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ADA: Degludec Deemed Non-Inferior to Glargine Regarding Cardiovascular Safety in High Risk Patients with Type 2

The DEVOTE trial compared cardiovascular safety in two basal insulins; insulin degludec was found to have additional benefits.

Insulin therapy, although effective in lowering blood glucose levels in patients with type 2 diabetes (T2DM), is typically reserved for those who have failed combination oral antidiabetic therapies. This is due to the extensive classes of oral antidiabetic agents available and the risk of hypoglycemia associated with insulin therapy. If untreated, severe hypoglycemia can lead to coma, seizures and death. Basal insulin therapies, compared to bolus insulin therapies, lowers the risk of hypoglycemia, particularly nocturnal hypoglycemia. In 2015, the FDA approved insulin degludec, an ultra-long acting insulin with approximately 42 hours of effect and low intra-patient variability. The DEVOTE trial, recently published in June 2017, investigated the cardiovascular safety of insulin degludec in patients with type 2 diabetes and high risk for cardiovascular events. Researchers compared degludec to glargine, because cardiovascular safety of glargine has already been established in the ORIGIN trial.

The DEVOTE trial randomized 7,637 participants in a 1:1 ratio and followed participants for approximately 2 years. Participants received glargine or degludec once daily in addition to standard of care. Majority of the participants (85.2%) had a history of cardiovascular disease and/or moderate chronic kidney disease; the remainder of the participants had high risk for developing cardiovascular complications. The two study groups had similar baseline characteristics; the mean age was 65 years old and the mean duration of diabetes was 16.4 years. The primary outcome was a composite of first occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke. The data was analyzed using a cox proportional-hazard regression model to test for non-inferiority. The secondary outcomes, including severe hypoglycemia and nocturnal severe hypoglycemia were analyzed using a negative binomial-regression model and a logistic-regression model.

Results of the DEVOTE trial indicated that degludec was not inferior to glargine in the primary outcome (8.5 vs 9.3%; HR: 0.91; 95% CI 0.78 to 1.06; one-sided p < 0.001). Individual components (first occurrence of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke) was not considered statistically different between the two study groups. Participants in the degludec study group had a lower incidence of severe hypoglycemia compared to the participants in the glargine study group (3.70 vs 6.25 events per 100 patient years; Ratio Rate: 0.60; 95% CI 0.48 to 0.76; one-sided p < 0.001). This corresponds to a 40% overall reduction in the total episodes of hypoglycemia in this study. Researchers consider degludec superior to glargine in reducing the risk of nocturnal severe hypoglycemia by 53% (0.65 vs 1.40 events per 100 patient years; Ratio Rate: 0.47; 95% CI 0.31 to 0.73; p < 0.001). Lastly, the authors observed a decreased rate in adverse effects in the degludec study group compared to the glargine study group.

The trial assures healthcare providers that insulin degludec is comparable to glargine in cardiovascular safety for adult patients with type 2 diabetes. Degludec also has the added benefit of reducing the risk of severe hypoglycemia and nocturnal hypoglycemia, two major concerns of insulin therapy. This is potentially explained by degludec’s ultra-long duration of effect and lower intra-patient variability.

Practice Pearls:

  •        The use of basal insulin therapy can increase glycemic control and decrease the risk of hypoglycemia for patients who fail first line oral antidiabetic combination therapies.
  •        Insulin degludec can be regarded as a safe option in patients with type 2 diabetes and high risk of cardiovascular complications.
  •        Insulin degludec demonstrated decreased risk of severe hypoglycemia and nocturnal hypoglycemia compared to insulin glargine.

References:

Marso S, McGuire D, Zinman B, et al. Efficacy and Safety of Degludec vs Glargine in Type 2 Diabetes. The New England Journal of Medicine. 2017. Epub 2017/06. doi: 10.1056/NEJMoa1615692

American Diabetes Association. New, Long-Acting Insulin Therapy Demonstrates Cardiovascular Safety and Reduces the Risk of Severe Hypoglycemia. Press Release. Available at: http://www.diabetes.org/newsroom/press-releases/2017/buse-and-marso-scientific-session-2017.html. Accessed June 15, 2017.

Joanna Martinez-Mendez, PharmD Candidate 2018, Lake Erie College of Osteopathic Medicine School of Pharmacy: FL Campus