June 9-13, 2017; San Diego, CA; Full Report – SGLT-2 Inhibitors – Draft

Executive Highlights

This document contains our coverage of SGLT-2 inhibitors at ADA 2017. Immediately below, we enclose our themes on the category, followed by detailed discussion and commentary. Talk titles highlighted in yellow were among our favorites from ADA 2017; those highlighted in blue are new full report additions from our daily coverage.

For comprehensiveness, we have included some talks in this report that also overlap with our ADA 2017 GLP-1 Agonist, DPP-4 Inhibitor, and Type 1 Diabetes Cures, Adjunct Therapies, and Pathophysiology reports.

SGLT-2 inhibitor-related sessions stole the show at ADA 2017. Of course, the very, very highly-anticipated CANVAS CVOT results for J&J’s Invokana (canagliflozin) were presented (see our initial breaking news coverage and full report, also below). We were also treated to additional analyses from the huge real-world CVD-REAL dataset. Looking to products on the horizon, the news flow for Merck/Pfizer’s phase 3 candidate ertugliflozin continued into ADA 2017. We’d be remiss not to mention the potential of this class in type 1 diabetes as well, underscored by the four abstracts presented by Lexicon for SGLT-1/2 dual inhibitor sotagliflozin in this population. The commentary from diabetes leaders underscored the immense excitement for the SGLT-2 inhibitor class, with Dr. Julio Rosenstock in particular forecasting wide-ranging current and future indications for these agents.

We were very moved by so much activity at ADA on the SGLT-2 class. This document features 21 talks and nine posters with brand new data. We write often about how we long for patient care to be easier, and this oral treatment that boasts excellent efficacy alongside what we increasingly believe to be a highly-manageable side-effect profile (including DKA risk associated with most agents and amputation risk so far associated with Invokana) bodes incredibly well for the field, given the substantial CV and renal benefits. We need patients to be able to take medicine that helps manage glucose and that helps reduce major risks, and we also need this medicine to be prescribed and dosed easily. The SGLT-2 inhibitor class has grown from $23 million in 2013, to $801 million in 2014, to nearly $2 billion in 2015, to $2.9 billion in 2016, and we think it has an incredibly long runway before it becomes generic starting in the later 2020s and then becomes available for all patients to take. We hope researchers are just as proud of creating a drug that has so much power to impact health starting in a decade as they are of making this therapy available to people now. These agents could truly transform public health now and later, and we very much hope for greater education and uptake in the class, given what we know today. 

Themes

CANVAS CVOT for Invokana: Affirmation of SGLT-2 Inhibitor CV and Renal Benefit, but Complicated Safety Story

• First, the good news – the CANVAS program demonstrated the cardiovascular superiority of Invokana (canagliflozin), as measured by the primary endpoint of three-point MACE (non-fatal MI, non-fatal stroke, and CV death). In the program, canagliflozin therapy reduced risk of MACE events by 14% (95% CI:0.75-0.97, p=0.0158 for superiority). Further, canagliflozin therapy produced an extremely impressive benefit for a secondary endpoint of hospitalization for heart failure, reducing risk by 33% (95% CI:0.52-0.87). As the second SGLT-2 inhibitor to report CV results – following the highly unexpected and impressive EMPA-REG OUTCOME findings demonstrating a CV benefit for Lilly/BI’s Jardiance (empagliflozin) – it’s perhaps only natural that many in the field are already drawing direct comparisons between the two trials, even though we stress they are not directly comparable for a number of reasons outlined below. Indeed, however, the CANVAS investigators themselves directly compared the hazard ratios and confidence intervals of a number of key endpoints across CANVAS and EMPA-REG OUTCOME – see the Dr. David Matthews “Implications for Clinical Practice” section below for more on this.
  
  • Several key differences in both the participant population and CV findings exist between the CANVAS and EMPA-REG OUTCOME trials. In terms of participant population, EMPA-REG OUTCOME exclusively enrolled those with a prior history of CV disease – thus, the generalizability of the results to a lower-risk patient population has been a major question in the 21 months since EMPA-REG OUTCOME was presented at EASD 2015. On the other hand, CANVAS sheds some light on this question – about one-third of participants enrolled in the trial had risk factors for cardiovascular disease but no established history, thus creating a primary prevention cohort. There was no heterogeneity of benefit (p-value for interaction was non-significant) between the primary prevention and secondary prevention cohort in the trial (see Dr. Bruce Neal’s presentation of the Effects on Cardiovascular Outcomes below for more detail on this). Thus, there’s some early suggestion of CV benefit for SGLT-2 inhibitors even in a primary prevention cohort – we expect the DECLARE CVOT for AZ’s Farxiga, with its 17,000+ participant population, will offer additional information on this front when it reports in 2019.
  • In terms of CV endpoints, CANVAS did not demonstrate a CV or all-cause mortality benefit for canagliflozin. While the point estimate for the hazard ratio of both findings was in the “right direction,” the confidence intervals crossed the line of unity and just missed statistical significance. For all-cause mortality, the hazard ratio was 0.87 (95% CI:0.74-1.01, p=0.24) – this was particularly disappointing since this was the second endpoint in the pre-specified hierarchical testing structure and thus the other endpoint results in the study can only be considered exploratory. For CV death, the hazard ratio was 0.87 (95% CI: 0.72-1.06). This contrasts with the strong 38% risk reduction for CV death (p<0.0001) and 32% risk reduction for all-cause death (p<0.001) in the EMPA-REG OUTCOME trial. It’s unclear what kind of label indication the CANVAS findings will be able to support, given that Jardiance is only indicated for CV death rather than for its primary MACE finding (in fact, some on the FDA Advisory Committee felt that the p-value for the primary endpoint in EMPA-REG OUTCOME may not be convincing enough – though the p-value for superiority in CANVAS is more compelling). On the plus side, canagliflozin did not demonstrate a signal for increased stroke as empagliflozin did – in fact, the point estimate for stroke and all other components of expanded MACE (including hospitalization for unstable angina) were on the right side of unity, a reassuring finding indeed.
• All in all, the CV findings of the CANVAS program offer further reassurance of the “validity” of the EMPA-REG OUTCOME benefit and suggest that the CV benefit, at least, is a class effect for SGLT-2 inhibitors. Given the highly unexpected and unprecedented nature of EMPA-REG OUTCOME, the question of class effect has been one of THE most frequently asked questions regarding SGLT-2 inhibitors and CV benefit over the last two years. The other most popular question is “what is the mechanism of benefit?” A non-inferiority CV finding in CANVAS would have potentially thrown into question the validity of the EMPA-REG OUTCOME benefit and may have led some to suggest the benefit demonstrated in the trial was a statistical fluke. Indeed, many key thought leaders – who often make up diabetes guidelines committees – have expressed the desire for more data from other agents in the class before wholeheartedly recommending SGLT-2 inhibitors (or even just empagliflozin) as a preferred therapy for those with a history of cardiovascular disease. With two positive CVOTs for the SGLT-2 inhibitor class, we imagine we might see more enthusiastic recommendations for the class for CV benefit in future guidelines. Thus far, the ADA 2017 Standards of Care recommend only the consideration of empagliflozin (and GLP-1 liraglutide) in those with established CV disease and the AACE guidelines have not yet changed recommendations based on CVOT data. On balance, the overall CANVAS findings appear at this stage to be more positive for Jardiance than for Invokana. We expect this further confirmation of CV benefit will boost the SGLT-2 inhibitor class as a whole and we expect Jardiance in particular will benefit, given its compelling CV benefit (and indication), as well as the lack of worrisome and unexpected safety signals in the trial (more on this below). Indeed, Invokana has already been losing market share largely to Jardiance (while Farxiga share has been relatively sustained) for several quarters now, and we expect this trend may continue in future quarters – this is not at all unexpected given that all “first to market” compounds do lose share. We do believe the unexplained amputation outcome, in particular, will be a focus of manufacturers, and we hope that Janssen is able to share more data on this front. Overall, while it’s too early to say definitively how patients and providers will react to these results, we expect the messaging from all three SGLT-2 inhibitor manufacturers to be positive on CV and mixed on amputation and fractures (we believe there is also more to be known about these risks for other manufactures).
• The more negative headline from CANVAS/CANVAS-R is the near doubling of lower-extremity amputation risk with canagliflozin vs. placebo (HR=1.97, 95% CI: 1.41-2.75, P<0.001). Although it is a low absolute risk overall (many fewer amputations take place than heart disease annually for people with diabetes), the risk appeared to occur across all patients, not just those who had previous amputations. That said, all patients in the study had a high degree of elevated risk, as two-thirds of participants had a previous history of a CV events and one-third of participants had at least two cardiovascular risk factors. There were 187 lower limb amputations across these two outcomes trials, occurring at a rate of 6.3/1,000 patient-years in the canagliflozin arm vs. 3.4/1,000 patient-years in the placebo arm. Approximately 71% of these amputations occurred at the level of the toes or forefoot, though some were above the ankle and a smaller number were above the knee. This leads to a murky risk/benefit profile for Invokana on the face of it though there are a number of confounders. On the negative side, Dr. David Matthews shared, for every 1,000 patients treated with canagliflozin over five years, we can expect 23 fewer MACE events, 17 fewer hospitalizations for heart failure, 16 fewer renal composite endpoints (renal death, renal replacement therapy, or 40% reduction in eGFR), and 15 additional lower limb amputations – 10 at the level of toe/forefoot, five above the ankle. What makes this even more challenging is that canagliflozin doubled amputation risk across all risk factors, including prior amputation and baseline peripheral vascular disease. Without any insight into what is mediating canagliflozin’s adverse impact on the lower limbs, the risk seems more likely to be associated with the molecule itself although this hasn’t been established and there are a number of points related to things like adjudication that aren’t discussed broadly but may have had a real impact. We look forward to seeing “real world data” like the data around pancreatitis and GLP-1 a few years ago. In the meantime, HCPs won’t at this stage be able to tailor prescriptions based on patient disposition; that is to say, if the effect on lower limb amputations was driven by a particular subgroup, such as participants with baseline peripheral vascular disease, this safety issue might be circumvented with a single black box warning not to prescribe Invokana to patients with peripheral vascular disease.
  
  • As a reminder, this trial included a very broad set of patients. In total, over 10,000 patients were enrolled and, notably, the CANVAS program enrolled both those with established cardiovascular disease at baseline (a secondary prevention cohort) and those with two or more CV risk factors but no history of cardiovascular disease (a primary prevention cohort). This contrasts with the EMPA-REG OUTCOME trial, which enrolled only patients with a history of cardiovascular disease at baseline.
  • We have very little information or insight at this stage as to how this will all play out in real-world prescribing habits and formulary negotiations. Dr. Dan Drucker foreshadowed a slow attrition away from Invokana, with new SGLT-2 starts favoring Lilly/BI’s Jardiance (with demonstrated cardioprotection and no associated amputation risk) or AZ’s Farxiga. On the other hand, Dr. Anne Peters suggested that some providers may keep patients on canagliflozin due to formulary requirements, or because of greater glucose-lowering and weight loss vs. empagliflozin (in her anecdotal clinical experience). While some have suggested a worst-case scenario of HCPs steering clear of SGLT-2 inhibitor products in general, once they learn of lower limb amputation risk, we doubt that will happen. While the EMPA-REG study group did not observe a similar increase in amputations in the EMPA-REG OUTCOME trial, that was a shorter trial with a more homogenous population.
  • While the heightened risk in CANVAS/CANVAS-R appeared fairly early on, at year one, the events were adjudicated very differently – with CANVAS/CANVAS-R prospectively and EMPA-REG retrospectively.
    • This reinforces yet again the need for more standardization on the global regulatory front. We expect to see manufacturers of SGLT-2 agents come together and invest in real-world data collection on this and other safety issues – we’d hate for lower-extremity amputations to define the narrative for this class, given the profound glycemic, CV, renal, and weight benefits and given the lack of standardized data from all trials.
  • This safety data from the CANVAS program also reminds us that strong education on foot care for people with diabetes is lacking. In fact, recent conversations have reinforced that this signal could shine a light on the importance of greater education on foot care for people with diabetes – we hope J&J and others will be a leader in expanding understanding/management of this complication. Currently, we don’t believe patients have much education at all about how to minimize this risk and in fact, perhaps key education could provide significantly more benefit. In general, messaging around this potential safety concern will be crucial not only for J&J, but for Lilly/BI around the Jardiance franchise and for AZ around the Farxiga franchise as well.
• The positive renal data was a key bright spot in the CANVAS results, and contributes to mounting evidence for a beneficial impact of SGLT-2 inhibitors in general on renal complications of diabetes. Canagliflozin showed impressive signs of renal protection, including a 27% risk reduction for progression to albuminuria and a 40% risk reduction for a renal composite outcome (encompassing renal death, renal replacement therapy, or 40% reduction in eGFR). This comes on the heels of positive renal outcomes in the EMPA-REG OUTCOME trial, where empagliflozin showed a 39% risk reduction (HR: 0.61; 95% CI: 0.53-0.70; p<0.001) for the trial’s main renal endpoint of incident or worsening nephropathy (progression to macroalbuminuria or doubling of serum creatinine accompanied by eGFR ≤45 ml/min/1.73 m² or renal replacement therapy or death due to renal disease). These results are truly profound given the currently enormous unmet need for new therapies to treat chronic kidney disease, and to this end all three of the main SGLT-2 inhibitors on the market are now being explicitly studied for renal outcomes – canagliflozin in the CREDENCE trial, dapagliflozin in the Dapa-CKD trial, and empagliflozin in a just-announced chronic kidney disease trial from Lilly/BI.

