Clinical Pearls & Morning Reports
Published August 23, 2017
Cardiovascular complications remain two to four times more common among patients with type 2 diabetes than among persons without diabetes. To comply with the Food and Drug Administration requirement that a dedicated preapproval trial of cardiovascular outcomes be conducted to assess the cardiovascular safety of degludec, as compared with glargine, Marso et al. conducted the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE). Read more in the Original Article.
Q. What is degludec?
A. The development of basal insulins with more stable pharmacodynamic profiles has allowed patients to aim safely for fasting glucose levels in the normal range by providing a consistent glucose-lowering effect with a half-life of more than 24 hours and thereby reducing the occurrence of hypoglycemia. Degludec is an ultralong-acting, once-daily basal insulin approved for use in adults, adolescents, and children with diabetes.
Q. How does the cardiovascular safety of degludec compare to that of glargine among patients with type 2 diabetes at high risk for cardiovascular events?
A. In the trial by Marso et al., the primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary composite outcome occurred in 325 patients (8.5%) in the degludec group and in 356 patients (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P<0.001 for noninferiority in a one-sided test). The demonstrated safety of degludec with respect to cardiovascular outcomes was reflected in the individual components of the primary composite outcome and was consistent across multiple prespecified subgroups.
Table 1. Primary Outcomes.
A: In the trial by Marso et al., one or more events of 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 (odds ratio, 0.73; 95% CI, 0.60 to 0.89; P<0.001 for superiority). In addition, there was a lower rate of nocturnal severe hypoglycemia in the degludec group than in the glargine group (0.65 vs. 1.40 events per 100 patient-years) for a rate ratio of 0.47 (95% CI, 0.31 to 0.73; P<0.001).
Figure 2. Severe Hypoglycemia and Glucose Control.
A: There was no significant between-group difference in changes in glycated hemoglobin levels throughout the trial. At 24 months, the glycated hemoglobin level was 7.5% (58 mmol per mole) in the two groups, with an estimated treatment difference of 0.01 percentage points (95% CI, –0.05 to 0.07; P=0.78 in post hoc analysis). At 24 months, the mean laboratory-measured fasting plasma glucose level was significantly lower in the degludec group than in the glargine group (128±56 vs. 136±57 mg per deciliter [7.1±3.1 vs. 7.5±3.2 mmol per liter]). Overall initiation of concomitant antihyperglycemic medications during the trial was similar in the two groups. The rate of adverse events was 44.7 events per 100 patient-years in the degludec group and 50.1 events per 100 patient-years in the glargine group; the corresponding rates of serious adverse events were 44.2 events versus 49.6 events per 100 patient-years.