Olá from Lisboa, where EASD 2017 continues full steam ahead. This report details 10 highlights from day #3 of the meeting, many of which came from two rapid-fire oral presentation sessions: One in the morning on incretins chaired by the highly-respected Professor Melanie Davies featured new analyses of DURATION-7 (AZ’s investigation of GLP-1 agonist Bydureon added onto insulin glargine) and SUSTAIN 6 (Novo Nordisk’s pre-market CVOT for GLP-1 agonist semaglutide). In an afternoon session on SGLT-2 inhibitors, Merck’s Dr. Brett Lauring presented full results from the one-year VERTIS SU trial (a head-to-head of SGLT-2 candidate ertugliflozin vs. sulfonylurea glimepiride) and Toronto’s Dr. David Fitchett discussed a post-hoc of EMPA-REG OUTCOME that rules out blood pressure, LDL, and A1c as mediating effects for Jardiance’s CV benefit. We’d be remiss not to call out Prof. Brian Frier’s Camillo Golgi lecture on the case for a link between recurrent hypoglycemia and long-term complications – a brilliant and packed talk.
Top 10 Highlights
1. Dr. Brett Lauring presented findings from VERTIS SU, a 52-week head-to-head trial of Merck/Pfizer’s SGLT-2 inhibitor candidate ertugliflozin vs. glimepiride (a sulfonylurea). The higher, 15 mg dose of ertugliflozin demonstrated non-inferiority vs. glimepiride on the primary endpoint of A1c-lowering; the more telling data from this study is, unsurprisingly, the SGLT-2’s notable superiority on body weight and hypoglycemia.
2. A poster authored by Dr. Juan Frias outlined compelling evidence that people with type 2 diabetes reach glycemic targets significantly faster with Sanofi’s fixed-ratio basal insulin/GLP-1 combination Soliqua (insulin glargine/lixisenatide) vs. standard of care Lantus (insulin glargine), based on post-hoc analysis of the phase 3 LixiLan-O and LixiLan-L trials. We remain very surprised why this drug hasn’t taken off faster (“clinical inertia!” is what we keep hearing).
3. Dr. Juan Frias returned to the EASD stage to discuss a new post-hoc analysis of AZ’s DURATION-7 study, investigating GLP-1 agonist Bydureon (exenatide once-weekly) as an add-on to insulin glargine (Sanofi’s Lantus), following his presentation of the highly-anticipated full results at ADA 2017. In positive news, 51% of Bydureon-treated patients experienced both A1c-lowering and weight loss vs. 23% of placebo-treated patients, and Dr. Frias emphasized that a two-fold greater likelihood for this simultaneous benefit is quite clinically-meaningful. We agree – and also point out our view that adherence may be much better relatively speaking due to the degree to which patients care about weight.
4. Dr. David Fitchett presented a new analysis of EMPA-REG OUTCOME, demonstrating that empagliflozin’s significant risk reduction for CV and all-cause death was not driven by the SGLT-2 inhibitor’s beneficial effect on CV risk factors such as blood pressure, LDL cholesterol, and A1c.
5. Dr. Agostino Consoli shared new data from Novo Nordisk’s SUSTAIN 6 trial of GLP-1 agonist semaglutide, demonstrating sustained weight loss over two years. The results on body weight, waist circumference, and proportion of participants meeting weight loss goals with semaglutide vs. placebo were resoundingly positive across the board. Needless to say, we’re very excited about this molecule, which is expecting an FDA decision on approval for type 2 diabetes in 4Q17, and which is slated to enter phase 3 studies for obesity in 1H18. We expect the latter to be very positive, particularly given frequency.
6. In the very prestigious (and absolutely packed) Camilo Golgi lecture, University of Edinburgh’s Professor Brian Frier gave a whirlwind overview of everything hypoglycemia, arguing that “while there’s no definitive proof that recurrent hypoglycemia causes cardiovascular disease, aggregating evidence suggests that it may be more than a minor inconvenience.”
7. EASD orals kicked-off with a new post-hoc analysis of Merck’s TECOS trial for DPP-4 inhibitor Januvia (sitagliptin), presented by Dr. Sam Engel. When added onto a background of metformin monotherapy (n=4,435) or metformin/sulfonylurea dual therapy (n=5,152), sitagliptin treatment significantly delayed insulin initiation for type 2 diabetes patients, which is clinically-meaningful in terms of avoiding hypoglycemia, weight gain, and high injection burden.
8. Kicking-off a series of oral presentations on the clinical utility of SGLT-2 inhibitors, Janssen Dr. Gill Hamilton shared findings from a retrospective cohort study conducted in the UK on time to next therapy for patients on Invokana (canagliflozin) vs. other diabetes drugs (including GLP-1 agonists, DPP-4 inhibitors, and other SGLT-2 inhibitors). The real-world analysis suggests that patients on canagliflozin (among other SGLT-2 inhibitors) may need less intensification with other agents, which adds treatment complexity, cost/co-pays, and may signify worsening glycemic control.
9. Is there a silver lining to the increase in ketones observed with SGLT-2 inhibitors? A research group from Sapporo today suggested yes, based on evidence from a rodent study of Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin).