SGLT-2 Inhibitor Safety and the Risk/Benefit Profile

• The amputation data in CANVAS certainly complicates how patients, providers, and payers will conceive of the risk/benefit profile for SGLT-2 inhibitors. With any new therapy or drug class, it’s easy to get swept up in the prospect of superior glucose-lowering and added benefits, from weight loss, to blood pressure reductions, to cardio- and renal protection. Based on the outcomes data we have so far on SGLT-2 inhibitors (CANVAS for canagliflozin and EMPA-REG OUTCOME for empagliflozin), all of these advantages hold true, and warrant tremendous excitement. On the other hand, because these agents are relatively new, real-world evidence is still accruing and additional safety signals may come to light. Questions ensue regarding canagliflozin and lower-extremity amputation risk, and above all else, we wonder – how will various players in diabetes care interpret the risk/benefit trade-offs for Invokana and other SGLT-2 inhibitors, given that there are not yet head-to-head CVOTs (and we don’t anticipate these will emerge)? Opinions from diabetes thought leaders have been mixed. Some, including Dr. George King (Joslin Diabetes Center, Boston, MA), suggest that the CV and renal results should overshadow amputation-related concerns, especially since this risk could be managed by improving patient education on foot care (it’s also true that amputations are far less common that heart attacks and strokes). Others, including Dr. Daniel Drucker (Mount Sinai Hospital, Toronto, Canada) forecast a gradual attrition of Invokana sales, as new SGLT-2 starts will favor Jardiance (or Farxiga) going forward. This has already been happening to some extent, even before the release of the CANVAS results, as Invokana’s share of the SGLT-2 inhibitor market has been decreasing in recent quarters. In another scenario, while it’s possible that busy healthcare providers will stay clear of all SGLT-2 inhibitor products because of red flags raised, we doubt this will happen due to safety (the access is another issue), even given other controversies surrounding SGLT-2s (bone fracture, DKA, etc). Overall, the amputation risk must definitely be conveyed to clinicians and we hope the education is good for them and that consensus builds on how to approach it. Overall, CANVAS CV results corroborate EMPA-REG OUTCOME CV results and point to a very real cardioprotective benefit to these agents. As one of the biggest headlines of ADA 2017 – if not the biggest – CANVAS forces all players in the diabetes field to appreciate safety data from outcomes trials, and begs for a safety-focused analysis of real-world SGLT-2 inhibitor datasets. We’re expecting a lot of back-and-forth on the risk/benefit profile of Invokana and other SGLT-2 inhibitors in the year to come.

Outcomes Beyond A1c: Cardiovascular, Renal, Hypoglycemia, Patient-Reported

• Renal endpoints were of major interest both in CVOTs and in shorter trials. One of the other big headliners of the CANVAS data was the impressive renal benefit that corroborated the benefit observed for Jardiance in EMPA-REG OUTCOME – in CANVAS, Invokana therapy was associated with a 40% risk reduction for a composite renal endpoint (renal death, renal replacement therapy, or 40% reduction in eGFR). While the trials and endpoints are not really comparable, the EMPA-REG OUTCOME trial demonstrated a 39% risk reduction for a composite endpoint of progression to macroalbuminuria or doubling of serum creatinine accompanied by eGFR ≤45 ml/min/1.73 m2 or renal replacement therapy or death due to renal disease. Outside of CVOTs, we saw intriguing data from the AWARD-7 trial, which compared Lilly’s GLP-1 agonist Trulicity (dulaglutide) head-to-head with insulin glargine, both on top of insulin lispro therapy. While the primary glycemic endpoint results were comparable, Trulicity was very intriguingly associated with a potential preservation of eGFR throughout the trial. We’re certainly looking forward to the REWIND outcomes trial for Trulicity to further investigate the impact of this therapy on renal outcomes.

Class Effects?

• More than ever, the diabetes field must grapple with the question of whether clinical trial findings – both positive or negative – can be considered class effects. On the one hand, we received confirmation that the cardiovascular and renal benefits of SGLT-2 inhibitors are very likely applicable to the entire class: the CANVAS trial demonstrated a remarkably similar reduction in risk for three-point MACE (non-fatal MI, non-fatal stroke, and CV death) for Invokana therapy as the EMPA-REG OUTCOME trial demonstrated for Jardiance. Like EMPA-REG OUTCOME, CANVAS also demonstrated a potential renal-protective benefit for the SGLT-2 inhibitor as well. Further corroborating the evidence that CV benefit is very likely a class effect, ADA 2017 featured additional analyses of the CVD-REAL massive, real-world, observational study that suggested a consistent cardioprotective effect across the class, in a data set of largely people taking Invokana or AZ’s Farxiga (dapagliflozin).
• On the other hand, there does appear to be some heterogeneity in individual components of the primary endpoint, as well as heterogeneity in safety signals. Most notably, the full CANVAS integrated program dataset revealed a roughly two-times increased risk for lower-limb amputations with Invokana compared to placebo – this safety signal came as a surprise, especially as it has not been identified in any previous trials of any SGLT-2 inhibitor, including the largescale EMPA-REG OUTCOME trial. The safety signal is particularly worrisome because there is no clear mechanism or consensus of understanding of what might be driving the increased risk. It’s not clear if the heterogeneity observed in SGLT-2 inhibitor trials thus far regarding this risk may be due to differences in trial design (be it patient population or adjudication methods or something else) or due to differences in the molecule. In any case, there are plenty of remaining mysteries and questions to keep us very, very invested in seeing the results from the DECLARE (April 2019) and VERTIS CV (October 2019) trials.
• To date, we’ve seen topline or full CVOT results for two SGLT-2 inhibitors, three DPP-4 inhibitors, and five GLP-1 agonists. Within every class, there appears to be some heterogeneity in either primary endpoint efficacy, safety concerns, or both. As discussed above, the SGLT-2 inhibitors demonstrated remarkable consistency in terms of CV and renal efficacy, but also hinted at serious differences in safety. Among the DPP-4 inhibitors, CVOTs demonstrated some heterogeneity in the secondary endpoint of hospitalization for heart failure, with both AZ’s Onglyza (saxagliptin) and Takeda’s Nesina (alogliptin) suggesting an increased risk while Merck’s Januvia (sitagliptin) was resoundingly neutral. That said, all three DPP-4 inhibitors with results thus far have reported CV neutrality for the primary endpoint of three-point MACE (non-fatal MI, non-fatal stroke, and CV death). Finally, we’ve seen quite a bit of heterogeneity within the GLP-1 agonist class over the question of cardioprotection – both the LEADER and SUSTAIN 6 trials for Novo Nordisk’s Victoza (liraglutide) and semaglutide demonstrated substantial CV benefits, but CVOTs for Sanofi’s Adlyxin (lixisenatide), AZ’s Bydureon (exenatide once-weekly), and Intarcia’s ITCA 650 (implantable exenatide mini-pump) have only demonstrated CV safety but not superiority (that said, Intarcia’s FREEDOM-CVO was a very small, pre-approval safety study that was not powered to demonstrate superiority). All in all, it appears that class effects for diabetes drugs cannot be taken for granted and it doesn’t seem to us that different agents within the same class are largely interchangeable. We hope that this key point can be effectively conveyed to providers and especially payers – in an era when formulary access, reimbursement, and rebates too often determine which drugs a particular patient takes, we hope that payers and PBMs recognize that the benefit-risk ratio for different agents can be quite different and do not force all their member patients to potentially take a less beneficial or even potentially harmful agent en masse. It’s clear that certain agents may be more helpful for some patients and a key cornerstone of therapy individualization is access to multiple options.

Combination Therapy Data Galore

• The co-administration of GLP-1 agonists and SGLT-2 inhibitors is a hot topic in the diabetes field, and new data at ADA 2017 only added fuel to the fire. The full 52-week results from the DURATION-8 trial extension (initial 28-week data was presented at EASD 2016) was a highlight of this meeting. Presented in a late-breaking poster, the findings showed how co-administration of Bydureon/SGLT-2 inhibitor Farxiga (dapagliflozin) results in superior A1c-lowering, weight loss, and blood pressure-lowering vs. either drug alone. After 52 weeks, dual therapy resulted in a mean 1.8% A1c reduction vs. 1.4% with exenatide monotherapy and 1.2% with dapagliflozin monotherapy (p<0.01 for both comparisons). Weight loss was an average ~7.2 lbs on dual therapy vs. ~3.3 lbs on exenatide monotherapy and ~5 lbs on dapagliflozin monotherapy (p<0.001 for both comparisons). As Dr. John Buse pointed out during a separate session, one dedicated entirely to combination treatment approaches, the weight loss benefits in DURATION-8 seem to be more additive than the glycemic benefits, since A1c-lowering is a more baseline-dependent measure. Dr. Buse suggested that the true value of GLP-1 agonist/SGLT-2 inhibitor regimens may manifest in body weight effects more so than in glycemic effects.
• Even ahead of the regulatory approval for Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin, the scientific focus for the franchise seems to be the fixed-dose combination with DPP-4 inhibitor sitagliptin (Merck’s Januvia). ADA presentations from this clinical program included trial extension data from VERTIS FACTORIAL, comparing ertugliflozin/sitagliptin vs. each monotherapy, and from VERTIS SITA2, investigating ertugliflozin as an add-on to sitagliptin/metformin. Both studies highlighted superior glucose-lowering and weight loss efficacy from the combination vs. either drug alone, and both oral presentations emphasized the real-world value of a single, convenient oral tablet that combines two agents with complementary mechanisms of action.
• Notably, in all these data-heavy presentations on combination therapy, there was a distinct emphasis on outcomes beyond A1c. Most of these diabetes drugs were, or will be approved based on superior A1c-lowering vs. placebo. Once these products are on the market, however, we’d love to see them used optimally, which more often than not involves combination with another, complementary agent as well as advice on diet, exercise, mental health, etc. Patients with diabetes care about so much more than A1c: they want to experience weight loss, they want smaller postprandial glucose excursions, they want lower cholesterol and blood pressure, they want to live without fear of hypoglycemia. Combination therapy is one way to achieve better outcomes across the board, as this collection of data from ADA 2017 seems to show (results from the VERTIS program, DUAL VII, DURATION-7 and -8, etc.). Insulin will be necessary for type 1 patients, and for type 2 patients in later stages of the disease, but co-administration of a GLP-1 agonist could lower daily insulin dose, could bring down hypoglycemia risk, and could at least neutralize weight effects without sacrificing glycemic control. Formulations of two drugs in one – either fixed-ratio injectable combos or fixed-dose oral combos – come with the additional benefit of patient convenience (lower injection/pill burden) and a single co-pay. We were pleased to see so much new data on combination therapy packed into the ADA 2017 agenda, and were happier still to note how scientists, researchers, and thought leaders are promoting combination approaches in terms of outcomes beyond A1c. It has been distressing, however, to see commercial uptake so low – this is the fault of the payers as we understand it (not to be too reductive).

Progress on Adjunct Therapies for Type 1 Diabetes

• ADA 2017 featured substantial forward momentum on adjunct therapies for type 1 diabetes. Particularly notable were the suite of results for Lexicon/Sanofi’s SGLT-1/2 dual inhibitor sotagliflozin in type 1 diabetes. Across two oral presentations and two posters, Lexicon shared full data from the phase 3 inTandem1 and inTandem2 trials, as well as the phase 2 inTandem4 dose-ranging study and a JDRF-partnered phase 2 study in young adults with poorly-managed type 1 diabetes. inTandem1, a double-blinded trial that randomized 793 patients to either placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg, impressively met its primary endpoint on top of optimized insulin therapy by producing a mean placebo-adjusted A1c reduction of 0.35% in the 200 mg arm (baseline A1c post-optimization=7.6%; p<0.001) and 0.41% in the 400 mg arm (baseline A1c post-optimization=7.6%; p<0.001) at 24 weeks. More than twice as many patients achieved net benefit (defined as the percentage of patients with A1c <7% at 24 weeks and no episodes of severe hypoglycemia or DKA during the study period) on sotagliflozin 400 mg compared to placebo: 44% and 34% of participants in the 400 mg and 200 mg arms respectively achieved net benefit at week 24, compared to just 22% of those in the placebo arm (p<0.001). Patients taking sotagliflozin further experienced a 1.6 kg (3.5 lbs) and a 2.7 kg (6 lbs) weight reduction at 24 weeks with the 200 mg and 400 mg doses, respectively – this compares to a mean weight gain of 0.8 kg (1.8 lbs) in the placebo group (p<0.001). The similarly-designed inTandem2 study demonstrated significant A1c reductions of 0.36% (200 mg dose) and 0.35% (400 mg dose) with sotagliflozin vs. placebo (p<0.001) in patients with type 1 diabetes on optimized insulin regimens (baseline A1c = 7.7-7.8% after insulin optimization). In addition to this primary endpoint, 32% of patients in both sotagliflozin groups achieved the secondary endpoint of “net benefit”:. The phase 2 inTandem4 study demonstrated statistically significant improvements in A1c and key primary endpoints such as secondary urinary glucose excretion, postprandial glucose, body weight, fasting plasma glucose (non-inferior), and blood pressure for sotagliflozin over placebo. Very notably, Lexicon shared data on beta-hydroxybutyrate (BHB) levels at baseline and at week 12 – as a measure of ketogenesis, BHB measurements are very helpful as we consider the potential DKA risk of sotagliflozin. Notably, the mean increase in blood BHB at week 12 was only 0.1 mmol/l, which is the lowest value detectable by a point of care BHB meter. Dr. Paul Strumph, Lexicon VP of Clinical Development, noted that this level of BHB increase is lower than what is typically seen with selective-SGLT-2 inhibitors – a promising nod toward a potentially better safety profile for SGLT-1/2 dual inhibitors like sotagliflozin in type 1 diabetes. Across these trials, there were fairly balanced adverse event rates across all three arms, somewhat higher rates of DKA with sotagliflozin, and somewhat lower rates of severe hypoglycemia. While there is some concern in some quarters about type 1 patients taking this class, there is no way to stop it so we advocate better education – as well, it may be valuable to look at gaps in therapy for type 1s in order to better understand patients taking SGLT-2 inhibitors off label. We applaud Lexicon for collecting so many outcomes and hope that these will be standardized soon.
  
