EASD 2018 (European Association for the Study of Diabetes)

October 1-5, 2018; Berlin, Germany; Day #4 Highlights – Draft

Executive Highlights
  • EASD 2018 is almost coming to a close! Day #4 was data rich to say the least, and it was capped off with The diaTribe Foundation’s Fifth Annual Solvable Problems in Diabetes event. 

  • We lead off our diabetes therapy coverage with exciting news of Lilly’s GLP-1/GIP dual agonist. To a packed house, Dr. Juan Frias delivered highly anticipated phase 2b results, which demonstrated an unprecedented 2.4% drop in A1c and ~25 pounds of weight loss, after 26 weeks and at the highest dose. However, this does appear to be high-risk, high-reward, with one in four participants discontinuing treatment due to adverse events. That said, the value proposition does seem more compelling at lower doses.
  • Full results from EASE (phase 3 for Jardiance in type 1) add another interesting wrinkle to the ever-growing story of SGLT inhibitor use in type 1 patients. Significant glycemic and weight benefits were seen with all three doses of empagliflozin tested (2.5, 10, and 25 mg doses); notably, the 2.5 mg dose conferred significant benefits without increasing DKA risk – a huge shake-up! Considerable DKA risk was still observed in the two higher empagliflozin doses. To be sure, A1c reductions, time-in-range benefits, and weight loss were all considerably reduced with the lower 2.5 mg dose; moreover, this dose showed most of its benefit in patients with higher A1c levels at baseline (>8%). It will be fascinating to track how patients, clinicians, and regulatory agencies weigh the risks and benefits of these adjunct therapies.  
  • Today was quite the day for dual-agonists, as we also got a first look at impressive phase 2a results for AZ/MedImmune’s GLP-1/glucagon candidate, MEDI0382. Very notably, those on-treatment saw a 25% absolute surge in time-in-range (with no increased time-in-hypoglycemia) along with ~7.4 lbs of weight loss – all in just seven weeks! Tolerability was also a concern with this candidate, with substantial nausea and vomiting in treatment groups but none with placebo, though not too out of range with current GLP-1 options in our assessment. Nonetheless, we were thrilled to see this efficacy and especially CGM data so early on! Also see inside for CARMELINA CVOT results, showing CV safety for DPP-4 inhibitor Tradjenta.
  • Drs. Chantal Mathieu and Partha Kar joined Adam Brown in a fascinating panel at diaTribe’s 5th annual Solvable Problems in Diabetes event. The speakers showed off their incredible range, offering brilliant takes on SGLT inhibitors in type 1 diabetes, CGM adoption and value proposition, alternate payment and care delivery models, and type 1 cure/prevention. Check out our favorite quotable quotes!

Hello from Berlin, where our team is writing from what was one of the more intriguing data days at what continues to be one of the more intriguing data EASDs. Today, we saw Lilly’s GLP-1/GIP dual agonist, SGLT-2 inhibitor in type 1 results from Lilly/BI, not to mention DPP-4 Tradjenta’s CVOT. See our highlights from day #3 (EXSCEL Post Hoc, new LEADER subgroup analysis), day #2 (HARMONY CVOT), and day #1 (KOLs on SGLTs for type 1). One day left at this year’s excellent meeting!

Top Six Highlights

1. Phase 2b Data for Lilly’s GIP/GLP-1 Dual Agonist: Highest Dose Gives 2.4% A1c Drop, ~25 Pounds Weight Loss at 26 Weeks – But 1 in 4 Discontinue Treatment Due to Adverse Events

In a very highly anticipated phase 2 readout, Dr. Juan Frias revealed highly impressive glycemic and weight loss results for Lilly’s LY3298176 (“LY”), a once-weekly GIP/GLP-1 dual agonist  (see Lilly’s press release and a publication in The Lancet). In this phase 2b, 26-week dose-ranging study (n=316), four doses of LY (1 mg, 5 mg, 10 mg, and 15 mg) were examined in comparison to both Trulicity (dulaglutide) 1.5 mg and placebo – we’ve tabulated all of the efficacy and safety results below. In addition to those prespecified endpoints, two additional, exceptional results were also presented: Weight loss ≥15% and percent achieving A1c <5.7%. On the former weight loss endpoint, 22% of those on LY 10 mg and 25% of those on LY 15 mg achieved at least 15% weight loss, which was significant vs. both placebo and Trulicity. Additionally, 6% of those on LY 5 mg achieved this weight loss, but this result was not significant. Moreover, 18% of those on LY 10 mg and 30% on LY 15 mg achieved an A1c <5.7%, both significant against placebo and Trulicity. For comparison, 2% of the placebo group, 2% of the Trulicity group, and 4% of the 5 mg group achieved this result. Of note, these are on-treatment analyses, excluding efficacy data after study drug was discontinued or rescue therapy was initiatied, if this occurred (the statistical principle Novo Nordisk has utilized in presenting phase 3 data for oral semaglutide). Still, both of these results reflect truly remarkable levels of efficacy, particularly at higher doses; the room truly came alive when Dr. Frias revealed the weight loss data in particular. To this end, we hope very much that Lilly will pursue LY for obesity and NAFLD indications too, as there’s no doubt in our minds that more efficacious pharmacotherapies that are accessible are desperately needed in these areas – so far, Novo Nordisk has really grown this industry from scratch with Saxenda. During Lilly’s 2Q18 update, management announced that LY would advance to phase 3 for type 2 by early 2019 – the first-ever dual agonist to make it to phase 3. Lilly also alluded to impressive efficacy, specifically by announcing that an investor call would take place following Dr. Frias’ presentation, and we have to admit: These results did not disappoint.

Efficacy Endpoints for LY3298176


Study Arm

Endpoint (26 weeks; on-treatment)

LY 1 mg (n=52)

LY 5 mg (n=55)

LY 10 mg (n=51)

LY 15 mg (n=53)

Trulicity 1.5 mg (n=54)

Placebo (n=51)

A1c Reduction






(0.1% increase)

Weight Loss

0.9 kg (2.0 lbs)

4.8 kg (10.6 lbs)*

8.7 kg (19.2 lbs) *#

11.3 kg (24.9 lbs) *#

2.7 kg (6.0 lbs)*

0.4 kg (0.9 lbs)

% Achieving  A1c ≤6.5%







% Achieving A1c <7.0%







% Achieving ≥5% Weight Loss







% Achieving ≥10% Weight Loss







* = p<0.05 vs. placebo

# = p<0.05 vs. Trulicity

  • As evidenced below, if there’s one concern over this candidate, it’s tolerability – and that’s a big concern. In our minds, these data (below) evoked an issue Sanofi recently saw with its GLP-1/glucagon dual agonist in phase 2 (the candidate is still advancing to phase 3 for obesity, as far as we know). However, one quarter of patients taking Sanofi’s SAR425899 dropped out due to tolerability issues – coincidentally equivalent to LY 15 mg. We think there’s a good chance that tolerability issues being more prevalent with dual agonists than standalone GLP-1 agonists might limit the uptake of these agents, particularly in lower-risk patients. Presumably, tolerability was also an issue with Trulicity to some extent. If, however, it is not too hard to work out which patients can tolerate the high dose easily – that’s where some magic would be.