10. At the fourth annual Solvable Problems in Diabetes event, attendees were treated to a panel discussion from Dr. Drucker, Prof. Melanie Davies, and Prof. David Matthews that surprised many by focusing largely on how to incite behavioral change to better augment pharmaceuticals. We also heard some commentary from Prof. Matthews on the amputation signal detected in the CANVAS trial. See our truly quotable quotes below.
Top 10 Highlights
1. VERTIS SU Compares Merck/Pfizer’s SGLT-2 Ertugliflozin Head-to-Head with Glimepiride, Highlights Hypoglycemia and Weight Gain as SU Disadvantages
Merck’s Dr. Brett Lauring, subbing in for Dr. Patricia Hollander (Baylor, Dallas, TX), presented findings from VERTIS SU, a 52-week head-to-head trial of Merck/Pfizer’s SGLT-2 inhibitor candidate ertugliflozin vs. glimepiride (a sulfonylurea). Type 2 diabetes patients on a background of metformin therapy (≥1,500 mg/day) were randomized to treatment with a 5-mg daily tablet of ertugliflozin (n=448), with a 15-mg daily tablet of ertugliflozin (n=440), or with glimepiride that could be uptitrated to a maximum of 6 mg/day or 8 mg/day per local drug labels (n=437). In total, 1,326 participants completed a full year of treatment: 340 in the 5 mg ertugliflozin group, 357 in the 15 mg ertugliflozin group, and 348 in the sulfonylurea group. The higher dose SGLT-2 demonstrated non-inferiority vs. glimepiride on the primary endpoint of A1c-lowering – from a baseline 7.8%, mean A1c drop at the end of 52 weeks was 0.6% in the high-dose SGLT-2 arm vs. 0.7% in the SU arm, culminating in an A1c treatment difference of 0.1% (95% CI: 0.0-0.2). The criterion for non-inferiority was pre-defined as an upper bound of the 95% confidence interval <0.3, which wasn’t met by low-dose ertugliflozin (mean A1c drop of 0.6%, A1c treatment difference of 0.2%, 95% CI: 0.1-0.3). While we would not have expected to see non-inferior A1c reductions for the ertugliflozin doses (many clinicians have told us that the A1c lowering with SFUs is said to be very good for awhile and then falls off significantly – beta cell burnout to follow is expected), we did expect positive data on body weight, blood pressure, and adverse events and indeed, that’s what we saw in VERTIS SU. From a baseline ~192 lbs, body weight decreased by a mean ~8 lbs for patients on 15 mg ertugliflozin and by ~7 lbs for patients on 5 mg ertugliflozin, whereas participants taking glimepiride experienced 2 lbs weight gain on average (p<0.001 for both comparisons). This was unsurprising – weight gain is one of the commonly-cited disadvantages to sulfonylureas, while SGLT-2 inhibitors are known to promote weight loss – but still important to show differences on this key outcome beyond A1c (one that matters so much to patients) in a head-to-head clinical trial. Systolic blood pressure declined from a baseline ~130 mmHg by 4 mmHg and 2 mmHg in the 15 mg and 5 mg ertugliflozin arms, respectively, increasing by 1 mmHg over 52 weeks in the glimepiride group (p<0.001 for both comparisons). While adverse events on the whole were well-balanced across all three treatment arms, symptomatic hypoglycemia was significantly more common in patients on glimepiride (19%) vs. 15 mg ertugliflozin (5%, p<0.001 vs. SU) or 5 mg ertugliflozin (3%, p<0.001 vs. SU). Again, this is the result we would have expected given the well-known high hypoglycemia risk associated with sulfonylureas, but is still enormously valuable to see from a head-to-head clinical trial. Given that cost is the main line of defense for sulfonylureas currently (keeping these agents in diabetes treatment algorithms despite these side-effects, plus beta burnout and possible CV harm with longer-term exposure), we’d hope the increase in weight gain and especially hypoglycemia would sway payers toward newer, safer, better diabetes drugs – the cost of hypoglycemia-related hospital admissions is extremely high ($7 billion in claims in 2015 according to Truven data). Of course, regulators and payers are compelled by empirical evidence, and to this end, head-to-head studies against sulfonylureas (including VERTIS SU) are immensely important. The real prize may be in head-to-head outcomes trials, and for this we eagerly await results from CAROLINA, Lilly/BI’s CVOT comparing DPP-4 inhibitor Tradjenta (linagliptin) vs. glimepiride, expected to complete in March 2019.
- For context, prior studies have shown canagliflozin (J&J’s SGLT-2 inhibitor Invokana) to offer superior A1c-lowering efficacy vs. glimepiride after one year and empagliflozin (Lilly/BI’s SGLT-2 inhibitor Jardiance) to offer superior A1c reductions vs. glimepiride after two years. Differences in trial design prevent us from deriving any meaningful conclusions from this regarding ertugliflozin’s differential benefits compared to other SGLT-2 agents already on the market, but we’ll be curious to learn more (especially from real-world data) on how the advanced SGLT-2 inhibitor class compares to sulfonylureas on A1c and outcomes beyond (including hypoglycemia episodes and CV events). Merck/Pfizer have filed ertugliflozin with the FDA and EMA (alongside fixed-dose combinations of ertugliflozin/metformin and ertugliflozin/ sitagliptin), and the companies are expecting regulatory decisions on all three products by year end.
Questions and Answers
Q: Did you see any signal for amputations?