  • A JDRF-partnered study of sotagliflozin in young adults with poorly controlled type 1 diabetes failed to demonstrate significant A1c reductions vs. placebo but showed promising improvements in other clinically relevant endpoints.  The trial enrolled 87 patients age 18-30 with type 1 diabetes and an A1c ≥9% and topline results were announced in December. Sotagliflozin produced placebo-adjusted A1c reductions of 0.35% (baseline = 9.7-9.9%) and the difference between groups was not statistically significant (p=0.10). However, sotagliflozin did appear to produce improvements vs. placebo on postprandial glucose, body weight, time in range, and A1c in patients with a baseline A1c of 9-10%. In addition, approximately 8 times as many patients in the sotagliflozin group achieved the “net benefit” endpoint of A1c <7% at 12 weeks with no severe hypoglycemia or DKA compared to the placebo group, though the absolute percentage of responders was low in both groups (16% vs. 2%). We were especially impressed by the CGM data from the study – sotagliflozin therapy produced a one-third increase in time spent in range of 70 mg/dl-180 mg/dl – mean proportion of time-in-range was 44% on sotagliglozin, compared to 33% at baseline. This study is a good example of the limitations of using A1c as the sole metric of efficacy for diabetes drugs, as other parameters like time in range and weight loss are likely more relevant for many patients.  

Growing Focus on Diabetes-Adjacent Indications

• Repurposing existing diabetes drugs (either alone or in combination with another agent) for diabetes-adjacent indications like obesity, NASH, and prediabetes was another notable theme this year. On the SGLT-2 inhibitor front, we heard the results of a new sub-analysis of the EMPA-REG OUTCOME trial demonstrating the efficacy of Lilly/BI’s Jardiance (empagliflozin) to reduce adiposity as well as an oral presentation offering further phase 2 data on canagliflozin/phentermine combination therapy for obesity. Two posters additionally showed promising data on AZ’s Farxiga (dapagliflozin) for prediabetes and J&J’s Invokana (canagliflozin) for improved liver metabolism in people with obesity. Additional posters examined Merck’s Januvia (sitagliptin) and the TZD pioglitazone for prediabetes. GLP-1 agonists continue to show promise for obesity in particular: we were especially impressed by a meta-analysis of the entire SUSTAIN clinical trial program showing superior and clinically meaningful reductions n body weight across all five studies, versus a range of tested comparator drugs and in a broad range of patient populations. Novo Nordisk recently shared positive phase 2 topline data for a once-daily injection of semaglutide for obesity, demonstrating impressive mean body weight reductions of nearly 14% and we’re eager to see this investigated further. Novo Nordisk has a particularly robust early- and mid-stage pipeline for obesity and we’re looking forward to the newsflow on this front at future ADA meetings.
• There is also a great deal of activity on the novel therapy front for diabetes-adjacent therapies. GLP-1 agonist combination therapy appear to be all the rage, and we were especially intrigued by posters demonstrating the ability of GABA/GLP-1 combination therapy to prevent the onset of diabetes in animal models by promoting beta cell regeneration and the efficacy of a long-acting GLP-1/glucagon/GIP tri-agonist developed by Hanmi Pharmaceuticals. Reflecting the increasingly robust obesity drug competitive landscape, entirely novel therapies for obesity also have a strong presence at this year’s conference. Posters demonstrated impressive efficacy data for early drug candidates such as Janssen’s oxyntomodulin agonist XTEN and ProMetic’s anti-fibrotic compounds PBI-4547 and PBI-4050 for obesity. On the NASH front, we saw impressive preclinical data for PB-718 from a group in Suzhou, China, as well as Spitfire Pharma’s SP-1373. 

Detailed Discussion and Commentary

Symposium: The Integrated Results of the CANVAS Program

Background to the Design of the Trials

Gregory Fulcher, MD (University of Sydney, Sydney, Australia)

Dr. Gregory Fulcher opened the symposium with a brief history of the SGLT-2 inhibitor drug class and of the FDA’s post-marketing CVOT requirement. SGLT-2 inhibitors work by increasing urinary glucose excretion, thereby lowering glucose levels in the blood. This mechanism gives reason to believe that SGLT-2 agents may be cardioprotective: For one, hyperglycemia in itself is a risk factor for CV events. SGLT-2 inhibitors also reduce blood pressure via osmotic diuresis, promote weight loss (by excreting more calories through the urine), and reduce albuminuria – each of these independently is a risk factor for CV morbidity and mortality, and there are hypotheses circulating in the diabetes field that SGLT-2 inhibitors (including canagliflozin) might confer CV benefit by attacking a variety of contributing risk factors. Importantly, this is all speculation at this stage, as research is ongoing to determine mechanism of cardioprotection. Switching gears, Dr. Fulcher described the intention behind the FDA’s post-marketing CVOT requirement, which went into effect in 2008 – these trials should demonstrate that a new anti-diabetic drug is not associated with an “unacceptable increase” in CV risk. The upper bound of the 95% confidence interval for hazard ratio on a primary CV endpoint (most often, three-point MACE consisting of non-fatal MI, non-fatal stroke, and CV death) must be <1.8 pre-approval in order to win marketing authorization. Post-approval, a larger, dedicated CVOT must demonstrate a hazard ratio <1.3 to convincingly show non-inferiority vs. placebo. The FDA does not explicitly encourage demonstration of CV superiority, which would be achieved by a hazard ratio and confidence interval bound under 1.0. Lastly, Dr. Fulcher reminded everyone that canagliflozin is branded as Invokana by J&J, and is approved in 100 mg and 300 mg oral doses.

Methods for the Trials and the Integrated Analyses

Kenneth Mahaffey, MD (Stanford University, Palo Alto, CA)

Dr. Kenneth Mahaffey provided an overview of the trial design and data analysis scheme. The CANVAS program studied a total of 10,142 people across the CANVAS (n=4330) and CANVAS-R (n=5,812) trials. After a two-week placebo run-in period, participants in CANVAS were randomized to 100 mg or 300 mg canagliflozin or placebo and participants in CANVAS-R were randomized to canagliflozin 100 mg (with optional up-titration to 300 mg) or placebo. As enrollment criteria, all participants had an A1c ranging from 7% to 10.5%, an eGFR >30 mL/min/1.73 min2, and were aged >30 years with a history of a prior cardiovascular event or >50 years with at least two cardiovascular risk factors. The primary outcome was 3-point MACE (the composite of cardiovascular death, non-fatal MI, and non-fatal stroke). Secondary outcomes included all-cause mortality and cardiovascular death. Exploratory outcomes included non-fatal MI, non-fatal stroke, hospitalization for heart failure, hospitalization for heart failure or cardiovascular death, total hospitalizations, albuminuria progression, albuminuria regression, and a renal composite endpoint encompassing 40% reduction in eGFR, end-stage renal disease, or renal death. Importantly, the CANVAS program employed a hierarchical statistical testing structure – thus, secondary endpoints were assessed in a pre-specified order and, if a secondary endpoint failed, all endpoint results following that one in the hierarchy would be considered only exploratory. On the statistics front, Dr. Mahaffey explained that across the entire CANVAS program data all participants on canagliflozin were pooled together such that the statistical analyses evaluated a “strategy of canagliflozin treatment” versus placebo, without differentiating between the 100 mg and 300 mg doses in CANVAS or the possible up-titration from 100 mg to 300 mg in CANVAS-R. 

Effects on Cardiovascular Outcomes

Bruce Neal, MB, ChB, PhD (The George Institute for Global Health, Sydney, Australia)

Dr. Bruce Neal presented the cardiovascular results from the integrated CANVAS and CANVAS-R program. The room waited with bated breath as Dr. Neal discussed the patient populations, baseline characteristics, and metabolic outcomes in the program (detailed below). Finally, Dr. Neal presented the primary three-point MACE (non-fatal MI, non-fatal stroke, CV death) endpoint: canagliflozin therapy was associated with a 14% risk reduction compared to placebo (HR=0.86, 95% CI: 0.75-0.97, p<0.0001 for non-inferiority, p=0.0158 for superiority) – and the room prompting burst into applause and cheers, interrupting Dr. Neal mid-sentence. With a rueful smile, Dr. Neal acknowledged that he had waited eight years for this moment – and the CV results at least were certainly worth the wait! By individual study, the hazard ratio point estimate for the primary outcome were fairly consistent across CANVAS (HR=0.88, 95% CI:0.75-1.03) and CANVAS-R (HR=0.82, 95% CI: 0.66-1.01), though the results were not significant for either trial individually (likely due to a lack of power). The trial just missed superiority for all-cause mortality (HR=0.87, 95% CI:0.74-1.01, p=0.24) – since this was the second endpoint in the pre-specified hierarchical testing structure, the other endpoint results can only be considered exploratory. 

• Hospitalization for heart failure: Very notably, canagliflozin was associated with a substantial and impressive 33% reduction in risk for heart failure (HR=0.67, 95% CI: 0.52-0.87). Canagliflozin also reduced risk for a composite endpoint of CV death/heart failure hospitalization by 22% (HR=0.78, 95% CI:0.67 to 0.91). Notably, the Kaplan-Meier curve for hospitalization for heart failure especially appeared to diverge early and drastically, mirroring the results we saw in the EMPA-REG OUTCOME trial for Lilly/BI’s Jardiance (empagliflozin).

• Individual components of MACE primary outcome: The hazard ratio for individual components of MACE trended in the right direction favoring canagliflozin, but none of them reached statistical significance even though three-point MACE did. For non-fatal MI, the hazard ratio was 0.85 (95% CI: 0.69-1.05). For non-fatal stroke, the hazard ratio was 0.90 (95% CI: 0.71-1.15). And for CV death, the hazard ratio was 0.87 (95% CI: 0.72-1.06).

• Canagliflozin produced pronounced effects on a number of metabolic and cardiovascular risk factors. The mean A1c difference between the canagliflozin and the placebo groups was 0.58% – canagliflozin produced a large drop in A1c within the first few months post-randomization that attenuated over the six year follow-up period. Canagliflozin also produced a mean placebo-adjusted systolic blood pressure reduction of 3.93 mmHg, which occurred early in the trial (within the first year) and was sustained throughout the six-year follow-up. Finally, participants on canagliflozin experienced a mean placebo-adjusted weight loss of 1.6 kg (3.5 lbs) that also occurred in the first year and was sustained throughout the follow-up period.
• Together, CANVAS and CANVAS-R enrolled 10,142 patients (4330 in CANVAS and 5813 in CANVAS-R). Across the program, 96% of participants completed the study and end-of-trial vital status was known for over 99% of participants. Mean follow-up across the program was 188 weeks – CANVAS initiated first and mean follow-up in that trial was 296 weeks, while mean follow-up in CANVAS-R was 108 weeks. At the end of the trial, 71% of canagliflozin and 70% of placebo patients remained on their assigned intervention.
• Baseline characteristics were well-matched between the combined canagliflozin arms and placebo. Mean age across the study was 63 years old, with a mean diabetes duration of 14 years. Very notably, about two-thirds of participants had a history of cardiovascular disease at baseline (and one-third had CV risk factors but no history of CV disease). 90% of participants in the canagliflozin group had hypertension at baseline (vs. 90% in the placebo group) and 14% of participants randomized to canagliflozin had heart failure at baseline (vs. 15% of the placebo group).
  
  • In terms of demographic baseline characteristics, about one-third of participants were female, nearly 80% of participants were white, and about 60% of participants were from North America or Europe. This is fairly typical for a global CVOT, though greater racial/ethnic and geographic representation in trials overall is needed, and we’d like to see this emphasized to a greater degree, particularly given the extent to which under-represented minorities have an outsized risk of type 2 diabetes and type 2 diabetes complications.
  • Participants in the CANVAS program were on a variety of background diabetes and cardiovascular medications. Nearly 80% of participants were taking metformin at baseline, about half were on insulin, 42%-44% were taking SUs, and 12%-13% were taking DPP-4 inhibitors. Notably, only 4% of participants in each arm were taking a GLP-1 agonist at baseline – we would love to see an analysis of cardiovascular and other outcomes in patients on dual canagliflozin and GLP-1 agonist therapy, but we assume that the small number of participants in this subgroup would make such an analysis difficult. In terms of cardiovascular medications, nearly 75%-80% of participants were on RAAS inhibitors, statins, and antithrombotic agents, respectively. A little more than half were on beta blockers and a little less than half were taking a diuretic.
• Dr. Neal also presented several subgroup analyses that probed the potential for heterogeneity of effect among different patient populations. The p-values for interaction were all non-significant for age (<65 years old or ≥65 years old), sex, race (White, Black/African American, Asian, or other), and region (North America, Central/South America, Europe, and Rest of the world). Similarly, there was no significant interaction for various risk factors, including BMI, blood pressure control, duration of diabetes, A1c, or eGFR. The primary outcome benefit was also consistent regardless of CV disease, peripheral vascular disease, heart failure, or amputation history.
  
  • In fact, the only potential heterogeneity of effect was observed in two background therapy subgroups. Those taking beta blockers at baseline were significantly more likely to benefit from canagliflozin therapy than those who were not (HR=0.75 for those on beta blockers, 95% CI: 0.64-0.88 vs. HR=1.04 for those not on beta blockers, 95% CI:0.85-1.28, p=0.01). Furthermore, the heterogeneity of benefit was even more pronounced among the subgroups of those taking or not taking a diuretic at baseline: the HR for those on a diuretic was 0.66 (95% CI:0.56-0.79) and the HR for those not on a diuretic was 1.11 (95% CI: 0.93-1.34) – the p-value for interaction was a highly-significant p<0.001. There was no significant difference in benefit among subgroups of patients taking insulin, statins, antithrombotic agents, or RAAS inhibitors at baseline.  