Safety Endpoints for LY3298176


Study Arm


LY 1 mg

LY 5 mg

LY 10 mg

LY 15 mg

Trulicity 1.5 mg


Treatment Discontinuation







Tx Disc. Due to Adverse Events







GI Events




























Total Hypoglycemia







Severe Hypoglycemia








  • Dr. Frias noted that, for the 10 mg and 15 mg doses of LY, participants were titrated to those doses relatively quickly. In his assessment, this is likely responsible – in part – for the high prevalence of adverse GI effects; in an interview with our team, Lilly’s Dr. Brad Woodward (Global Brand Development Lead and Senior Medical Director) emphasized the same explanation. Indeed, GI side effects with 15 mg were concentrated in the earlier part of the trial but seemingly took a very long time to taper off (below). We’d add that these GI effects (nausea, vomiting, diarrhea) could also have augmented the weight loss observed, both by getting patients to the full dose more quickly (i.e. more time at most effective doses for weight loss), but also potentially through the GI side effects themselves. We expect more analyses on this front – we also think that might not be the case and overall we aren’t sure – this question always used to come up back in the day in phase 3 trials for Amylin’s Byetta. For the 10 mg dose, participants spent two weeks on 5 mg before escalating to 10 mg; for the 15 mg dose, participants spent two weeks at 5 mg then four weeks at 10 mg before escalating to 15 mg. Trulicity was started at 1.5 mg, and the 1 mg and 5 mg doses were not titrated.

    • We’re also eager to see any analyses aimed at teasing apart what mechanism drove glucose lowering. On this front, we’re curious what impact weight loss might have had on pushing down A1c (in addition to the well-characterized incretin effects of GLP-1) – an attendee also raised this issue during Q&A, noting that weight loss can unload the demand on the beta cell and actually result in a more durable long-term effect. Dr. Frias explained that insulin sensitivity did improve beyond what has been observed with selective GLP-1 agonists alone, so some improvement in glycemia is likely due to weight loss. We imagine the proportion of patients achieving an A1c <5.7% is much more meaningful if this effect is being driven by weight loss, rather than the artificial glucose-lowering mechanism of GLP-1 and GIP agonism.

    • We learned from Lilly's investor call following the presentation that the phase 3 SURPASS program investigating this agent in type 2 diabetes will include 5, 10, and 15 mg doses. SURPASS is expected to begin "no later than early 2019" and will be powered for superioty to determine a benefit in MACE reduction. We remain intrigued by the dynamics surrounding the different doses of this agent. Concerning the higher 15 mg dose, while the efficacy is certainly higher, that added benefit – in our view – is almost entirely offset by the lower tolerability. On the other hand, the 10 mg dose is about twice as efficacious on A1c lowering and three times as powerful on weight loss as Trulicity, with a much smaller jump in GI side effect incidence. If we had to pick, this is the one we’d zero in on. How will Lilly view these distinct profiles? SURPASS will definitely shed more light on this important issue. 

    • We’ll be interested to see whether Lilly pursues the 15 mg dose in future trials. While the efficacy is certainly higher, that added benefit – in our view – is almost entirely offset by the lower tolerability. On the other hand, the 10 mg dose is about twice as efficacious on A1c lowering and three times as powerful on weight loss as Trulicity, with a much smaller jump in GI side effect incidence. If we had to pick, this is the one we’d zero in on. How will Lilly view these distinct profiles?


  • At baseline, participants were what Dr. Frias characterized as a very typical population of people with type 2 diabetes. Across all six treatment arms, mean age was 50-56 years, diabetes duration 8-9 years, A1c 8.0%-8.2%, and BMI 32-33 kg/m2. Given the impressive reductions on A1c and body weight, we might have expected a population with somewhat higher A1c and BMI – which makes the effects seen with LY all the more notable, in our view. On the other hand, this likely made it easier to achieve certain endpoints (i.e. A1c <5.7%). We find it interesting to think about this population, as we’d actually anticipate Lilly positioning this candidate for a set of patients farther along in the course of disease. Indeed, Dr. Frias’ first slide rightly noted that, despite highly-efficacious GLP-1 agonists coming to market in recent years, some patients still need greater efficacy on glucose-lowering and weight loss. Of course, this was a phase 2 dose-ranging study and Lilly will likely investigate LY in a variety of patient populations in phase 3.

  • LY is a 39 amino-acid peptide based on the native GIP peptide, with modifications to allow GLP-1 receptor binding as well. Of note, the molecule actually has similar agonist activity compared to native GIP, but is 5-10 fold less potent at the GLP-1 receptor than native GLP-1 (based on in vitro studies) – so it causes more GIP than GLP-1 activation. Mean half-life is five days, on par with once-weekly GLP-1s. Our observation is that no one truly yet understands the mechanism by which GIP offers additional benefit in the presence of GLP-1; we absolutely expect and look forward to increased scholarship in this area.

2. EASE Results: Phase 3 Program for Jardiance in Type 1 Finds Significant Glycemic + Weight Benefits with Three Doses of Empagliflozin; Further Support of Dose-Response Relationship on both Safety + Efficacy

Results from the phase 3 EASE program for Lilly/BI’s Jardiance in type 1 diabetes – comprised of EASE-2 (n=730) and EASE-3 (n=977) – identified significant A1c, time-in-range, and weight loss benefits with three doses of empagliflozin (2.5 mg, 10 mg, 25 mg) – see the full paper, just published in Diabetes Care, and watch the webcast here. However, results also indicate a consistent dose-response relationship, in line with two other phase 3 programs of SGLTs in type 1 (AZ’s DEPICT program and Lexicon/Sanofi’s inTandem program). Following announcement of very topline results at ADA 2018 (i.e. no numbers), all eyes were on the 2.5 mg empagliflozin dose investigated in 241 EASE-3 participants only: According to Dr. Julio Rosenstock’s ADA presentation, this dose gave significant improvements on A1c and body weight with no increased risk of DKA – we’ve taken a deep dive into EASE safety data in the highlight below this. Dr. Rosenstock returned to the stage at EASD to present a truly enormous amount of data from both EASE trials, which we’ve summarized in the table below. At a high level, these results are consistent with other phase 3 trials of SGLTs in type 1. Across all three SGLT-in-type 1 programs, higher doses seem to offer considerably higher efficacy, but at the apparent cost of greater DKA risk – more on this one highlight below.

