor. To some, transplantation of beta-like cells into a mouse and thereby curing diabetes is the gold standard, he said. Poking holes in that logic, he then showed a graph of improved glycemia in a mouse brought on by an insulin pump or pellet – “a pump or pellet can rapidly reverse diabetes in mice. Reversal should not be considered a high bar or gold standard for assessing cells.” Instead, Dr. Johnson advocated for transplantation of the cells into mouse eyes, where they can be visualized at the individual level. In Q&A, he expanded his recommendations – “electron microscopy, super-resolution, live-cell…You name it, we need it.” Another barrier to progress is unknowns about source human islets – are they the ideal comparison for in vitro differentiated cells? What is the normal insulin response to glucose and other nutrients? Beta cells are so heterogeneous, both inter- and intra-individually – what parameters should we be aiming to recreate? On top of that, islets from cadaveric donors have all sorts of factors making them unnatural/un-generalizable. “We need to think carefully about what we need to make. We need to build heterogeneity into the system.” Because of this heterogeneity, Dr. Johnson implored scientists to stop showing single cell traces in studies, calling the tactic a cop-out (and arguably a scientifically dishonest one at that). He called for an online database of pooled data where one could look up every studied human islet and how they respond to certain stimuli – and he believes this should all be public information, even offering to be the host. We’d love to see this move forward as well – in vitro-generated beta cells should be compared to a standard; not whatever cells came in the mail that day.

• In Q&A, prominent beta cell biologist Dr. Decio Eizirik asked if we should focus on completely recapitulating the islet, or simply generating a population of cells that responds to glucose in a near-physiological manner, leading to a decrease in A1c. Dr. Johnson agreed that helping the patient is the bottom line, but he only focused on heterogeneity in his talk because he fears it may be necessary for proper functioning. We found this to be the perfect answer, and we hope, for the sake of time, that scientists don’t have to generate every beta cell phenotype to be successful.
• Dr. Johnson left the audience with an important thought on expectation-management: “This is really exciting stuff, but we need to be measured as scientists – we can’t get so excited that we lead patients down false roads of hope. We’re working on it, but there’s a lot left to do.” This was and remains a major concern with hybrid closed loop systems. We believe the messaging around them is improving, but some still expect the MiniMed 670G to be a true “artificial pancreas” that requires no user input.
• Other barriers to progress mentioned by Dr. Johnson include: (i) It seems that the more beta-like a cell is, the less chance it survives implantation due to a stronger immune response. Is there a happy medium where the cell is beta-like enough to approximate physiological function but avoid a hefty immune assault? (ii) Generating the beta cell is just the first step! From there, it has to evade the immune system by a mechanism involving immune suppression, encapsulation, cloaking, etc; something Viacyte’s de-prioritization of its ambitious phase 1/2 PEC-Encap therapy demonstrates is equally non-trivial.

6. 150 ug Xeris Mini-Dose Glucagon Safe & Effective at Preventing Exercise-Induced hypoglycemia in Small HCT-Funded Study

University of Pennsylvania’s Dr. Michael Rickels presented compelling data (n=15) demonstrating that 150 ug of Xeris’ soluble mini-dose glucagon (G-Pen mini) prevents exercise-induced hypoglycemia more effectively than a basal rate reduction and with less hyperglycemia than seen with glucose tablets. In the small Helmsley Charitable Trust-funded crossover study, 15 people with well-controlled type 1 diabetes (baseline A1c: 7.1%; duration ≥2 years; on pumps; regular exercisers) each participated in four moderate exercise sessions consisting of brisk uphill treadmill walking at 50%-55% VO2 max for 45 minutes. Five minutes before beginning exercise, patients received in separate trials: (i) sham basal reduction and placebo glucagon injection; (ii) 50% basal rate reduction and placebo injection; (iii) 20 grams oral glucose five minutes before the start of the exercise and another 20 grams 30 minutes after the start of exercise; and (iv) sham basal reduction and a 150 ug subcutaneous injection five minutes before the start of exercise. The figure below shows that, after onset of exercise, blood glucose levels in both the control and basal reduction groups drop and remain low through recovery – the glucose tab and glucagon conditions both elevate similarly during exercise, but the glucagon intervention causes glucose to plateau after exercise, while glucose tabs caused levels to increase further during recovery. At a high-level, ~33% of control and basal reduction cases saw hypoglycemia (“a few serious”), while none of the glucose tabs or glucagon experiments saw a glucose go below 70 mg/dl. On the other end of the spectrum, hyperglycemia was present in ~73%  (>250 mg/dl) occurred with glucose tabs than with glucagon (five to one). Following exercise, patients ate a standardized meal and were monitored for the rest of the day and overnight. After the meal, glucose levels in all groups converged around 180 mg/dl, and there were no differences in CGM metrics between the conditions that night. These findings suggest that 150 ug mini-dose glucagon given before moderate aerobic exercise is safe and an effective alternative for preventing hypoglycemia – Dr. Rickels concluded that the findings warrant longer-term investigation. We’re not sure if the choice of a flat 20 grams of glucose tabs, dosed twice, was really a fair comparator in this study. Arguably it should have been individualized based on the person – 40 grams of glucose tabs was likely overkill for many, given that this was treadmill walking for 45 minutes. An n=1 example: Adam finds 40 grams of glucose tabs raise his blood glucose by roughly +200 mg/dl (on average), while 45 minutes of brisk walking would drop his blood sugar anywhere from -45 to -90 mg/dl (on average). In the context of this experiment, 40 grams would have been more than double what he would need to counteract walking.

• When asked about glucagon dosing in Q&A, Dr. Rickels said that it needs to be investigated in future protocols, but 150 ug has been shown to be more effective than 75 ug at correcting hypoglycemia after a recent bolus. The question was raised due to a figure that depicted super-physiologic levels of glucagon after glucagon injection. We hope a mini-dose glucagon pen would allow for smaller/larger doses, depending on circumstances – e.g., down trending arrow, small child, heavy exercise, etc. This seems like the kind of drug that should allow for individualization, rather than a flat dose.
• Xeris’ mini dose glucagon is in phase 2 and no timing has been shared on a phase 3 trial. The phase 3 for Xeris’ G-Pen auto-injector for severe hypoglycemia rescue is currently recruiting participants, with an expected completion date this month. See the ClinicalTrials.gov posting here and our glucagon competitive landscape for more information.

Selected Questions and Answers

Prof. Stephanie Amiel (King’s College London): Am I correct in thinking that glucagon has really dealt well with immediate hypoglycemia, but we need a strategy for delayed nocturnal hypoglycemia?

A: We didn’t see any nocturnal hypoglycemia in this study. That’s probably the case because of how well-controlled we conducted the study so the conditions could be comparable. The participants took part in fasting exercise in morning, and the patients had to start out with good glucose before the study. There’s certainly a greater risk for nocturnal hypoglycemia following afternoon or evening hypoglycemia – that should be studied in the future.

7. Claude Bernard Awardee Dr. Bernard Thorens Discusses the Body’s Network of Glucose-Sensing Neurons

EASD’s scientific sessions opened on Tuesday morning with the prestigious Claude Bernard award and lecture, which this year went to Dr. Bernard Thorens of the University of Lausanne in Switzerland. His work on the neuronal role of glucose regulation interestingly enough explains some of Claude Bernard’s observations that lesioning parts of the brain can impact blood glucose levels. Dr. Thorens led his audience – well over a thousand strong – through a whirlwind tour of fascinating basic science from rodent models. For example, did you know that there are networks of neurons in multiple parts of the brain that sense and respond to glucose via the Glut2 receptor? These networks play a role in triggering adaptation to incoming glucose in the short term, modulating glucose-seeking behavior in the medium term, and even stimulating beta cell proliferation in the long term. A lot of this work is still making the jump from mice to humans, but existing human research does suggest that mutations in the Glut2 receptors are associated with risk of conversion from impaired glucose tolerance to type 2 diabetes – and perhaps the glucose-sensing neuronal network plays a role.

Diabetes Technology Highlights

1. Compelling Belgian CGM Study: 12-Month Data Shows Significant Reductions in Hospitalizations and Work Absenteeism

A very compelling poster shared 12-month healthcare outcomes from a national Belgian reimbursement of CGM in 515 insulin pump users (RESCUE). The hospitalization and work absenteeism outcomes were outstanding and a tremendous win for CGM. This academic study tracked outcomes in the 12 months prior to CGM initiation and then in the 12 months following CGM in a population of type 1 adults on pumps. Most notably, the percentage of patients experiencing a hypoglycemia/DKA hospitalization declined by a striking 75% following CGM initiation (16% of patients without CGM to 4% with CGM; p<0005). Meanwhile, CGM drove a 64% decline in the percentage of patients experiencing a work absence (25% to 9%; p<0005). From these data, the poster estimates a nationwide cost reduction of €345,509 – assuming this was calculated from the sub-set of 379 users with 12-month CGM data, it implies €911 saved per person. We’re not sure if this cost estimate included the price of CGM, but saving this many days from work and hospitalizations is very encouraging for CGM’s cost-effectiveness. Notably, the observed A1c reduction of approximately 0.3% (baseline: 7.6%) with CGM over 12 months would have significantly understated these outcomes. As we’ve seen in other CGM studies, the benefit was slightly larger for those with higher A1c levels at baseline. CGM drove an improvement in quality of life (SF-36, though numerical numbers were not given), and both fear of hypoglycemia (HFS-Worry) and emotional burden due to diabetes (PAID-SF) improved significantly. It was not clear from the poster or the ClinicalTrials.gov page what CGM device(s) were used in this study. What a victory for the field and something we hope to see repeated in other countries and health systems!