Effects on Renal Outcomes

Dick De Zeeuw, MD (University Medical Center Groningen, Netherlands)

Next up, Dr. Dick De Zeeuw presented the effects of canagliflozin on renal outcomes. To complement its impressive cardioprotective effects, canagliflozin also showed signs of renal protection, including a 27% risk reduction for progression to albuminuria (HR=0.73, 95% CI: 0.67-0.79), a 70% increase in the regression of albuminuria (HR=1.70, 95% CI: 1.51-1.91), and a 40% risk reduction for the composite endpoint of renal death, renal replacement therapy, or 40% reduction in eGFR (HR=0.60, 95% CI: 0.47-0.77). Canagliflozin was further associated with an 18% (95% CI: -16% to -20%) reduction in urinary albumin:creatinine ratio (UACR). For the subset of participants with microalbuminuria and macroalbuminuria, canagliflozin decreased UACR by 34% and 36%, respectively. Together, these results suggest a potential renal-protective effect of canagliflozin treatment in people with type 2 diabetes, and Dr. De Zeeuw underscored these findings as a highlight of the CANVAS and CANVAS-R integrated full results. This data is particularly impressive in light of the fact that the CANVAS program enrolled a low renal risk population in which 70% of participants had normoalbuminuria (an albumin:creatinine ratio <30 mg/g) and a sizeable proportion had a normal eGFR (25% and 24% of participants in the canagliflozin and placebo arms respectively had mean eGFR >90 ml/min/1.73 m2, and 56% and 54% had mean eGFR between 60-90 ml/min/1.73 m2). Our curiosity is piqued for J&J’s CREDENCE trial investigating Invokana specifically for renal outcomes in patients with type 2 diabetes and diabetic kidney disease (expected to complete in June 2019).

Effects on Safety Outcomes

Vlado Perkovic, MD (Georgia Institute for Global Health, Sydney, Australia)

The safety data makes CANVAS a more complicated story. Dr. Vlado Perkovic presented these results, the headline being a near doubling of lower limb amputations with canagliflozin vs. placebo (HR=1.97, 95% CI: 1.41-2.75, p<0.001). In total, there were 187 lower limb amputations across the two outcomes trials (CANVAS and CANVAS-R), occurring at a rate of 6.3/1,000 patient-years in the canagliflozin arm vs. 3.4/1,000 patient-years in the placebo arm. Approximately 71% of these amputations occurred at the level of the toes or metatarsals, though some were above the ankle and a smaller number were above the knee. The Kaplan-Meier curves for lower-extremity amputations separate around ~year one and continue to diverge for six years post-randomization. Dr. Perkovic presented a multivariate analysis of common risk factors for amputation, which disappointingly showed consistently higher risk with canagliflozin vs. placebo, regardless of a patient’s prior history of amputation, peripheral vascular disease, etc. (see below for a breakdown of this data). While prior history of amputation leads to the greatest chance of a subsequent amputation, this risk is still intensified to the same degree by canagliflozin vs. placebo. Without any insight into what is mediating canagliflozin’s adverse impact on the lower limbs, most experts with whom we have spoken (admittedly still a small number) say that the risk appears to be associated with the molecule itself. This suggests that HCPs won’t be able to tailor prescriptions based on patient disposition (i.e. if the effect on lower limb amputations was driven by a particular subgroup. For example, if this risk were limited to participants with a risk like baseline peripheral vascular disease, this safety issue might be circumvented with a single black box warning not to prescribe Invokana to patients with peripheral vascular disease. At present, that does not appear to be the case. The FDA initiated an investigation of lower limb amputations based on interim CANVAS results in May 2016, and then just last month issued a boxed warning on all products in the Invokana family, so of course we knew this was likely to be an upsetting outcome regardless of the CV data.

• J&J now faces the very challenging task of promoting a favorable risk/benefit profile for its SGLT-2 inhibitor. Will patients risk a toe (or possibly lower limb) for the chance to prevent MI, stroke, and CV death with other in-class choices available? Will providers prescribe Invokana when there’s another SGLT-2 inhibitor with the same demonstrated risk reduction for three-point MACE and no signal for amputations? How will this all be reflected on formularies? We’ve heard mixed opinions from thought leaders so far: Some say they’ll keep patients on Invokana, while others advocate for switching to Jardiance. Some suggest (with hope!) that the lower limb amputation risk could be manageable if further investigations identify a confounding variable apart from the canagliflozin molecule itself – we do think it’s critical to separate out the confounders, like, for example, adjudication. Others are wary that this risk may apply to empagliflozin as well and the EMPA-REG OUTCOME trial just wasn’t long enough to pick up on it. We’re hopeful that this latter point isn’t the case, since the heightened amputation risk with canagliflozin vs. placebo appears early on, beginning at year one. We’ll be heartbroken if amputation risk comes to define the narrative surrounding first-in-class SGLT-2 inhibitor Invokana or the drug class more broadly, given demonstrated CV superiority and renal benefits. We can foresee a future, however, where busy HCPs steer clear of any product in this class because of concerns surrounding lower limb amputation. Or, perhaps this risk will hurt the Invokana business but will encourage patient switches to Jardiance or Farxiga (AZ’s dapagliflozin). We’ll be watching these trends closely. Bottom line: This is a major safety concern that can’t be ignored, nor would we expect it to be by providers, patients, payers, or regulatory agencies. Amputation is a particularly vivid diabetes complication for patients and in the public eye, and we expect J&J will have to be exceptionally thoughtful in how it proceeds. Dr. List suggested to us that this signal could shine a light on the importance of greater education on foot care for people with diabetes – we hope J&J will be a leader in expanding understanding/management of this complication. Currently, we don’t believe patients have much education at all about how to minimize this risk and in fact, perhaps key education could provide significantly more benefit.
• In a separate call with us, Dr. Robert Cuddihy (VP of Medical Affairs for Cardiovascular and Metabolism) underscored Janssen’s continued commitment to the Invokana franchise, and suggested that amputation risk could be managed with improved patient education on foot care and regular screening. As he pointed out, amputations didn’t appear out of nowhere, but were usually preceded by infection or another warning sign. Moreover, the patient population enrolled in CANVAS was particularly prone to this complication (with high CV risk corresponding to an elevated risk of lower-extremity amputations as well). In contrast, a metaanalysis of phase 3 canagliflozin studies found a much lower base rate of lower limb amputations in the background diabetes population vs. the high-risk diabetes population (0.6/1,000 patients vs. 2.4/1,000 patients, respectively). On the other hand, Dr. Cuddihy acknowledged that there’s something quite visceral about an amputation (vs. a heart attack) that may affect an individual patient’s decision on whether or not to start or continue Invokana treatment. Further post-hoc analyses of CANVAS and CANVAS-R will certainly provide more answers. Again, Dr. Cuddihy emphasized that J&J received the final data from these outcomes trials with little time remaining before ADA – continued analysis will come with more time.
• The hazard ratio for low-trauma bone fractures was 1.23 in favor of placebo, but this did not reach statistical significance (95% CI: 0.99-1.52). Fractures were another safety concern to watch out for in CANVAS and CANVAS-R, given the FDA’s strengthened label warning on this front, and it was reassuring to see no statistically significant signal across the two outcomes trials. Interestingly, there was a statistically significant increase in fracture risk in CANVAS (HR=1.55, 95% CI: 1.21-1.97) but not in CANVAS-R (HR=0.86, 95% CI: 0.62-1.19), and Dr. Perkovic reported a statistically significant p-value of 0.005 for this interaction. Further investigations will have to unpack this and determine how concerned patients/providers should be about canagliflozin and bone health. Said Dr. Neal, “I’m not easily persuaded by things happening by chance, but this is a weird result. We don’t see a fracture signal in EMPA-REG OUTCOME, nor in CANVAS-R, nor in any of the other CANVAS trials, so it’s possibly by chance.”
• As expected, genital mycotic infections were significantly more likely among females taking canagliflozin (HR=4.37, 95% CI: 2.78-6.88) and among males taking canagliflozin (HR=3.76, 95% CI: 2.91-4.86). DKA was another prespecified point-of-interest, but no statistically significant signal was detected. The DKA event rate was 0.6/1,000 patient-years in the canagliflozin group vs. 0.3/1,000 patient-years in the placebo group (HR=2.33, 95% CI: 0.76-7.17). Of 18 total cases of DKA, five patients were later found to have autoimmune/type 1 diabetes. In general, the concerns surrounding SGLT-2 inhibitors/DKA are more pronounced for a type 1 patient population, so this was a reassuring safety finding for canagliflozin as a type 2 diabetes therapy. That said, we continue to believe that SGLT-2 inhibitors could be advantageous for some patients with type 1, provided there is strong education on ketone monitoring and other DKA risk management.
• For all other adverse events, there was no significant difference in frequency between the canagliflozin and placebo arms. Serious adverse events occurred at a rate of 104/1,000 patient-years among canagliflozin-treated participants and 120/1,000 patient-years among placebo-treated participants (HR=0.93, 95% CI: 0.87-1.00). There were 1,025 total adverse events that led to study discontinuation – 35/1,000 patient-years vs. 33/1,000 patient-years in the canagliflozin and placebo groups, respectively (HR=1.13, 95% CI: 0.99-1.28). Hospitalization due to any cause occurred at a rate of 119/1,000 patient-years in the canagliflozin group vs. 131/1,000 patient-years in the placebo group (HR=0.94, 95% CI: 0.88-1.00). Data was also collected on UTIs, hypoglycemia, osmotic diuresis, volume depletion, severe hypersensitivity/cutaneous reaction, hepatic injury, venous thromboembolic events, photosensitivity, and acute pancreatitis, with no statistically significant difference in event rates between the canagliflozin and placebo groups.

Implications for Clinical Practice

David Matthews, DPhil (University of Oxford, UK)

To put the benefit-risk profile into perspective, Dr. David Matthews shared the expected incidence rate for a number of endpoints in the CANVAS program. For every 1000 patients treated with canagliflozin over five years, we can expect 23 fewer patients to experience a MACE event, 16 fewer patients to experience hospitalization for heart failure, and 17 fewer patients to experience the renal composite endpoint (renal death, renal replacement therapy, or 40% reduction in eGFR). In total, 56 fewer patients would be expected to experience on of these cardiovascular or renal events – this is especially notable considering that patients with diabetes face an excess residual cardiovascular risk and that few treatments are available for heart failure or diabetic nephropathy. On the other hand, these substantial wins would be expected to occur at the cost of 15 additional patients experiencing a lower-limb amputation (including 10 toe or forefoot amputations and five above-the-ankle amputations). For comparison, based on EMPA-REG OUTCOME, for every 1,000 patients treated over three years (a shorter time period than the CANVAS figures), clinicians can expect 22 fewer CV deaths, 25 fewer deaths overall, and 14 fewer hospitalizations for heart failure with empagliflozin therapy. The only strong safety signal observed in the trial was genital infections – treatment with empagliflozin in 1,000 patients would be expected to produce 53 additional genital infections over three years.

• Dr. Matthews highlighted the analysis presented earlier by Dr. Neal a lack of significant interaction between cardiovascular disease status at baseline and the CV benefit for canagliflozin. He emphasized that there’s no clear difference in outcome or size of the hazard ratios or confidence intervals when subgroups of those with and without CV disease are examined. That said, he also underscored that the study is not powered to distinguish between the primary and secondary prevention populations (we may have to wait until the much larger DECLARE trial (n=17,000) for a clearer understanding of this). Overall, Dr. Matthews stated that results hold for a patient population that matches the one in CANVAS, that is one third primary prevention and two thirds secondary prevention.
• Dr. Matthews also offered a direct comparison of primary and secondary endpoint hazard ratios and confidence intervals between CANVAS and EMPA-REG OUTCOME. While acknowledging the caveat that it’s extremely difficult to draw comparisons across trials due to differences in participant population, trial design, analytic approaches, and drug effects, Dr. Matthews nonetheless presented a helpful slide superimposing the key CANVAS hazard ratios and confidence intervals with that of EMPA-REG OUTCOME (see below). Overall, Dr. Matthews characterized the findings of the two trials as “effectively concordant” – indeed, it appears that the hazard ratios and confidence intervals between the two trials are generally very consistent. In fact, Dr. Matthews pointed out that the hazard ratios and confidence intervals for the primary MACE outcome in the two trials were almost identical. For comparison, the hazard ratio in the CANVAS program was 0.86 (95% CI: 0.75-0.97, p=0.0158 for superiority) and the hazard ratio in the EMPA-REG OUTCOME trial was also 0.86 (95% CI: 0.74-0.99, p<0.001 for non-inferiority, p=0.038 for superiority). Notably, the “nearly insignificant” p-value for the primary endpoint was a sticking point in the FDA Advisory Committee discussion on the Jardiance CV indication, so we’ll be curious to see how the FDA digests the CANVAS data for a label update. Additionally, the CV death component of MACE was not individually significant in CANVAS, whereas the risk of CV death was highly significantly reduced in EMPA-REG OUTCOME and the indication ultimately received for Jardiance was only for CV death. J&J management has already confirmed that the company will submit a Supplemental New Drug Application (sNDA) seeking an expanded indication to the FDA by the end of September – we’ll be following closely to see what kind of language this data will support from a regulatory standpoint (and in guidelines as well).
  
