Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events - DEVOTE

Contribution To Literature:

The DEVOTE trial showed that degludec is similar to insulin glargine in improving glycemic control and noninferior for reducing cardiovascular events in patients with type 2 diabetes and high cardiovascular risk, with a lower risk of severe hypoglycemia.

Description:

The goal of the trial was to assess the cardiovascular safety of insulin degludec compared with insulin glargine in patients with type 2 diabetes at high risk of cardiovascular events.

Study Design

Patients were randomized in a 1:1 fashion to either degludec (n = 3,818) or insulin glargine  (n = 3,819) administered once daily between dinner and bedtime. All patients were on at least one other agent for diabetes.

  • Total number of enrollees: 7,637
  • Duration of follow-up: 1.99 years
  • Mean patient age: 65 years
  • Percentage female: 37%

Inclusion criteria:

  • Type 2 diabetes
  • Age ≥50 years with predefined previous cardiovascular disease(s) or renal disease, or age ≥60 years with predefined cardiovascular risk factors
  • Glycated hemoglobin (HbA1c) ≥7.0% or HbA1c <7.0% and current insulin treatment corresponding to ≥20 U of basal insulin per day
  • One or more oral or injectable antidiabetic agent(s)

Exclusion criteria:

  • An acute coronary or cerebrovascular event in the previous 60 days
  • Planned coronary, carotid, or peripheral artery revascularization
  • Chronic heart failure (New York Heart Association) class IV
  • Current or past (within the last 5 years) malignant neoplasms (except basal cell and squamous cell skin carcinoma)

Other salient features/characteristics:

  • Diabetes duration: 16.4 years
  • Mean HbA1c: 8.4%
  • Established chronic kidney disease: 16%
  • Established cardiovascular disease: 63%
  • Statins: 79%
  • Aspirin: 65%

Principal Findings:

The primary outcome, cardiovascular death, nonfatal myocardial infarction (MI), or stroke for degludec vs. glargine, was 8.5% vs. 9.3% (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.78-1.06, p < 0.001 for noninferiority; p = 0.21 for superiority).

  • Cardiovascular death: 3.6% vs. 3.7%, p = 0.71 
  • Nonfatal MI: 3.8% vs. 4.4%, p = 0.15
  • Nonfatal stroke: 1.9% vs. 2.1%, p = 0.50

Secondary outcomes for degludec vs. glargine:

  • HbA1c at 24 months: 7.5% vs. 7.5%, p > 0.05
  • All-cause mortality: 5.3% vs. 5.8%, p = 0.35
  • Severe hypoglycemia: 4.9% vs. 6.6%, p < 0.001
  • Neoplasms: 3.2% vs. 3.0, p > 0.05

Interpretation:

The results of this trial indicate that degludec is similar to insulin glargine in improving glycemic control and noninferior for reducing cardiovascular events in patients with type 2 diabetes and high cardiovascular risk. The risk of severe hypoglycemia was lower with degludec. Degludec is an ultra-long acting once daily formulation of basal insulin. Following the much publicized cardiovascular safety concerns with rosiglitazone, the Food and Drug Administration mandated that all new diabetes drugs conduct studies demonstrating cardiovascular safety. The upper limit of the 95% CI for the HR had to be <1.8 for premarketing studies and <1.3 for postmarketing studies. This trial thus establishes the cardiovascular safety profile of degludec for use in patients with type 2 diabetes, compared with insulin glargine.

References:

Marso SP, McGuire DK, Zinman B, et al., on behalf of the DEVOTE Study Group. Efficacy and Safety of Degludec Versus Glargine in Type 2 Diabetes. N Engl J Med 2017;Jun 12:[Epub ahead of print].

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention

Keywords: Blood Glucose, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Hemoglobin A, Glycosylated, Hypoglycemia, Insulin, Insulin, Long-Acting, Metabolic Syndrome X, Myocardial Infarction, Primary Prevention, Risk Factors, Stroke, Thiazolidinediones


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