• This was a real-world, observational study of CGM, meaning there are some limitations. First, there seemed to be some patient dropout between the pre-post evaluation – n=515 were enrolled, n=496 had 12-month data before CGM, and then n=379 had 12-month data post-CGM. (This is why we focused on percentage of patients and not number of events in the above.) We’re not sure if this was a lost data issue or if people actually stopped wearing CGM. There is likely some selection bias from no inclusion criteria or randomization – patients for CGM were “selected by the diabetes teams.” Last, the study only enrolled pumpers at specialized diabetes centers, meaning generalizability is a question. We’re not sure how these limitations would influence the impressive results.
• The ClinicalTrials.gov page notes that Belgian CGM reimbursement was granted for an initial period of three years, with this study serving as an evaluation of the decision. This trial will continue out to 24 months, meaning we should see follow-on data at some point. If outcomes are positive, we’d have to assume reimbursement will be extended.

2. Diabetes Technology Exhibit Hall Updates – mySugr US Bundle Launches; One Drop Direct BGM->Apple Watch in Q4; Cellnovo FDA Delay; Medtronic absent!

We visited booths from Abbott, Ascensia, Cellnovo, Dexcom, EOFlow, Glooko, IDX, J&J One Touch, Kaleido, One Drop, POCTech/Diamesco, Roche (including mySugr and Senseonics), Valeritas, and Ypsomed. Medtronic was notable absent from the hall. The most notable updates are succinctly mentioned below, with more detail in the exhibit hall section:

• Roche / mySugr / Senseonics – mySugr launches US bundle for $39.99/month for unlimited strips, Accu-Chek Guide BGM, app, CDE coaching; “When can I get it” questions for Senseonics; excitement for new Roche diabetes care vision
• One Drop – Plans to launch direct Chrome BGM-to-Apple Watch transmission in 4Q17 (no nearby phone needed). Featured as a Health app in Apple Watch Series 3 page,
• Cellnovo – FDA review delay, as a second round of questions came from the Agency.
• Dexcom – Diabeloop added to “partners slide”, J&J Animas removed from slide; excitement for Apple Watch Series 3 updates
• J&J OneTouch – Lots of buzz about One Touch Via, but no timing updates.
• Kaleido – Colorful patch pump hopes to launch in Netherlands by end of 2017/early 2018.
• EOFlow – Patch pump aims to launch in Korea by end of 2017/early 2018.
• POCTech/Diamesco – Chinese CGM hopes to launch in 2018 in Europe (CE Marked), smart reusable pen and insulin pump reportedly coming this fall.

3. Prof. O’Brien, Dr. Polonsky, & Prof. Montanya on Poor Adherence in Type 2 Diabetes and Potential Remedies

Melbourne’s Prof. Richard O’Brien, UCSD’s Dr. William Polonsky, and Barcelona’s Prof. Eduard Montanya discussed real- world challenges in type 2 diabetes, identifying adherence as the primary driver for the gap between outcomes observed in clinical trials versus real life. Dr. O’Brien cited a recent study (from Dr. Polonsky’s group) demonstrating that 75% of the differences in A1c reductions seen in clinical trials for GLP-1 agonists vs. real-world data can be explained by non-adherence. For DPP-4 inhibitors, the paper suggests that 72% is due to non-adherence. Dr. O’Brien urged physicians to discuss adherence with their patients, citing that one third of prescriptions for diabetes medications are never filled. Dr. Polonsky took adherence a step further, diving into critical patient beliefs surrounding medication. The issue, he said, is that diabetes medications lack short-term, tangible benefits, while cons such as burden and real/imagined adverse effects are plentiful – we wonder if VR, simulation, and higher tech education might help close this gap. For example, here’s what happens to the body when glucose levels are high, here’s how you will age when glucose levels are high, etc. Dr. Polonsky provided the telling example of an exercise he performs with type 2 patients, in which he shows them the profiles of two hypothetical patients, one of whom has at-goal A1c but takes two medications and is on insulin, while the other has a high A1c, but is not on any medications. When asked which patient is doing better, the vast majority say it’s a tough question. In other words, some people with diabetes equate more medication with failure. Yikes! The onus for this misconception is largely on providers, who sometimes threaten patients with more medication if they don’t improve behavior. Dr. Polonsky emphasized working on the patient-provider relationship, citing several studies demonstrating that improved trust is associated with greater adherence. So how do we shift the paradigm? Dr. Montanya mentioned a study demonstrating that triple combination therapy immediately following diagnosis (instead of a step-wise add-on approach over four months) conferred a greater A1c improvement. His argument was in favor of early combination therapy, but this could also tie in to adherence: Presumably, a stepwise approach is perceived as consecutive failures, while the immediate intensification is simply a medication regimen that drives right to success, so patients are more likely to stick to it. Dr. Montanya also suggested telemedicine as a potential approach to improve adherence, although acknowledged that meta-analyses yield mixed results and tend to demonstrate only short-term efficacy. He, and many thought leaders we’ve heard from recently, are particularly excited about ITCA 650, the six-month implantable exenatide pump from Intarcia. He discussed the FREEDOM-1 and -2 trials demonstrating significant reductions in A1c and body weight, and sees real potential in the pump to drive adherence. Once implanted, it works! We also see very high potential in novel ways to take and track medication, such as the super brilliant Pill Pack (“Pharmacy Simplified”). Poor adherence is a complicated affair, one that costs the health system huge sums of money – addressing it will take a carefully-crafted combination of support, technology, and design.

Questions and Answers

Q: What is the best way to approach a patient about being adherent?

Dr. Polonsky: What we see is healthcare providers will say, “I don’t know this data regarding adherence, I don’t see that.” That probably has to do with how we ask the question. It’s common for providers to say: “Look you haven’t had any problems managing your meds, have you?” The patient is almost guaranteed to answer no. There’s an opportunity to normalize the situation. Instead say, “I know people struggle taking medication, what kind of trouble do you have with your medication?” It’s important to open up the door to normalize the issue. Bravo!

4. Ascensia Announces Global Innovation Competition - €200,000 for Winning Digital Solutions that Address Type 2 Diabetes

At the end of an excellent Ascensia symposium on behavioral change, CEO Mr. Michael Kloss took over the mic to announce a global innovation competition (The Ascensia Diabetes Challenge) – €200,000 in cash prizes are available for digital solutions that improve the lives of people with type 2 diabetes. He began by thanking the panelists for “pointing out that our technology is frustrating for patients,” and cited this fact as the reason for the competition. Submissions will be welcome from Europe, the Americas, and Asia Pacific with entries opening on October 1 for Europe and November 6, 2017 for Asia Pacific and the Americas. Finalists will then be announced in early 2018, with a finalist event in spring 2018 and winner announced in June 2018. The expert panel of judges will include UCSD’s Dr. Bill Polonsky, Dr. Masood Nazir (a GP from the UK), and Robin Swindell (a person with type 2 and on the board of Diabetes UK) – nice! Criteria includes user experience, innovation, efficacy, sustainability, and scalability. The challenge is done in partnership with yet2, an innovation and technology consultant that has run several similar efforts. We’ll be interested to see who applies, what ultimately wins, and whether it comes to market or stimulates further innovation inside Ascensia. Prize competitions create nice financial incentives for applicants, though we wonder how entrepreneurs think about them – Do they worry about making their ideas public? Are they excited by the chance to bring an idea to a big company and do something with it? Of course, this also sends a big message to Ascensia’s internal team that innovation can come from anywhere, including outside of the company’s walls. In a press conference on the challenge, we asked whether the competition and associated cash prize bring any strings attached. We were referred to the challenge's terms and conditions (fine print), which do seem pretty hands off – “the winner will also have the opportunity to work with Sponsor on the development of their solution, using the expertise and resources from the company to help towards bringing their solution to market.  Such collaboration is subject to a mutually agreed upon business relationship with mutually agreeable terms.” Ascensia does not automatically get any IP from ideas, which is great to see. We’re glad to see the standalone company trying to broaden and think differently, as relying on the BGM+strips market will not prove sustainable long term.        

• Will we see more of these innovation challenges moving forward? These seem like a great deal for companies to crowdsource innovation, assuming the ideas are solid and applicant quality is high. Amazon/Merck launched the Alexa Diabetes Challenge in April, and we’ll be at the Demo Day to see the finalist voice-enabled solutions for type 2 diabetes. We wonder what the IP parameters are for contests like this – does the winning content automatically belong to the funding company? Or is the winner independent, just with some extra cash in pocket? Or somewhere in between?

5. Healthimation Integrated with Connected Scale, Smartwatch, and BGM (Including Ascensia)

The respected Dr. Osama Hamdy gave an overview of Healthimation’s weight management program (using animation, gaming, and leveraging Joslin’s Why WAIT program), which he co-founded, sharing that the platform now integrates with device data. Pictured on the slide were a connected scale, a smartwatch, and a series of Ascensia meters. An Ascensia rep later told us that the picture did not denote an exclusive relationship, though the talk did come in an Ascensia symposium. We’re glad to see Healthimation pushing forward with connectivity, and of course, to see Ascensia embracing up-and-coming digital tools that expand its addressable market. Based on Dr. Hamdy’s remarks, the company aims to create an ecosystem, in which “every part of a day is connected.” The original WhyWAIT intervention has shown encouraging data, driving average weight loss of 6.4% at five years, 21% of enrollees stopping insulin, and 50%-60% experiencing a reduction in their diabetes medications. The question is, can this program translate to the digital setting with the help of machine-learning assisted personalization, Hollywood style animation and gaming, and coaching? How will it stack up to Virta’s approach? No outcomes were shared today, which was disappointing following the beta launch in December. According to the website, the product is available as a free seven-day trial, with a steep direct-to-consumer price of $49.99 per month. Many attempts to turn weight management virtual have fallen short because the programs aren’t sticky, but Dr. Hamdy firmly believes that “Lena,” the fit, young, quirky avatar that guides users through the course and the Hollywood magic (surprises, new games, etc.) will keep people from getting bored – we like the out-of-the-box thinking and hope he is right. Following the presentation, UCSD’s Dr. William Polonsky plainly said that “most apps we see in type 2 diabetes are pretty darn boring.” He (naturally) didn’t seem as positive about Healthimation as its founder did, but if it can provide the right mix of cheerleading, connectivity, and support to make sense of data, then Dr. Polonsky believes it can be successful.