  • There also appears to be some heterogeneity in the non-fatal stroke results – while neither finding was significant, risk for non-fatal stroke trended toward reduction in CANVAS while there was actually signal for increased stroke in EMPA-REG OUTCOME. The confidence intervals for both were fairly wide and cross the line of unity in both trials, however, so we certainly don’t think any definitive comments can be made on the stroke effect of either drug or the class as a whole.

Independent Commentary

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

In his independent commentary, Dr. Clifford Bailey put these integrated CANVAS/CANVAS-R results into context with EMPA-REG OUTCOME for Lilly/BI’s SGLT-2 inhibitor Jardiance (empagliflozin). He posited that CV and renal benefits are highly likely to be class effects for SGLT-2 inhibitors, based on the parallel data in CANVAS and EMPA-REG OUTCOME. The risk reduction for three-point MACE is exactly the same in both trials (14%). Canagliflozin demonstrated a 33% risk reduction for heart failure hospitalization, while empagliflozin demonstrated a 35% risk reduction for this endpoint (p=0.002 vs. placebo). Empagliflozin also significantly reduced risk for diabetic nephropathy by 39%, in comparison to canagliflozin’s 27% risk reduction for progression to albuminuria and 40% risk reduction for the composite endpoint of renal death, renal replacement therapy, or 40% reduction in eGFR. Dr. Bailey mentioned CVD-REAL, the AZ-sponsored real-world analysis that found a significant 39% risk reduction for heart failure hospitalization associated with SGLT-2 inhibitors (including Invokana, Jardiance, and Farxiga) vs. other glucose-lowering drugs (p<0.001). He suggested that all signs so far point to a cardioprotective class effect for SGLT-2 inhibitors, with especially strong signals for a heart failure benefit (though this will have to be determined through RCTs, such as Lilly/BI’s EMPEROR HF program and AZ’s Dapa-HF program). One of the clear bright spots of this new CVOT data is reassurance that EMPA-REG OUTCOME results were not a fluke. For now, these integrated results have created a complicated risk/benefit profile for Invokana, and Dr. Bailey emphasized that the near doubling of risk for lower-extremity amputations is a very real safety concern. Some have said the biggest win from CANVAS may actually manifest for the Jardiance franchise, since empagliflozin’s CV benefits now have more credence without any associated amputation risk – obviously, we would not imagine that anyone would see the troubling safety data as a win for any manufacturer or any patients.

• Dr. Bailey drew attention to the different patient populations in CANVAS and EMPA-REG OUTCOME. Whereas 99% of EMPA-REG OUTCOME participants has established CV disease at baseline or were at very high CV risk, CANVAS enrolled a much lower proportion of high-risk individuals, only 65%. “The 65% is much more reminiscent of the population you’d see in routine practice,” Dr. Bailey explained, which highlights another important contribution of CANVAS to our understanding of SGLT-2 inhibitors. He argued that the positive CV effects of this therapy class may apply in primary as well as secondary prevention. If this primary cardioprotection is confirmed further by AZ’s CVOT DECLARE, which also enrolls a large subset of lower-risk participants, it could be truly transformative for diabetes care – we could give patients a glucose-lowering, weight-lowering, convenient oral medication that protects stroke, heart attacks, and CV death early on.
• That the hazard ratio for stroke trended in the right direction in CANVAS is also reassuring, Dr. Bailey suggested. In EMPA-REG OUTCOME, strokes were actually more common in the treatment vs. placebo arm, though the 1.24 hazard ratio did not reach statistical significance (95% CI: 0.92-1.67, p=0.16). In a separate conversation with our team, Dr. Neal suggested that Lilly/BI may have been “unlucky” on this stroke endpoint. Ideally, further investigations of mechanism help elucidate differential effects of canagliflozin and empagliflozin on non-fatal MI, non-fatal stroke, and CV death. For now, we hope the focus remains on the significant risk reduction for three-point MACE and CV events in general. Janssen’s Dr. List announced that a Supplemental New Drug Application (sNDA) for inclusion of the canagliflozin CV data on the Invokana label will be submitted to the FDA by the end of September.

Close Concerns Questions

Q: What are the risk factors for amputation? Are there clear patient populations that should avoid Invokana?

Q: What are the logical next steps to investigate amputation risk using data from databases used in the CVD-REAL study or comparable datasets such as those used by major US insurance companies? Since Invokana has been out the longest, what is the best way to compare compounds?

Q: What is the best way to interpret the different adjudication approaches of amputations used in various CVOTs?

Q: To what extent might the amputation risk be a class effect?

Q: How much will J&J continue to invest in the Invokana franchise? There has previously been discussion of a prediabetes CVOT for the drug, as well as the potential for a phase 3 obesity program for the combination of canagliflozin and phentermine.

Q: What’s going to happen to prescribing habits? Is there a reason an HCP might still prescribe Invokana over Jardiance beyond formulary and how would typical clinicians trade off better glycemic or weight advantages associated (at least for some patients) with the relatively higher amputation risk (despite low overall numbers)? Will the amputation risk is going to deter HCPs from Invokana, specifically, or perhaps from the whole SGLT-2 class? How much more

Q: How will these results impact formularies?

Q: How will patients and providers and professional groups view the trade-off between lowering CV events and increasing chances of a lower limb amputation?

Q: How does the “do no harm” tenet for healthcare providers play into decisions around drugs to use in this class?

Q: What concerns exist over patients enrolled in CANVAS-R who may be at higher than typical risk of amputations?

Q: What components of outcomes trials should be changed to make them more comparable? Would it be a useful investment to have an outcome trial with all SGLTs?

Oral Presentations: ADA Presidents Oral Session

Hospitalization for Heart Failure and Death in New Users of SGLT2 Inhibitors in Patients With and Without Cardiovascular Disease—CVD-REAL Study

Matthew Cavender, MD (University of North Carolina, Chapel Hill, NC)

Dr. Matthew Cavender shared new findings from the AZ-sponsored CVD-REAL study, showing consistent CV benefits to SGLT-2 inhibitor therapy across primary and secondary prevention populations. Approximately 87% of registered participants (n=306,156) had no prior history of CV disease at baseline, as we learned at ACC 2017 during the initial results presentation, and these individuals still experienced an impressive 46% relative risk reduction for all-cause mortality with an SGLT-2 inhibitor (n=133,549) vs. another glucose-lowering drug (n=133,294) such as metformin (most common), sulfonylureas, DPP-4 inhibitors, TZDs, GLP-1 agonists, or insulin (HR=0.54, 95% CI: 0.44-0.66). Patients with established CV disease experienced a 53% relative risk reduction for all-cause death with an SGLT-2 inhibitor (HR=0.47, 95% CI: 0.36-0.61) – as expected, the absolute risk reduction is greater because this high-risk subset had a larger total number of events. Dr. Cavender reminded everyone that the risk reduction for all-cause mortality was 51% across the entire study (p<0.001), which falls between 46% for a primary prevention cohort and 53% for a secondary prevention cohort. Initiation of SGLT-2 inhibitor therapy lowered a high-risk patient’s risk for heart failure hospitalization by 31% (HR=0.69, 95% CI: 0.59-0.8) and a low-risk patient’s risk for this endpoint by 55% (HR=0.45, 95% CI: 0.32-0.63), compared to a 39% relative risk reduction across CVD-REAL in its entirety (p<0.001). For the composite endpoint of hospitalization for heart failure/death from any cause, SGLT-2 inhibitors reduced risk for the primary prevention group by 41% (HR=0.59, 95% CI: 0.52-0.67) and for the secondary prevention group by 48% (HR=0.52, 95% CI: 0.44-0.61), compared to a 46% relative risk reduction across the whole trial (p<0.001). It’s unclear why lower-risk participants experienced even greater absolute risk reductions for heart failure hospitalization and the composite endpoint vs. patients with a history of CV events – it’s possible that SGLT-2 inhibitors may exert a preventive or protective effect against heart failure in relatively more healthy hearts, though of course this is speculation since the mechanism of benefit is still largely a mystery. All in all, this data suggests a broad CV benefit to SGLT-2 inhibitors. There was not information shared on amputations but we will be eager to learn anything on this front, as well as on fractures.

• Dr. Cavender emphasized the real-world nature of this investigation. While there are limitations to observational research, CVD-REAL also translates findings from EMPA-REG OUTCOME into real clinical settings – and in an enormous population. “It gives us some degree of confidence that data from randomized controlled trials (RCTs) like EMPA-REG OUTCOME has to do with how drugs are playing out in real-world clinical practice,” he explained. We agree that there’s excitement in this real-world dataset showing profound CV benefits for the SGLT-2 class, including Lilly/BI’s Jardiance (empagliflozin), J&J’s Invokana (canagliflozin), and AZ’s Farxiga (dapagliflozin), even if they are slightly inflated. We’ve heard from many thought leaders, including CVOT expert Dr. Silvio Inzucchi and Dr. Matthew Riddle at this very meeting, that demonstrating primary CV prevention is the next frontier for SGLT-2 inhibitors. CVD-REAL offers a big hint for a primary cardioprotective class effect, one that will hopefully be confirmed by ongoing RCTs and post-hoc analyses of completed RCTs. The CANVAS CVOT for Invokana, presented yesterday, showed 14% relative risk reduction for three-point MACE (p=0.02 for superiority vs. placebo) and the participant population included about ~1/3 participants without established CV disease at baseline. AZ’s DECLARE trial will feature an even larger primary prevention cohort, and is expected to complete in April 2019.

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

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

John Buse, MD, PhD (University of North Caroline, Chapel Hill, NC)

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

inTandem1 Primary and Secondary Efficacy Endpoint Results

inTandem1 Safety Results

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

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

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

inTandem4 Primary and Secondary Efficacy Endpoint Results

inTandem4 Safety Results

Oral Presentations: Landscape of Therapeutic Trials in Type 2 Diabetes

Safety and Efficacy of Ertugliflozin Plus Sitagliptin vs. Either Treatment Alone after 52 Weeks in Subjects with T2DM Inadequately Controlled on Metformin: VERTIS FACTORIAL Trial Extension

Richard Pratley, MD (Florida Diabetes and Endocrine Center, Orlando, FL)

Dr. Richard Pratley shared one-year findings from the VERTIS FACTORIAL trial, underscoring the glucose-lowering and weight loss efficacy of Merck/Pfizer’s SGLT-2 inhibitor ertugliflozin in combination with sitagliptin (Merck’s DPP-4 inhibitor Januvia). This is particularly exciting as we await FDA decisions on ertugliflozin, ertugliflozin/metformin (fixed-dose combination), and ertugliflozin/sitagliptin (fixed-dose combination) expected by January 2018 – we’ve been looking forward to this data for a long time! In VERTIS FACTORIAL, 1,233 patients with type 2 diabetes on stable metformin therapy were randomized to one of five arms: (i) a 5 mg dose of ertugliflozin, (ii) a 15 mg dose of ertugliflozin, (iii) a 100 mg dose of sitagliptin, (iv) a combination regimen of 5 mg ertugliflozin/100 mg sitagliptin, or (v) a combination regimen of 15 mg ertugliflozin/100 mg sitagliptin. Initial 26-week results were presented in a poster at EASD 2016, and Dr. Pratley discussed data from the trial extension out to 52 weeks, which demonstrated sustained superior reductions in A1c and fasting plasma glucose for the SGLT-2/DPP-4 combinations vs. either agent alone. After one year of treatment, A1c dropped by 1.4% from a baseline 8.6% for both the combo therapy groups vs. an A1c decline of 1%, 0.9%, and 0.8% for the 5 mg ertugliflozin, 15 mg ertugliflozin, and 100 mg sitagliptin groups, respectively (and that’s in an RCT – unlikely that would be seen in “real life” from our admittedly speculative view). In both combo arms, 40% of participants reached an A1c goal of <7% after one year vs. 26% of patients on 5 mg ertugliflozin, 23% of patients on 15 mg ertugliflozin, and 27% of patients on sitagliptin. A “global” word on findings such as these – we’d love to see what the A1c goals would look like with other interventions combined after the initial findings (diet, exercise, behavior modification, peer to peer counseling, etc.)

• Ertugliflozin also demonstrated a profound weight loss benefit in VERTIS FACTORIAL. Dr. Pratley showed that ertugliflozin was associated with 2.4 kg (5.3 lbs) weight loss at a 5 mg dose, 3.2 kg (7.1 lbs) weight loss at a 15 mg dose, 2.4 kg (5.3 lbs) weight loss at a 5 mg dose in combination with sitagliptin, and 2.8 kg (6.2 lbs) weight loss at a 15 mg dose in combination with sitagliptin. Meanwhile, patients on sitagliptin alone in VERTIS FACTORIAL experienced 0.1 kg (0.22 lbs) weight loss on average over the course of a full year. Baseline body weight was 87 kg-89 kg (192 lbs-196 lbs) across all study arms. Weight loss is one of the key aspects to SGLT-2 inhibitors that makes these products so appealing for type 2 diabetes patients (not to mention the superior A1c-lowering and possible CV benefits). We’re not at all surprised to see marked improvements in body weight with ertugliflozin treatment vs. sitagliptin or placebo, but we’re always happy to see corroborating evidence on this front. We’re also pleased to see that combination with sitagliptin does not appear to substantially attenuate the weight loss effect of ertugliflozin.
• Dr. Pratley’s presentation highlighted SGLT-2/DPP-4 fixed-dose combination tablets as an important advancement in type 2 diabetes care. He began with the statement that SGLT-2 inhibitors and DPP-4 inhibitors have complementary mechanisms of action, which suggests that a combination of the two could be a more efficient way to get patients to goal – especially those with high baseline A1c. VERTIS FACTORIAL provides hard evidence for the benefits to this particular combination vs. either monotherapy, with more patients getting to A1c goal while also losing weight and facing a lower pill burden.