EASE-2 and EASE-3 Efficacy Results




Endpoint (26 weeks)

Placebo (n=243)

Empa 10 mg (n=243)

Empa 25 mg (n=244)

Placebo (n=241)

Empa 2.5 mg (2=241)

Empa 10 mg (n=248)

Empa 25 mg (n=245)

A1c Reduction (placebo-adjusted)


0.54% (95% CI: -0.65, -0.42; p<0.0001)

0.53% (95% CI: -0.65, -0.42; p<0.0001)


0.28% (95% CI: -0.42, -0.15; p<0.0001)

0.45% (95% CI: -0.58, -0.32; p<0.0001)

0.52% (95% CI: -0.66, -0.39; p<0.0001)

Weight Loss


2.7 kg (6.0 lbs) (95% CI: -3.3, -2.1; p<0.0001)

3.3 kg (7.3 lbs) (95% CI: -3.8, -2.7; p<0.0001)


1.8 kg (4.0 lbs) (95% CI: -2.3, -1.2; p<0.0001))

3.0 kg (6.6 lbs) (95% CI: -3.6, -2.5; p<0.0001)

3.4 kg (7.5 lbs) (95% CI: -4.0, -2.9; p<0.0001)

Time-in-Range Increase

-1% (-14 minute)

+10% (+2.4 hours)

+12% (+2.9 hours)

+2% (-29 minutes)

+6% (+1.4 hours)

+12% (+2.9 hours)

+8% ( +1.9 hours)

Percent Change in Total Daily Insulin Dose


13% (p<0.0001)

13% (p<0.0001)


6% (p<0.0001)

10% (p<0.0001)

13% (p<0.0001)

Systolic Blood Pressure (placebo adjusted)


-2.1 mmHg (NS)

-3.7 mmHg (p<0.001)


-2.1 mmHg (p<0.001)

-3.9 mmHg (p<0.001)

-3.7 mmHg (p<0.001)





  • An analysis of A1c reduction by baseline A1c found numerically greater benefit in those with a starting A1c ≥8.0%. Among the ~60% of participants in this group, the 2.5 mg dose gave a higher 0.35% A1c drop, vs. 0.53% with 10 mg and 0.62% with 25 mg. All of these were significant at p<0.0001 vs. placebo. For those with baseline A1c <8.0%, a 0.18% drop with 2.5 mg empagliflozin was not significantly, but a 0.35% drop with 10 mg and a 0.39% drop with 25 mg were both significant vs. placebo (p<0.001). This furthers a point of discussion we’ve heard elsewhere: Should SGLTs be initiated in patients with type 1 and higher A1cs? We don’t imagine many would balk at using an SGLT-2 in a patient with an A1c of 8.2%, for example, but some have expressed concern that using these in those with very sub-par glycemic control would expose them to a very high risk of DKA. On the other hand, this analysis supports the notion that those patients could actually benefit the most. Our sense is that the field has not reached a clear consensus of these aspects of patient selection.    

    • In presenting efficacy results, Dr. Rosenstock strongly emphasized that “2.5 mg is efficacious in those with A1c over 8% at baseline. In our view, however, the lack of efficacy in those who already have good glucose control may be a sticking point for this dose (though a larger sample size may have demonstrated a significant effect). Clearly, there are some concerns about the fairly substantial drop in efficacy from 10/25 mg to 2.5 mg and aren’t convinced this will hold clinically meaningful benefit for most patients, but we’re also very reassured by the safety data. Could a 2.5 mg dose of empagliflozin be easier for HCPs to prescribe and patients to take? Or should there just be recommendations that reduce the DKA risk for all SGLTs? Clearly, substantial safety protocols should be in place regardless – and while EASE-3 has raised interesting questions on this front, we do come back to the fact that patients want better glucose control and so too reduced efficacy will probably not make this worthwhile for a decent range of patients.

    • We would love to see all SGLT inhibitors investigated for cardiovascular benefit in people with type 1 diabetes. There’s an enormous unmet need for therapies to lower the higher cardiovascular risk that people with type 1 diabetes face, and we think it’s very possible that the most meaningful benefits SGLTs will offer patients with type 1 are not actually through glucose lowering, but rather cardio- and renal-protection. 

  • Study design and baseline characteristics: Both EASE-2 and EASE-3 were designed with six weeks of insulin optimization and a two-week placebo run-in period (with CGM) prior to randomization. In EASE-2, participants were randomized equally to placebo, 10 mg empagliflozin, or 25 mg empagliflozin, and CGM was used for weeks 23-26 and week 52. The primary endpoint was at 26 weeks, followed by another 26 weeks of treatment plus three weeks of post-study follow-up. In contrast, EASE-3 randomized patients equally to placebo or one of three empagliflozin doses (2.5, 10, or 25 mg). EASE-3 was only 26 weeks and included CGM at the start and end of the trial, as well as three weeks of post-study follow-up. All participants were adults with type 1 for ≥one year, on stable MDI or CSII, with an A1c ≥7.5% or ≤10% and eGFR ≥30 ml/min/1.73 m2. Severe hypoglycemia or DKA in the prior three months excluded any participant. EASE-2 and EASE-3 were well-balanced on baseline characteristics, including age (45 and 43 years), BMI (29 and 28 kg/m2), time since diagnosis (23 and 21 years), mean A1c (8.1% and 8.2% after insulin optimization), and insulin delivery (59% and 66% MDI; 41% and 34% CSII), all respectively.

    • We wonder why EASE-3 was not also extended to 52 weeks; we might speculate that Lilly/BI were in a rush to finish the phase 3 program, given two others in this area have completed. Mostly importantly, we think it would be very valuable to have longer-term data on the 2.5 mg dose. We’re not sure how heavily this will be considered a limitation of EASE’s data.

    • As background, the design to investigate a 2.5 mg dose of empagliflozin was based on the phase 2 EASE-1 study led by Dr. Thomas Pieber, which found that urinary glucose excretion was largely maintained (at ~73 g/day) with 2.5 mg in people with type 1 diabetes. The 10 mg dose gave ~103 g/day of UGE and the 25 mg dose ~102 g/day – so, virtually identical. While people with type 2 diabetes see a steady decline in UGE as the empagliflozin dose decreased, it seems like there might be an upper limit on UGE among those with type 1; empagliflozin 2.5 mg comes close to this limit. In attempting to explain this phenomenon, Dr. Rosenstock cited greater glucose variability (i.e. more opportunities to spill glucose), higher renal filtration rate, and greater expression/activity of SGLT-2 as potentially combining for the higher urinary glucose excretion in type 1 diabetes. Based on these results – including comparable A1c reductions across all three doses in phase 2 – the phase 3 program was designed.

  • We’ll be back with more on EASE later, including stellar commentary from Drs. Lori Laffel and Thomas Pieber!

Close Concerns’ Questions

  • Will AZ and Sanofi/Lexicon consider investigating lower doses of Farxiga and Zynquista, respectively?

  • What are the clinical implications of the 2.5 mg results, in terms of how easy it will be for prescribers and patients to adopt empagliflozin?

  • How will regulatory agencies consider the risk/benefit ratio of different SGLT inhibitor doses?