Big Picture

1. CDC’s Dr. Gregg Overviews Changing Character of US Diabetes Epidemic

The CDC’s highly respected Dr. Edward Gregg shared fascinating insights on the changing character of the US diabetes epidemic: A diversification of complications and maintained cumulative incidence and secondary events.

• The first factor that Dr. Gregg believes may be underlying these trends is progress in the treatment of older adults, thanks to improvements in clinical and public health efforts. As a consequence, we are likely seeing greater reductions in macrovascular complication and decreased mortality, which could cause reduced competing risk (i.e. allowing other complications to manifest) and extended exposure (i.e. people have diabetes longer).
• Dr. Gregg suggested that factor #2 contributing to the observed trends is an increase in type 2 diabetes in youth and young adults in virtually all ethnic groups except for non-Hispanic whites. He explained that the improvements we’ve seen in the care of older adults are not apparent in youth (this is probably because research in this demographic is sorely lacking). Millennials (born between 1980-2000) are the most obese generation yet; within this generation, smoking prevalence is higher in people with diabetes than in those without diabetes; these patients are most likely to have very poor glycemic control; and youth have seen the smallest improvements in CVD hospitalization and mortality.
• Taken together, diagnosis at young age plus a lack of quality care leads to extended exposure. We found this analysis to be particularly interesting, and on the whole, a positive outlook. Improved outcomes in adults speaks for itself – our tools and drugs are getting better. While the trends in young people are heading in the wrong directions, we believe that studying this at-risk cohort in greater depth would yield improved preventative and care measures. Dr. Gregg believes the field has hit a tipping point, as everyone in behavioral research and otherwise is talking about behavioral research/intervention and healthy environment design. This is terrific, of course – we’re still wary that most numbers we see on the “most” obese are getting worse.
• Overall diabetes complication incidence in the US has been ~flat since 2010. There hasn’t been much of a decline in the last four years in CV hospitalization rates; over time, as long as they were reimbursed, the advent of cardioprotective diabetes drugs will bend that curve meaningfully. On a quite worrisome note from our view, there has actually been an increase in amputations in the past four years, largely driven by men, and by toe amputations.
• Diabetes appears to take a larger toll on disability-free life than overall life-expectancy. A recent study showed that if a woman has diabetes and is 50 years old, she can expect disability onset (on average) at age 70, and then live to 80 years. Meanwhile, a 50-year-old woman without diabetes can expect to live disability-free until she’s 79, and then live to 86 years. That’s a nine-year difference in disability-free living, and just a six-year gap in life expectancy. It’s clearly not enough to just make patients live longer, because we risk creating a population of elderly unwell who will not only have compromised qualities of life, but also cost the healthcare system boatloads.
• Increased incidence + decreased mortality = increased lifetime risk. The average 60-year-old man spent 15 years with diabetes in the 1990s; 18 years in the 2000s. Put in a population context, the total years spent with diabetes for the average community of 1,000 was 5,463 years in the 1990s; in the 2000s, it was 12,199 years. That’s more than a doubling of exposure to diabetes. Even if diabetes management continues to improve dramatically and complication rates continue to drop, there will still be a huge burden attributable to the sheer size of the epidemic and longer lifespans.

Detailed Discussion and Commentary

Exhibit Hall – Diabetes Technology

Abbott

The bustling Abbott booth, tucked into the corner of the hall, showed off the real world and clinical data (both from adults and pediatrics) of FreeStyle Libre, along with the slogan “You can view it – Anytime, anywhere.” The “anywhere” part of that phrase is becoming more literal by the day – Abbott has caught up to Dexcom, with Libre availability in 41 countries, and full or partial reimbursement in 17 of them. The big news today was the achievement of reimbursement status in the UK – see our report here. The other recent milestone was national reimbursement in Japan, and a rep told us that she believes FreeStyle Libre Pro will enter the French market in 2018 (Libre consumer has already secured national reimbursement). The public figure for user base stands at “over 300,000,” but we’re hoping for another update in the 3Q17 call. FreeStyle Libre remains under FDA review after its 3Q16 submission. As typically shown at Abbott’s booths, there were a slew of patient testimonials on the device: “Discovering FreeStyle Libre was like someone turning the light on.” “FreeStyle Libre has also washed away my parents’ anxious feelings overnight.” “It’s allowed me to do things that I would have never considered.”

Ascensia

The Ascensia booth advertised the Contour Next One and Next Plus BGMs (identical meters branded differently for separate markets). Representatives shared that they were receiving lots of questions surrounding the Contour Next One, mostly on how the new system functions. Visitors were also curious to learn more about Contour NextLink, which is available with Medtronic’s MiniMed 670G in the US (630G and 670G pumps) and in the MiniMed 640G outside the US. The booth bore the following campaign message: “Confidence in calibration: Recommend the highly accurate Contour Next Link 2.4 meter to calibrate their compatible CGM device and help avoid hypoglycemia.” This is a smart move for Ascensia, given Contour’s widely appreciated accuracy and the new partnerships with Dexcom (Medicare bundle) and Insulet (OmniPod Dash). As a reminder, Medtronic’s next-gen Bluetooth-enabled pumps will switch to Roche’s Accu-Chek Guide.

• Today, Ascensia announced a new technology partner: The Contour Next One BGM system will connect via Bluetooth to the CE-marked Balansio Mobile app and directly plug glucose readings into the app’s CE-certified class IIb bolus calculator. The integration is already complete and available in Finland, Sweden, and the UK, where Balansio has launched (Balansio has plans to launch in more countries soon). We have never heard of this app, and according to Google Play, it has 1,000-5,000 downloads (a strong 4.2/5 stars). To receive a bolus recommendation, users will simply have to enter the carbohydrates they plan to eat. Balansio can also automatically collect physical activity data to help users better understand the effects of activity on blood glucose. We wonder if Ascensia will also integrate with mySugr, as the Logbook’s bolus calculator has a much wider user base to help. mySugr is still an independent company, even though Roche now owns it.

Cellnovo

The Cellnovo patch pump system is now available in 10 countries (including the UK, Australia, Italy, France, Spain, Israel, the Netherlands, and Greece), but a previously proposed 4Q17 US launch has now been pushed back. A 510(k) submission was filed with FDA in November 2016, but the company shared last week that the Agency has requested a second set of further information. No updated timing was shared, just that it will be delayed. This is a blow to the company, though commercializing in the competitive US market would be quite a challenge for the company right now anyway. In other news, a remote-upgradable Android handset will launch in the next month with international technology standards for Bluetooth and Android (the handset was previously a locked-down Windows phone), and a handout indicated that “Large-scale, automated production” of the new insulin cartridge is now available – good to hear, since acceleration in pump shipments has been severely hindered by the manufacturing handover to Flex. Will the product finally scale and start bringing in meaningful revenue before cash runs out? Elsewhere in the small booth, there was a mannequin wearing the pump on its arm, and the messaging for “simplicity” was prevalent. We asked about the two closed loop programs in which Cellnovo is involved, but received no updates. Diabeloop’s system presented with promising data at ADA, and the companies have since launched a CE mark pivotal trial with results expected by end of 2017 (launch possible in 2018). In April, Cellnovo and TypeZero separately announced a non-exclusive worldwide licensing agreement, giving Cellnovo the right to commercialize TypeZero’s automated insulin delivery technology within a Cellnovo patch pump (possible launch in 2018, presumably in Europe). The latter is starting to seem less likely at this stage.

Dexcom

The most notable update in Dexcom’s booth was a slide that flashed across a large plasma screen: “Collaborations developing new insulin delivery products (closed loop systems, smart pens & more).” Listed on the slide were Tandem, TypeZero, Insulet, Beta Bionics, and the University of Virginia, with first-time-appearances (that we’ve seen) for diabeloop and Oregon Health and Science University. Though we’ve long known Dexcom CGM would be used in diabeloop’s CE Mark pivotal trial, it was great to see the French company on a Dexcom slide. The OHSU team under Dr. Jessica Castle has long used Dexcom CGM in closed-loop studies, though we cannot recall the institution appearing on a Dexcom slide. The focus of the booth was G5 on Android, with phones around the booth demoing the app. A slogan at the back of the booth proudly proclaimed that Dexcom is the “first and only” CGM on both mobile operating systems. Reps in the booth seemed very excited about the new Apple Watch Series 3 and WatchOS4 – read our coverage of those here.

EOFlow

Korea-based EOFlow advertised its disposable insulin patch pump EOPatch, which a rep described as the Omnipod but, “thinner, narrower, and lighter.” The Bluetooth-enabled EOPatch is pending regulatory approval in Korea, which the company expects to receive next month. A Korean launch is expected by the end of 2017 or start of 2018. Previous guidance from ADA 2017 called for a launch in 2017. The company is also working on CE mark and FDA clearance, and hopes for decisions in the first half of 2o18 and late 2018, respectively. It would be surprising if the company could get all those submissions in at once. It plans on working with distribution partners in Europe and the US, and wants to troubleshoot any kinks before attempting a launch in larger markets such as France or Germany. EOFlow also hopes to include the EOPatch in a closed-loop system with Chinese CGM company POCTech for a launch as early as late 2018 in Korea. (See our comments below on POCTech, which are very low-confidence.) Long-term, the company is reportedly developing an integrated closed-loop system (sensor+pump+algorithm all in one patch), with a launch timing hoped for in 2021. We would be shocked if EOFlow figures out how to align infusion set and CGM wear times and build everything into small device. Heavy skepticism is all we could leave this booth with…

Glooko

A Glooko rep reinforced that the new touchscreen, NFC- and Ethernet-enabled transmitter (see picture of a prototype), which is currently piloting in Sweden, is expected to launch later this year. She told us that many stoppers-by were unaware of the Glooko/Diasend merger (more of the EU audience had heard of Diasend), but were excited to hear of the additional software solutions that Glooko has added on top of both companies’ vast device compatibility (160+ devices!). Glooko also has lots happening on the decision support, remote monitoring, population health, and a patient-facing app. We’re equally enthused by the merger – see why in our report from exactly a year ago today!