Safety and Efficacy of Ertugliflozin after 52 Weeks in Subjects with T2DM Inadequately Controlled on Metformin and Sitagliptin: Results from the Extension Phase of the VERTIS SITA2 Trial

Jie Liu, MD (Merck & Co., Kenilworth, NJ)

Dr. Liu presented 52-week results from VERTIS SITA2 investigating ertugliflozin as an add-on to a metformin/sitagliptin regimen – a follow-up to the 26-week data shared in an oral presentation at EASD 2016. Participants (n=464) with type 2 diabetes experienced a mean 0.8% A1c decline from a baseline of 8.1% with 5 mg ertugliflozin after one year, while patients in the placebo arm showed essentially flat A1c from baseline 8%. Similarly, people randomized to 15 mg ertugliflozin experienced a mean 0.8% A1c reduction from a baseline of 8%. Dr. Liu displayed graphs to clearly depict this sustained glucose-lowering effect out to one year, which is certainly compelling, in our view. In VERTIS SITA2, 33% of patients on ertugliflozin reached an A1c target <7% at week 52, regardless of dose, compared to only 14% of the placebo group. We’re glad to see such strong data from the VERTIS program, and we’re excited by the prospect of a fourth SGLT-2 inhibitor coming soon to the commercial market by a group that could more successfully get this class to the patients that need it. Expanded options within this class will be a noteworthy win, and we look forward to seeing how ertugliflozin may grow whole class sales – while patients and clinicians in the US are rarely “choosing” compounds anymore, as much as the formularies are making choices for them, we do believe that a powerhouse combo of Merck/Pfizer marketing in this class would be positive for all.

• Weight loss effects were consistent between week 26 and week 52 in VERTIS SITA2. According to Dr. Liu, body weight decreased by a mean 3.5 kg (7.7 lbs) from a baseline 88 kg (194 lbs) for the 5 mg ertugliflozin group, by a mean 2.8 kg (6.2 lbs) from a baseline 87 kg (192 lbs) the 15 mg ertugliflozin group, and by 1 kg (2.2 lbs) from a baseline 87 kg (192 lbs) for the placebo group.
• As Dr. Liu put it, DPP-4 inhibitors are already commonly considered as a second-line therapy option after metformin. He suggested that this data supports earlier intervention with an SGLT-2 inhibitor alongside. Merck’s Januvia (sitagliptin) leads the DPP-4 inhibitor class in sales and has surely cultivated familiarity among diabetes care providers, so we’re hopeful that a fixed-dose combination of ertugliflozin/sitagliptin – if approved – also becomes an early consideration for type 2 diabetes treatment. That said, frustratingly in the US, clinicians and payers seem to be less comfortable with fixed dose combinations than do their counterparts in other geographic regions. We’d love to get more patient sentiments, particularly that relate to adherence, to the payers.

The Long-Term Efficacy and Safety of Canagliflozin in Combination with Insulin in Japanese Patients with T2DM

Shinichi Harashima, MD (Kyoto University, Japan)

Dr. Shinichi Harashima presented results from a one-year study of SGLT-2 inhibitor canagliflozin (n=76) vs. placebo (n=70) added onto a background of insulin therapy. Canagliflozin, branded by Mitsubishi Tanabe Pharma as Canaglu in Japan (and branded by J&J as Invokana ex-Japan), was associated with superior A1c reductions vs. placebo for type 2 diabetes patients on premixed, basal only, or basal-bolus therapy at baseline (p<0.001 for all comparisons). After 16 weeks, the A1c treatment difference between the two study arms was 1.1% (p<0.001). All participants then entered a 36-week open label period, and patients switched from placebo onto canagliflozin achieved similar levels of A1c decline by week 52. The SGLT-2 inhibitor was also associated with superior reductions in fasting plasma glucose, body weight, and HOMA2-%B, which reflects beta cell function (p<0.001 vs. placebo for all comparisons). While hypoglycemia rates were similar across the two study arms – 4.85 events per subject-year of exposure vs. 4.51 events per subject-year of exposure with canagliflozin vs. placebo, respectively – patients on canagliflozin who experienced a meaningful reduction in daily insulin dose did face substantially lower risk for hypoglycemia. Dr. Harashima reported that mean daily insulin dose for the 19 patients experiencing >8 hypoglycemia episodes over the course of the trial was 35.7 units, compared to only 27.4 units for the 72 patients who experienced no hypoglycemia events during the trial. The implication here is that a larger, longer study might show a beneficial effect of canagliflozin therapy on hypoglycemia risk, mediated by a change in daily insulin requirements. We’d love to see that data.

Oral Presentations: Translating Therapeutics to the Real World

Dapagliflozin in Renal Impairment: The Association of British Clinical Diabetologists Nationwide Dapagliflozin Audit

Robert Ryder, MD (City Hospital, Birmingham, UK)

Dr. Robert Ryder presented data from the UK’s Association of British Clinical Diabetologists (ABCD) nationwide audit, demonstrating the efficacy of dapagliflozin in type 2 diabetes patients with normal, mild, and moderate renal impairment. The ABCD audit collected anonymous data of real type 2 diabetes patients (baseline A1c of ~9.5%; disease duration of 8.2 to 11 years) treated with dapagliflozin between 2014 and 2016 (n=2,027). The patients were categorized into three groups, depending on baseline eGFR: CKD group 1 (normal, eGFR > 90 ml/min), group 2 (mild renal impairment, eGFR 60-90 ml/min), and group 3 (moderate renal impairment, eGFR 30-59ml/min). Study results found that the drug reduced A1c, weight, BMI, systolic blood pressure, and ALT by similar statistically and clinically significant amounts in normal and mild renal impairment. In moderate renal impairment, there was a reduction in weight and ALT but there was no significant impact on A1c or systolic blood pressure. Specifically, over approximately four months, comparing groups, mean A1c fell by 1.1 ± 1.1% from 9.7±1.4 to 8.6±1.5% (p=0.000) in group 1, 0.9±1.4% from 9.4±1.5 to 8.5±1.4% (p<0.001) in group 2, but did not change significantly in group 3 (9.3±1.4 to 9.1±1.8% [p=0.510]). Weight fell by 3.2±5.2 kg from 106.8±22.1 to 103.5±22.0 (p<0.001) in group 1, 2.1±4.8 kg from 101.1±22.4 to 99.0±22.0kg (p<0.001) in group 2 and 3.5±7.7kg from 105.9±18.3 to 102.4±18.1kg (p=0.003) in group 3. These data are reassuring in the versatility of SGLT-2 inhibitors’ benefits and also add to the conversation on how clinicians can better personalize therapies with regard to their patients’ comorbidities.

Questions and Answers

Q: I know that in the UK, they can stop medications after a couple of years. What criteria did you use to measure the stopping and restarting of medications?

A: There aren’t any particular criteria. Clinicians do whatever clinicians do. Some will stop if the med doesn’t work; others will continue. There isn’t any specific thing driving this for people. They do whatever they think is best for their patient.

Q: Was there a difference across side effect profiles?

A: The side effects were similar across groups.

Posters

DURATION-8 Randomized Controlled Trial 1-Year Results: Efficacy and Safety of Once-Weekly Exenatide (ExQW) Plus Once-Daily Dapagliflozin (DAPA) vs. ExQW or DAPA Alone (141-LB)

C Guja, J Frias, A Ahmed, E Hardy, H Wang, P Ohman, and S Jabbour

AZ presented new one-year DURATION-8 results, demonstrating that the combination of AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) and once-weekly GLP-1 agonist Bydureon (exenatide) maintained improvements in glycemic control, body weight, and SBP compared to either drug alone. These results represent the 24-week extension from the promising 28-week DURATION-8 results presented at this past EASD meeting. In this double-blind, multicenter study, adults with type 2 diabetes were randomized to either exenatide plus dapagliflozin, exenatide alone, or dapagliflozin alone. Of the initial 695 patients randomized, 564 (81%) completed the full 52-week treatment period. The findings demonstrated that at week 52, the combination therapy group continued to achieve greater reductions in A1c, FPG, 2-hour PPG, body weight, and SBP compared to either treatment group alone. Specifically, the -1.8% A1c reduction for exenatide/dapagliflozin dual therapy significantly exceeded those of exenatide (-1.4%; p<0.01) and dapagliflozin (-1.2%; p<0.01) alone. Notably, Body weight reductions were -3.3 kg for the dual therapy arm, significantly greater than -1.5 kg for exenatide monotherapy (p<0.001) and -2.3 kg for dapagliflozin monotherapy (p<0.001). SBP reductions were 4.5 mmHg, 0.7 mmHg (p<0.001), and 2.7 mmHg, respectively. Regarding safety and tolerability, the combination therapy was well tolerated, with slightly more adverse events vs. either drug alone (66.2% vs. 62.2% [exenatide] and 61.8% [dapagliflozin]), though the three groups had comparable rates of serious adverse events. In general, patients treated with exenatide unsurprisingly reported more GI adverse events. These results confirm the promising findings that made waves at last EASD and the excitement surrounding the GLP-1/SGLT-2 combination approach. As both of these classes have the potential for CV risk reduction, we would be interested to see if a combination therapy could provide further additive benefits. For more on DURATION-8 and AZ’s latest, please see our EASD 2016 and 1Q17 coverage.

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

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

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

12-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT-1 and SGLT-2 Inhibitor, as Adjunct Therapy to Insulin in Young Adults with Poorly Controlled Type 1 Diabetes (JDRF Study) (147-LB)

B Bode, P Banks, S Sawhney, P Strumph, and The Sotagliflozin JDRF Study Writing Group

The JDRF-partnered study of sotagliflozin in young adults with poorly controlled type 1 diabetes failed to demonstrate significant A1c reductions vs. placebo but showed promising improvements in other clinically relevant endpoints. Lexicon announced topline results from the study in December. The trial enrolled 87 patients age 18-30 with type 1 diabetes and an A1c ≥9%. Patients were randomized to receive either 400 mg sotagliflozin or placebo for 12 weeks in addition to insulin; the primary endpoint was change in A1c at 12 weeks. Sotagliflozin produced placebo-adjusted A1c reductions of 0.35% (baseline = 9.7-9.9%) and the difference between groups was not statistically significant (p=0.10). Because the primary endpoint was not significant, p-values for secondary endpoints could not be used to declare statistical significance. However, sotagliflozin did appear to produce improvements vs. placebo on postprandial glucose, body weight, time in range, and A1c in patients with a baseline A1c of 9-10%. In addition, approximately 8 times as many patients in the sotagliflozin group achieved the “net benefit” endpoint of A1c <7% at 12 weeks with no severe hypoglycemia or DKA compared to the placebo group, though the absolute percentage of responders was low in both groups (16% vs. 2%). We were especially impressed by the CGM data from the study – sotagliflozin therapy produced a one-third increase in time spent in range of 70 mg/dl-180 mg/dl. This study is a good example of the limitations of using A1c as the sole metric of efficacy for diabetes drugs, as other parameters like time in range and weight loss are likely more relevant for many patients. While there is almost exclusive focus on A1c at the regulatory level (though JDRF and The diaTribe Foundation among others are actively advocating for regulatory consideration of outcomes beyond A1c), it’s important to note that this was a phase 2, non-pivotal trial in an extremely challenging population. See our discussion of the topline results for more of our thoughts on this study.

Effect of Ertugliflozin on Glycemic Control, Body Weight, Blood Pressure, and Bone Mineral Density in Type 2 Diabetes Mellitus Inadequately Controlled with Metformin Monotherapy: VERTIS MET Trial (1168-P)

J Rosenstock, J Frias, D Páil, B Charbonnel, R Pascu, D Saur, A Darekar, S Huyck, H Shi, B Lauring, and S Terra

In VERTIS MET, Merck/Pfizer’s SGLT-2 inhibitor candidate ertugliflozin showed superior lowering of A1c, fasting plasma glucose, body weight, and blood pressure vs. placebo. The study enrolled 621 patients with type 2 diabetes and a mean baseline A1c of 8%, randomizing them to ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo. After 26 weeks, participants in the 5 mg ertugliflozin arm experienced a mean A1c treatment difference of 0.7% (p<0.001 vs. placebo), while those in the 15 mg ertugliflozin arm experienced a mean A1c treatment difference of 0.88% (p<0.001 vs. placebo). Body weight dropped similarly, although these reductions were not dose dependent, meaning patients taking 5 mg ertugliflozin actually lost more weight on average compared to patients taking the higher-dose, 15 mg ertugliflozin. This data supports the efficacy of Merck/Pfizer’s SGLT-2 inhibitor candidate, which was accepted for review by the FDA earlier this year – a regulatory decision is expected by January 2018, and we look forward to a four-product SGLT-2 inhibitor market (ertugliflozin would join J&J’s canagliflozin, Lilly/BI’s empagliflozin, and AZ’s dapagliflozin).