3. EASE Safety Data Deep Dive: No Elevated DKA Risk in 2.5 mg Arm of EASE (n=241; 3 Events vs. 2 with Placebo); 3-4% Risk Over 6 Months with Higher Doses

Dr. Bruce Perkins presented much-anticipated safety data for the EASE-2 and EASE-3 studies, highlighting the absence of increased DKA risk with the 2.5 mg dose of empagliflozin. In EASE-3 over 26 weeks, there were two certain DKA events among 241 participants randomized to 2.5 mg (1.2%), compared to three certain events in the placebo group (0.8%). Dr. Perkins provided a thorough analysis of data pertaining to general safety, adverse events, and DKA. Methodology wise, data sets for 10 mg and 25 mg empagliflozin treatment groups were pooled separately across the two studies to generate a larger data pool; placebo groups were also pooled. Separately, the 2.5 mg empagliflozin arm from EASE-3 was compared to the placebo group from EASE-3 only. Broadly speaking, there was a dose-dependent response in DKA risk inasmuch as DKA risk was increased with both the 10 mg and 25 mg doses, but not with the 2.5 mg dose; however, there were actually more confirmed DKA events in the 10 mg group (21 events; 4.3%) than the 25 mg group (18 events; 3.3%), though both were meaningfully higher than placebo (6 events; 1.2%). The higher doses were also generally associated with elevated rates of other adverse events, including genital infections, volume depletion, and DKA. This dose-response relationship for risk is generally in line with what has been observed in other trials of SGLTs in type 1.


  • Looking past “certain DKA” to “potential DKA” the proportion of patients with potential DKA or potential ketosis both trended towards a higher fraction in the 2.5 mg group when compared to placebo (3 events/1.2% vs. 1 event/0.4%, and 7 events/2.9% vs. 2 events/0.8%, respectively), indicating a potential residual risk for DKA even with lower doses of treatment.


  • There was one death in the 25 mg empagliflozin arm due to DKA, which to our understanding is attributable to empagliflozin. There is a write up of the clinical case in the paper’s supplementary materials, which serves as a poignant reminder of just how serious this complication can be. Moreover, we’re more convinced than ever that, if approved, SGLT use in type 1 needs to be accompanied not only by extensive patient and provider education but also a widescale effort to make HCPs and other stakeholders more aware of this risk, what it looks like, and how to treat it.

  • A few sizable limitations of this data (the 2.5 mg finding in particular), in our view, are that (i) the sample size is small, (ii) the event rate overall is low, and (iii) this is a single trial. We do think there’s an important historical lesson to keep in mind: When DEPICT 1, one of two phase 3 trials for AZ’s Farxiga in type 1, read out at EASD 2017, there was no real signal for DKA. However, almost one year later when DEPICT 2 was presented at ADA 2018, we learned that an imbalance had been identified in this second, nearly-identical study. In contrast, all three phase 3 trials for Sanofi/Lexicon’s sotagliflozin in type 1 (inTandem 1, inTandem 2, and inTandem 3) have identified an increased and apparently dose-dependent DKA risk with the SGLT-1/2 dual inhibitor. Indeed, our sense is that many already considered DKA a class effect of SGLTs in type 1 diabetes despite the reassuring data from DEPICT 1. All of this being said, a 2.5 mg dose of empagliflozin is almost certainly the most “mild” SGLT inhibition to be investigated to date in a phase 3 program; this represents one-quarter of the lowest dose approved for type 2 diabetes. The DEPICT program investigated the two approved doses of Farxiga (5 mg and 10 mg), while Lexicon/Sanofi investigated 100 mg and 200 mg sotagliflozin. As such, there’s very little to compare this finding to, and we expect significant discussion as to whether a single 241 person arm with only five “certain” events (three in the EASE-3 placebo arm and two in the 2.5 mg arm) is enough evidence to draw strong conclusions on low-dose safety. Moreover, the efficacy trade-off seriously complicates the discussion.

  • Intensive ketone monitoring procedures were set during the placebo run-in and the first four weeks of treatment, as patients were asked to perform daily beta-hydroxybutyrate (BHB) measurements to establish baseline ketone levels. For the remainder of the trial, this recommendation was eased to only two to three measurements per week, or in situations where clinical symptoms of DKA were present. The face that this level of monitoring/checking was implemented and an increased incidence of DKA still occurred is meaningful to the ongoing debate about ketone monitoring when using SGLTs for type 1: How can this procedure be more effective? Complicating things further, these monitoring requirements represent a significant burden on the patient (in terms of both cost and effort), and we are curious about how patients would receive these recommendations in real-world settings (thought leaders also remain conflicted on this topic of ketone monitoring frequency).

    • DKA events were adjudicated upon certain trigger events: An investigator reporting symptoms related to DKA, even if absent of a corresponding BHB measurement; all BHB measurements between 1.5-3.8 mmol/l accompanied by clinical symptoms of DKA; and any BHB measurement greater than 3.8 mmol/l. These cut points arbitrated by study investigators generally align with those agreed upon by thought leaders, as gleaned by conversations our team has had, but nevertheless still remain a point of discussion. A total of 196 adjudicated cases emerged over the two trials, with 86 of these determined to be DKA events. Of these 86 cases, nine were classified as severe (defined as pH <7 or bicarbonate <10 mEq/L or stupor/coma), 25 as moderate (pH between 7-7.24 or bicarbonate between 10-15 mEq/L), and the remaining 52 cases as mild (pH between 7.25-7.30 or bicarbonate between 15-18 mEq/L or no neurological symptoms).

    • Euglycemic DKA (euDKA) events were only present in treatment groups and did not occur in placebo. Nine out of the 21 DKA events in the 10 mg group were classified as euDKA (<250 mg/dl), while five out of 16 in the 25 mg group and one out of two in the 2.5 mg group were also classified as euDKA. No such events occurred in placebo. The paradoxical nature of euDKA presents a significant challenge in clinical practice and patient education, as it complicates the recognition and diagnosis of DKA and can delay proper and effective treatment. These safety data clearly establish euDKA as a risk with SGLT-2 inhibitors; the question now becomes how educational efforts with HCPs and patients can better mitigate this risk.

  • DKA risk was increased in women in the empagliflozin treatment group, while no difference was seen in DKA rates for men between placebo and treatment groups. Women in the 10 and 25 mg groups had rates of certain or potential DKA of 10.5% and 8.7%, respectively, compared to 3.1% in the placebo group. On the other hand, men showed no such effect: Rates of DKA were 2.6% and 2.5% for 10 and 25 mg groups, respectively, compared to 3.1% for placebo. This is certainly an interesting finding, and we are currently trying to learn more about why this may be, as well as if other trials have observed a similar effect.

  • Insulin pump use was also associated with higher risk of DKA. Patients using CSII in the 10 mg and 25 mg treatment groups had rates of potential or certain DKA of 12.6% and 9.9% respectively, compared to 3.9% for placebo. Conversely, those on MDI had more balanced (and lower) rates of DKA, albeit still higher in treatment groups: 3.2% for both 10 and 25 mg groups compared to 1.3% for placebo. These results further reinforce pump failure as a major risk factor for DKA.

  • Hypoglycemia: Hypoglycemia data was collected both as investigator-reported events (n=~13,000) and as patient-reported events (n>23,000). Describing the distinction between these two categories, Dr. Perkins noted that while investigator-reported events are inherently influenced by subjective judgement, patient-reported events consider the totality of data and also encompass the investigator-reported events as a result. Generally, investigator-reported events did not find a difference between hypoglycemic events in treatment and placebo; however, patient-reported events did show a reduction in hypoglycemic events, including a reduction in nocturnal hypoglycemia events, across all doses of empagliflozin treatment. The screenshots below show point estimates and confidence intervals for this data; of particular note is the consistent trend seen in the patient-reported event data favoring empagliflozin treatment. We’re looking forward to learning more about the relative validity and meaning or investigator-reported vs. patient-reported events.