IDx

At the IDx booth, we learned that the multi-center FDA clinical trial (n>1,000) testing the company’s diabetic retinopathy screening software, IDx-DR, has wrapped up, aligning nicely with the company’s timeline released earlier this summer. IDx is currently preparing the data, and hopes to submit to the FDA by the beginning of 2018. The software has already received its CE mark as a class IIa medical device, and the representatives cited multiple European customers. In addition to filing with the FDA, IDx is focused on applying the screening software for other diseases, especially Glaucoma. Reps told us they even hope to expand applications even further to include cardiovascular events and Alzheimer’s (yes, with eye screening). The representative predicted that a test for Glaucoma will be available in “October or November.” We see automated diabetic retinopathy screening tools having the potential to massively improve care, especially for those living in remote areas, as per NIDDK Director Dr. Judith Franklin’s inspiring talk given at this year’s ADA.

J&J – OneTouch

The LifeScan/Animas booth was buzzing with questions surrounding timing for the OneTouch Via bolus-only patch delivery device. Unsurprisingly, the representatives were unable to provide any timeline details, nor could they share news pertaining to the US launch. As a reminder, the OneTouch Via has received FDA clearance, but has yet to launch in the US. Representatives said that they’re working to ramp up manufacturing at the Calibra plant in Puerto Rico and are in discussions with payers, but couldn’t say for sure when we might expect a rollout. It does sound close. We did learn that the last patient has completed the major multi-center clinical trial investigating changes in A1c, glycemic variability, and patient reported quality of life in type 2 patients using the OneTouch Via for boluses vs. bolus insulin pens, and the company hopes to publish sometime next year. Representatives were unable to comment on the OneTouch Vibe Plus with Dexcom G5 –FDA and Health Canada approval was announced in December, but no launch timing has ever been shared. The Dexcom booth didn’t even list LifeScan/Animas as a partner, so it’s hard to imagine this is ever coming to market. We also were unable to receive updates on the WellDoc integration.

Kaleido

The colorful patch pump company had an expansive booth – arguably outsized, given that it still doesn’t have a product on the market. Following a CE Mark in 2016, a Netherlands launch is now expected by the end of 2017/early 2018, and a UK launch will follow sometime in 2018. This is about ~1-2 years delayed from the “end of 2016” launch timeline given at EASD 2016. The company has integrated feedback from ~30 users, making pretty small changes to the user interface (e.g., temp basal in %, using hours instead of minutes, bolus calculator tweaks, adding Glooko/Diasend integration). The company has “a long waiting list” to get on the pump, and the rep told us it has 98% reimbursement in the Netherlands. With the massive delays at this stage and Cellnovo’s own struggles, it’s hard to be optimistic about Kaleido’s prospects. The company has a nice “consumer” feel, though it’s hard to build a pump company on this alone. Can it scale and compete in an increasingly competitive market?

Medtronic – Absent From the Exhibit Hall

The biggest tech gossip in the exhibit hall was Medtronic’s absence, which surprised many attendees. The pump+CGM giant was nowhere to be found, and only two posters on the 670G were shared in the hall (both cuts of the pivotal data, but nothing highly notable). Medtronic’s international business is really carrying the company’s sales (see 2Q17), so it was even more surprising to see the absence – particularly in Europe where the 640G has been doing well. At JPM, Medtronic expected an international launch of the MiniMed 670G in May-October, a timeline that is fast-approaching. We would not be surprised to see this delayed, given the ongoing sensor supply shortage that has slowed MiniMed 670G shipments in the US (see 2Q17). Many in the hall were also gossiping about the new infusion set recall, announced on Monday. Upon further reflection, we wonder if the adverse events stem from the waterproof MiniMed 630G/670G – perhaps more Medtronic pumps are being used around water now, leaving higher chances of water getting on top of the reservoir during the set change process. 

One Drop

One Drop made its first exhibit hall appearance at EASD, and the team was especially excited about the new Apple announcements on Watch and iOS 11. CEO Jeff Dachis told us that direct Chrome BGM-to-Watch transmission (no nearby phone needed) will launch in 4Q17 – this will likely be the first meter to take advantage of WatchOS4’s Core Bluetooth addition, something we hope many diabetes devices will move to. Notably, One Drop is also the only diabetes app shown on the Apple Watch Series 3 “Health Tools” page, an impressive vote from Apple (see picture below). One Drop reps were also excited about AR Kit (augmented reality) and ML Kit (machine learning), which will launch with iOS 11 next week and give app developers even more tools to implement in next-gen products. Imagine looking at your diabetes data in augmented reality! The One Drop team is now up to 27 people, including recent hire Dr. Lindsay Sears joining the clinical team with Dr. Chandra Osborn.

POCTech/Diamesco

The POCTech and Diamesco booths were merged, as the latter will apparently market the Chinese-developed CGM. The booth proudly displayed a CE Mark certificate for the POCTech CGM, which looked to have come through in August. Commercialization is reportedly expected in 2018 in France, Spain, and Italy; as we have in the past, it is hard to take this company seriously based on what we’ve seen thus far. The seven-day wear CGM reportedly needs one calibration per day, and a brochure advertised an MARD of 8.7% vs. venous blood glucose (n=73). No study details or protocol were shared (e.g., Was it in people with diabetes? How many matched pairs? Percent of points in hypoglycemia?). The CGM sends data to a receiver or smartphone and collects a value every three minutes. To say we are skeptical would be an understatement. Meanwhile, Diameso advertised a new reusable smartpen (DiaPen) and clunky-looking tubed pump (i-Jet). The rep said both products will launch in “Fall 2017” in Europe, though the i-Jet poster said is is already “distributed in major European countries.” We’re not holding our breath.

Roche – Diabetes Care

Roche’s Diabetes Care booth was absolutely packed with attendees hoping to hear more about the company’s “integrated diabetes ecosystem” (which we learned a lot about earlier this week – see demo slides here). The ecosystem, which will leverage Accu-Chek BGMs, the mySugr app, GoCarb (an AI carb quantification app), Accu-Chek Connect app, Eversense CGM, Accu-Chek View (a digital diary with HCP data sharing portal for prediabetes), the connected Pendiq pen, and other pieces, will “hopefully” be available before next year’s EASD. We look forward to learning about the business model and making this experience truly seamless. In the booth, we haven’t sensed this much excitement from Roche reps in a long time. One said “this is a very exciting moment for us. It’s a little fuzz, but we’re going to an open ecosystem, and this is the direction we need to go.” Open ecosystem, she added, means that the platform – whatever business model it is based upon – will be device agnostic in 1.5-2 years. As we understand it, individual pieces of the ecosystem are rolling out: mySugr has been available for quite some time now (used by over one million patients; Pro bundle reimbursed by a large payer in Germany), Accu-Chek View is already available in Germany, Pendiq will be available in Germany starting in late September, and GoCarb should launch next year (more work is needed to optimize its machine learning algorithms). It’s great to see the Roche diabetes business appear so revitalized, when there were (believable) rumors of divestment just seven months ago. The transition from a product-focused business to a service/digital health-based one will not be automatic for a large company, but it is the right move and all about bravery and execution.

• We learned more details about how Roche is moving forward with the Accu-Chek Insight CGM: On Monday, we heard that Roche will not launch further versions of Insight. Today, we confirmed that the sensor will stay in existing limited launch markets (“specialized diabetes centers” in the Netherlands, Norway, Denmark, and Sweden), but the rep wasn’t sure if Roche would expand the offering to other countries. We ultimately think the decision to focus on Senseonics’ Eversense is a prudent one, otherwise the company would be competing against itself to some degree – plus we’ve long wondered how the Insight sensor would have stacked up against Dexcom and Abbott sensors that have strong user experiences and deep pipelines.
• Roche hopped on the VR train at this meeting, sitting visitors down in a chair (both real and virtual) and having them watching videos telling the stories of patients and how the Roche ecosystem can help them. When will we see virtual reality leveraged outside of an exhibit hall to help patients? How far away is for product training and diabetes education?

Roche – mySugr

mySugr launched a direct-to-consumer (DTC) Pro bundle in the US just yesterday morning! The package consists of unlimited test strips delivery, an Accu-Chek Guide BGM, the mySugr app, and 24/7 CDE access for $39.99 per month. Nice! The mySugr bolus calculator, offered in Europe, is obviously not included in the bundle and a rep we spoke to wasn’t sure it has been submitted in the US. As a reminder, the all-in package is reimbursed by a large payer in Germany and mySugr has noted that it is talking to payers in other markets – presumably including the US – but this launch is exclusively direct-to-consumer. We like this move, and the $39.99/month pricing is quite competitive. For comparison, Livongo’s DTC offering is $65/month (which may be explained by higher touch, more hands-on coaching), and One Drop’s Premium plan launched in December with unlimited strips at a slightly less expensive $33-$39.95 per month. It was great to see mySugr featured so prominently in the Roche booth – when we first arrived, a mySugr rep was giving a talk about the platform in front of a sizable crowd, and there was a lime green corner of the large booth dedicated to mySugr.