Dr. Lauring: There were two in the trial, one occurring in the glimepiride group and one in the 15 mg ertugliflozin group. Both were toe amputations, in patients who had several baseline risk factors such as smoking, neuropathy, and peripheral arterial disease.
Q: For most of the 52-week period, it appears that glimepiride is actually superior on A1c. Should we not instead be using area under the curve to analyze this dataset?
Dr. Lauring: That’s a fair point. We have looked at the data that way, but I think a lot of practitioners are interested in what’s going to happen over time. (Editor’s note – we always have widely heard from clincians that SFU impact on A1c is very positive at the start and then “wears off” – we’d love to see longer-term data because this superiority sounds like it is not sustained but gets considerably worse in many cases).
Q: You say serious adverse events were uncommon – what were they, and were they more common with the low dose or the high dose?
Dr. Lauring: There was no particular pattern to serious AEs. They didn’t cluster into one disease area or biology of disease. We look at dozens of safety-related endpoints across lots of trials, and sometimes the 5 mg dose has more and sometimes the 15 mg dose has more, which is not surprising because both doses are near the top of the dose-response curve.
Q: What was the incidence of DKA?
Dr. Lauring: There was one case in the 15 mg ertugliflozin group. If I remember correctly, the patient had an episode of sepsis preceding DKA.
Dr. Chantal Mathieu: Your study nicely demonstrates that in people with A1c of 7.8%, if you hit them with an SU, you can really bring down A1c even though you have a price to pay in hypoglycemia. Did you adjudicate hypoglycemia? It also looks like you had two annoying severe hypoglycemia events in the ertugliflozin groups.
Dr. Lauring: There was general education around hypoglycemia, people were supplied with a meter and told how to record their symptoms. Keep in mind that when severe hypoglycemia is defined as requiring assistance, someone bringing you juice would then be defined as severe hypoglycemia, and it’s hard to get that number down to zero in a trial of ~1,300 patients, with ~440 per arm.
2. Post-Hoc of LixiLan-O and LixiLan-L Reveals Faster Time-to-Target with Sanofi’s Soliqua vs. Lantus
A poster authored by Dr. Juan Frias outlined compelling evidence that people with type 2 diabetes reach glycemic targets significantly faster with Sanofi’s fixed-ratio basal insulin/GLP-1 combination Soliqua (insulin glargine/lixisenatide) vs. standard of care Lantus (insulin glargine). This data, also highlighted in a Sanofi press release, comes from a post-hoc analysis of the phase 3 LixiLan-O (n=1,170) and LixiLan-L (n=736) trials, which showed superior A1c-lowering efficacy for Soliqua vs. Lantus in type 2 diabetes. In both trials, a significantly higher proportion of participants on Soliqua achieved A1c <7% vs. their counterparts in the Lantus arm at 12 weeks: 60% vs. 45% in LixiLan-O (p<0.0001), and 46% vs. 24% in LixiLan-L (p<0.0001). Moreover, the time required for study participants to collectively reach a median A1c <7% was significantly shorter with Soliqua than with Lantus: 85 vs. 166 days in LixiLan-O (HR=1.5, 95% CI: 1.3-1.7, p<0.0001) – this suggests that dosing intensification is required with Lantus. In LixiLan-L, Soliqua-treated patients took 153 days to achieve this median A1c level, whereas Lantus-treated patients did not collectively reach this goal by the end of the 30-week study (HR=2.0, 95% CI: 1.7-2.5, p<0.0001). In contrast, median time required to reach the fasting plasma glucose target <130 mg/dl was identical for participants treated with Soliqua and Lantus: 56 vs. 57 days in the LixiLan-O trial, and never for either group in the LixiLan-L trial. This suggests that the faster time to target A1c with Soliqua may be attributable to the product’s action on postprandial excursions in addition to fasting glucose, thanks to its short-acting GLP-1 agonist component. This study reinforces our enthusiasm for Soliqua as an agent that packs the punch of two drugs in one single injection. We are extremely moved by the notion that, beyond lowering A1c to a greater extent than standard of care Lantus, Soliqua gets patients to goal more rapidly. We hope that payers are taking note – the efficacy profile of Soliqua (and, indeed, its counterpart Xultophy [insulin degludec/liraglutide] from Novo Nordisk) represents a major advance over traditional basal insulin therapy, and access remains a major barrier preventing commercial uptake of these agents despite tremendous enthusiasm from diabetes thought leaders.
- To complement this, a separate poster demonstrated that Soliqua reduces A1c to a greater extent than Lantus regardless of baseline A1c. This post-hoc analysis stratified existing data from the LixiLan-L trial based on entry A1c into three categories: (i) <8% (n=97), (ii) 8%-9% (n=161), and (iii) >9% (n=69). Soliqua lowered A1c to a significantly greater extent than Lantus across each of these categories, with a treatment difference of 0.56% (95% CI: 0.66-0.42, p<0.0001) for those with baseline A1c <8%, 0.4% (95% CI: 0.59-0.22, p<0.0001) for those with baseline A1c between 8%-9%, and 0.66% (95% CI: 0.93-0.39, p<0.0001) for those with baseline A1c >9%. For the entire study population overall, A1c-lowering was a mean 0.54% greater with Soliqua vs. Lantus (95% CI: 0.66-0.42, p<0.0001). Importantly, this superior glycemic control with Soliqua vs. Lantus came without an increased risk of hypoglycemia.