4. Phase 2a Data on AZ’s MEDI0382 (GLP-1/Glucagon Dual Agonist): 22% Drop in Glucose AUC; ~7.4 Pounds of Weight Loss After Only Seven Weeks; +25% Time-in-Range

In a riveting oral presentation, MedImmune’s Dr. Victoria Parker provided tremendously positive phase 2a efficacy results for AZ/MedImmune’s GLP-1/glucagon dual receptor agonist MEDI0382, including an exciting first-look at emerging time-in-range data. The 49-day study (n=65) randomized participants into two cohorts, each pitting MEDI-382 vs. placebo. In cohort one, FreeStyle Libre Pro was worn across the entire trial and participants were titrated more quickly; in cohort two, there was no Libre use and participants were titrated more slowly – see below. All participants had type 2 diabetes and an A1c ≥6.5% and ≤8.5; the primary and secondary outcomes presented only considered cohort one.


On the first co-primary endpoint, MEDI0382 demonstrated a significant (p=0.02) weight loss of 3.4 kg (~7.4 lbs) over the 49-day trial, compared to 0.1 kg with placebo (below). Dr. Parker was quick to point out that this weight loss began immediately and did not plateau after 50 days. However, weight did jump back up immediately following removal of therapy, which she attributed to the study’s short duration and the fact that no diet or lifestyle interventions were recommended to patients after the study.


On the second co-primary endpoint of percent change from baseline to end-of-study glucose area-under-curve (AUC) in the first four hours after a mixed-meal tolerance test (MMTT), 300 μg (the highest dose) of MEDI0382 demonstrated a significant (p<0.001) 22% reduction. This was compared to a 6% increase in the placebo group. Notably, a pooled analysis of both cohorts on this endpoint at the lowest dose (50 μg), after the 7-day titration (see above), exhibited an equally significant 29% reduction compared to a 2% drop with placebo. To our understanding, this means that an ~equal percent reduction in hyperglycemia was found with 50 μg and 300 μg of MEDI0382 compared to placebo, suggesting this particular effect may not be dose-dependent. This postulation is supported by the steady difference in the mean daily glucose levels throughout the trial, seen in the CGM figure below.


  • A1c dropped a significant 0.7% (vs. 0.1% with placebo, p<0.001 for comparison) in cohort one and 0.8% (vs. 0.4% with placebo, p=0.037) in cohort two. This was from already-low baselines of 7.3% for cohort one and 7.5% for cohort two, and we view this as very positive for such a short duration. One audience member noted that these low baseline A1c’s presumably translate to relatively low insulin resistance in these groups – an important variable to consider. Similarly significant reductions in fasting plasma glucose were also found (below).


  • Those randomized to MEDI0382 in cohort 1 experienced an additional ~25% absolute time-in-range – defined quite stringently as 70-140 mg/dl – vs. placebo and over the course of the study (68% vs. 43% of a 24-hour day, p=0.002 for comparison). What’s more is that Dr. Parker assured the audience that there was no increased time in hypoglycemia – wow! We really think this is an incredible result (and we’re wondering about 70-180 mg/dl), particularly for patient quality-of-life. Dr. Parker also suggested that the glycemic benefits and reduced variability offered by MEDI0382 may begin within hours of the first dose, as demonstrated in the decreased mean glucose levels in the pop-out CGM tracing below.


  • On tolerability – which has really emerged as the Achilles heel of dual-agonists, as we see it – MEDI0382 results were somewhat less inspiring, but not severely so. In cohort one, 22 members (85%) of the therapy group experienced a treatment-emergent adverse event (TEAE), compared to 6 (46%) in the placebo group; 19% and 12% of those on MEDI0382 in the first cohort experienced nausea and vomiting, respectively, compared to 0% with placebo for both. Safety/tolerability was similar in cohort 2, despite a more gradual titration; 15 (75%) of participants randomized to MEDI0382 experienced a TEAE compared to 3 (50%) in the placebo group; 35% and 20% of those on the dual-agonist experienced nausea and vomiting, respectively, again compared to 0% with placebo for both. One injection-site reaction and one viral/respiratory tract infection with MEDI0382 led to study discontinuation, but diarrhea was notably low (<5% of those on MEDI0382, according to Dr. Parker). Importantly, Dr. Parker noted that longer titration of MEDI0382 in the second cohort did not significantly improve the candidate’s tolerability profile. Indeed, we find it important to note that nausea and vomiting actually increased in the more gradual MEDI0382 titration group (cohort 2), though the small sample size in this study really limits strong conclusions on tolerability.

  • With results from Lilly’s GLP-1/GIP dual agonist LY3298176 also presented today at EASD (above), we thought it might be interesting to compare the available data for each (while acknowledging that they are inherently different molecules). At the highest dose (15 mg), Lilly’s candidate demonstrated extraordinary 11.3 kg (~25 lbs) weight loss over 26 weeks – about four times longer than this 49-day study of MEDI0382. Assuming that MEDI0382 continued the weight-loss trajectory observed in this seven-week trial (a huge assumption, granted), the candidate could give very similar mean weight loss. For sure, this conjecture makes many assumptions, but Thursday’s presentations made us very excited about the potential of dual agonists, particularly for weight loss. It’s worth noting that side-by-side comparisons point to greater weight loss, faster with the Lilly molecule, at least in the early weeks of the phase 2b study above (below). Both molecules, we think, represent a huge leap forward in incretin therapeutics, diabetes treatment, and even obesity pharmacotherapy – the hype is shaping up to be real. Here’s an approximate side-by-side comparison of weight reduction in the first few weeks of each study:


  • If you’re looking for more information on this exciting dual-agonist, check out this presentation on the candidate’s promising efficacy in reducing hepatic fat content in type 2 diabetes (indicating potential in NAFLD/NASH!), and this presentation demonstrating a very significant (p<0.0001) reduction in glucose AUC compared to placebo. See our GLP-1/glucagon competitive landscape for more context on this exciting emerging therapy class, which has implications for type 2 diabetes as well as obesity and NASH.

5. CARMELINA CVOT Results for Tradjenta: Reassuring Heart Failure Results, Neutrality on CV Outcomes, Benefit on Albuminuria

Ahead of publication, results from the CARMELINA CVOT for Lilly/BI’s DPP-4 inhibitor Tradjenta (linagliptin), which completed in January 2018, were presented (see the announcement). As expected, results on cardiovascular outcomes were neutral, but there was indication of benefit on albuminuria in this very high-risk population. Now, we’re eager for outcomes from the CAROLINA CVOT, which puts Tradjenta up against SU glimepiride – but first, get a rundown of CARMELINA results below!

  • Study Design and Statistical Plan: Dr. Robert Toto kicked off this very well-attended session by emphasizing the scope of CARMELINA (n=6,979) as an international trial that randomized patients from 605 sites across 27 different countries; 3,494 were randomized to 5 mg linagliptin and 3,485 to placebo, on top of standard-of-care. HCPs were encouraged to treat all CV risk factors according to local guidelines. Inclusion criteria included baseline A1c between 6.5% and 10% plus high risk of CV events defined by either (i) albuminuria and macrovascular disease or (ii) impaired kidney function. The primary outcome was three-point MACE (CV death, non-fatal MI, and non-fatal stroke), and the key secondary outcomes was a composite renal endpoint (more below). CARMELINA was powered to determine non-inferiority of linagliptin vs. placebo on the primary endpoint.

