American Diabetes Association 77th Scientific Sessions

June 9-13, 2017; San Diego, CA; DEVOTE Results First Look – Draft

Executive Highlights

Full results from the DEVOTE cardiovascular outcomes trial (CVOT) for Novo Nordisk’s next-generation basal insulin degludec (Tresiba) were just presented at ADA 2017 and simultaneously published in NEJM (company announcement here). What we see as the “headline” (albeit expected due to SWITCH1 and SWITCH2) is the incredibly impressive severe hypoglcyemia benefit. The CV results, which we go into below, show non-inferiority. The details: To start with CV (it’s a CVOT, after all). The randomized, double-blind trial (n=7,637) demonstrated non-inferiority for Tresiba compared to standard of care insulin glargine (Sanofi’s Lantus) for the primary 3-point MACE composite endpoint (non-fatal MI, non-fatal stroke, and CV death). That said, the hazard ratio (HR) point estimate was in the “right direction” at 0.91 (95% CI:0.78-1.06, p<0.001 for non-inferiority, p=0.21 for superiority). There are a lot of numbers below – that’s because some of you want all the confidence intervals etc. (let us know how you feel about this presentation if you feel strongly).

Expanded MACE (including hospitalization for unstable angina) was non-inferior as well (HR=0.91, 95% CI:0.80-1.05, p=0.22). Tresiba also demonstrated non-inferiority for each component of the MACE endpoint, with point estimates to the “left of unity” (meaning 1.0) in each case, including non-fatal MI (HR=0.85, 95% CI: 0.68-1.06, p=0.15), non-fatal stroke (HR=0.90, 95% CI: 0.65-1.23, p=0.50), and hospitalization for unstable angina (HR=0.95, 95% CI:0.68-1.31, p=0.74). Similarly, point estimates for all reported mortality endpoints were on the “right side,” though non-inferior, including CV death (HR=0.96, 95% CI: 0.0.76-1.21), all-cause mortality (HR=0.91, 95%CI:0.76-1.11), CV death excluding undetermined cause of death (HR=0.91, 95% CI: 0.69-1.20), and non-CV death (HR=0.84, 95% CI: 0.60-1.16). All in all, we can certainly rest assured that Tresiba is at the very least safe from a CV standpoint, though we cannot draw any definitive conclusions about potential benefit. That said, non-inferiority in and of itself is reassuring given Tresiba’s long and complicated regulatory history. As a reminder, the product’s first regulatory submission in the US received a Complete Response Letter (CRL) from the FDA, requesting a CVOT to further investigate a signal for increase expanded MACE risk observed in the phase 3 trials. The FDA’s eventual approval based on firewalled interim data was certainly reassuring on this front and we’re pleased to get our hands on full CVOT data that suggests not even a whiff of increased risk for Tresiba.

More notable than the CV results, in our view, are the very impressive severe hypoglycemia findings. Tresiba was associated with a very significant 40% relative risk reduction for severe hypoglycemia compared to Lantus (HR=0.60, 95% CI 0.48-0.76, p<0.001 for superiority) and a whopping 53% reduced risk for nocturnal severe hypoglycemia (HR=0.47, 95% CI: 0.31-0.73, p<0.001). (Amazing confidence intervals.) Severe hypoglycemia was adjudicated in the study and defined as low blood glucose requiring the assistance of another person. 4.9% of participants in the Tresiba group experienced one or more episodes of severe hypoglycemia, compared to 6.6% of participants in the Lantus group (odds ratio: 0.73; 95% CI: 0.60-0.89; p<0.001 for superiority). Notably, these reductions in hypoglycemia occurred in the context of virtually identical low mean A1cs of 7.5% at the end of the trial (baseline A1c=8.4%) – end-of-trial A1c difference between the two arms was estimated at 0.01% (p=0.78). On the other hand, mean fasting plasma glucose (FPG) was 7.2 mg/dl lower in the Tresiba group compared to the Lantus group at the end of the trial (128 mg/dl vs. 136 mg/dl, p<0.001). This was driven by a larger reduction in FPG in the Tresiba group – 40 mg/dl vs. 35 mg/dl. The end-of-trial average basal insulin dose was slightly but significantly higher in the Tresiba group (2 units higher than average in Lantus group, p=0.04). We are not sure the impact on weight and we’ll be back with that and other outcomes beyond A1c (we hope to have hypoglycemia as well in addition to severe hypoglycemia).

We’re looking forward to further analysis and data disclosures from this trial in the coming months and years – and we’ll be back soon with more details and initial commentary on this trial from the University of Minnesota’s Dr. Betsy Seaquist. In the meantime, we’re excited and intrigued the benefit that Tresiba has repeatedly demonstrated on hypoglycemia, an extremely important outcome beyond A1c (following the SWITCH 1 and SWITCH 2 data). We would love to better understand the impact of Tresiba on glycemic variability and time-in-range(s) as well – we continue to hope that Novo Nordisk will consider inclusion of CGM data in future largescale studies of Tresiba and Xultophy (insulin degludec/liraglutide). We are also extremely eager to see patient-reported outcome results on the impact of Tresiba on quality of life, etc. – we’ll certainly be keeping our eyes peeled for and will be asking about additional data disclosures.

  • DEVOTE enrolled 7,637 patients with type 2 diabetes at high cardiovascular risk on at least one oral or injectable antihyperglycemic agent. The trial enrolled both primary and secondary CV prevention populations. CV risk eligibility criteria was similar to that of the Novo Nordisk-sponsored LEADER and SUSTAIN 6 trials: participants were required to be either (i) at least 50 years old with established cardiovascular or renal disease; or (ii) at least 60 years old with at least one cardiovascular risk factor. At baseline, 85% of participants had established cardiovascular disease or moderate chronic kidney disease. Mean age at baseline was 65 years, mean duration of diabetes was 16 years, and mean A1c was 8.4%. 55% of participants were on basal-bolus therapy at baseline. Unlike many other CVOTs, DEVOTE included an active comparator rather than a placebo control – participants were randomized 1:1 to receive either Tresiba or Lantus in a double-blind manner.
  • Tresiba was safe and well-tolerated in the trial, with numerically lower rates for all adverse events, serious adverse events, and events leading to treatment discontinuation compared to Lantus. The incidence of externally-classified neoplasms in both the Tresiba and Lantus groups were low – 1.7% in both groups.
  • For more of our initial thoughts, see our coverage of the topline results announcement in November 2016.

 

-- by Helen Gao and Kelly Close