No significant difference in incidence of infections, cancer, renal failure, or severe hypoglycemia…
In patients with type 2 diabetes and cardiovascular disease, the use of sitagliptin (Januvia, Merck), a dipeptidyl peptidase-4 (DPP-4) inhibitor used to lower HbA1c levels, is not associated with an increased risk of cardiovascular events, according to a large outcomes trial designed specifically to answer this question.
Most important, investigators did not observe any increase in the number of patients hospitalized for heart failure with sitagliptin, a critically watched secondary end point, given that other drugs in the class, most notably saxagliptin (Onglyza, AstraZeneca) in the SAVOR TIMI- 53 study, showed an increase in heart-failure events. There was also a trend toward an increased risk of heart-failure events among type 2 diabetic patients treated with alogliptin (Nesina, Takeda Pharmaceuticals) in the EXAMINE study.
Study investigators said the TECOS trial, presented at the American Diabetes Association (ADA) 2015 Scientific Sessions and published concurrently in the New England Journal of Medicine, should reassure physicians about the cardiovascular safety of the agent when given to high-risk diabetic patients.
Dr. Eric Peterson (Duke Clinical Research Institute, Durham, NC), cochair of the TECOS executive committee, told the media during a press conference announcing the results, “In this study, we specifically looked at the rates of heart-failure events and found there were no differences. As a matter of fact, there was no hint of heart failure seen in the sitagliptin-treated patients relative to placebo. Given the size of our study, the long duration of follow-up, as well as the higher risk of our population, we feel that this very adequately addresses and puts to bed the question that there is any risk for heart failure with this drug.”
TECOS was a large-scale cardiovascular-outcomes study that enrolled 14,671 patients with type 2 diabetes and established cardiovascular disease to sitagliptin or placebo on top of their existing therapy. At baseline, the mean HbA1c level was 7.2% — the trial enrolled patients with a baseline HbA1c level ranging from 6.5% to 8.0% — and patients had been living with their diabetes for 11.6 years.
Regarding the primary endpoint — a composite of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina — there was no significant difference among those treated with sitagliptin and those treated with placebo. In excluding unstable angina from the primary end point, there was also no significant increase in the risk of cardiovascular death, nonfatal MI, or nonfatal stroke. Overall, there was no signal of cardiovascular risk among any of the end points when analyzed separately or in combination.
The ADA meeting devoted a 2-hour block for the TECOS study, with investigators given time to explain the study rationale, the design, and the clinical outcomes. During the presentation, Holman provided data from multiple subgroups, including patients stratified by age, race, baseline renal function, and geographic region. In all these analyses, there was no signal of cardiovascular toxicity with sitagliptin. There was an interaction with body-mass index — with heavier patients faring better — but Holman said not to make too much of the finding, given how many subgroups were analyzed.
In the trial, approximately 18% of patients in both treatment arms had a prior diagnosis of congestive heart failure. Even among these high-risk patients, the use of sitagliptin did not increase the risk of cardiovascular events, nor did its use increase hospitalizations for heart failure, report investigators.
Regarding the safety of sitagliptin, there was no significant difference in the overall incidence of infections, cancer, renal failure, or severe hypoglycemia. Numerically, there were more confirmed cases of acute pancreatitis among patients treated with sitagliptin — 23 events vs 12 events in the placebo arm — but the difference was not statistically significant. The rates of pancreatic cancer were very low in both treatment arms, but it was numerically less frequent among those who received sitagliptin.
- There was no signal of cardiovascular toxicity with sitagliptin.
- Regarding the safety of sitagliptin, there was no significant difference in the overall incidence of infections, cancer, renal failure, or severe hypoglycemia.
- Overall, there was no signal of cardiovascular risk among any of the end points when analyzed separately or in combination.
American Diabetes Association 2015 Scientific Sessions; June 7, 2015; Boston, Massachusetts; New England Journal of Medicine June 2015.