April 21, 2016
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Januvia safe for high-risk patients with type 2 diabetes, CVD

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The DPP-IV inhibitor Januvia does not confer incremental heart failure risk in patients with type 2 diabetes and prevalent atherosclerotic vascular disease, according to a secondary analysis of the TECOS trial.

“There appear to be differential effects on heart failure (HF) risk associated with medications within the DPP-IV inhibitor class,” Darren K. McGuire, MD, MHSc, professor and Dallas Heart Ball chair for research on heart disease in women at the University of Texas Southwestern Medical Center in Dallas, told Endocrine Today. “While saxagliptin (SAVOR TIMI 53 trial [Onglyza, AstraZeneca]), alogliptin (EXAMINE trial [Nesina, Takeda]) and sitagliptin (TECOS trial [Januvia, Merck]) each met the primary outcome objective of demonstrating clear safety for [cardiovascular] death, [myocardial infarction] and stroke, there was a significant increase in HF hospitalization with saxagliptin and a numeric imbalance that did not achieve statistical significance for alogliptin, with our subanalysis detecting no adverse HF signal at all with sitagliptin.”

Darren K. McGuire

McGuire and colleagues analyzed data from the TECOS CV outcomes study, a worldwide randomized, double blind, placebo-controlled trial evaluating the CV safety of sitagliptin in patients with type 2 diabetes and prevalent atherosclerotic vascular disease and HbA1c between 6.5% and 8% (n = 14,671 adults; mean age, 65 years; 29% women; 68% white; mean BMI, 30.2 kg/m2). The mean duration of diabetes was 11.6 years among participants; mean HbA1c was 7.2%; 18% of participants had a history of HF. The majority of patients were assigned metformin (approximately 81%); nearly 25% were using insulin.

Participants were assigned sitagliptin monotherapy, sitagliptin with metformin, sulfonylurea or pioglitazone, or insulin alone or combined with metformin. Within the cohort, 7,332 were assigned sitagliptin 100 mg/day; 7,339 were assigned placebo.

Secondary analyses compared the effect on hospitalization for HF, composite hospitalization for HF or CV death, and composite hospitalization for HF or all-cause death, overall and in prespecified subgroups.

Hospitalization for HF occurred in 3.1% (n = 228) of sitagliptin patients and 3.1% (n = 229) of placebo patients (unadjusted HR = 1; 95% CI, 0.83-1.19). There was no difference in total hospitalizations for HF between the sitagliptin (n = 345) and placebo (n = 347) groups (unadjusted HR = 1; 95% CI, 0.8-1.25). Researchers found similar rates between the sitagliptin and placebo groups after hospitalization for HF all-cause death (29.8% vs. 28.8%, respectively) and CV death (22.4% vs. 23.1%, respectively).

Researchers did not observe heterogeneity for the effect of sitagliptin on hospitalization for HF in subgroup analyses across 21 factors (P > .1 for all interactions). Meta-analysis of the hospitalization for HF results from the three reported DPP-IV CV outcomes trials revealed moderate heterogeneity (I² = 44.9; P = .16).

“The etiology of the incremental [HF] with some DPP-IV inhibitors is unclear,” McGuire told Endocrine Today. “Better information about cardiac structure and function would be helpful, along with evaluations for other potential contributors, such as whether there is increased risk for valvular disease, arrhythmia, effects on kidney sodium handling or other mechanisms that could contribute to excess [HF].” by Regina Schaffer

For more information:

Darren K. McGuire, MD, MHSc, can be reached at the division of cardiology at University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235; email: darren.mcguire@utsouthwestern.edu.

Disclosure: The TECOS study was funded by Merck Sharp and Dohme. McGuire reports receiving honoraria for clinical trial leadership from AstraZeneca, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Janssen Research and Development LLC, Lexicon, Lilly USA, Merck Sharp and Dohme, Novo Nordisk and Takeda Pharmaceuticals North America, and consulting for Lilly USA, Merck Sharp and Dohme, Novo Nordisk, Regeneron and Sanofi-Aventis Group. Please see the full study for the other authors’ relevant financial disclosures.