SAN DIEGO (FRONTLINE MEDICAL NEWS) – For patients with type 2 diabetes at high risk of cardiovascular disease, the ultra–long-acting, once-daily basal insulin degludec produced a similar risk of major adverse cardiovascular events as glargine with a significantly lower risk of severe hypoglycemia, new data show.

Nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death occurred in 325 (8.5%) patients on degludec and 356 (9.3%) patients on glargine (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P = .21) in DEVOTE (the Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events). Rates of severe hypoglycemia were 4.9% and 6.6%, respectively (P less than .001), investigators reported at the annual scientific sessions of the American Diabetes Association and simultaneously in the New England Journal of Medicine (2017 Jun 12. doi: 10.1056/NEJMoa1615692 ).

“DEVOTE confirmed the cardiovascular safety of insulin degludec, compared with insulin glargine,” said study investigator John B. Buse, MD, PhD , who is professor of medicine, chief of the division of endocrinology, and director of the diabetes care center at the University of North Carolina, Chapel Hill. “In addition, a 40% lower risk of severe hypoglycemia was confirmed at similar levels of hemoglobin A1c, and a 53% lower rate of nocturnal severe hypoglycemia was confirmed at a lower fasting plasma glucose level.” Those differences count, he told a packed auditorium at ADA. In past studies, patients with type 2 diabetes often cut their insulin dose after a hypoglycemic event and more than 70% of providers said concerns about hypoglycemia prevented them from aggressively treating diabetes, he noted.

Insulin degludec injection (Tresiba®, Novo Nordisk) is a basal insulin analog, the long, soluble hexamer chains of which are metabolized only at the ends, yielding at least a 42-hour duration of action, Todd Hobbs, MD , chief medical officer of Novo Nordisk, Princeton, N.J., explained in an interview. In contrast, glargine has about a 12-hour half-life. Previous trials of degludec did not adjudicate cardiovascular endpoints, which the U.S. Food and Drug Administration only recently began requiring for insulins, Dr. Hobbs said. In response to an FDA request, the phase III, international, randomized, double-blind DEVOTE trial compared the cardiovascular safety of daily basal insulin degludec (100 U per mL) with that of glargine U100 in more than 7,600 adults with type 2 diabetes.

Participants were typically obese, with HbA1c levels of 8.4% and fasting plasma glucose levels of about 170 mg per dL. About 85% of patients had cardiovascular disease or chronic kidney disease and were at least 50 years old, and the rest had multiple cardiovascular risk factors.

Fully 98% of patients completed the 2-year trial. The overall risk of major adverse cardiac events resembled that of each individual component, including cardiovascular death (HR, 0.96; 95% CI, 0.76-1.21; P = .71), nonfatal myocardial infarction (HR, 0.85; 95% CI, 0.68-1.06; P = .15), and nonfatal stroke (HR, 0.90; 95% CI, 0.65-1.23; P =. 50). Degludec remained noninferior to glargine when researchers added unstable angina to the primary endpoint and accounted for patient location, treatment duration, length of follow-up, and age, sex, body mass index, and renal function.

Both insulins produced similar HbA1c levels of about 7.5%, but degludec cut fasting plasma glucose by about 5 mg per mL more, compared with glargine (P less than .001), the investigators reported. Furthermore, the odds ratio for severe hypoglycemia significantly favored degludec (HR, 0.73; 95% CI, 0.60-0.89; P less than .001). In other words, 40 patients would need to receive degludec rather than glargine to prevent one event of severe hypoglycemia. Previous studies have shown similar results, Dr. Buse said. In a pooled analysis of all five trials of type 2 diabetes in the degludec clinical development program, degludec was associated with a significantly lower risk of hypoglycemia, particularly nocturnal episodes, than was glargine ( Diabetes Obes Metab. 2013;15:175-84 ).

Findings were similar in the double-blind SWITCH 2 trial ( Diabetologia. 2016;59[Suppl 1]:1-581 ).

DEVOTE identified no safety issues for degludec, compared with glargine. Each arm had similar rates of serious or severe adverse events, leading to treatment discontinuation, and neoplasms. Nonetheless, DEVOTE had several limitations, said Elizabeth R. Seaquist, MD , of the University of Minnesota, Minneapolis, who was not involved in the study. “Investigators could modify the titration protocol based on clinical judgment, and it isn’t clear whether this modification was applied equally in both arms,” she said at ADA. “Another weakness is that there were no data collected about moderate symptomatic hypoglycemia, the most common type of hypoglycemia that patients experience.” DEVOTE also did not examine how often blood glucose dropped below 54 mg per dL, the point at which patients often do not know they are hypoglycemic. Investigators also should examine whether degludec cuts health care costs or improves sleep or quality of life, whether its glycemic benefits extends to patients who are insulin-naive or have severe kidney disease, and how it compares with glargine U300, she added.

Insulin degludec received FDA approval in September 2015, based on interim results of DEVOTE. Novo Nordisk makes insulin degludec and sponsored the trial. Dr. Buse disclosed consulting fees from Novo Nordisk and ties to many other pharmaceutical companies. Dr. Seaquist disclosed ties to Novo Nordisk, Eli Lilly, Locemia, and Lucera. Dr. Hobbs is chief medical officer for Novo Nordisk.