Dapagliflozin is Associated with Lower Risk of Hospitalization for Kidney Disease, Heart Failure, and All-Cause Death Compared to DPP-4i: CVD-REAL Nordic (165-LB)

A Norhammar, JW Eriksson, J Bodegard, M Thuresson, P Fenici, D Nathanson, M Kosiborod, HL Gulseth, T Nyström, and KI Birkeland

A subgroup analysis of CVD-REAL compared real-world renal and cardiovascular outcomes between type 2 diabetes patients starting treatment with SGLT-2 inhibitor dapagliflozin (AZ’s Farxiga) vs. DPP-4 inhibitors. Mean follow-up time was 0.94 years in the dapagliflozin arm vs. 0.99 years in the DPP-4 arm. Dapagliflozin (n=8,582) reduced risk for hospitalization for kidney disease by 62% (HR=0.38, 95% CI: 0.29-0.51, p<0.00) compared to DPP-4 inhibitors (n=25,746). The SGLT-2 agent was also associated with a 37% risk reduction for heart failure hospitalization (HR=0.63, 95% CI: 0.50-0.81, p<0.001) and with a 27% risk reduction for all-cause death (HR=0.73, 95% CI: 0.59-0.91, p=0.004) compared to DPP-4 inhibitors. CVD-REAL is an AZ-sponsored observational analysis of SGLT-2 inhibitors vs. other glucose-lowering drugs, and the “real-world” nature of the trial means that events were not adjudicated as they are in randomized controlled trials, and the findings are subject to possible confounding. That said, even if these values for relative risk reduction are somewhat inflated, the renal and cardioprotective benefits to SGLT-2 inhibitor therapy are quite remarkable. It’s great to see real-world evidence to back-up findings from major randomized controlled outcomes trials, including EMPA-REG OUTCOME for Lilly/BI’s Jardiance (empagliflozin) and CANVAS for J&J’s Invokana (canagliflozin). This is also the first post-hoc analysis of CVD-REAL (the initial results were presented at ACC 2017 in March) that compares SGLT-2 inhibitors vs. another specific therapy class – we’re eager to see more of these comparative analyses, especially SGLT-2 inhibitors vs. GLP-1 agonists since certain agents in both of these classes have positive CVOT data. We salute AZ and all the researchers for making this happen.

Combination Therapy of Canagliflozin and Teneligliptin in Japanese Patients with T2DM: Results from Phase 3 Studies (1194-P)

K Kaku, T Kadowaki, N Inagaki, K Kondo, K Nishimura, G Kaneko, N Maruyama, N Nakanishi, H Iijima, Y Watanabe, and M Goda

This poster displayed an integrated analysis of three phase 3 studies comparing canagliflozin/teneligliptin co-administration vs. monotherapy with either the SGLT-2 inhibitor (canagliflozin) or the DPP-4 inhibitor (teneligliptin). Two 24-week trials randomized Japanese participants with type 2 diabetes to canagliflozin vs. placebo as an add-on to a background of teneligliptin (n=138), or to teneligliptin vs. placebo as an add-on to a background of canagliflozin (n=154). Both studies showed superior A1c-lowering with the SGLT-2/DPP-4 combination vs. either agent alone: In the former, the A1c treatment difference was 0.88% in favor of canagliflozin (p<0.001 vs. placebo), dropping from a baseline A1c ~8%. In the latter, the A1c treatment difference was 0.94% in favor of teneligliptin (p<0.001 vs. placebo), also from a baseline A1c ~8%. A third, 52-week open label trial added canagliflozin onto a baseline regimen of teneligliptin (n=153). Sustained A1c improvements on combination therapy were observed throughout the one-year trial duration, and 82% of participants achieved clinically-meaningful A1c reductions and body weight reductions. This highlights one of the key benefits to SGLT-2/DPP-4 combos, in that they show superior glucose-lowering efficacy and weight loss efficacy, all the while offering a milder side-effect profile vs. either drug alone. Indeed, adverse events were well balanced across all groups, with the exception of genital mycotic infections which are expected to be higher with SGLT-2 inhibitor treatment (occurring in 1% of male trial participants and 11% of female trial participants in the third, 52-week study). These integrated results were the basis for a New Drug Application jointly-submitted by Mitsubishi Tanabe Pharma (which markets canagliflozin in Japan as Canaglu) and Daiichi Sankyo (which markets teneligliptin as Tenelia) to Japanese regulatory authorities earlier this year. A decision on this fixed-dose combination candidate, MT-2412, is expected in 2Q18.

Safety and Efficacy of Ertugliflozin in Combination with Sitagliptin in Subjects with T2DM Inadequately Controlled on Diet and Exercise: The VERTIS SITA Trial (1197-P)

B Lauring, S Miller, T Krumins, H Zhou, S Huyck, J Johnson, G Golm, S Terra, J Mancuso, and S Engel

This poster displayed 26-week results from Merck/Pfizer’s VERTIS SITA trial comparing combination therapy with SGLT-2 ertugliflozin/DPP-4 inhibitor sitagliptin (Merck’s Januvia) vs. placebo. The study randomized participants (n=291 patients with type 2 diabetes) to one of three arms: (i) 5 mg ertugliflozin/100 mg sitagliptin once-daily, (ii) 15 mg ertugliflozin/100 mg sitagliptin once-daily, or (iii) placebo. Patients in the lower dose combo group experienced a mean A1c reduction of 1.6% from a baseline 8.9% vs. a mean A1c reduction of 0.44% from a baseline of 9% for patients on placebo (p<0.001). Similarly, patients in the higher dose combo group experienced superior A1c reductions of 1.68% from a baseline 9% (p<0.001 vs. placebo). Defining A1c goal as <7%, 36% of 5 mg ertugliflozin participants and 31% of 15 mg ertugliflozin participants (both on top of sitagliptin) achieved this target by week 26 vs. only 8% of placebo participants (p<0.001 for both comparisons). The dual therapy was also associated with significant reductions in weight and systolic blood pressure. On average, body weight dropped 2.9 kg (6.4 lbs) for people on 5 mg ertugliflozin/100 mg sitagliptin vs. 0.9 kg (2 lbs) for people on placebo (p<0.001). Patients on 15 mg ertugliflozin/100 mg sitagliptin lost a mean 3 kg (6.6 lbs) over 26 weeks (p<0.001 vs. placebo). Baseline body weight was 91 kg (201 lbs) in the two dual therapy arms and was 95 kg (209 lbs) in the placebo arm. Systolic blood pressure declined by 2 mmHg in the lower dose combo group and by 4 mmHg in the higher dose combo group, but actually increased by a mean 2.4 mmHg among patients on placebo (p=0.011 and p<0.001, respectively). This trial saw little difference in adverse events across groups (and a generally low incidence of safety issues overall) as well as great retention – 291 were randomized, 282 completed all 26 weeks, and 254 completed on study medication. Fewer participants (~2% of both ertugliflozin/sitagliptin groups) discontinued treatment due to an adverse event vs. placebo (~3%). Ultimately, in patients with type 2 diabetes not at goal, co-initiation of ertugliflozin and sitagliptin could provide better glycemic control, weight loss, and lower blood pressure.

• These poster results were part of a range of VERTIS program studies presented at this ADA (also VERTIS MONO, VERTIS SITA2, and VERTIS FACTORIAL). Across the board, these posters and oral presentations emphasized the value of a fixed-dose SGLT-2/DPP-4 combination due to superior glucose-lowering, weight loss, and blood pressure-lowering efficacy. If approved by the FDA (and decisions on standalone ertugliflozin as well as this fixed-dose combination and a fixed-dose combination of ertugliflozin/metformin are expected by January 2018), this new oral combination will join a class with AZ’s Qtern (dapagliflozin/saxagliptin) and Lilly/BI’s Glyxambi (empagliflozin/linagliptin). We’re eager to see this approval, as we see the Merck/Pfizer duo as particularly fit to make a fixed-dose SGLT-2/DPP-4 combination a commercial success and to ensure wide patient access.

Long-Term Efficacy and Safety of Ertugliflozin Monotherapy in Patients with Inadequately Controlled T2DM Despite Diet and Exercise: The 52-Week VERTIS MONO Study (1208-P)

R Aronson, A Goldman, J Frias, A Darekar, B Lauring, S Huyck, and S Terra

Merck/Pfizer’s VERTIS MONO study of ertugliflozin (which was accepted for review by the FDA earlier this year) showed the SGLT-2 inhibitor’s A1c-lowering, weight loss, and blood pressure-reducing efficacy vs. placebo. Patients with type 2 diabetes and baseline A1c ~8% (n=461) were randomized to 5 mg ertugliflozin, 15 mg ertugliflozin, or placebo for 26 weeks, and then entered a “phase b” of the trial in which participants allocated to placebo and who also did not receive rescue therapy also received metformin for 26 weeks in phase B. Ertugliflozin was associated with dose-dependent, superior A1c reductions vs. placebo at week 26 (with a greater decline in the 15 mg arm vs. the 5 mg arm), but the mean A1c across all groups (including placebo) evened out once metformin was added to medication regimen. At week 52, the mean A1c drop was 1% for the placebo/metformin group, 0.9% for the low-dose ertugliflozin group, and 1% for the high-dose ertugliflozin group; 27.5% of participants in the placebo/metformin group achieved A1c goal <7% vs. 25.6% of those in the low-dose SGLT-2 group and 28.5% of those in the high-dose SGLT-2 group. Change in fasting plasma glucose was also similar across all study arms after one year: -29.3 mg/dl, -29 mg/dl, and -32.7 mg/dl for the placebo/metformin, 5 mg, and 15 mg cohorts, respectively (all from a baseline fasting glucose ~180 mg/dl). Both ertugliflozin groups experienced clinically-meaningful reductions in body weight and systolic blood pressure, though comparable results on body weight were also seen in the placebogroup after metformin was added. As expected for an SGLT-2 inhibitor, ertugliflozin was associated with an increased frequency of female genital mycotic infections, affecting 27% and 29% of the low- and high-dose groups, respectively (vs. 10% of the placebo/metformin group). All in all, the poster concludes that ertugliflozin offers good glycemic control and weight loss benefits to patients with type 2 diabetes inadequately controlled on diet/exercise alone, even though it’s unclear how the benefits distinguish the agent from metformin – we imagine there is more to the story here, although we also recognize cost as a key consideration and must note that metformin is generic and relatively inexpensive compared to the pricing we’d expect for a newly-approved SGLT-2 inhibitor.

Effect of Empagliflozin on Cardiac and Vascular Hemodynamic Markers by Subgroups of Age, SEx, and Hypertension in Patients with T2DM and High CV Risk: EMPA-REG OUTCOME (1452-P)

R Chilton, L Gullestad, D Fitchett, S Inzucchi, M Mattheus, H Woerle, and O Johansen

This new sub-analysis of the EMPA-REG OUTCOME trial explored the effect of longer-term (164 weeks) empagliflozin therapy on hemodynamics, arterial stiffness, and myocardial work burden. The EMPA-REG OUTCOME trial’s primary analysis had previously shown empagliflozin treatment to reduce the risk of cardiovascular death by 38%. The trial enrolled 7020 patients with type 2 diabetes and known CV disease who were randomized to either placebo, or 10 or 25 mg of empagliflozin. Median treatment duration and observation time were 2.6 and 3.1 years, respectively. Empagliflozin treatment resulted in significantly greater reductions in pulse pressure, mean arterial pressure, and double product (a measure of cardiac workload and an indirect measure of myocardial oxygen demand) at week 164 as compared to placebo. Reductions in these measures with either empagliflozin dose versus placebo held across age, gender, and systolic blood pressure groups.

Symposium: SGLT2 Inhibitors—Still More to Explore

Clinical Impact of SGLT2 Inhibitors on Bone—The FDA Perspective

Hyon J. Kwon, PhD (FDA, Silver Spring, MD)

With the safety of SGLT-2 inhibitors currently under a microscope, FDA’s Dr. Hyon Kwon provided insight on the fracture risk associated with J&J’s Invokana (canagliflozin) and AZ’s Farxiga (dapagliflozin) but not Lilly/BI’s Jardiance (empagliflozin). He positioned the label warnings for Invokana and Farxiga not as deterrents, but as a means to encourage thoughtful patient selection to mitigate fracture risk in the real world – we were happy to hear this perspective from FDA, since we’d hate for safety concerns to define the SGLT-2 inhibitor story when there are also tremendous glycemic, weight loss, and CV benefits to consider. Dr. Kwon noted that canagliflozin was only associated with a significantly increased risk for fractures in the CANVAS trial, but not in other studies within the Invokana clinical program, so heightened fracture risk may only apply to patients at high CV risk. An interim analysis of CANVAS found a hazard ratio of 1.51 in favor of placebo (95% CI=1.04-2.19), which doesn’t cross the line of unity and thus meets the threshold for statistical significance. Non-CANVAS studies reported a hazard ratio of 1.09 in favor of placebo (95% CI=0.71-1.66), but this fracture risk did not meet statistical significance. Dr. Kwon displayed graphs for time to first fracture in CANVAS, in which the curves diverge early on. He explained that a separation of curves <12 weeks after randomization suggests that fractures are due to falls rather than an impact on bone metabolism, an effect that would only accrue with longer duration of treatment. Moreover, interim CANVAS results showed a 60% increased risk of falls for participants on 300 mg canagliflozin vs. placebo (HR=1.60; 95% CI=1.11-2.32), which contributes to this hypothesis. It’s unclear if this increase in falls is a chance finding or if something about the canagliflozin causes increased risk of falls (through balance issues or confusion, perhaps?). As such, based on current data, the FDA cannot rule out that this particular SGLT-2 inhibitor may confer excess fracture risk for all patients, regardless of their CV risk factors. A pooled analysis of CANVAS and other Invokana clinical trials resulted in a hazard ratio of 1.32 in favor of placebo (95% CI=1.00-1.74). That said, we’re reserving judgement until we see the full, integrated results from CANVAs and CANVAS-R, which will be presented on Monday. In addition to long-awaited CV data, our ears will be perked for any safety details on the bone fracture risk (and the newly characterized amputation risk). Turning to Farxiga, Dr. Kwon showed that there was no imbalance in fractures between dapagliflozin-treated patients and placebo-treated patients overall, but that one study enrolling individuals with moderate renal impairment did find excess fracture risk associated with AZ’s SGLT-2 inhibitor. Fractures were most common in participants with eGFR between 11-45 ml/min/1.73m². This was added to the drug label under the “warnings & precautions” section, but again, this risk could be well-managed through diligent patient education, allowing many people with diabetes to still benefit from a highly-effective, advanced therapy.

