TECOS: No Differences in Heart Failure Outcomes When Sitagliptin Added to Usual Care in Diabetics

LONDON, England—Adding sitagliptin to usual diabetes care does not increase the risk of heart failure, according to results from a prespecified secondary analysis of the TECOS study presented on August 31, 2015, at the European Society of Cardiology Congress.

Take Home: TECOS: No Differences in Heart Failure Outcomes When Sitagliptin Added to Usual Care in Diabetics

In TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin), 14,671 patients with type 2 diabetes and cardiovascular disease were randomized to usual care plus sitagliptin (Januvia; Merck; n = 7,332) or placebo (n = 7,339) between December 2008 and July 2012. According to the main results published earlier this year, the primary composite outcome (cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina) did not differ between the groups after a median follow-up of 3 years.

In a secondary analysis, researchers led by Frans Van de Werf, MD, PhD, of University Hospitals Leuven (Leuven, Belgium), took a closer look at patients who were hospitalized for heart failure (n = 457). These patients were typically older (mean age 68.5 vs 65.4 years) and were more likely to have histories of MI (58.2% vs 42.1%) or heart failure (41.8% vs 17.3%) compared with those without the complication (n = 14,214).

Time to first hospitalization for heart failure did not differ between the sitagliptin and placebo groups over the study period (HR 1.00; 95% CI 0.84-1.20); the results were consistent after adjustment for baseline heart failure. Additionally, there were no differences in heart failure hospitalization rates among any of the prespecified subgroups, including those with prior heart failure (P for interaction = .666).

Moreover, clinical outcomes were similar in the sitagliptin and placebo arms within the group of patients with prior heart failure at baseline (table 1).

Table 1. Outcomes in Patients with History of Heart Failure: Sitagliptin vs Placebo  
All-cause mortality (29.8% with sitagliptin vs 28.8% with placebo) and cardiovascular mortality (22.4% vs 23.1%) did not differ between between groups among those with at least 1 hospitalization for heart failure.

Safety Established

In a meta-analysis combining TECOS with SAVOR-TIMI 53 and EXAMINE—which each tended to favor placebo over saxagliptin (Onglyza; AstraZeneca) and alogliptin (Nesina; Takeda), respectively—hospitalization for heart failure was not more likely with active treatment vs placebo (HR 1.14; 95% CI 0.97-1.34). There was modest heterogeneity among the 3 trials (P = .16).

The potential reasons for the disparate findings in TECOS compared with SAVOR-TIMI 53 and EXAMINE could have to do with baseline patient differences, varying background care, multiple definitions of heart failure events, intrinsic pharmacological differences, and the play of chance, Dr. Van de Werf said. But the results confirm “sitagliptin can be safely used in type 2 diabetes patients without concern for worsening heart failure,” he added.

Discussing the study, Jaakko Tuomilehto, MD, PhD, of the National Institute for Health and Welfare (Helsinki, Finland), said he agrees with the reasons Dr. Van de Werf lists. Dr. Tuomilehto pointed out that there have been calls for clinical trials with heart failure as the primary endpoint. That is “very easy to say,” he commented, “but how can they design a trial when the [incidence of the] primary endpoint would be… lower than total mortality?

“We’ll see what will happen, but at the moment there’s no big safety issue,” Dr. Tuomilehto said.

Additionally, all of the increase in risk was already seen within 6 months, he noted. “It did not increase over time, which means that the cumulative exposure did not produce more cases of heart failure,” he said, adding that it remains unclear why that is.

Panelist Philippe Gabriel Steg, MD, of Hôpital Bichat (Paris, France), asked whether RCTs are legitimately needed “to monitor safety of drugs that are so widely used when the incidence of some of the side effects are extremely rare.… You could spend the entire resources of all clinical research doing safety studies, which really should be the work of pharma vigilance.”

Dr.Van de Werf replied that the FDA asked for TECOS “to exclude any potential negative impact on cardiovascular outcomes.”

Van de Werf F. Impact of sitagliptin on heart failure and related outcomes. Presented at: European Society of Cardiology Congress; August 31, 2015; London, England.

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  • TECOS was funded by Merck, Sharp & Dohme.
  • Dr. Tuomilehto reports holding research contracts and stocks, receiving royalties and consulting fees, and owning a healthcare company.