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Commentary Regarding the Primary Results of EXAMINE

EXAMINE showed that treatment with the DPP-4 inhibitor alogliptin resulted in rates of major cardiovascular events comparable to those of placebo in type 2 diabetic patients with high levels of cardiovascular morbidity and risk. The safety findings of alogliptin were consistent for the individual primary end point components of cardiovascular death, myocardial infarction, and stroke and for deaths from any cause. These comparative rates of the primary end point were observed in the context of modestly better glycemic control in patients treated with alogliptin. This finding is not surprising in light of other recent trials such as ACCORD and ADVANCE that found no effects of larger reductions in glycated hemoglobin on similar endpoints over 5 years. However, due to its median duration of 18 months, EXAMINE does not rule out longer-term benefits or risks of alogliptin with respect to cardiovascular end points.

The primary safety outcome of EXAMINE determined the effects of alogliptin versus placebo on a composite of major cardiovascular events adjudicated by a blinded cardiovascular endpoint committee. The EXAMINE population included patients at substantially high cardiovascular risk with event rates of over 11% during the median followup of 18 months. EXAMINE represented the first completed cardiovascular safety trial of an anti-diabetic drug in patients with acute coronary syndromes and demonstrates no increase in cardiovascular risk in this population with alogliptin. Hence, for those who are likely candidates for the drug in clinical practice with elevated CV risk, including those with a recent acute coronary syndrome, it is reassuring that alogliptin does not increase cardiovascular morbidity or mortality.

EXAMINE was among the first large cardiovascular safety studies in patients with type 2 diabetes that followed and successfully executed the recommendations of the 2008 FDA guidance on the evaluation of new therapies for type 2 diabetes. The nuances of EXAMINE required a unique interaction among the members of the Steering Committee, Data Monitoring Committee and Sponsor. Following the interim analysis that excluded risk in excess of 1.8, the Sponsor established an entirely separate unblinded team to prepare the new drug application for alogliptin while all members of the Steering Committee and clinical operations personnel of the Sponsor remained blinded to any results of this interim analysis. Hence, the integrity of the trial was preserved during subsequent enrollment and followup as well as during the months of study close-out by ensuring that data were collected only by individuals blinded to results of interim analyses.

In conclusion, in patients with type 2 diabetes who had a recent acute coronary syndrome, treatment with alogliptin resulted in similar rates of cardiovascular death, myocardial infarction, and stroke compared with placebo. These data could guide clinicians to choose among the many anti-diabetic agents available when treating patients with type 2 diabetes and very high cardiovascular risk.