  • Baseline Characteristics and Metabolic Outcomes: Dr. Steven Kahn reviewed baseline characteristics and metabolic outcomes. CARMELINA’s population was ~63% male, with an average baseline A1c of ~8.0% and average duration of type 2 diabetes of ~15 years. Per the inclusion criteria, 57% of participants had established CVD, 74% had prevalent CKD, and 33% had both conditions. Only 20% of participants had normo-albuminuria, while the other 80% had either micro- or macroalbuminuria. Moreover, 62% of patients had an eGFR below 60 ml/min/1.73 m2. In terms of metabolic outcomes, the linagliptin arm experienced a significant (and expected) reduction in A1c compared to placebo after 3.5 years (treatment difference = -0.36%, p <0.0001). Participants receiving linagliptin were also less likely to require additional glucose-lowering therapies post-baseline, and they were also less likely to initiate or need a dose increase of insulin (HR=0.72, 95% CI: 0.65-0.81, p <0.0001). Consistent with established profile of DPP-4s, no significant weight loss or blood pressure reductions were seen over time.

  • Cardiovascular Outcomes: In presenting cardiovascular outcomes, Dr. Darren McGuire opened by revealing that CV death comprised the majority (52%) of the 854 MACE events, followed by non-fatal MI (34%) and stroke (14%). He emphasized a high placebo event rate of 5.63/100 person-years, nearly three times the CVD equivalent. On three-point MACE, linagliptin was neutral vs. placebo (HR=1.02, 95% CI: 0.89-1.17, p=0.0002 for non-inferiority, p=0.7398 for superiority). This remained true when hospitalization for unstable angina was added (HR=1.00, 95% CI: 0.88-1.13, p<0.0001 for non-inferiority, p=0.9598 for superiority). Sensitivity analyses indicated no significant differences in risk for major CV events, and splitting MACE by select baseline characteristics found no significant effects, though there was a moderate trend with A1c (p value for interaction=0.0407 when splitting baseline A1c at 8%; lower A1c favors linagliptin more strongly). Individual endpoints were also neutral, including (i) CV death (HR=0.96, 95% CI: 0.81-1.14), (ii) non-fatal stroke (HR=0.88, 95% CI: 0.63-1.23), and (iii) non-fatal MI (HR=1.15, 95% CI: 0.91-1.45). All-cause mortality was also neutral (HR=0.98, 95% CI: 0.84-1.13).

    • Perhaps the most notable endpoint was hospitalization for heart failure, which trended solidly in favor of linagliptin (HR=0.90, 95% CI: 0.74-1.08, p=0.2635 for superiority). In the placebo group, 226 patients had events vs. 209 patients in the linagliptin group. Given the complex history of DPP-4 inhibitors and heart failure, this was an extremely reassuring and overall excellent result to see.

  • Renal outcomes: Dr. Vlado Perkovic presented the renal outcomes from CARMELINA. On the key secondary renal endpoint, a composite of time to first occurrence of: (i) sustained decrease of ≥40% in eGFR from baseline (504 total events), (ii) sustained end-stage kidney disease (127 total events), or (ii) death due to kidney disease (2 total events), the study found a neutral effect with linagliptin vs. placebo (HR=1.04, 95% CI: 0.89-1.22, p=0.6164). 327 events were experienced in the linagliptin group vs. 306 with placebo. After removing sustained decrease in eGFR from this composite (which accounted for a majority of the first events in the key secondary endpoint), the hazard ratio shifted somewhat in favor of linagliptin but remained non-significant (HR=0.87, 95% CI: 0.69-1.10, p=0.2371). Not included in either of these endpoints was time to first occurrence of albuminuria progression (change from normo- to micro- or macroalbuminuria, or from micro- to macroalbuminuria), for which linagliptin demonstrated a significant reduction vs. placebo (HR=0.86, 95% CI: 0.78-0.95, p=0.0034) with 819 events in the placebo event and 763 events in the linagliptin group. This endpoint then drove the superiority of linagliptin vs. placebo (HR=0.73, 95% CI: 0.78-0.95, p=0.0032) on a larger microvascular composite outcome consisting of time to first occurrence of (i) albuminuria progression (as defined above), (ii) sustained decrease of ≥50 in eGFR (as opposed to 40 in the key endpoint), (iii) sustained ESKD, (iv) death due to kidney disease, (v) retinal laser coagulation or anti-VEGF injection for diabetic retinopathy, (vi) vitreous hemorrhage, or (vii) diabetes-related blindness. Notably, it was pointed out that 745 of the 785 events in the linagliptin group and 810 of the 845 events in the placebo on this endpoint were albuminuria progression; with ~95% of events coming from one of seven outcomes, this endpoint should be interpreted in that light. No clear effects on progression of the ocular component of this was observed (HR 0.73, 95% CI 0.47-1.12, p=0.015). Regardless, these are certainly intriguing results in the context of previous DPP-4 CVOTs. SAVOR-TIMI-53 for AZ’s Onglyza (saxagliptin) is the only other trial in the class to have prevented progression of microalbuminuria. To be sure, CARMELINA certainly provides evidence to support the idea that DPP-4s can prevent progression of albuminuria, though our sense is that the jury is still out on the impact on other microvascular complications (in that most don’t consider albuminuria a microvascular complication).

  • Hypoglycemia and Safety: Dr. Mark Cooper presented safety outcomes; consistent with the well-established safety profile of DPP-4s, no major adverse safety data was unearthed in the trial. Rates of adverse events (77% vs. 78%), adverse events leading to trial discontinuation (10% vs. 12%) and serious adverse events (37% vs. 39%) were well balanced between linagliptin treatment and placebo, respectively. Safety events of particular interest, including hypersensitivity reactions and renal adverse events, were also balanced between treatment and placebo. Rates of acute pancreatitis, although relatively low across the entire population (~0.2%), were higher in treatment than placebo (total events were 9 vs. 5; 0.3% vs 0.1% for linagliptin vs. placebo). Finally, rates of hypoglycemia were well balanced in the overall group (~20% for both), in insulin-treated participants (30% vs. 33%), sulfonylurea-treated participants (16% vs. 14%), and those with kidney disease (28% vs. 29%) for treatment vs. placebo, respectively. A similar well-balanced trend emerged for rates of severe hypoglycemia as well.

