Published in Diabetes, Obesity and Metabolism

Cardiovascular Safety of the Dipeptidyl Peptidase-4 Inhibitor Alogliptin in Type 2 Diabetes Mellitus

W. B. White, R. Pratley, P. Fleck, M. Munsaka, M. Hisada, C. Wilson3 & V. Menon

Aim

As there have been concerns that some classes or agents for the treatment of type 2 diabetes may increase CV risk, we evaluated the cardiovascular profile of the dipeptidyl peptidase-4 inhibitor alogliptin.

Method

We evaluated the incidence of CV events in patients treated with alogliptin, placebo or comparator antihyperglycaemic drugs in the clinical trial database for alogliptin using the composite major adverse cardiovascular event (MACE) endpoints of CV death, non-fatal myocardial infarction and non-fatal stroke.

Results

The pooled analysis included 4168 patients exposed to alogliptin 12.5 and 25 mg daily for 2,023 patient-years compared to 691 patients treated with placebo for 263 patient-years and 1,169 patients treated with other antidiabetic agents (metformin, sulfonylureas and thiazolidinediones) for 703 patient-years. CV events were adjudicated by an expert endpoint committee blinded to treatment allocation. The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies (hazard ratio=0.635, 95% confidence interval, 0.0, 1.41). Additionally, other types of serious CV events were not significantly different between patients treated with alogliptin and comparator therapies.

Conclusion

These analyses have not shown a signal of increased CV risk with alogliptin in patients with type 2 diabetes. Future results from the adequately powered EXAMINE trial will definitively assess the CV safety profile of alogliptin in patients with type 2 diabetes mellitus.

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Published in American Heart Journal

EXamination of CArdiovascular OutcoMes with AlogliptIN versus Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome (EXAMINE): A Cardiovascular Safety Study of the Dipeptidyl Peptidase 4 Inhibitor Alogliptin in Patients with Type 2 Diabetes with Acute Coronary Syndrome

William B. White, M.D., George L. Bakris, M.D., Richard M. Bergenstal, M.D., Christopher P. Cannon, M.D., William C. Cushman, M.D., Penny Fleck, B.S.,  Simon Heller, M.D., Cyrus Mehta, Ph.D., Steven E. Nissen, M.D.Alfonso Perez, M.D., Craig Wilson,  Ph.D., and Faiez Zannad, M.D.,  Ph.D.; Farmington, CT; Chicago, and Deerfiield, IL; Minneapolis, MN; Boston, MA; Memphis, TN; Sheffield, United Kingdom; Cleveland, OH; and Nancy, France

Comprehensive safety evaluation of new drugs for diabetes mellitus is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk. Alogliptin, a dipeptidyl peptidase 4 inhibitor, is under development for the treatment of type 2 diabetes mellitus alone or in combination with other antidiabetic therapies. Long-term CV safety of alogliptin is being established in a randomized, placebo-controlled clinical study in patients with acute coronary syndrome (ACS) using an analytical approach that has both an interim and final assessment. The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. Approximately 5,400 men and women with type 2 diabetes and ACS (acute myocardial infarction or unstable angina) are being recruited and will be followed up for up to 4.5 years postrandomization. The statistical plan for the trial uses a design that evaluates the hazard ratio (HR) of alogliptin to placebo first based on the primary CV composite end point after accrual of 80 to 150 primary CV events and again when there are 550 to 650 primary CV events. In the first series of analyses, the upper bound of a group-sequential 1-sided repeated CI for the HR must be ≤1.8 for registration in the United States. At end of study, the upper bound of a subsequent group-sequential 1-sided repeated CI for the HR must be ≤1.3. For both group sequential analyses, the repeated CIs are calculated to insure simultaneous coverage probabilities of 97.5% for the true HR. Study progress: More than 2,000 ACS patients were randomized as of June 2011. EXAMINE will define the CV safety profile of this dipeptidyl peptidase 4 inhibitor in patients at high risk for CV events. (Am Heart J 2011;162:620-626.e1.)

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