The long-awaited results, presented Monday at the 75th Scientific Sessions of the American Diabetes Association, are expected to strengthen sitagliptin's position against its competitors in the DPP-4 inhibitor class.
A giant, international trial involving more than 14,000 patients found that the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin, marketed by Merck as Januvia, does not cause adverse cardiovascular (CV) effects, including the risk of hospitalization due to heart failure. The trial showed, however, that the drug did not produce any CV benefits, either.
The findings, presented Monday at the 75th Scientific Sessions of the American Diabetes Association and published in the New England Journal of Medicine, are expected to strengthen sitagliptin’s position against its competitors in the class of DPP-4 inhibitors. Two other DPP-4 inhibitors face the prospect of an FDA order to change their labels to indicate the hospitalization risk, after studies revealed this.
The study presented Monday, known as the TECOS trial, examined patients who were at least 50 years old and had both T2DM and a history of CV issues. Patients in 673 sites in 38 countries were randomized to take sitagliptin in a dose of 100 mg per day or placebo. Of significance, researchers noted this was a CV safety trial and not a trial to gauge the effectiveness of how well sitagliptin worked to control glycated hemoglobin (A1C). Thus, patients in the placebo group were given additional therapies to control their A1C.
The primary result was a composite of CV outcomes, which were found in 11.4% of the patients in the sitagliptin group (4.06 per 100 person-years) compared with 11.6% of the patients who took the placebo (4.17 per 100 person years). The average follow-up was 3 years.
Rury R. Holman, MD, ChB, professor of Diabetic Medicine and Diabetes Trials at the University of Oxford, reviewed the data with attendees in the massive convention hall. He reviewed comparative data for multiple individual CV measures, all of which showed no difference between the sitagliptin and placebo groups. Dr Holman noted no differences were found between male and female patients, and there were no differences among racial groups.
The only interesting difference, he said, was a “modest” sign of sitagliptin being beneficial in BMI reduction for patients who were obese; however, he said, “We need to be cautious before we go out and claim that.”
Results from TECOS, he said, “showed that sitagliptin did not increase the risk of cardiovascular events in a diverse group of patients with type 2 diabetes at a high cardiovascular risk.”
Monday’s results represent the result of FDA’s effort to keep closer watch on cardiovascular safety of newer diabetes therapies, following the fallout over rosiglitazone in the last decade. That drug, marketed as Avandia, was a blockbuster until a 2007 meta-analysis in NEJM linked the drug’s use to increase heart attack risk; subsequent FDA action caused it to be sold under restrictions until a later trial refuted the 2007 claims. FDA has since lifted restrictions, but the episode changed the way regulators approach newer diabetes therapies.
The question of whether the TECOS trial followed patients for a long enough period remains, and was even noted at the end of the NEJM article, as authors (including Holman) wrote, “These results cannot exclude possible benefits or risks with longer durations of therapy or in patients with more complicated coexisting illnesses.”
Merck had released topline results of TECOS on April 27, 2015.
Green JB, Bethel A, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes [published online June 8, 2015]. N Engl J Med. DOI:10.1056/NEJMoa1501352