Roche – Senseonics

The glucose monitoring section of the Roche Diabetes Care exhibit was bustling – despite the absence of the Insight CGM – due to live demos of Senseonics Eversense insertions. Eager attendees crowded around a Roche rep as she slid the inserter into a mock piece of tissue (see the demo kit below). We overheard many say that they’ve “heard very good reviews” and all wanted to know when the sensor would be available in their respective countries. Per the 2Q17 call, Senseonics expects availability in 14 countries by the end of the year. One woman from France asked about availability, to which the rep replied, “we’re hoping we’ll have it in France by the end of the year, probably with reimbursement. Maybe we need more study results, I don’t know. It would be a missed opportunity, I think.” At the moment, there has been a very slow rollout in the EU, with >340 implantations thus far (outside of trials). We wonder if the now CE marked 180-day indication, just announced yesterday, will ready Eversense’s launch to ramp up. Roche has been heavily featuring Eversense of late, and it seems like this is the sensor it will pour resources into, as opposed to its own Accu-Chek Insight (see more in the Roche Diabetes Care booth write-up).

Valeritas

The Valeritas booth was unstaffed when we stopped by, but we were able to grab a flier advertising the basal-bolus patch insulin delivery device, V-Go. The pamphlet emphasized simplicity (no batteries or programming), comfort (user rating: 8.7/10), patch form-factor, positive outcomes (published data demonstrate V-Go lowers A1c with less insulin), and no need for accessory needles or pens. The pamphlet also indicated that nine out of ten patients who try V-Go want to stay on it, although this statistic was cited only as “Data on File.” We were hoping to receive updates on the connected “V-Go Link” and a pre-filled V-Go. Valeritas’ quarterly sales have now been almost exactly flat for the past two years – what will it take for this device, which has encouraging health and economic data, to ramp? The one-day wear and device clunkiness may be limiting appeal, though awareness and accessibility (solvable problems) are likely the biggest issues.

Ypsomed

A portion of Ypsomed’s sprawling booth was still dedicated to Insulet’s Omnipod, which Ypsomed will continue to distribute internationally only through June 30, 2018 – perhaps ironically, the slogan was, “Enjoy Freedom,” relevant to both the pump and the partnership. The expiration of the agreement will definitely challenge Ypsomed’s business, as international Omnipod sales have seen YOY growth of 63%, 35%, and 33% over the last three half-year reports. Ypsomed now plans to launch its own patch pump, the YpsoPod, in the second half of 2020 (calendar year), though this was obviously not discussed in the booth. Elsewhere, reps were excited to share the vision for the near future: A connected network of proprietary devices/software that include the durable YpsoPump, Unio BGM, mylife app, and mylife desktop software. There was no specific time horizon shared. CGM integration with the YpsoPump is on the roadmap, according to the FY17 update, but reps indicated that it will not be an internally-developed CGM. Presumably this means Dexcom, Abbott, or Senseonics will be used. Ypsomed will obviously need to move towards automation fairly quickly to stay competitive.

Exhibit Hall – Diabetes Therapy

AstraZeneca

AZ’s booth held a significant amount of real estate at the north side of the exhibit hall, where the company opted for an earthy bright white and wood grain display with touches of artificial grass. Bydureon (exenatide once-weekly) and Farxiga (dapagliflozin) were most prominently featured on either front corner, alternately promoted with the slogans “Bydureon first…insulin later” (an adage we’re hearing applied frequently to GLP-1 agonists) and “glucose out, results in.” Touch screens and headphones were readily available to learn more about each product. DPP-4 inhibitor Onglyza (saxagliptin) was less prominently featured on a changing display. Grass-lined couches and low white chairs led attendees through a door in the booth’s middle wall, which had coffee bars on either side. The back side of AZ’s booth hosted purple couches and white coffee tables, with a large TV screen and a panel dedicated to EXSCEL results, promoting their Thursday announcement and noting that it’s the largest CV outcomes trial, conducted in >14,000 patients across 687 sites, with a pragmatic trial design including patients at a wide range of CV risk. This side also dedicated a wall to the DapaCare clinical program, investigating the CV and renal effects of dapagliflozin in patients with and without diabetes. There was no mention of Qtern (dapagliflozin/saxagliptin) anywhere in AZ’s booth and representatives had little to offer, which is disappointing because the drug (approved but not yet marketed in the US) is actually available in Europe, where it was first-to-market in this SGLT-2/DPP-4 class.

J&J – Janssen

About half of J&J’s booth was dedicated to SGLT-2 inhibitor Invokana (canagliflozin), the remainder focused on the company’s diabetes device business. Both standalone Invokana and Invokamet (canagliflozin/metformin fixed-dose combination) were advertised, and one banner announced that more than one million patients globally have been treated with Invokana. On interactive screens, booth visitors could review the safety/efficacy data on canagliflozin, and graphs particularly emphasized weight loss and blood pressure-lowering.

Lilly

Located right at the main entrance to the exhibit hall, Lilly’s large booth dedicated nearly half its square footage to BI-partnered SGLT-2 inhibitor Jardiance (empagliflozin) and GLP-1 agonist Trulicity (dulaglutide). The bright display, set atop large white tiles, promoted Trulicity as a “simple approach to a first injection,” highlighting the GLP-1 agonist’s patient-friendly, IDEO-designed pen. Another slogan read, “for those who are reluctant, Trulicity can help make it click.” BI-partnered DPP-4 inhibitor Tradjenta (linagliptin) had a smaller presence, but was still actively promoted as “Simple. Every day,” on a set of displays along the main walkway. A display on Lilly’s “Streetwise” program, which produces informational pamphlets for teens and young adults with diabetes, accompanied another on Lilly’s partnership with Disney, which has produced materials and resources designed for families with young children who have diabetes. Around the back of the booth, we found a timeline of developments at Lilly, starting with its 1876 founding (and detailing an amazing history of pharmaceutical advances). A decently-sized corner of Lilly’s booth was dedicated to the company’s insulin offerings: Visitors could compare each of the five pen options for rapid-acting insulin Humalog, and also had the chance to learn more about biosimilar basal insulin Basaglar (this product is also partnered with BI, and we saw lots more on the biosimilar in Lilly/BI’s combined exhibit).

Lilly/BI

Across the way from Lilly’s booth, BI’s exhibit featured interactive attractions around Jardiance and EMPA-REG OUTCOME. Attendees could play a Wii-based game in which they slashed a sword to choose trivia answers about Jardiance and the groundbreaking CVOT, and a moving arrow advertised 38% relative risk reduction in CV death. This was very similar to the messaging we saw around Lilly/BI’s SGLT-2 inhibitor in the ESC exhibit hall last month. Notable square footage was devoted to Basaglar in a soothing light blue and green style, where insulin initiation was likened to an airplane flight, promoting the product’s patient support kit and featuring stuffed baby animals in suitcases to ease the “turbulence” of insulin initiation. Large picnic tables drew guests to the coffee bar, next to a bean bag toss game where you could answer questions about Basaglar by throwing a bean bag through a specific hole.

MSD

MSD boasted a large booth along the edge of the exhibit hall, dedicated entirely to DPP-4 inhibitor Januvia (sitagliptin) and fixed-dose combination Janumet (sitagliptin/metformin). Curving teal carpets surrounded a round hardwood floor at the center of the company’s large, open space, where tall white stools and colorful sofas drew a sizeable crowd of conference-goers relaxing in between sessions. MSD’s exhibit once again celebrated the 10th anniversary of Januvia, launched in 2006.

Mylan

Mylan’s mid-size booth was positioned in the middle of the exhibit hall, swathed in the company’s typical light blue and white color scheme. As a nod to the company’s impending entrance into diabetes with Biocon-partnered biosimilar insulin glargine (submitted to the EMA in 3Q16, FDA submission pending after several delays), the booth’s entrance featured an array of touchscreens containing a survey about HCP awareness of biosimilars. Adjacent to a popular espresso bar and circle of comfortable white lounge chairs, handouts featured descriptions of the INSTRIDE 1 and INSTRIDE 2 trials of the candidate in type 1 and 2 diabetes. If approved, this biosimilar insulin glargine could be the third-to-market biosimilar insulin glargine in the US, after Lilly/BI’s Basaglar and Merck’s tentatively-approved Lusduna Nexvue.

Novartis

Novartis’ sizeable booth at the front of the exhibit hall was dedicated largely to DPP-4 inhibitor Galvus (vildagliptin), in contrast to last year’s display in which the company’s diabetic retinopathy drug Lucentis (intravitreal ranibizumab) took center stage. We attribute this enthusiasm for Galvus to the fact that 2017 marks 20 years since the agent was invented – a milestone that Novartis commemorated with a winding corridor bisecting the exhibit, leading attendees on a tour of the milestones in the history of DPP-4 inhibitor development. On one side of this divider, modern while panels ensconced a calm circle of plush gray chairs where attendees could rest between sessions. On the other side of the divider stood a 10-foot tall hourglass, which attendees could enter to partake in a virtual reality experience consisting of a video defining the problem of clinical inertia, and the urgency of addressing diabetes before complications like CV disease, renal disease, and blindness take hold. Consistent with this hourglass imagery, messaging emphasized that “the time is now” and when time is running out, patients with diabetes should turn to Galvus.

