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SILVER SPRING, MD.– Alogliptin’s cardiovascular risk profile is acceptably safe for high-risk patients with type 2 diabetes, a Food and Drug Administration advisory panel has unanimously agreed.
At a meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee on April 14, panelists reviewed the results of the results of a large cardiovascular outcomes study of the dipeptidyl peptidase-4 (DPP-4) inhibitor, the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) study, an international, randomized, double-blind, placebo-controlled trial of about 5,400 people with type 2 diabetes and established cardiovascular disease.
The FDA is requiring CV outcomes trials for all type 2 diabetes drugs, including those in development, and issued a guidance for industry for these trials in December 2008, which states that the trials should evaluate the major adverse cardiovascular event (MACE) incidence in patients at increased risk for CVD and that a 30% or greater excess CV risk over placebo should be excluded to meet the criteria for acceptable CV safety.
Alogliptin, marketed as Nesina by Takeda Pharmaceutical USA, was approved in January 2013. It also is combined with metformin (Kazano) and with pioglitazone (Oseni). The EXAMINE study, which was underway at the time of approval, enrolled people who had an acute coronary syndrome event (acute MI or unstable angina requiring hospitalization) within 15-90 days of enrollment.
Over a median follow-up of 1.5 years, there was no increase in the MACE composite endpoint of CV death, nonfatal MI, and nonfatal stroke among those on alogliptin (11.3%), compared with those on placebo (11.8%), for a hazard ratio of 0.96 – meeting the FDA criteria for CV safety (N. Engl. J. Med. 2013;369:1327-35).
Some of the issues raised with the study included a lower-than-planned proportion of patients enrolled in the United States and Canada – less than 16% of the total – and a subgroup analysis showing that, in the North American patients, the MACE rate among those on alogliptin was elevated compared with placebo (HR, 1.28). The FDA reviewers said that the North American population had some characteristics that might explain this difference.
Another finding discussed was the higher number of hospitalizations for heart failure in patients on alogliptin (106) than for those on placebo (89), for a rate of 2.6 vs. 2.3 cases per 100 patient-years (HR, 1.19), according to the FDA. In the CV outcomes study of another DPP-4 inhibitor, saxagliptin, which the panel reviewed earlier in the day, there was a similar signal for an increased risk of heart failure hospitalizations associated with the drug.
Panelists, however, said they were not convinced that the geographic differences represented a real effect, which they said could be due to chance and did not affect the overall results – although they would have preferred to have more people from the United States enrolled in the study. Panelists also were not overly concerned about the risk of heart failure, but they pointed out that the risk of heart failure risk should be monitored in patients on the drug because of the signal seen with saxagliptin. Several panelists said that they suspected that heart failure may turn out to be a class effect. CV outcomes trials for the two other approved DPP-4 inhibitors – sitagliptin (Januvia) and linagliptin (Tradjenta) – are ongoing.
“It’s clear that the trial achieved its primary objective in a manner consistent with the 2008 guidelines,” said one of the panelists, Dr. Thomas Wang, director of the division of cardiovascular medicine at Vanderbilt University, Nashville, Tenn. Although there were some limitations of the study, such as the low proportion of U.S. participants and the relatively short duration of follow-up, “these limitations do not come close to negating the conclusion” regarding the cardiovascular risk profile, he commented.
In another vote, 13 of the 16 panelists said that the new safety information should be added to the alogliptin prescribing information. “This trial represented a huge effort and we know a lot about the outcomes related to this drug now,” and that information should be included in the label, said one of the panelists, Dr. Susan Heckbert, professor in the department of epidemiology, University of Washington, Seattle.
Three panelists voted not to add any information to the label. The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest
