Study: Sitagliptin Safe For High-Risk Diabetes Patients

Boston—Results from TECOS (Trial to Evaluate Cardiovascular Outcomes After Treatment with Sitagliptin), a study of sitagliptin in patients with type 2 diabetes and cardiovascular disease, showed no increased risk of cardiovascular events, according to data presented during a symposium Monday at the American Diabetes Association (ADA) 75th Scientific Sessions and simultaneously published online in the New England Journal of Medicine. The study investigators said that the TECOS trial should reassure clinicians about the cardiovascular safety of this incretin drug for this high-risk patient population.

Heart disease and stroke are the number 1 causes of death and disability among people with type 2 diabetes, who are 2 to 4 times more likely than those without diabetes to suffer from these conditions.
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“In this study, we specifically looked at the rates of heart failure events and found there were no differences,” said Eric Peterson, MD, Duke Clinical Research Institute, co-chair of the TECOS executive committee, during an ADA press conference preceding the release of the results. “There was no hint of heart failure seen in the sitagliptin-treated patients relative to placebo. Given the size of our study, the longer duration of follow-up, as well as the higher risk of our population, we feel that this very adequately addresses the question and puts to bed the question that there is any risk for heart failure with this drug. We feel quite confident this drug can be used very safely in patients with cardiovascular disease.”

TECOS is the third major cardiovascular trial of dipeptidyl peptidase-4 (DPP-4) inhibitors. Two previous cardiovascular outcome trials of other DDP-4 inhibitors—SAVOR-TIMI and EXAMINE—did not show an increase or decrease in the number of major adverse cardiovascular events but did raise safety concerns regarding a possible elevated risk of hospitalization for heart failure. TECOS enrolled its first patients in 2008, around the same time the FDA mandated more stringent clinical trials for all new diabetes drugs. The FDA now requires that all new drugs approved for diabetes to lower glucose rule out cardiovascular toxicity. The agency requires that these glucose-lowering agents have an upper limit of harm no more than 1.3.

TECOS was a randomized, double-blind, placebo-controlled, large-scale, cardiovascular outcome study that included 14,671 patients with type 2 diabetes and established cardiovascular disease in the intent-to-treat analysis. The study was conducted at 673 sites in 38 countries. Patients were at least 50 years old with a hemoglobin A1c (HbA1c) of 6.5% to 8.0% and treated with stable doses of 1 or 2 oral antihyperglycemic agents. Patients were randomized 1:1 to sitagliptin 100 mg daily (n=7332) or placebo (n=7339), in addition to usual care. The primary composite was a 4-endpoint defined as the first confirmed event of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina (UA). The secondary composite endpoint was the same as the first with exclusion of hospitalization for UA. Other secondary endpoints included death from any cause and hospitalization from heart failure.

During a median follow-up of 3.1 years, there was a small difference in HbA1c (least-squares mean difference for sitagliptin vs placebo,−0.29%; 95% confidence interval [CI], −0.32-−0.27). Speaking at the press conference, study co-chair Rury Holman, FRCP, director, University of Oxford Diabetes Trial Unit, and co-chair of TECOS executive committee, emphasized that the study was designed to achieve “glycemic equipoise” between the 2 treatment arms. “This is a glucose-lowering drug being tested for cardiovascular benefit or harm,” he said. “The idea was not to see a glucose difference. That’s important because we don’t want a glucose difference that might have influenced the cardiovascular outcomes one way or another.”

Overall, the primary endpoint occurred in 11.4% of sitagliptin-treated patients compared with 11.6% of placebo-treated patients (hazard ratio [HR], 0.98; 95% CI, 0.89-1.08). In addition, rates of hospitalization for heart failure did not differ between the 2 study cohorts (3.1% for each; HR, 1.00; 95% CI, 0.83- 1.20), and rates of all-cause mortality were similar in both treatment groups (7.5% in the sitagliptin group vs 7.3% in the placebo group; HR, 1.01; 95% CI, 0.90-1.14).

In terms of safety, there was no significant difference in the overall incidence of infections, cancer, renal failure, or severe hypoglycemia between the sitagliptin group and the placebo group. Confirmed acute pancreatitis events were uncommon overall but numerically more frequent in the sitagliptin group than in the placebo group (23 vs 12 events; respectively), but the difference was not statistically significant. Confirmed pancreatic cancers were also uncommon overall but numerically less frequent in the sitagliptin group than the placebo group (9 vs 14 events; respectively).

When asked how clinicians can take the data from the 3 cardiovascular trials of DDP-4 inhibitors and put into clinical practice, Peterson said, “As cardiologists, we’re driven by the evidence. We can look at only the evidence we have from studies. These are not cross-comparative studies, so the degree to which we extrapolate from one drug to another is done with caution. That said, if you look at sitagliptin specifically, it is remarkably clean with just about every signal looked at, every subgroup looked at, and in every way we can look at the data. We teased this data backward and forward. Everything comes up looking like the drug does not have a cardiovascular safety signal.”

—Eileen Koutnik-Fotopoulos

Reference:

Green JB, Bethel A, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015 June 8 [epub ahead of print]