Novo Nordisk

At Novo Nordisk’s booth, we got to try out a new, in-progress app based on the DEVOTE dataset. You input variables such as age, A1c, diabetes duration, and insulin status (naïve, basal, or basal-bolus therapy), and the app outputs your risk for hypoglycemia and MACE events (MI, stroke, CV death). While the precise purpose of this app is still being decided (it’s not yet available to the public), company reps described this project as an effort to make hard scientific data more patient-friendly, which could encourage people to better understand data at the frontline of advances in diabetes care. Moreover, the app could facilitate and enrich patient/provider conversations to determine optimal treatment. Regardless, we thought this was very cool, and we’ll be excited to see a real-world product come out of a clinical outcomes trial – on an easy-to-use digital platform, no less. The DEVOTE CVOT, first presented at ADA 2017, showed Novo Nordisk’s Tresiba (basal insulin degludec) to be non-inferior to Sanofi’s Lantus (insulin glargine, and largely the standard of care) on CV outcomes but far superior on hypoglycemia (40% relative risk reduction for severe hypoglycemia, 53% relative risk reduction for severe hypoglycemia overnight). New analysis of DEVOTE will be presented Friday morning at this meeting, and you can bet we’ll be in the front row.

We also noticed more space dedicated to Xultophy (insulin degludec/liraglutide fixed-ratio combination) in Novo Nordisk’s EASD booth compared to conferences past. The product was featured on a colorful sign hanging from the ceiling, and messaging presented Xultophy as a “simple intensification treatment” to improve diabetes care. We were drawn to this, given previous statements from Novo Nordisk management and reps that Xultophy would be less of a commercial priority in the near-term vs. standalone insulin degludec (Tresiba) and standalone liraglutide (GLP-1 agonist Victoza). Perhaps the “near-term” is over – we’d certainly love to see the company put more commercial resources behind Xultophy, especially because we’ve been underwhelmed by early numbers for prescription volume and quarterly sales. This class of basal insulin/GLP-1 combos (also including Sanofi’s Soliqua) posted only $19 million in 1Q17 and $34 million in 2Q17, even though it represents a major advance in diabetes therapy. Novo Nordisk’s obesity drug Saxenda (liraglutide 3.0 mg) was hosted in its own nearby booth, and reps were on hand to discuss three-year SCALE data showing 80% risk reduction for new-onset type 2 diabetes with Saxenda vs. placebo.

Sanofi

Sanofi’s expansive booth was divided into sections for each of its major diabetes products (plus PCSK9 inhibitor Praluent), including – for the first time – its newly-approved biosimilar Insulin lispro Sanofi. EMA-approval came in July, and earlier this month, the FDA granted tentative approval pending resolution of patent disputes (from Lilly, over Humalog). A tall video monitor summarized data from SORELLA 1 and 2, demonstrating non-inferiority of Sanofi’s biosimilar mealtime insulin vs. Humalog, and one poster read, “Everything you’d expect from a mealtime insulin, without the brand name.” Messaging around this new product also emphasized sustainable cost, availability in SoloStar pens (which are familiar to patients), and the company’s long history of expertise in diabetes and insulin manufacturing. We were happy to see a substantial presence from Insulin lispro Sanofi in Sanofi’s booth, a quick turnaround following EMA-approval in July, and we hope this is indicative of the company’s commitment to swift commercial rollout, getting this lower-cost biosimilar mealtime insulin into the hands of as many patients as possible.

Takeda

Takeda’s colorful puzzle piece booth made a re-appearance in this year’s exhibit hall. Large puzzle piece shapes in red, purple, and blue were suspended from the ceiling and placed around the corners of the booth, amidst tall white stools and sleek low-slung couches. To complement the puzzle theme, catchy messaging for the company’s DPP-4 inhibitor Vipidia (alogliptin, Nesina in the US) read “every piece counts when managing type 2 diabetes.” Signage also emphasized other members of the alogliptin franchise – Vipdomet (alogliptin/metformin, Kazano in the US) and Incresync (alogliptin/pioglitazone, Oseni in the US) – with large screens scrolling through the clinical data for these products.

An Emerging and Innovative Therapeutic Approach in Type 1 Diabetes with Dual SGLT-1 and SGLT-2 Inhibition: The Sotagliflozin Clinical Program

The Unique Mechanism of Action of Sotagliflozin: A Dual SGLT1 and SGLT2 Inhibitor

Clifford Bailey, MD (Aston University, Birmingham, UK)

Dr. Clifford Bailey kicked-off this star-studded symposium by reviewing the concept of SGLT-1 and SGLT-2 inhibition, the heterogeneity of the SGLT-2 inhibitor class, and the theorized and observed effects of dual SGLT-1/2 inhibition in patients with type 1 diabetes. SGLT-1 and SGLT-2 are both co-transporters that use the sodium gradient, created by Na^+/K⁺ ATPase, to carry glucose into cells, but SGLT-2 is concentrated almost entirely in the kidney while SGLT-1 is found in the small intestine, muscle, heart, and kidney. Moreover, SGLT-1 has a high affinity for glucose but low transport capacity, while SGLT-2 has a lower affinity for glucose and high transport capacity. When uninhibited, these transporters reabsorb nearly 100% of glucose from glomerular filtrate. SGLT-2 inhibitors increase kidney excretion by preventing this reabsorption. The concept of dual inhibition doubles down, also targeting SGLT-1 transporters in the gut to prevent the initial absorption of glucose into the bloodstream. This reduces initial glucose absorption, while SGLT-2 inhibition reduces reabsorption, for a greater cumulative lowering of the glucose profile via 60-90 g/day worth of glucosuria. Inhibitors vary in affinity for their transporters, and sotagliflozin is unique in its level of SGLT-1 affinity, with an IC₅₀ of 36 nmol/L, rivaled only by canagliflozin at 663 nmol/L. For reference, dapagliflozin’s IC₅₀ for SGLT-1 is 1,400 nmol/L. Sotagliflozin’s affinity for SGLT-2 is comparable to other approved SGLT-2 inhibitors.

• Dr. Bailey noted that in type 2 diabetes, SGLT-2 inhibitors have consistently shown persistent glucosuria and A1c-lowering, with low hypoglycemia risk, sustained weight loss, and improved systolic blood pressure. In a small study (n=36) of sotagliflozin in patients with type 2 diabetes, sotagliflozin gave significant reductions in A1c and plasma glucose, and an increase in urinary glucose (as expected). Moreover, sotagliflozin increased GLP-1 in patients with type 2 diabetes, an effect of delayed glucose absorption to the later part of the small intestine. With the knowledge that dual SGLT-1/2 inhibitors act independently of insulin, and that they have glycemic benefits in type 2 diabetes, the question remained of their efficacy in helping to manage type 1 diabetes.

Unmet Medical Needs in Adult Patients with Type 1 Diabetes: Sotagliflozin and the Phase 2 Results of the inTandem Clinical Program

Julio Rosenstock, MD (Dallas Diabetes and Endocrine Center, TX)

Building toward the highly-anticipated inTandem3 full results (a topline release in June announced that 400 mg sotagliflozin showed superiority on a primary endpoint of A1c <7% with no severe hypoglycemia or DKA), Dr. Julio Rosenstock emphasized the need for new adjunct therapies in type 1 diabetes. Despite advances in insulin analogs, glucose control in patients with type 1 diabetes remains difficult. Only about one-third of patients with type 1 diabetes are meeting glycemic goals, and CGM data shows that “good” A1c scores can mask wide fluctuations into hypo- and hyperglycemia. Severe hypoglycemia remains a major issue, and its frequency increases with diabetes duration.  T1D Exchange data indicates an overall 5% yearly risk of DKA for a background type 1 population, which peaks around 10% in teenage years. Further, patients with type 1 diabetes progressively gain weight and experience increased hypertension and CV risk 5-6x higher than the background population. Dr. Rosenstock sees limited value in off-label use of metformin as adjunct therapy in type 1 diabetes: He articulated how clinical trials have not convincingly demonstrated metformin’s benefits in type 1 diabetes in terms of long-term A1c decline or reduced insulin dose. While we see particular promise in both SGLT-1/2 dual inhibitors and SGLT-2 inhibitors as adjunct type 1 therapies, these drugs will have a difficult time reaching the vast majority of patients without an FDA indication. To this end, there’s clearly room – and unmet need – for a new non-insulin type 1 diabetes drug on the market.

• Dr. Rosenstock summarized phase 2 and proof-of-concept data on sotagliflozin as a launching pad for inTandem3. In phase 2, sotagliflozin showed dose dependent A1c reductions and postprandial glucose-lowering even in patients with type 2 diabetes and low eGFR (pointing to effective SGLT-1 action in the gut). An initial four-week proof-of-concept study in patients with type 1 diabetes on both MDI and pump therapy demonstrated significant A1c, body weight, and bolus insulin reductions, as well as reduced hypoglycemia. Most notably, time-in-range was increased from 56% to 68%. In four weeks, two cases of DKA occurred and were determined to be pump-related; neither case was euglycemic. Based on this positive data, sotagliflozin was advanced into phase 3 trials in type 1 diabetes. Full results from inTandem1 and inTandem2 were presented at ADA 2017, while inTandem3 is Lexicon’s third and final trial for its phase 3 sotagliflozin program.

The Phase 3 inTandem Clinical Program: Efficacy and Safety of Sotagliflozin in Adults with Type 1 Diabetes

Melanie Davies, MD (University of Leicester, UK)

Dr. Melanie Davies took the stage for the main event, announcing new inTandem3 findings, published simultaneously in the NEJM. This was a 24-week trial (n=1,402) investigating 400 mg sotagliflozin vs. placebo on a primary endpoint of the proportion of patients achieving target A1c <7% with no severe hypoglycemia or DKA. Of note, this was a global trial (whereas inTandem1 took place in the US/Canada and inTandem2 took place in Europe/Israel) without an insulin optimization period, making it closer to “real life.” The primary endpoint was met by 29% of people in the sotagliflozin arm vs. 15% in the placebo arm (p<0.001). Mean A1c reduction was 0.8% with sotagliflozin vs. 0.3% with placebo, culminating in a treatment difference of 0.5% (p<0.001). Notably, A1c was blinded throughout the 24 weeks, which may have led to less aggressive insulin adjustment. Sotagliflozin was associated with ~5 lbs weight loss vs. ~2 lbs weight gain for participants on placebo, for a treatment difference of ~7 lbs (p<0.001). These weight effects were particularly positive, as >70% of study participants had a BMI >25 kg/m² at baseline. In patients with systolic blood pressure ≥130 mm Hg at baseline, sotagliflozin gave a treatment difference of 3.5 mmHg (p<0.002 vs. placebo) at 16 weeks. Treatment differences for total, basal, and bolus insulin doses were -5, -3, and -3 units/day, respectively (p<0.002 for all comparisons).

