A noninferiority study of a new drug for type 2 diabetes found that patients with a very high cardiovascular risk did not have any increased major cardiovascular events while taking alogliptin, but did have better glycemic control, compared with patients taking a placebo. The results of the double-blind study were reported online in the New England Journal of Medicine [doi:10.1056/NEJMoa1305889].
New antidiabetic agents have been required to undergo cardiovascular safety assessments before and after they receive approval from the FDA since the agency issued new guidelines in 2008. The FDA asked for the additional requirements after concerns emerged about possible adverse cardiovascular outcomes for patients taking antidiabetic agents. Alogliptin, the focus of this latest study, is a selective inhibitor of dipeptidyl peptidase 4 (DPP-4) approved for treatment of type 2 diabetes.
Researchers in the EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial conducted a noninferiority study comparing alogliptin to a placebo through a double-blind study design that assessed major cardiovascular events in type 2 diabetes patients with very high cardiovascular risk.
The study included 5380 patients who had an acute coronary syndrome, including an acute myocardial infarction or unstable angina requiring hospitalization within the previous 15 to 90 days.
Patients were randomly assigned to receive either alogliptin or placebo in addition to their existing antihyperglycemic and cardiovascular medications. The daily dose of alogliptin varied based on the patient's kidney function because the drug is cleared by the kidney. As a result, those patients who had glomerular filtration rates (GFRs) of at least 60 mL/min/1.73 m2 of body-surface area received 25 mg, while those with an estimated GFR of 30 to <60 mL/min/1.73m2 of body-surface area received 12.5 mg, and those with an estimated GFR of <30 mL/min/1.73 m2 of body-surface area received 6.25 mg.
The primary end point of the study was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or a nonfatal stroke. Researchers reported that the prespecified noninferiority margin was 1.3 for the hazard ratio (HR) for the primary end point.
They also identified a principal secondary safety end point that was comprised of the primary end point with the addition of urgent revascularization due to unstable angina within 24 hours after being admitted to a hospital.
Researchers found that there was no significant difference between the 2 groups in terms of the primary end point. Based on the results, 11.3% of patients in the alogliptin group experienced the primary outcome during the study period of a median of 18 months while 11.8% of patients in the placebo group experienced the primary outcome in the same time period (HR, 0.96; upper boundary of the one-sided repeated confidence interval [CI], 1.16; P<.001 for noninferiority, P=.32 for superiority).
There was also no significant difference between the 2 groups in terms of the principal secondary end point. The trial authors reported that this end point occurred in 12.7% of those in the alogliptin group and 13.4% of those in the placebo group (HR, 0.95; upper boundary of the one-sided repeated CI, 1.14).
When evaluating adverse events, the researchers were unable to find a significant difference between either group and reported that adverse events occurred in 33.6% of those in the alogliptin group and 35.5% of the placebo group (P=.14).
They did note, however, that those patients who were taking alogliptin had significantly lower glycated hemoglobin levels than those who were taking a placebo (mean difference, -0.36 percentage points; P<.001).