3. In DURATION-7, Patients on Bydureon vs. Placebo Twice as Likely to Experience Simultaneous A1c-Lowering/Weight Loss
Dr. Juan Frias returned to the EASD stage to discuss a new post-hoc analysis of AZ’s DURATION-7 study, investigating GLP-1 agonist Bydureon (exenatide once-weekly) as an add-on to insulin glargine (Sanofi’s Lantus), following his presentation of the highly-anticipated full results at ADA 2017. According to Dr. Frias, 81% of participants in the Bydureon group (n=231 in an intent to treat analysis) experienced at least some reduction in A1c over the course of the 28-week trial, vs. only 60% of participants in the placebo group (n=230). Similarly, a higher proportion of patients on Bydureon (62%) vs. placebo (40%) experienced at least some reduction in body weight during DURATION-7. Dr. Frias presented very interesting scatter plots, with each dot representing a patient and placed in one of four quadrants: (i) increased A1c + increased body weight, (ii) decreased A1c + increased body weight, (iii) decreased A1c + decreased body weight, and (iv) increased A1c + decreased body weight. Quadrant no. 3 is where you’d want to be (reaping glycemic and weight loss benefits from once-weekly exenatide injections) and indeed, 51% of Bydureon-treated patients were in this lower left quadrant vs. 23% of placebo-treated patients, a quite noticeable difference. Conversely, only 7% of Bydureon-treated patients were in quadrant no. 1 (upper right, reflecting worsening A1c and body weight) vs. 23% of placebo-treated patients. That people receiving once-weekly exenatide were twice as likely to experience simultaneous improvements in A1c/body weight vs. placebo is quite clinically meaningful, Dr. Frias emphasized. He also summarized some key DURATION-7 data announced at ADA, including that 25% more participants on Bydureon vs. placebo achieved A1c target <7% by study end, and that 20% more people on Bydureon achieved the composite endpoint of A1c <7% with no severe hypoglycemia or weight gain. While AZ doesn’t have any insulin products in its diabetes portfolio or pipeline, combination therapy with a basal insulin/GLP-1 agonist is gaining more attention now that fixed-ratio combinations (Novo Nordisk’s Xultophy and Sanofi’s Soliqua) have been approved for type 2 diabetes. We certainly see value in demonstrating Bydureon’s benefits in the context of a basal insulin regimen, as it lends more evidence in support of safety/efficacy for basal insulin/GLP-1 combination treatment (whether simultaneous or sequential). Moreover, these results establish strong safety/efficacy for AZ’s once-weekly GLP-1 agonist in particular for the many real-world patients taking Lantus as standard of care. On the subject of “real-world,” HCPs in DURATION-7 were permitted to continue titrating glargine with an aim toward optimal glycemic control, even after the eight-week run-in period prior to Bydureon/placebo randomization, though it’s unclear how successfully this was done – Dr. Melanie Davies pointed out during Q&A that investigators could maybe have been proactive in encouraging optimal insulin titration throughout the study. That said, given how insulin is titrated far from optimally in real clinical settings, perhaps these clinical trial results underscoring Bydureon’s efficacy will actually translate better to the real world.
4. New EMPA-REG OUTCOME Analysis Rules Out Blood Pressure, LDL, and A1c as Explanations for Jardiance’s Cardioprotection
Dr. David Fitchett presented a new analysis of EMPA-REG OUTCOME, demonstrating that empagliflozin’s significant risk reduction for CV and all-cause death was not driven by the SGLT-2 inhibitor’s beneficial effect on CV risk factors such as blood pressure, LDL cholesterol, and A1c. The hazard ratio of 0.62 for CV death in the trial’s primary analysis (corresponding to a 38% relative risk reduction) did not substantially change when adjusting for empagliflozin’s effect of reducing blood pressure (HR=0.61), LDL cholesterol (HR=0.59), A1c (HR=0.62), or all three of these CV risk factors together (HR=0.61). The same was true for the hazard ratio of 0.68 for all-cause mortality with empagliflozin (reflecting 32% relative risk reduction), which was essentially unchanged after adjustment for empagliflozin’s reductions in blood pressure (HR=0.67), LDL cholesterol (HR=0.66), A1c (HR=0.67), and all three together (HR=0.67).
- Two years after the original presentation of the EMPA-REG OUTCOME results at EASD 2015 in Stockholm, the mechanism underlying empagliflozin’s famed cardioprotective effect remains unclear, though the notion of an overarching atherosclerotic effect (the hypothesized mechanism for GLP-1 agonists liraglutide and semaglutide based on LEADER and SUSTAIN 6 data) has been widely ruled out due to early rather than gradual divergence of Kaplan-Meir curves. At ADA 2016, Dr. Silvio Inzucchi presented a univariate mediation analysis of EMPA-REG OUTCOME, which attributed 52% of empagliflozin’s cardioprotection to volume contraction, as reflected by an increase in hematocrit. The same analysis attributed 24% to decreased uric acid concentration and only 3% to between-group A1c differences. At EASD 2016, we learned from Dr. Bernard Zinman that a multivariate analysis is underway – while a more complicated method to be sure, the multivariate analysis could offer more compelling information on empagliflozin’s CV mechanisms. Still, we recognize that it may be quite a while before we have a consensus around mechanism, and we underscore that we don’t think it’s crucial to understand mechanism before prescribing a drug for cardioprotection (particularly now that Jardiance has a CV indication on its label). As Dr. Juris Meier articulated at last year’s EASD congress, “at a certain point, it’s okay to be pragmatic and say even if we don’t know exactly how we’re saving lives, let’s save lives.”
