Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes

Abstract

Background: Degludec is an ultralong-acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-to-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec.

Methods: We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-to-target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-to-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-adjusted secondary outcome.

Results: Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P<0.001 for noninferiority). At 24 months, the mean glycated hemoglobin level was 7.5±1.2% in each group, whereas the mean fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter, P<0.001). Prespecified adjudicated severe hypoglycemia occurred in 187 patients (4.9%) in the degludec group and in 252 (6.6%) in the glargine group, for an absolute difference of 1.7 percentage points (rate ratio, 0.60; P<0.001 for superiority; odds ratio, 0.73; P<0.001 for superiority). Rates of adverse events did not differ between the two groups.

Conclusions: Among patients with type 2 diabetes at high risk for cardiovascular events, degludec was noninferior to glargine with respect to the incidence of major cardiovascular events. (Funded by Novo Nordisk and others; DEVOTE ClinicalTrials.gov number, NCT01959529 .).

Figure 1. Kaplan–Meier Analysis of the Composite Primary Outcome

Shown are plots of time until the primary outcome (Panel A) and its composite events — death from cardiovascular causes (Panel B), nonfatal myocardial infarction (Panel C), and nonfatal stroke (Panel D) — in the degludec group and the glargine group. The noninferiority of degludec as compared with glargine was confirmed because the upper limit of the two-sided 95% confidence interval for the hazard ratio was less than 1.3. The results were determined by the event-adjudication committee on the basis of Cox proportional-hazards regression analysis in the intention-to-treat population. Data for patients without an event were censored at the time of the last contact (telephone or visit). The inset graphs show the same data on expanded y axes.

Figure 2. Severe Hypoglycemia and Glucose Control

Shown are the observed cumulative number of events of severe hypoglycemia (Panel A) and nocturnal severe hypoglycemia (Panel B) per patient in the degludec group and the glargine group. For severe hypoglycemia, the superiority of degludec over glargine was confirmed because the upper limit of the two-sided 95% confidence interval for the estimated rate ratio was below 1.0. Nocturnal severe hypoglycemia was defined as an episode with an investigator-reported onset between 12:01 a.m. and 5:59 a.m. Also shown are measures of treatment efficacy, according to the glycated hemoglobin level (Panel C) and the fasting plasma glucose level (Panel D) in the two groups, with both comparisons performed in post hoc analyses.