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Degludec Compared with Glargine in Study

New insulin formulation emerges as safe alternative to long-acting insulins and inconsistent glycemic levels, but could have higher risk of cardiovascular events.

Type 2 diabetes is a progressive disease that is initially treated with glucose-lowering oral agents. As it advances, it can present with higher risk of vascular complication prompting a more intense therapy, eventually leading to the use of insulin in certain patients.

Major issues related with the treatment of insulin are the episodes of hypoglycemia and glycemic variability, which has also associated with adverse cardiovascular events. A new ultra-long insulin formulation Degludec (Tresiba) was approved recently to achieve stable pharmacodynamic profile with lower variability in glucose-lowering action when compared with insulin glargine. Previous studies have studies similarity in terms of glycemic control for both agents, and less incidences of hypoglycemia for degludec. The DEVOTE trial was designed to compare these insulin agents in terms of glycemic variability, major cardiovascular events and mortality.

DEVOTE was a multicenter, randomized, double-blind, active-comparator cardiovascular outcomes trial designed to continue until at least 633 major adverse cardiovascular events confirmed by a blinded Event Adjudication Committee (EAC).  All participants had type 2 diabetes treated with at least one antidiabetic agent with HbA1C > 7.0% or treated with > 20 units/day of basal insulin. Patients were eligible for the trial if they were over 50 years old with co-existing cardiovascular or renal condition. The participants were randomized 1:1 to receive either degludec or gargline once daily, and they were allowed to continue their non-insulin therapy. The insulins were titrated to reach glucose level between 72 and 126 mg/dL. (4-7 mmol/L). Primary outcomes included the first occurrence of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes included severe hypoglycemia. Each month, 3 self-monitored blood glucose readings were used to determine day-to-day fasting glycemic variability.

At the end of study, a total of 7,637 patients were randomized to either insulin degludec (n = 3818) or insulin glargine (n = 3819). The median observation time was 1.99 years. Depending on their glucose level fluctuations they were classified in 3 groups from low to high variability. The high variability group was also the one with the overall longer duration of diabetes (18.8 years vs 14.1 [low variability group] and 16.3 [medium variability group] years). Higher fasting glycemic variability was significantly associated with higher risks of severe hypoglycemia (hazard ratio = 4.11, p < 0.001), major adverse cardiovascular events (hazard ratio =1.36, p = 0.0023) and all-cause mortality.

After 2 years, major CV events occurred in 8.5% of the degludec group vs. 9.3% of the glargine group (Hazard ratio = 0.91; p < .001 for noninferiority). Also, results for all parameters of the primary composite endpoint were consistent for all participants: first occurrence of cardiovascular death (HR = 0.96), nonfatal MI (HR = 0.85) and nonfatal stroke (HR = 0.9). The degludec group had a significant reduction in the rate of severe hypoglycemia as compared to the glargine group. The rate of detected severe hypoglycemia was 6.6% in the glargine group vs. 4.9% in the degludec group (relative rate = 0.6; p < 0.001 for superiority. Furthermore, the rate of nocturnal severe hypoglycemia was significantly lower in the degludec group (RR = 0.47).

A limitation of this study was that glycemic variability was only based on fasting self-monitored blood glucose values, excluding any post-prandial readings. Strengths of this study include a large sample size, the double-blind design, an elevated level of cardiovascular risk of the participants, the prospective design and multicenter, international nature of this trial. The authors found degludec as safe as glargine regarding cardiovascular outcomes. The extent of glycemic variability was similar for both groups of participants treated with either degludec or glargine; high variability was correlated to a high risk of major cardiovascular events and severe hypoglycemia. Glargine, overall, was related to lesser number of hypoglycemic incidences.

Practice Pearls:

  • Degludec is as safe as glargine controlling type 2 diabetes and reducing the risk of cardiovascular complications.
  • Patients with high glycemic variability were found to have higher risk of cardiovascular events.
  • Patients who were treated with glargine showed less incidences of hypoglycemia.

References:

Bernard Zinman. Steven P. Marso. Day-today fasting glycemic variability in DEVOTE: associations with severe hypoglycemia and cardiovascular outcomes. Diabetologia. August 2017.

Marso SP. Symposium 3-CT-SY22. Presented at: American Diabetes Association 77th Scientific Sessions; June 9-13, 2017; San Diego.

Fabio Rodriguez, PharmD. candidate 2018, LECOM School of Pharmacy