5. Dr. Consoli Presents New Weight Loss Data from SUSTAIN 6 Trial of Semaglutide
Dr. Agostino Consoli shared new data from Novo Nordisk’s SUSTAIN 6 trial of GLP-1 agonist semaglutide, demonstrating sustained weight loss over two years. While the 104-week study (n=3,297) was designed primarily to assess CV outcomes with once-weekly semaglutide vs. placebo – and indeed, showed significant 26% risk reduction for the primary MACE endpoint – the agent’s weight loss effects were also noteworthy. At week 104, 0.5 mg and 1.0 mg doses of semaglutide gave a mean weight loss of ~8 lbs and ~11 lbs, respectively, compared to ~1.5 lbs and ~1.1 lbs for the corresponding placebo doses (p<0.0001 for both comparisons). Waist circumference fell a significant 2.7 cm with semaglutide 0.5 mg and 4.2 cm with semaglutide 1.0 mg vs. 0.6 cm and 0.9 cm with each placebo dose (p<0.0001 for both comparisons). Moreover, 36% of participants on lower-dose and 47% of participants on higher-dose semaglutide achieved ≥5% weight loss from baseline by the end of SUSTAIN 6. These values were approximately double the proportion of patients on low- and high-dose placebo reaching ≥5% body weight loss, at 18% and 19%, respectively (p<0.0001 for both comparisons). Looking at an even greater goal of ≥10% weight loss from baseline, 13% of people on 0.5 mg and 20% of people on 1.0 mg semaglutide achieved this vs. 6% and 7% of each placebo arm (p<0.0001 for both comparisons). Another impressive piece of data from this new analysis was that 77% of the 0.5 mg semaglutide group and 81% of the 1.0 semaglutide group experienced no weight gain at two years vs. 52% and 53% of the corresponding placebo groups. Dr. Consoli further mentioned that the significance of weight loss results was maintained across baseline BMI categories. A separate post-hoc mediation analysis found that the impact of nausea and vomiting (common side-effects of GLP-1 agonists) on body weight was minimal – indirect weight loss effects mediated by nausea and vomiting were estimated at a mere ~0.3 lbs and ~0.09 lbs for the 0.5 mg and 1.0 mg doses, respectively. With these results, the SUSTAIN program extends its groundbreaking series of data, showing that semaglutide confers significant and clinically-meaningful reductions in weight and waist circumference over an extended treatment period in people with type 2 diabetes and high CV risk. Importantly, 5% weight loss seems to be the necessary level to delay new-onset type 2 diabetes, and semaglutide could have an impact in prediabetes if its efficacy is sustained in that population. The emphasis on positive body weight effects for semaglutide, in addition to profound A1c-lowering efficacy and cardioprotection, is fitting since Novo Nordisk is also conducting clinical trials of the potent GLP-1 agonist toward an obesity indication (phase 3 to begin in 1H18). Management reviewed remarkable phase 2 data on semaglutide in obesity during the company’s 2Q17 earnings call, and Chief Science Officer Dr. Mads Thomsen alluded to a “new level of efficacy” seen with semaglutide on weight loss. Once-weekly semaglutide has been submitted to the FDA for a type 2 diabetes indication, and a regulatory decision is expected in 4Q17. Needless to say, we’re very excited about this molecule and its enormous and diverse therapeutic potential …
6. Prof. Brian Frier’s Camilo Golgi Lecture: Recurrent Hypoglycemia May be More than a “Minor Inconvenience” w/ Respect to CV Complications
In the very prestigious (and absolutely packed) Camilo Golgi lecture, University of Edinburgh’s Professor Brian Frier gave a whirlwind overview of everything hypoglycemia, arguing that “while there’s no definitive proof that recurrent hypoglycemia causes cardiovascular disease, aggregating evidence suggests that it may be more than a minor inconvenience.” His hypothesis is that as the natural history of diabetes progresses, hyperglycemia underlies a steady increase in the prevalence of vascular complications. Then, after 10 years or so, the effects of hypoglycemia kick in and cause a rapid uptake in complication rate. The data supporting the impact of hypoglycemia on microvascular complications in type 1 diabetes is circumstantial – rapid improvement of glycemic control has been shown to cause acute worsening of retinopathy, and severe hypoglycemia coupled with a surge in blood pressure can leave patients more susceptible to renal disease than those who had severe hypoglycemia without a blood pressure surge. On the other hand, an analysis of DCCT data found no link between severe hypoglycemia frequency and retinopathy/nephropathy risk (of course severe hypoglycemia is not the only concern, so is “regular” hypo – to say nothing of retinopathy/nephropathy risk not being the only concern related to severe hypoglycemia). On the macrovascular side, there is correlational data suggesting that arteries may thicken, lose elasticity, and fill with calcium, and a retrospective cohort study (Zhao et al., 2012) indicated that patients with higher rates of hypoglycemia develop more micro- and macro-vascular complications. A separate study from a group in Spain suggested that suggests that hypoglycemia may actively promote atherosclerosis – a finding Prof. Frier called "disconcerting." Given the pathophysiology underlying hypoglycemia (which looks spookily similar to that underlying hyperglycemia) and the lasting metabolic effects of a single episode of hypoglycemia – longer than Prof. Frier believes has been realized in the past – we wouldn’t be surprised to eventually find that hypoglycemia (biochemical+severe) contributes to CV disease. That said, in DEVOTE, Tresiba was non-inferior to Lantus on CV outcomes, while reducing hypoglycemia by 40% (53% overnight), though Prof. Frier pointed out that that conclusions are limited by the facts that the number of severe hypoglycemic events was low and the study was not powered to examine an effect of hypoglycemia on cardiovascular events. Similarly, hypoglycemia was ruled out as a mediating factor between liraglutide and reduced risk for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) in LEADER. There hasn’t been a study inducing recurrent hypoglycemia over the long term and studying outcomes for obvious ethical reasons, but recent secondary outcomes data makes a convincing case against a link. Even in the absence of solid evidence at present, hypoglycemia is a huge driver of diabetes quality of life at the very least, so interventions should aim to reduce it, regardless of CV effects.