• There were four DKA events (0.6%) in the placebo group vs. 21 (3%) in the 400 mg sotagliflozin group, leading to 11 treatment discontinuations in the latter arm. In the sotagliflozin group, DKA was adjudicated in 4% of pump users and 2% of patients on MDI. In an NEJM editorial published alongside the inTandem3 paper, Dr. David Nathan gives a lot of weight to this DKA signal, arguing that this risk persisted despite trial protocol offering a high amount of patient education around DKA. We’re very curious to learn more about the nature of this education, but we also point out that there’s a lack of consensus in the field about best practices for managing DKA risk. We continue to believe this risk can indeed be managed (even if we haven’t optimized education/monitoring strategies just yet).
• Dr. Davies presented additional safety data, with more serious adverse events seen in the sotagliflozin group (7%) vs. placebo (3%). She also noted incidence of diarrhea (4% vs. 2%, respectively) and genital mycotic infections (6% vs. 2%, respectively, and unsurprisingly). Severe hypoglycemia occurred in 3% of sotagliflozin-treated patients and 2% of placebo-treated patients, but documented hypoglycemia <55 mg/dl was significantly less frequent in the sotagliflozin group vs. the placebo group (11.8 events/person-year vs. 15.4 events/person-year, respectively).
• Last week, Lexicon released positive pooled CGM data from inTandem1 and inTandem2. At week 24, patients treated with 200 mg and 400 mg doses of sotagliflozin spent an additional 5% and 12% of the day in-range (70-180 mg/dl), respectively, compared to those taking placebo (p=0.026 and p<0.001, respectively). These percentages translate to an additional 1.3 and 2.8 hours in-range, respectively –we feel confident saying that this additional time-in-range would be an enormous win for anyone with diabetes. This is time not spent in hypo- or hyperglycemia, meaning that patients can feel well for nearly three more hours each day – and not have to spend time trying to get back into range. It’s unfortunate that inTandem3 didn’t make use of CGM, given that time-in-range data may be a crux of the selling point for sotagliflozin. Lexicon is planning to file sotagliflozin with the FDA toward a type 1 indication in 1Q18.

Commentary

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

The renowned Dr. John Buse provided the discussant on inTandem3, bringing the symposium full circle with a description of the high unmet need for adjunct therapy in type 1 diabetes management. He reminded everyone that 3% of patients, according to the T1D Exchange, have reported at least one DKA event in the prior three months (alluding to the background rate of this type 1 complication). Dr. Buse shared his view that it is possible – even probable – that sotagliflozin’s dual inhibition provides distinguishable benefits vs. single SGLT-2 inhibition in type 1 diabetes. He expressed hope that there’s a clinical path forward for SGLT inhibition in type 1 diabetes management, with the caveat that communication around the issue of DKA is essential for people to feel comfortable with this therapy. That said, he also suggested that the DKA episodes observed in inTandem3 were less severe than what real-world clinicians normally see because patients were trained to more closely monitor for this – the flip side of this is that the absolute number of DKA events may have been inflated by the lower severity episodes. In a separate conversation with us, Dr. Buse remarked that the DKA-related education was probably not optimal in this study, despite what Dr. David Nathan refers to in his NEJM editorial as extra steps taken by the investigators to mitigate DKA risk. In addition, Dr. Buse pointed out that a large proportion of type 1 diabetes patients in the US are treated by an endocrinologist, likely offering better DKA-related education vs. a primary care physician.

• In our view, Dr. Nathan’s editorial in NEJM minimized the profound glycemic and weight loss benefits seen in this sotagliflozin study, while overemphasizing the DKA signal. One of his main points alludes to the training of inTandem3 participants on ketone monitoring, and he argues that if there was still an imbalance in DKA after patients received concerted education, this safety issue will surely persist in the real world. Dr. Buse provided a rebuttal in his comment that DKA-related education in the trial was probably far from optimal, likely because there’s still a lack of consensus on what optimal DKA management should be. It would be a shame for a manageable safety issue to overshadow the glycemic and weight loss efficacy of sotagliflozin, and as Drs. Rosenstock and Buse clearly established, there is an unmistakable need for adjunct therapy in type 1 diabetes care. That sotagliflozin is an oral medication only adds to our excitement (AZ’s Symlin is an injectable adjunct type 1 treatment that has never quite taken off commercially). In Dr. Nathan’s closing paragraph, he suggests that automated insulin delivery (AID) will outpace pharmaceutical development for type 1, eventually making new, non-insulin drugs for this population unnecessary. To this, we respond that it’s a false reality to think AID will be affordable and accessible to everyone in the very near future – in the meantime, while the treatment options we have are just not good enough, sotagliflozin could be a significant stride.

Effects on the Incidence of Cardiovascular Events of the Add-On of Pioglitazone as Compared with a Sulfonylurea in Type 2 Diabetic Patients Inadequately Controlled with Metformin: The TOSCA.IT Study

Introducton

Gabriele Riccardi, MD (University of Naples, Italy)

Dr. Gabriele Riccardi introduced TOSCA.IT, a large (n=3,028) multicenter CVOT conducted across Italy to compare TZD pioglitazone head-to-head with sulfonylureas, including glimepiride, glibenclamide, and gliclazide. This effort was supported by the non-profit Italian Diabetes Association, which according to Dr. Riccardi, had been saying for >10 years prior that the diabetes field needs a pragmatic trial comparing sulfonylureas and TZDs in real-world clinical practice conditions. Indeed, these are two generic – and therefore low-cost – second-line therapy options after metformin for people with type 2 diabetes. While we’d love to see widespread access to SGLT-2 inhibitors and GLP-1 agonists with demonstrated cardioprotective benefit (from the recent EMPA-REG OUTCOME, LEADER, and CANVAS trials), we hear time and time again how cost is the main driver of diabetes treatment decision (this was a major theme at AADE 2017, it was unavoidable in conversations among diabetes educators). Given this, we absolutely see value in a comparison of outcomes between two accessible, widely-used generic drugs, and we applaud the Italian Diabetes Association for taking this on. The TOSCA.IT team set out with objectives to evaluate the long-term effects of pioglitazone vs. SUs on incidence of CV events and mortality, glucose control and its durability, and safety.

• Providing background, Dr. Riccardi presented mixed evidence from prior studies regarding sulfonylureas and CV risk, with some showing neutrality and others showing CV harm. Despite this uncertainty around CV effects, not to mention all the SU side-effects we do know with certainty (namely hypoglycemia), Dr. Riccardi explained that agents in this class are still prescribed in high volume due to their low cost and familiarity factor (“general practitioners feel more confident in sulfonylureas vs. newer drugs”).
• On pioglitazone, he described minimal risk of hypoglycemia seen in previous clinical research and a mechanism of action that works against insulin resistance. Moreover, he mentioned the IRIS trial (published last year) as evidence that pioglitazone reduces risk for atherosclerosis CV events (stroke, MI), speculating that this may have something to do with a deceleration of carotid intima-media thickening (cIMT).

Design and Baseline Data

Olga Vaccaro, MD (Federico II University, Naples, Italy)

Dr. Olga Vaccaro outlined trial design and baseline characteristics of the study population, and was the first of several presenters to emphasize that TOSCA.IT enrolled patients with diabetes at relatively low risk for CV disease. On average, participants were 62 years-old with a BMI of 30 kg/m², eight years diabetes duration, and baseline A1c 7.7%. Baseline LDL was ~103 mg/dl in both the pioglitazone (n=1,535) and sulfonylurea groups (n=1,493), while systolic blood pressure was a mean 134 mmHg and 17%-18% of participants were smokers. There were 187 people randomized to pioglitazone (12%) and 148 randomized to sulfonylureas (10%) with a prior CV event at baseline – looking at this another way, 89% of patients enrolled in the study did not have a history of CV disease. Moreover, Dr. Vaccaro remarked that nearly 70% of participants were on antihypertensive drugs, nearly 60% on lipid-lowering drugs, and nearly 40% on antiplatelet agents, highlighting that CV risk factors were “pretty optimally controlled” with other recommended therapies in this study population. In fact, risk for CV events was low enough that TOSCA.IT did not reach its pre-specified goal of collecting 498 primary endpoint events (non-fatal MI, non-fatal stroke, all-cause death, or urgent coronary revascularization). A futility analysis recommended that TOSCA.IT be terminated after 57.3 months (nearly five years) median follow-up, as it seemed unlikely that sufficient CV events would occur.

• Within the sulfonylurea group, 50% of patients were on glimepiride, 49% on gliclazide, and <2% on glibenclamide. This is noteworthy, given commentary from some thought leaders that there are clinically-meaningful in-class differences to various SUs (though we still believe the class as a whole should be switched out in favor of safer, more effective therapies). Average daily metformin dose was 2,000 mg across both study arms, while mean dose of pioglitazone was 23 mg/day. This was an open-label trial, conducted in 57 different Italian clinics, which Dr. Vaccaro asserted is highly-representative of the clinical reality of diabetes care nationwide in Italy.

