BOSTON — In patients with type 2 diabetes and established cardiovascular disease (CVD), the dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin did not appear to increase the risk for CV events or hospitalization for heart failure, according to data from the TECOS trial.

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), which was presented at the American Diabetes Association (ADA) 75th Scientific Sessions, was a large CV outcomes trial designed to assess the long-term CV safety of adding sitagliptin to usual care in this high-risk patient population.

It was launched prior to the U.S. Food and Drug Administration (FDA) Guidance for Industry on evaluating CV risk in diabetes, with the first patient enrolled in December 2008.

The trial’s primary CV outcome was a composite of CV death, nonfatal myocardial infarction (MI), nonfatal stroke or hospitalization for unstable angina.

TECOS Design, Data

In the randomized, double-blind study, researchers from the University of Oxford Diabetes Trials Unit and the Duke Clinical Research Institute (DCRI) assigned 14,761 patients with type 2 diabetes and CVD from 38 countries to add sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged, as necessary, to help patients achieve glycemic targets.

During the median 3-year follow-up, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients (11.6%; 4.17 per 100 person-years) in the placebo group, according to the data. These results demonstrated the noninferiority of sitagliptin to placebo for the primary CV outcome (HR=0.98; 95% CI, 0.88-1.09), the researchers noted.

The researchers also observed no difference in rates of hospitalization for heart failure between the sitagliptin and placebo arms (HR=1.00; 95% CI, 0.83-1.20).

Study co-chair Rury Holman FRCP FMedSci, professor of diabetic medicine at the University of Oxford in England, said observational studies and meta-analyses of short-term trials have suggested that DPP-4 inhibitors may reduce CV risk, but all three outcomes trials to date, including SAVOR-TIMI 53, EXAMINE and TECOS, have shown no increase or decrease in the number of major adverse CV events.

“Importantly, there was also no impact on the risk for hospitalization for heart failure, as was seen unexpectedly with saxagliptin in SAVOR-TIMI 53 and with a nonsignifcant numerical increase with alogliptin in EXAMINE,” Holman told Endocrinology Advisor.

Additionally, the study showed that concerns about possible links between incretin-based therapies and effects on the pancreas were not borne out. In TECOS, acute pancreatitis (P=.07) and pancreatic cancer (P=.32) were uncommon and not statistically significant different between groups.

In terms of glycemic control, there was also a small, –0.29% (95% CI, –0.32 to –0.27) difference in HbA1c levels for sitagliptin vs. placebo. However, the study was not designed to examine this effect, according to the researchers.

“TECOS was a cardiovascular outcome study, not a glucose efficacy trial. It showed that adding sitagliptin to usual care did not alter risk for major adverse cardiovascular events in patients with type 2 diabetes and established cardiovascular disease,” Holman said.

Conclusions

Eric Peterson, MD, DCRI executive director at Duke University and joint chair of the study, said TECOS is an excellent example of academic and industry collaborative research. He noted the findings are important because of the large numbers of patients included and from different parts of the world.

Cardiovascular disease (CVD) patients with diabetes have two-fold greater risk for mortality. While we know that controlling glucose in patients with antihyperglycemic agents can reduce microvascular complications, there are concerns that these agents may also increase the risk for CV events,” Peterson told Endocrinology Advisor.

“While the overall CV outcomes data in TECOS were similar to other trials of DPP-4 drugs, TECOS was different in that it didn’t give any hint of increasing patients’ risk for heart failure.”

Reference

  1. Holman RR et al. Results from the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS). Presented at: American Diabetes Association (ADA) 75th Scientific Sessions; June 5-9, 2015; Boston.
  2. Green JB et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1501352.