- Professor Frier indicated that consensus has been reached on thresholds for clinically relevant hypoglycemia bins – at 3.9 mmol/L (70 mg/dl; “alert level hypoglycemia”) and at 3.0 mmol/L (54 mg/dl; “significant hypoglycemia”). See the slide below for a visual. When we last heard discussion on hypoglycemia “bins” at the diaTribe Foundation’s Glycemic Outcomes Beyond A1c meeting in July, a breakout session moderated by Profs. Frier and Stephanie Amiel at that meeting expressed agreement on the cut-offs of <70 mg/dl and <54 mg/dl to divide the different classes of hypoglycemia, though had less unanimity on terminology. Prof. Frier’s told us that the International Hypoglycemia Study Group has agreed on how to call these bins since then but awaits consensus with other groups. It’s so important for all stakeholders to get on the same page so we can move on with standardizing the measurement and reporting of hypoglycemia in clinical trial and real world data.
- According to Prof. Frier, the Clark and Gold surveys are sensitive to IAH, but have a number of limitations, so an expert committee (including Profs. Frier and Simon Heller) developed the HypoA-Q for use in the HYPO-COMPaSS trial. The HypoQ-A is a 33-item (seven-minute) questionnaire that has undergone psychometric validation, performing with sensitivity and predictive ability for IAH. “It looks like this is the way moving forward, but we need a longitudinal prospective validation study now.” It would be excellent to see consensus develop around an IAH detection instrument, because as Prof. Frier pointed out, there isn’t even an internationally-recognized definition at this point – IAH means different things to different people and is ignored in many studies of new insulins.
- The detrimental effects of hypoglycemia on the individual are notable, and notably, Prof. Frier reminded attendees that caregivers of patients with impaired hypoglycemia awareness also require support. This was extraordinary to hear so much attention paid to this area in such a prestigious lecture – as well, we would note that although he didn’t name patient-reported outcomes, the impact on the family is critical for most individuals. Caregiver support is important across the spectrum of diabetes, but extremely crucial when the patient has impaired awareness. Caregivers often feel that their lives are restricted because they always have to treat lows, that their loved one has a sort of “Jekyll and Hyde” syndrome, that they have difficulty treating some events, that they too have fear of hypoglycemia, and that there is a major unmet need for information and support.
7. New TECOS Analysis from Dr. Engel: DPP-4 Inhibitor Januvia Delays Insulin Initiation in People on Metformin or Metformin/SUs at Baseline
EASD orals kicked-off with a new post-hoc analysis of Merck’s TECOS trial for DPP-4 inhibitor Januvia (sitagliptin), presented by Dr. Sam Engel. When added onto a background of metformin monotherapy (n=4,435) or metformin/sulfonylurea dual therapy (n=5,152), sitagliptin treatment significantly delayed insulin initiation for type 2 diabetes patients. Among CVOT participants only on metformin at baseline, the incidence of insulin initiation (defined as continuous use over at least three months) was 5.5% in the placebo arm vs. 3.8% in the DPP-4 arm over a median three years follow-up, which corresponds to a hazard ratio of 0.67 in favor of sitagliptin (95% CI: 0.51-0.89). Among patients on both metformin and a sulfonylurea at baseline, the incidence of insulin initiation was 20.4% in the placebo arm vs. 14% in the DPP-4 arm (HR=0.64, 95% CI: 0.56-0.73). Among those on baseline sulfonylurea monotherapy, a higher proportion started insulin treatment anew in the placebo arm (11.3%) vs. the DPP-4 arm (10.7%), corresponding to a hazard ratio of 0.96 in favor of sitagliptin (95% CI: 0.68-1.34), though this did not reach statistical significance since the upper bound of the 95% confidence interval is >1. Dr. Engel reviewed earlier findings showing Januvia’s association with a decreased likelihood of new insulin therapy start across the entire TECOS trial (542 patients on placebo vs. 744 patients on sitagliptin, p<0.0001). The more granular data he discussed today supports that Januvia can effectively delay the need for insulin in people with type 2 diabetes, which is not at all trivial – DPP-4 inhibitors are weight neutral where insulin promotes weight gain, they come with lower hypoglycemia risk compared to insulin, and they offer enhanced quality of life vs. insulin due to the weight neutrality, lower hypo risk, and reduced injection burden.
