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Overview

Study Background and Purpose

Comprehensive evaluation of the cardiovascular safety profile of new drugs for type 2 diabetes mellitus is now required by regulatory agencies. The EXAMINE Trial evaluated major cardiovascular outcomes with alogliptin, a new dipeptidyl-peptidase 4 (DPP-4) inhibitor, versus placebo in patients with type 2 diabetes and a recent acute coronary syndrome.

Study Methods and Results

Patients with type 2 diabetes who had either an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days were randomly assigned to receive alogliptin or placebo added to existing anti-hyperglycemic and cardiovascular drug therapy. The study design was a double-blind, non-inferiority trial with a pre-specified non-inferiority margin of 1.3 for the primary end point of a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. A total of 5,380 patients were randomly assigned and followed for a median of 18 months and up to 40 months. The primary end point occurred in 305 patients (11.3%) assigned to alogliptin and in 316 patients (11.8%) assigned to placebo (hazard ratio, 0.96, one-sided repeated confidence upper bound, 1.16 (p <0.001 for non-inferiority). Glycated hemoglobin levels (HBA1c) were significantly lower on alogliptin than placebo (mean difference of -0.36%, (p< 0.001). Incidences of hypoglycemia, malignancy, pancreatitis, and dialysis were similar for alogliptin and placebo.

EXAMINE Major Safety End Points
End Point Placebo  (n = 2679) Alogliptin (n = 2701) Hazard Ratio for Alogliptin Group (95% CI) P value*
Primary end point: CV death, nonfatal MI, or nonfatal stroke — no. (%) 316 (11.8) 305 (11.3) 0.96 (<1.16)** 0.315
  • CV death
111 (4.1) 89 (3.3) 0.79 (0.60, 1.04) 0.097
  • Nonfatal MI
173 (6.5) 187 (6.9) 1.08 (0.88, 1.33) 0.467
  • Nonfatal stroke
32 (1.2) 29 (1.1) 0.91 (0.55, 1.50) 0.707
Secondary end point: CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent revascularization — no. (%) 359 (13.4) 344 (12.7) 0.95 (< 1.14)** 0.258
Other end points — no. (%)
  • Death from any cause
173 (6.5) 153 (5.7) 0.88 (0.71, 1.09) 0.230
  • Death from CV cause†
130 (4.9) 112 (4.1) 0.85 (0.66, 1.10) 0.212

* p – values for testing superiority of alogliptin to placebo calculated using Cox regression analysis

** – one-sided repeated confidence intervals using alpha = 0.01; CI=confidence interval; CV = cardiovascular; MI = myocardial infarction

† – death from CV cause includes the CV deaths that occurred in the primary end point and those that occurred following a nonfatal primary end point

Study Conclusion

In patients with type 2 diabetes and recent acute coronary syndrome, major adverse cardiovascular event rates for the DPP-4 inhibitor alogliptin were not increased compared with placebo. (Clinicaltrials.govNCT00968708)