  • Summary, conclusions, clinical perspectives, and implications for practice. According to Dr. Bernard Zinman, CARMELINA fills an important gap in data for the DPP-4 inhibitor class. Specifically, he pointed to the high proportion of patients with kidney disease (eGFR <60 ml/min/1.73 m2), comprising 63% of the total population. For comparison, 16% of patients in the SAVOR-TIMI trial for AZ’s Onglyza (saxagliptin) had an eGFR <50, 29% in the EXAMINE trial for Takeda’s Nesina (alogliptin) had an eGFR <60, and 9% in the TECOS trial for Merck’s Januvia (sitagliptin) had an eGFR <50. Additionally, CARMELINA had a markedly higher average proportion of participants with macroalbuminuria, clearly differentiating its population from that of other DPP-4 CVOTs (below left). Also separating CARMELINA from the pack is the fact that it found CV safety with the best trend for hospitalization for heart failure in the class to date (below right) – though we note that all trials apart from SAVOR-TIMI were statistically neutral on this endpoint. Continuing to renal outcomes, Dr. Zinman pointed to linagliptin’s significant reduction in albuminuria progression and the microvascular composite outcome as bright spots from the trial, and noted that CARMELINA is unique in the DPP-4 class inasmuch as its key secondary kidney outcome was pre-specified, adequately powered, and adjudicated. From our point of view this likely makes little clinical difference, as linagliptin was found to be renally safe compared to placebo – an opinion which most seem to already hold, from where we stand. Bringing things full circle, Dr. Zinman highlighted linagliptin’s reassuring safety profile despite the generally worse renal health of the study’s population – an important finding for a population that is often uniquely difficult to treat.


  • Commentator: In providing independent commentary, the great Prof. Philip Home first focused on what’s good about the study, namely:

    • Linagliptin was established as safe, in the medium-term, in a high-CV-risk population.

    • Consistency with other DPP-4 inhibitor CVOTs in lower-risk populations and for longer time periods is encouraging.

    • There was no safety signal on heart failure.

    • CARMELINA confirms the albuminuria reduction found with other glucose-lowering agents.

And then, Prof. Home discussed what could have been better about the study:

  • Discontinuation from allocated therapy was 26% over 2.2 years.

  • Investigation in two separate populations (i.e. some had only CKD, and some had only CVD) may not make sense or be easy to apply – these populations should be analyzed separately.

  • There was a relatively low number of patient years of exposure (6,639).

  • Most events were CV death, which doesn’t ring true with most diabetes patients.

  • The microvascular endpoint is not truly a microvascular endpoint, as the effect was driven by albuminuria – which is a marker of vascular inflammation, not microvascular complications. Moreover, he says, it’s not reasonable to expect renal outcomes to be impacted in such a short study of a drug that does not act on the kidney.

6. LifeScan’s OneTouch Verio Reflect BGM Submitted to FDA and Health Canada and Under Review for CE Mark; Welldoc Bluestar/Verio Flex Integration Branded Under OneTouch Reveal Plus App (1,000+ Downloads)

At an evening LifeScan symposium, Head of Portfolio Strategy Mr. David DeJonghe shared that the new OneTouch Verio Reflect is not only under review for CE Mark, but has also been submitted to the FDA and Health Canada. The Verio Reflect, which we saw up close at the LifeScan booth, includes the Blood Sugar Mentor, a feature that pushes real-time insight and encouragement both to the meter and the OneTouch Reveal app. This meter will be branded as “Ultra Plus Reflect” in certain markets. We learned that Blood Sugar Mentor has a library of 30-40 messages, and that patients testing once or twice a day might receive two messages per week. Mr. DeJonghe stressed that LifeScan wants to avoid inundating patients with too much information, while still prompting them to consider their glycemic patterns. He acknowledged that a lot of the guidance is “germane enough to encourage behavior while not directly telling the patient what to do.” To this end, he noted that LifeScan has had “to walk a line” in developing the Blood Sugar Mentor so as not to stray too far into therapeutic territory, which would warrant more intense regulatory scrutiny. We’re not sure if/when it’s on the roadmap, but it would be great to see integration of more robust decision support in the future.

  • We were thrilled to hear Mr. DeJonghe mention the OneTouch Verio Flex integration with Welldoc’s Bluestar, as despite launching last March, we’ve received very few updates. Tonight, we learned that it is branded under OneTouch Reveal Plus, an in-app coaching experience for adults with type 2 diabetes. Patients can create an account once they have received an activation code from their health plan or employer. Mr. DeJonghe noted that OneTouch Reveal Plus looks a bit different depending on the country. For example, in Italy, the app is called OneTouch24 and collects data in the background, facilitating video calls between patients and providers. Since its rollout in March, Google Play lists just 1,000+ installs with a low rating of 2.1/5 stars (15 reviews). OneTouch Reveal Plus is also available on the App Store, but reviews are not provided. From a quick glance through the app reviews in Google Play, it seems that users are frustrated by the required code – it’s possible that many are trying to access the app without the necessary sponsorship, and therefore skewing its ratings low. The screenshots have a fresh, clean design, although the advice (at least in the below example!) seems a bit basic (e.g., “When your BG is a little high even before breakfast, it is a good idea to be extra careful with your food choices”). Still, we think there’s a lot of potential for OneTouch Reveal Plus to educate type 2s and hope that reimbursement discussions are going well to expand access quickly.


  • Mr. DeJonghe highlighted LifeScan’s incentives partnership with Walgreens. For each fingerstick performed on their LifeScan meter, patients receive “points,” which they can then redeem towards purchasing diabetes supplies at Walgreens. We think solutions like these can be excellent motivators for patients! We wonder if this project is exclusive to LifeScan, or if Walgreens has similar programs with other BGM companies.

  • Mr. DeJonghe asserted that OneTouch Reveal is one of the most downloaded diabetes apps in the world. In fact, he said it is the number one most downloaded diabetes app in US, Canada, Italy, Portugal, and France, with over one million patients having downloaded it to date.

  • LifeScan Director of Clinical Affairs Dr. Mike Grady presented several studies demonstrating the accuracy and efficacy of OneTouch BGMs. We were particularly impressed by a 12-week, randomized controlled trial (n=163 type 2s) conducted across three UK sites comparing A1c between those who switched to Verio BGMs and those who remained on other BGMs. While the control group saw no significant change in A1c, patients who switched to Verio BGMs achieved a significant 0.36% A1c reduction (baseline A1c: 8.8%). Dr. Grady noted that A1c reductions were greater in type 1 diabetes (-0.50%) as compared to type 2 diabetes (-0.59%), although he did not include a statistical analysis. Of course, the finding could reflect differences in baseline A1c, which were not provided. We’d be interested to know how many patients in the control group, if any, were using connected BGMs. If the control group consisted only of non-connected BGMs, the results might suggest a broader benefit associated with connectivity.