8. Janssen’s Gill Hamilton Presents Cohort Study Suggesting Patients Stay on Canagliflozin Longer than Other Drugs
Kicking-off a series of oral presentations on the clinical utility of SGLT-2 inhibitors, Janssen Dr. Gill Hamilton shared findings from a retrospective cohort study conducted in the UK on time to next therapy for patients on Invokana (canagliflozin) vs. other diabetes drugs (including GLP-1 agonists, DPP-4 inhibitors, and other SGLT-2 inhibitors). Using the UK’s Clinical Practice Research Datalink, a sample of 46,349 patients who initiated a drug from one of these three classes between 2012-2015 was collected and analyzed for time to next therapy, including both add-on to existing regimen and switching to a new agent. Time to next therapy was significantly longer with canagliflozin vs. all DPP-4 inhibitors: Compared to sitagliptin (Merck’s Januvia), the hazard ratio was 1.43 (p<0.001), while these hazard ratios were even higher in comparison to saxagliptin (AZ’s Onglyza) and linagliptin (Lilly/BI’s Tradjenta), at 1.76 and 1.57, respectively (p<0.001 for both comparisons). J&J’s canagliflozin also showed significantly longer time to next therapy vs. AZ’s GLP-1 agonists Byetta (exenatide twice-daily) and Bydureon (exenatide once-weekly), with hazard ratios of 1.84 and 1.44, respectively (p<0.001 for both comparisons). The hazard ratio for time to next therapy was 1.43 in favor of canagliflozin vs. liraglutide (Novo Nordisk’s GLP-1 agonist Victoza) and was 2.46 in favor of canagliflozin vs. lixisenatide (Sanofi’s GLP-1 agonist Adlyxin, both p<0.001). Invokana did not show a statistically significant delay in next therapy when compared to in-class competitors, AZ’s Farxiga (dapagliflozin) and Lilly/BI’s Jardiance (empagliflozin). Dr. Hamilton shared that time to insulin therapy initiation was significantly longer with canagliflozin vs. linagliptin, short-acting exenatide, liraglutide, lixisenatide, and empagliflozin, but not for sitagliptin, saxagliptin, long-acting exenatide, or dapagliflozin. The real-world nature of this study limits definitive conclusions to some degree, but we found the suggestion notable that patients may benefit from canagliflozin (among other SGLT-2 inhibitors) in the sense of lower need for intensification with other agents, which adds treatment complexity, cost/co-pays, and may signify worsening glycemic control.
9. Increase in Ketone Levels Seen with SGLT-2 Inhibitors May Improve Survival After MI
Is there a silver lining to the increase in ketones observed with SGLT-2 inhibitors? A research group from Sapporo today suggested yes, based on evidence from a rodent study of Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin). In rat models of diabesity, higher ketone levels stimulated from empagliflozin treatment may provide a more efficient fuel source for the ailing heart after a heart attack, improving post-MI survival. In addition to serving as a better fuel source, the ketones appear to stimulate production of protective antioxidant proteins. The end effect was an improvement in 48-hour survival from 40% without empagliflozin to 70% with it. These findings could explain some of the improvement in CV outcomes – specifically CV death – seen in EMPA-REG OUTCOME. As with all animal studies, much more work needs to be done to prove this hypothesis, but it’s good to see progress being made towards exposing the mechanisms underlying empagliflozin’s cardioprotective effects. Moreover, we’re intrigued by ketone-based hypotheses since ketones have been a thorn in SGLT-2 inhibitors’ side from some perspectives since the specter of euglycemic ketoacidosis arose. From our view, this is such an incredibly important class that the field should focus more on reducing DKA risk and then treating it as well as possible – there’s a long way to go since so many patients are unaware of the risk, do not have ketone meters, and are not aware of healthy levels.
10. Prof. Davies, Dr. Drucker, & Prof. Matthews Lament Patient Progress, Discuss Behavior Change, Technology, CANVAS
At The diaTribe Foundation’s fourth annual Solvable Problems in Diabetes gathering, attendees were treated to a valuable and wide-ranging panel discussion from Dr. Drucker, Prof. Melanie Davies, and Prof. David Matthews that surprised many by focusing largely on how to incite behavioral change to better augment pharmaceuticals. We also heard some commentary from Prof. Matthews on the amputation signal detected in the CANVAS trial. Read on for some of our notable quotes from the session – we will be expanding this preliminary report soon.