Efficacy on Blood Glucose Control and Cardiovascular Risk Profile

Stefano Del Prato, MD (University of Pisa, Italy)

The great Dr. Stefano Del Prato presented glycemic results, including an A1c treatment difference of 0.06% after 60 months (p=0.01 for superiority). He emphasized that the trend is important here: sulfonylureas were associated with a greater initial drop in A1c, but based on rate-of-change data, the TZD pioglitazone demonstrated greater durability of glucose-lowering effect over time. Also on this point, treatment failure (defined as A1c >8% at two consecutive clinician visits) was 37% more likely for SU-treated patients vs. pioglitazone-treated patients over 60 months (HR=0.63, 95% CI: 0.52-0.75, p<0.0001), underscoring durability of effect for pioglitazone. Dr. Del Prato remarked that these durability findings are consistent with past RCTs. Fewer patients in the TZD arm required new initiation of insulin therapy vs. the SU arm, at 11% and 16%, respectively (p<0.0001). Dr. Del Prato paused to mention the double whammy of a drug class that heightens hypoglycemia risk and also increases need for insulin, although he acknowledged the alternative possibility, that greater hypoglycemia rates seen for SU-treated patients in TOSCA.IT were perhaps driven by more insulin use. Severe hypoglycemia (blood glucose <60 mg/dl, requiring assistance) occurred in 2% of SU-treated patients and in <0.2% of pioglitazone patients (p<0.0001), while moderate hypoglycemia (blood glucose <60 mg/dl, not requiring assistance) occurred in 32% of the SU group and only 10% of the TZD group (p<0.0001). There were no significant between-group differences on BMI (though weight tended to increase early on sulfonylurea therapy, later on pioglitazone therapy), LDL, blood pressure (systolic or diastolic), eGFR, UACR, or high-sensitivity c-reactive protein (a biomarker for inflammation). HDL cholesterol was mostly flat in the sulfonylurea arm, but rose slightly (~2 mg/dl) with pioglitazone over the course of the trial (p<0.0001), which Dr. Del Prato interpreted to mean that the TZD does change lipid profile for the better. He pointed out that triglycerides also declined slightly more, on average, with pioglitazone vs. sulfonylureas, though this did not reach statistical significance (p=0.29).

Cardiovascular Outcomes

Antonio Nicolucci, MD (Center for Outcomes Research and Clinical Epidemiology, Pescara, Italy)

When the futility analysis recommended that the TOSCA.IT trial be stopped, 213 CV events had been adjudicated, and Dr. Antonio Nicolucci reported “absolutely no difference” in the primary outcome (non-fatal MI, non-fatal stroke, all-cause death, or urgent coronary revascularization) between pioglitazone and sulfonylureas (HR=0.96, 95% CI: 0.74-1.26, p=0.79). There was similarly no imbalance in any individual component of the composite endpoint. Dr. Nicolucci quickly reviewed post-hoc on-treatment analyses for each of these endpoints, all supporting the CV neutrality of pioglitazone vs. sulfonylureas in this particular study. However, an on-treatment analysis of a key secondary outcome (sudden death, fatal or non-fatal MI including silent MI, fatal and non-fatal stroke, above-the-ankle leg amputation, or any revascularization of the coronary, carotid, or leg arteries) did reflect a benefit to pioglitazone vs. sulfonylureas (HR=0.67, 95% CI: 0.47-0.96, p=0.03) – Dr. Nicolucci recognized that this must be “interpreted with caution.” Admittedly, we would have liked to see some hint of CV benefit to pioglitazone vs. SUs, for one because we want all people with diabetes to gain access to medicine better than sulfonylureas, and TZDs (also generic) circumvent the cost argument. Moreover, many diabetes thought leaders have touted IRIS trial results and the risk reduction for stroke/MI, recommending low doses of pioglitazone to real-world clinicians, and it would be tremendous to see a generic drug with some cardioprotective value for people with diabetes. Despite this disappointing result, some very clinically-meaningful and not-to-be overlooked differences appeared in the hypoglycemia and A1c durability data from this trial (see above).

Safety Profile of the Study Drugs

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

Dr. Aldo Maggioni took the stage to discuss safety findings from the study, showing no significant difference in serious adverse events between pioglitazone (14%) and SU (13%) groups (p=0.69). He zoomed in on bladder cancer – the crux of a media storm that hit TZDs a few years ago, and a concern that still lingers in the minds of some HCPs – to highlight the reassuring absolute balance of a 1% event rate in both groups (p=1.00). Heart failure also occurred at a ~1% event rate across both arms (p=0.11). There was no difference in pathological fractures, macular edema, or new/worsening nephropathy between study drugs. Treatment discontinuation was substantially higher in the pioglitazone arm, at 28% vs. 16% in the sulfonylurea arm (HR=1.98, 95% CI: 1.67-2.34, p<0.0001), but this was attributed to the aforementioned media storm, which scared many patients away from the TZD class. During Q&A, Dr. Silvio Inzucchi corroborated how challenging it has been to conduct clinical trials of TZDs for this exact reason, and he praised the TOSCA.IT committee for pushing forward with this important outcomes research nonetheless. Dr. Maggioni also reiterated the hypoglycemia data, underscoring pioglitazone’s clear benefit on this relevant safety measure – and, we would add, a critical outcome beyond A1c. We also wonder about the link between sulfonylureas and beta cell burnout in TOSCA.IT, though this is an effect that may take much longer to appear – but is still such an important one, given how many type 2 patients are treated only with a sulfonylurea for the entire duration of their disease. Ultimately, the safety of pioglitazone vs. SUs on heart failure, fractures, and cancer is a reassuring finding from this study, and an important message, in our view, for the diabetes community to hear.

Implications for Clinical Practice

Enzo Bonora, MD (University of Verona, Italy)

Dr. Enzo Bonora reiterated that both pioglitazone and sulfonylureas are commonly used type 2 diabetes drugs around the world, suggesting that a head-to-head study like TOSCA.IT comparing the two generics was long overdue. He summarized that pioglitazone showed distinct advantage on A1c-lowering, durability of A1c-lowering, and hypoglycemia vs. sulfonylureas, and while there was no significant difference in terms of CV or all-cause death, the on-treatment analysis of key secondary outcome (HR=0.67, p=0.03) hints at a benefit to pioglitazone for ischemic CV disease (notably, this would fall in line with IRIS trial results). Dr. Bonora argued that changing the natural history of disease should be a key goal in diabetes management – this means counteracting insulin resistance, which TZDs are uniquely poised to do. Moreover, the superior A1c reductions with pioglitazone lasting over a longer term imply a decrease in microvascular disease (retinopathy, neuropathy, and nephropathy). This builds a fairly compelling case, in our view, that pioglitazone should be the generic agent of choice for second-line diabetes therapy after metformin. While we’re eager for the day when DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors go generic, we’d certainly advocate for pioglitazone over sulfonylureas when more advanced agents are simply unaffordable. We were also reminded of strong commentary in favor of pioglitazone from Drs. Steve Edelman and Robert Chilton on EASD day #2, and given the recent resurgence of interest in this agent that we’ve noticed in the field, we’re curious to see how TOSCA.IT will contribute to the conversation. On head-to-heads against sulfonylureas, Dr. Bonora also mentioned Lilly/BI’s ongoing CAROLINA CVOT of DPP-4 inhibitor Tradjenta (linagliptin) vs. glimepiride, which will provide key insight.

• Dr. Bonora warned against extrapolating these findings to a different, higher-risk patient population, meaning that the CV neutrality shown here wouldn’t necessarily apply in people with diabetes and established CV disease. A key exclusion criterion for this trial was a documented CV event in the prior six months. Would a more traditionally-designed diabetes CVOT, with an enriched study population to power faster event rate, would have shown a CV benefit to pioglitazone compared to sulfonylureas?

Commentator

Marja-Riitta Taskinen, MD (University of Helsinki, Finland)

Dr. Marja-Riitta Taskinen from the University of Helsinki provided independent commentary on TOSCA.IT, and reexamined the data through a rather critical lens. Her main point was calling into question whether this study population was truly “lower risk” for CV disease, since many participants were smokers, had baseline microalbuminuria, and/or started the trial with LDL levels >45 mg/dl. Plus, she articulated that diabetes itself confers a significantly higher CV risk compared to a background population, and she pointed out that there was no difference in LDL cholesterol, triglycerides, or hs-CRP between the two treatment arms. While true, we think the baseline population in TOSCA.IT looked remarkably different from the baseline population in EMPA-REG OUTCOME or LEADER, with a much larger proportion representing primary prevention. Dr. Silvio Inzucchi chimed in during Q&A, suggesting that the diabetes field perhaps needs two treatment algorithms, one for people at high CV risk and another for those at low CV risk – we’d love to see these drafted. Dr. Taskinen also questioned the primary outcome of four-point MACE including all-cause death. Lastly, she referred to the on-treatment analysis for key secondary endpoint (the only positive, statistically significant CV finding in the trial) as “problematic” from a statistical perspective, and earlier in the symposium, Dr. Nicolucci cautioned against over-interpreting this.

• On the whole, we still found many reasons from this data why HCPs should be writing far, far fewer SU prescriptions. A mix of three agents from this drug class showed high hypoglycemia risk and an attenuation of glycemic efficacy (in the real world, this might encourage providers to up-titrate, and higher doses of SUs may only exacerbate the hypoglycemia, weight gain, and beta cell burnout). Yes, sulfonylureas are cheap, but so are TZDs now that they’re generic. While the CV results were resoundingly neutral, the durability of A1c-lowering associated with pioglitazone in this study was intriguing, and we mention again the significantly lower risk of hypoglycemia (we can’t emphasize enough the importance of this outcome beyond A1c). Renowned cardiologist Dr. Robert Chilton, a well-respected voice in the field, said on Monday that he “can’t think of a better drug” in defense of pioglitazone, and we’d certainly be happy to see the generic diabetes market move away from sulfonylureas more toward pioglitazone.

-- by Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, Manu Venkat, Maeve Serino, Adam Brown, and Kelly Close