• We think we speak for many at this meeting when we say we’re anxious for CANVAS to report full results on Monday afternoon. No matter what, this data will be telling – we have our fingers crossed for a statistically significant CV benefit that builds evidence for a cardioprotective class effect (following EMPA-REG OUTCOME) and highlights the therapeutic advantages of SGLT-2 inhibitors, but we’ll also need to scrutinize fracture data from the completed trial as well as data on amputations considering the FDA’s decision to add safety warnings for lower limb amputations to the Invokana label. All in all, our sense is that SGLT-2 inhibitors have a complicated risk-benefit profile and we’re always eager for more data to aid patients and providers in clinical decision-making regarding this class.

Clinical Role of SGLT2 Inhibitors – Current and Future

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

In a very candid presentation, Dr. Julio Rosenstock provided an overview of the many indications he envisions in the future of the SGLT-2 inhibitor class. While acknowledging that there has been a steady stream of safety warnings for the class, he emphasized that most of the concerns are manageable and the overall risk-benefit profile for these agents favor their use in a number of indications. Within type 2 diabetes, based on the EMPA-REG OUTCOME data and the CVD-REAL data, Dr. Rosenstock asserted that, it would be highly questionable for a patient with type 2 diabetes and a prior history of cardiovascular disease to not be on an SGLT-2 inhibitor, unless there was a contraindication, intolerance issues, or other clinical concern – he also appeared optimistic that the impressive cardiovascular benefit observed in EMPA-REG OUTCOME is a class effect, based on CVD-REAL. We certainly look forward to the CANVAS results presentation this Monday to potentially substantiate this! Further, Dr. Rosenstock suggested that SGLT-2 inhibitor and metformin combination therapy will increasingly become the preferred first line treatment for all patients with newly-diagnosed type 2 diabetes, not just those with established CV disease. He also suggested that SGLT-2 inhibitor/DPP-4 inhibitor fixed-dose combinations (FDC) will become the preferred second-line treatment for patients who are not well managed on metformin monotherapy – he argued that it makes little sense to intensify with only an SGLT-2 inhibitor or only a DPP-4 inhibitor when the combination of the two has been demonstrated to be more efficacious than either component. Beyond type 2 diabetes, Dr. Rosenstock forecasted a role for SGLT-2 inhibition in type 1 diabetes adjunct therapy. He acknowledged that there are clear safety issues – characterizing the highly publicized DKA risk as “real” – but emphasized that the risk is predictable, detectable and preventable. That said, Dr. Rosenstock shared rumors that Janssen is unlikely to pursue a type 1 diabetes indication for Invokana (canagliflozin) further, following phase 2 results. On the other hand, he was more optimistic about Janssen pursuing an obesity indication for a combination of canagliflozin/phentermine, which reported promising phase 2 data at ADA 2016. Dr. Rosenstock was also excited about the potential of SGLT-2 inhibitors in chronic kidney disease and in heart failure – several trials are ongoing for both of these indications and we’re similarly excited to see these results. Finally, Dr. Rosenstock also highlighted a potential role of SGLT-2 inhibitors in prediabetes and primary CV prevention. Indeed, J&J has previously shared plans to conduct a CVOT for Invokana in people with prediabetes and we’re very intrigued by this prospect as well.

SGLT-2 Inhibitors, Diabetic Ketoacidosis, and the Kidney

Matthew Weir, MD (University of Maryland, Baltimore, MD)

Dr. Matthew Weir reviewed the pathophysiology of SGLT-2 inhibitors, describing potential mechanisms for diabetic ketoacidosis (DKA) and for the CV and renal benefits associated with multiple members of the class, ultimately concluding that the “risk is very small and the upside is very substantial” for this therapy class as a whole. He compared the biochemical pathways of starvation to DKA and pointed to glomerular hyperfiltration, pro-inflammatory processes, and increased ATP production as possible mechanisms for SGLT-2 inhibitors’ renal and CV benefits. Dr. Weir discussed some of the more recent data on eGFR reductions with SGLT-2 agents (specifically looking at the findings in EMPA-REG OUTCOME), and shared that these reductions are likely not of significant concern. Looking forward, he called attention to additional considerations about newer therapies, including (i) their ability to be complementary with RAAS blockers, (ii) if effects remain at various blood pressures, and (iii) whether effects persist after treatment cessation. In conclusion, Dr. Weir strongly endorsed the use of SGLT-2 inhibitors, emphasizing the improvements in glycemic control, blood pressure reductions, and opportunities for CV and renal risk reduction, all of which outweigh the manageable DKA risk in his view (and ours).

Corporate Symposium: DCRI Evidence to Practice Series – Management of Diabetes for Heart Failure Patients (Sponsored by BI)

Latest Research Findings and Knowledge Gaps

Jennifer Green, MD (Duke University, Durham, NC)

In her introduction to this bright and early corporate symposium, Dr. Jennifer Green highlighted the substantial overlap between diabetes and heart failure (28%-44% of patients with heart failure also have diabetes) and reviewed the current evidence on the effects of specific diabetes drugs on heart failure. She explained that while the FDA-mandated cardiovascular outcomes trials of diabetes drugs have provided valuable information about heart failure outcomes, significant knowledge gaps remain. Specifically, she noted that i) CVOTs for diabetes drugs were not designed specifically to enroll patients with heart failure or evaluate heart failure outcomes; ii) the percentage of participants with heart failure varied in the different trials; iii) minimal details about heart failure outcomes were collected; iv) heart failure hospitalization was typically the only heart failure endpoint measured, leaving out a number of other relevant outcomes; and v) the physiological basis of the drugs’ positive or negative effects on heart failure has not been fully explained. Looking forward, Dr. Green argued that at a minimum, investigators should collect more detailed information on heart failure outcomes in future trials of diabetes drugs. We’ve heard a great deal about assessing BNP (a marker for heart failure) at baseline in diabetes CVOTs – of course, hindsight is 20/20 and we don’t expect this is possible in CVOTs that have already initiated, but we expect more rigorous assessments of heart failure at baseline will become the norm as heart failure is seen as an increasingly important endpoint in these trials. She also expressed interest in investigating diabetes drugs specifically in patients with heart failure (as Lilly/BI are currently doing in the EMPEROR trials of Jardiance [empagliflozin] and AZ is doing in the Dapa-HF trial of Farxiga [dapagliflozin]), conducting trials to determine the best drug for these patients, and assessing the effects of older diabetes drugs on heart failure risk. 

Case Presentations

Robert Mentz, MD (Duke University, Durham, NC), Darren McGuire, MD (UT Southwestern, Dallas, TX), Eldrin Lewis, MD (Brigham and Women’s Hospital, Boston, MA)

The majority of the corporate symposium centered around three case presentations involving patients with both type 2 diabetes and heart failure. The speakers agreed that metformin is currently the treatment of choice for this patient population. Dr. Darren McGuire noted that many physicians still shy away from using metformin in patients with heart failure because it was previously contraindicated, but many cardiologists are now specifically endorsing the drug for this population. The speakers were cautiously optimistic about the positive effects of Lilly/BI’s Jardiance (empagliflozin) on heart failure demonstrated in EMPA-REG-OUTCOME.  All three speakers expressed excitement about the results demonstrating a 38% risk reduction for cardiovascular death and 35% risk reduction for heart failure hospitalization with Jardiance vs. placebo in patients with type 2 diabetes and high cardiovascular risk. However, the consensus seemed to be that only results from the EMPEROR trials, which are specifically designed to investigate the impact of Jardiance on heart failure, will be able to establish the drug as a standard treatment for this population. This was interesting to hear – of course, we do not expect the FDA will include any indication for heart failure on the Jardiance label until results from these trials are available (given the fairly dismissive discussion of the heart failure secondary endpoint finding at last year’s Advisory Committee meeting on the EMPA-REG OUTCOME results). On the other hand, the ESC heart failure guidelines have already been updated to recommend empagliflozin as a potential treatment for those with type 2 diabetes and comorbid heart failure.

Questions and Answers

Dr. Darren McGuire (UT Southwestern, Dallas, TX): I’m convinced there’s heterogeneity among DPP-4 inhibitors. I would avoid saxagliptin and alogliptin because sitagliptin has a completely clean heart failure label. If a DPP-4 is used, I would use sitagliptin, but I’m not sure I would use one in this patient [in the hospital after an acute MI with diabetes and heart failure]. I think metformin is great. The EMPA-REG results were impressive but we didn’t have acute MI patients in that trial so I don’t really know what I’m doing. My gut instinct is that it’s logical and probably indicated to do empagliflozin. There’s a relatively preserved ejection fraction and little concern about GLP-1 agonists, so I’d probably prefer that over DPP-4 inhibitors. I’m comfortable with an A1c target of 7-8%.

Dr. Jennifer Green (Duke University, Durham, NC): If you switched from saxagliptin to sitagliptin, you would probably get the same glycemic control. If you stopped the DPP-4 inhibitor, you could increase the empagliflozin dose but would probably have an A1c increase. In the EMPA-REG trial, there were essentially comparable benefits with both doses, so I wouldn’t feel compelled to up-titrate the dose. There are lots of nuances.

Q: If you used sitagliptin, how would you handle the dose because of the patient’s impaired renal function?

Dr. McGuire: I would use a lower dose. But I would lean away from DPP-4 inhibitors because of the impaired renal function.

Q: How reliable is her eGFR?

Dr. McGuire: She’s having an acute MI and heart failure, so there’s likely acute kidney injury. We have to use the best evidence we have but we don’t know what her real kidney function is.

Q: Should we be focusing on obesity management?

Dr. McGuire: Absolutely. We need your help. People think about cardiac rehab as a treadmill and exercise, but it’s a structured comprehensive program. We should use cardiac rehab resources for eligible people. Obesity should be a focus of the intervention as well.

Dr. Eldrin Lewis (Brigham and Women’s Hospital, Boston, MA): You hear about the obesity paradox in heart failure. I don’t think it’s a paradox. If you’re obese, you may be short of breath for other reasons, so you may be healthier than someone of normal weight who has the same degree of dyspnea. We should be emphasizing weight loss for control of diabetes and heart failure symptoms.

Dr. Green: There’s some data on the association between glucose-lowering therapies and their effect on weight and heart failure outcomes. The suggestion is that therapies associated with weight loss are associated with reduced heart failure risk and those associated with weight gain are associated with higher risk. It’s an area ripe for further exploration.

Corporate Symposium: CVOTs and Combination Therapy: Updates and Advances at ADA 2017 (Sponsored by AstraZeneca)

Cardiovascular Outcomes Trials (CVOTs): Clinical Application of Current Data and a Sneak Peek into the Future

Carol Wysham, MD (University of Washington, Spokane, WA); Hertzel Gerstein, MD (McMaster University, Ontario, Canada)

Drs. Carol Wysham and Hertzel Gerstein reviewed all the major CVOT data on diabetes drugs that has been published so far, and shared pearls of wisdom about how to translate these findings into real-world clinical practice. Dr. Gerstein positioned GLP-1 agonists as the frontrunners in terms of demonstrating CV benefit, with both the LEADER trial for Novo Nordisk’s Victoza (liraglutide) and the SUSTAIN 6 study for Novo Nordisk’s semaglutide showing meaningful CV risk reduction. That said, SGLT-2 inhibitors like Lilly/BI’s Jardiance (empagliflozin) and J&J’s Invokana (canagliflozin) have also demonstrated superiority vs. placebo in reducing risk for three-point MACE (non-fatal MI, non-fatal stroke, or CV death), and these agents come with the convenience of oral dosing (whereas GLP-1 agonists are injectable therapies). Dr. Wysham emphasized that CVD-REAL showed SGLT-2 inhibitors to be associated with a very dramatic risk reduction for heart failure hospitalization and all-cause death. A majority of European participants in CVD-REAL (92%) were taking AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin), while a majority of US participants were taking Invokana (76%) – Dr. Wysham underscored this point to clarify that she wouldn’t necessarily recommend switching patients off dapagliflozin onto empagliflozin right now. AZ’s own CVOT for dapagliflozin, DECLARE, is scheduled to complete in April 2019.

Oral Combination Therapy for T2D: What, Why, and How Explored

Julio Rosenstock, MD (University of Texas, Dallas, TX); Melanie Davies, MD (University of Leicester, UK)

Drs. Julio Rosenstock and Melanie Davies led this interactive discussion on oral combination therapies for type 2 diabetes, covering DPP-4/metformin tablets, SGLT-2/metformin tablets, and SGLT-2/DPP-4 tablets including AZ’s Qtern (dapagliflozin/saxagliptin). The duo positioned combination therapy as a solution to therapeutic inertia. The status quo in diabetes management is still the treat-to-fail paradigm, with healthcare providers trying medications in a stepwise fashion. Instead, Drs. Rosenstock and Davies advocated for early intervention with simultaneous medications, or better yet, with a fixed-dose combination therapy. They presented Qtern (and other SGLT-2/DPP-4 combo products like Lilly/BI’s Glyxambi) as a rational choice in diabetes care: These agents come in convenient oral doses, they lower risk of hypoglycemia and promote weight loss, they show superior glucose-lowering efficacy vs. either drug alone, and they eliminate some patient barriers by turning two co-pays into one. Diabetes treatment guidelines are starting to recommend combination therapy earlier on, especially for patients with high baseline A1c, but Drs. Rosenstock and Davies suggested that this change needs to happen faster. We’re certainly intrigued by the promise of fixed-dose SGLT-2/DPP-4 combinations, and we’re glad to note AZ’s commitment to Qtern given its strong clinical profile. Moreover, we love the argument that combination therapy could circumvent therapeutic inertia, which continues to be a problem leading to suboptimal diabetes care.

-- by Melissa An, Ann Carracher, Abigail Dove, Helen Gao, Payal Marathe, Emily Regier, Lisa Rotenstein, and Kelly Close