- On Behavioral Intervention and Supporting People with Diabetes
- “We really need to get a grip on how to apply the stuff that the marketers know to drive behavior. There’s no reason why we couldn’t drive better behavior in public health, we’ve just lagged behind. And we need to catch up quickly. To me this is the greatest opportunity: cradle to grave buy-in of understanding your consumer, which is a mixture of the healthcare provider and patient. Design incentives to make the drug or device really attractive to prescribe, use and not stop. We need to think differently about how to achieve goals. That doesn’t mean stop doing research, but we must completely change how we think about goals and sustained consumer/patient satisfaction and adherence every step along the way.” – Dr. Daniel Drucker
- “If I were starting today, I might not go into basic science, but I’d go into behavioral science, because that’s where I think we can make a big difference.” – Dr. Drucker
- “When I was a medical student, they told us you can change knowledge, not behavior. I believed this for many years, until the Irish government said that it was illegal to smoke in Irish pubs. I thought, ‘my goodness, no one will ever go and drink Guinness in an Irish pub again.’ And that lasted about 24 hours. You can change people’s behavior, but it’s difficult. Technology, that’s the way we can change this part of society.” – Prof. David Matthews
- “An intervention is needed in type 1 focused on self-compassion, on feeling better and less guilty. We have to apply similar robustness in behavior change intervention as we do with drugs and devices.” – Prof. Melanie Davies
- “We say to patients, ‘you need to be engaged in your health.’ But we also have to be able to say, ‘if you are engaged, we can deliver things that will allow you to transform your lives.’” – Prof. Matthews
- “You can’t blame people with type 2 diabetes. We need to understand the messaging, behavior, and motivation to treat disease. People don’t associate diabetes as the serious illness that drove them to heart attack or stroke. We have failed our patients. We haven’t communicated effectively, and until we learn how to do so, it’s going to be a missing part. We can make stem cell-derived beta cells and new co-agonists, but if our patients don’t get the message – that this disease is going to kill and disable them – then they’re going to continue not to take the latest and greatest. We need to really understand.” – Prof. Matthews
- “Behavior change around incentives in interesting, but there’s a whole issue around depression, diabetes distress, social isolation, social deprivation. There are a lot of other aspects that at some point may be solved by incentivizing and making treatment simpler, but diabetes is a long-term condition requiring long-term support.” – Prof. Davies
- “We just did a structured education program where we looked at a number of patients and most didn’t think type 2 diabetes was a lifelong disease. Most didn’t associate that diabetes would shorten their life.” – Prof. Davies
- On Where the Field is Going/Should Go
- “As a biologist, the engineers have kicked our butts over the last 15 years in type 1 diabetes. That’s where all the advances have come from in type 1 diabetes. Glucose sensitive beta cells for safe and sustained prime time clinical use are far away. As a biologist, my money over the next 5 years is still on the engineers.” – Dr. Drucker
- “I think we should definitely have self-management and education, but I think giving good information and support right from diagnosis is important. We also need to make drugs and therapies more accessible to patients more quickly and increase the multi-professional team. We need really good dieticians, specialist nurses, and psychologists, not just physicians.” – Prof. Davies
- “If you’re a payer, why not look at available data critically and decline to pay a premium in the absence of sustained long term efficacy? Here you come with a fancy drug, wanting a 10%-20% premium, and people are not even using current drugs properly. Until we start to help them use what they have more effectively, don’t come to me with yet another new drug. If I were running a reimbursement scheme, that’s how I might react.” – Dr. Drucker
- “We as patients want to feel normal; diabetes is a lonely disease. Being able to look at your blood glucose on an iPhone or swipe your arm and not feel stupid [or worried that blood might accidentally shoot into the air, as everyone with diabetes has experienced] has made a big difference for those lucky enough to access this. I’m optimistic on what we can see data deliver if we invest more in technology [and interpretation].” – Ms. Kelly Close
- “I’m pretty disappointed in the fact that the persistence, adherence, A1c, that we’re delivering with all these new drugs is kind of abysmal in type 2 diabetes. It doesn’t make sense to put a huge amount of effort in making new drugs even better without new thinking around and tools to show how we get patients to use the last group of drugs we developed more effectively.” – Dr. Drucker
- “I think there’s a huge gap between the specialists reading the latest outcomes study and immediately thinking the entire world will change. Primary care doctors who do the lion’s share of diabetes management are unbelievably focused on safety and not being burdened by new drugs. The primary care doctors are much more concerned about not getting caught out yet again with a promise of fantastic new benefits that are elusive or are yanked away from them due to safety concerns. Primary care doctors stick with what they know that’s safe and hasn’t hurt them, because we’ve betrayed some of their trust before.” – Dr. Drucker
- On Artificial Intelligence
- “Once we have AI algorithms, endocrinologists managing glucose fluctuations might be out of business. A human won’t be in the business of looking at numbers.” – Dr. Daniel Drucker
- “It’s SO much better to have a machine running the numbers for sure. My doctor and I have been trying to figure out for 20 years what my basal rates should be … optimal basal rates change every day. The idea that we thought we could figure this out when a computer can do it so much better, that new knowledge blows me away. There’s plenty to still talk about with her. Having artificial intelligence “in charge” of the numbers could make doctors feel and be feel more successful as they’d have more space to address other major problems [wellness measures like Adam Brown talks about in “Bright Spots and Landmines” – food, mindset, exercise, sleep – short- and long-term complications, emotional well-being, etc.]” – Ms. Kelly Close
- On CANVAS
- “That data about amputation in CANVAS is sufficiently robust. There are uncertainties, but the science is good and that’s what we need to keep saying. Now we have another question, is this a class effect or not?” – Prof. David Matthews
- “Every time a patient says they have an amputation and are on SGLT2-inhibitors, you make that report. If someone else comes along and their toe is black for any number of reasons, you send them on their way without even thinking of reporting. That’s reporting bias, which is horrendous in real world data.” – Prof. David Matthews
-- by Ann Carracher, Abigail Dove, Brian Levine, Payal Marathe, Manu Venkat, Maeve Serino, Adam Brown, and Kelly Close