The diaTribe Foundation’s Fifth Annual Solvable Problems in Diabetes Forum

1. diaTribe Foundation’s “Solvable Problems in Diabetes” Brings Drs. Mathieu, Kar, and Adam Brown Together to Discuss CGM, SGLT-2 in T1, New Type 2 Diabetes Care Paradigms, +++

Last night, in the historic Wasserwerk Berlin building, the diaTribe Foundation hosted the 5th Annual Solvable Problems in Diabetes, putting together a panel featuring Portsmouth Hospital NHS Trust’s Dr. Partha Kar, Katholieke Universiteit Leuven’s Dr. Chantal Mathieu, and diaTribe Senior Editor Mr. Adam Brown. Below, we’ve provided a number of quotable quotes from a panel that one attendee said made her feel like a “voyeur,” listening in on a private conversation. Topics spanned the gamut of relevant diabetes and EASD topics, from CGM, SGLT-2 inhibitors in type 1 diabetes, type 2 diabetes care paradigms, type 1 cures, and more! Without further ado, our favorite quotes from the night:

On SGLT-2 inhibitors in type 1 diabetes

  • “Honestly, in the EU, most type 1s are with specialists. In Europe, we can deal with this, we can train them. But when I hear that in the US a lot of type 1s are with primary care and risk having one guy out there saying, ‘I have this pill for you and it will take care of your diabetes,’ it wouldn’t go well.” – Dr. Mathieu

  •  “When you look in studies, and we have done so carefully, if you look at the moment in time when DKA happens, there’s no learning curve when it happens. If it happens once, it happens a third, fourth, and fifth time. It’s a thing that regulators will have to deal with. On the one hand, you have A1c improvement, less weight, you feel better, and you have more time-in-range, and on other hand, you have the price of DKA that is rare but that will happen. With EASE, we had one person dying; it will happen.” – Dr. Mathieu

  • “It’s not about, ‘Oh my god, we have a new drug in type 1 to use.’ If I were to spend my euro, would I put that on SGLT-2 inhibitors or on education? Or on non-invasive glucose monitoring? I think those questions will come through. It’s about evidence, another tool, but categorically, no we don’t use it. We handpick patients. It does drop A1c and weight, but with risk of DKA and infection.” – Dr. Kar

  • “All adjunct therapies in type 1 come with some risk of ketosis, because if you give a therapy to a person with type 1 that lowers glucose, you need to bring down insulin dose, and that means that levels of insulin drop. We need insulin not only to control glucose, but also to keep fat tissue built up. When you bring down insulin, in some people, you will be at the edge of keeping fat built up. If you break down fat, your liver makes ketones. We saw that with adjunct therapies – liraglutide, metformin – all adjunct therapies. In SGLT-2 or SGLT-1/2 inhibitors, you also have probably stimulation of ketosis by the drug itself. DKA is rare in studies, but it is the reality. So, patients love SGLT-1/2 or SGLT-2 inhibitors because the moment you swallow this pill, in the evening, you see your glucose curves [makes shrinking motion with hands]. You feel in control, happy, and your weight goes down. They love it. But shit happens. Despite education, despite a plastic card I give them telling them to check ketones if feeling nauseous, telling the ER doc it’s ketosis, etc. Despite all that, shit happens.” – Dr. Mathieu

On CGM adoption and value proposition

  • “It’s different when you think about spending euros in people on glucose-lowering agents that can’t give you hypoglycemia. I would rather spend my euro on giving them all access to GLP-1 or SGLT-2 than on CGM. Type 2 diabetes is so much more than just glucose… [CGM] is expensive, and I’d rather spend my euro somewhere else.” – Dr. Mathieu

  • “I’m still surprised that many of our type 1s still say, ‘I want nothing to do with that, leave me alone with my multiple daily injections, I want no one to know I live with type 1.’ In Belgium we have full reimbursement of CGM/FGM, and still penetration of CGM is just 80% in type 1s in my clinic… It’s free, and still 20% say, ‘No thanks.’… Let’s be honest, with pumps and sensors, burden of diabetes not decreased.” – Dr. Mathieu

  • “We published that if you introduce CGM in a country, you save big on DKA and hypoglycemia. So now all CGM companies travel the world with that paper.” – Dr. Mathieu

On outcomes-based contracting

  • “If you have an innovative way of contracting, come to the table now [with NHS]. Everyone knows, but you have to put it on the table. Put some money down, and we shall see.” – Dr. Kar

  • “Outcomes-based, we talk a lot about it, and no one really knows what it is. One company says my technology ‘X’ is fine. If it is so fantastic, what do I do if it doesn’t work? Do I not pay you? Do I get the next one for free, some kind of two-for-one deal? Or do I just pay you regardless? Or if GLP-1 agonist reduces A1c by X%, what do I do if it doesn’t?” – Dr. Kar

On a type 2 diabetes treatment considerations

  • “I don’t know about the rest of the world, but in the UK, hypoglycemia admissions in frail elderly have now overtaken DKA admissions. That is just poor care, we are bringing people in. She is 94, just let her be, stop trying to get her A1c to 6%. It’s time to update the guidelines based on frailty, weight, and CV disease.” – Dr. Kar

  • “Type 2 diabetes is about lifestyle, statins, blood pressure, new agents, SGLT-2, GLP-1 – not just glucose. If we make them live long enough and beta cells fail further and further, then insulin comes in, then prandial insulin comes in. If you have type 2 diabetes where the beta cell almost doesn’t work anymore, then I agree that sensors, MDI, and pumps can play a role. But in the period before, we should be using other agents.”

  • “If I may ask industry, we need trials in non-classical populations. Like frail elderly for instance, there’s zero evidence. We were very frustrated in the EASD/ADA Consensus committee, we couldn’t say anything about the elderly, let alone the frail elderly. Yeah, we need some gutsy studies in people over 75 years old, demonstrating safety and efficacy of drugs (or not).” – Dr. Mathieu

  • “So now we’re bringing together the specialist, the primary care physician and the patient and having them agree together on a plan for care. And a primary care physician gets 80 euros a year to take care of the diabetes patient.” – Dr. Mathieu

On type 1 prevention and cure

  • “We haven’t prevented type 1 diabetes yet, and honestly when I look at everything we’ve done in past 20 years, I think we have a good clue of what to do with immune system. Immune interventions do work on the immune system. Biomarkers change, Tregs go up, but that alone is not enough to change type 1 diabetes. The big lesson of PD-1, PDL-1 checkpoint inhibitors, is when you give agents that eliminate regulatory cells in cancer, they survive cancer, but come to endocrinologist with thyroiditis, adrenalitis…rarely do they get type 1. This is really, for me, the proof that to get type 1 diabetes, it’s not enough to really screw up the immune system. You need an exceptionally vulnerable beta cell. I think industry, put diabetes on agenda, be bold, be confident. In type 1, the immune system, we’re nearly there, so give us something for the beta cell.” – Dr. Mathieu

On the importance of celebrity advocacy and the patient voice

  • “One of the reasons we’ve had so much attention on diabetes is because our prime minister has type 1. No one knew about metatarsal bones until David Beckham broke his foot. That’s the power of celebrity…We need somebody super special, loved by everyone, with type 1 or type 2 diabetes to come forward.” – Dr. Kar

  • “I’m a big believer in the power of the patients. In Belgium, everything is around cancer. We have a project called “Let’s Fight Cancer,” and they sell little plants, and they had the good fortune that the weather guy is their supporter, so every evening, when the guy says it’ll rain tomorrow, he says ‘and do not forget, fight cancer.’ So it’s high on the agenda, so many expensive drugs, and when we come with something for diabetes, oh, they need to discuss for 700 days. Patients are central, they need to voice why it’s important to have attention for non-sexy chronic diseases.” – Dr. Mathieu


-- by Ann Carracher, Martin Kurian, Brian Levine, Peter Rentzepis, Maeve Serino, and Kelly Close