Patients with type-2 diabetes and cardiovascular disease may be able to safely take sitagliptin without an increased risk of cardiovascular complications – even if they have a history of heart failure – according to a new analysis of the TECOS study presented Aug. 31 during ESC Congress 2015 in London.

The study involved 14,671 patients with type-2 diabetes and established cardiovascular disease, who were randomized to receive sitagliptin (n=7,332) or placebo (n=7,339) added to usual care, with the addition of other antihyperglycemic medications when necessary in both groups to achieve glycemic control.

Previously reported TECOS findings showed sitagliptin met the primary endpoint of non-inferiority compared to placebo for the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina after a median follow-up of 2.9 years. Additionally there was no difference in hospitalization for heart failure between the two groups after adjustment for baseline heart failure status (HR 1.00; 95 percent CI 0.83-1.20). The new unadjusted results and multivariable analyses show an identical picture (HR 1.00; 95 percent CI 0.84-1.20; and HR 1.02; 95 percent CI 0.83-1.26).

"Through extensive complementary analyses, we observed the same reassuring signal of heart failure safety of sitagliptin when analyzing all heart failure events (first and recurrent); when analyzing heart failure in composite analyses with cardiovascular and all-cause death; and across extensive subgroup analyses of 22 factors-importantly including presence or absence of heart failure at baseline," said Darren McGuire, MD, MHSC, FACC, of the University of Texas Southwestern Medical Center, in Dallas, TX. "Adding these data to those from SAVOR TIMI-53 and EXAMINE with regard to hospitalization for heart failure, the two key observations are that there is a moderate degree of heterogeneity between the results from each of these trials of dipeptidyl peptidase-4 inhibitors; and that, when pooled in meta-analysis, the incremental risk for heart failure is no longer statistically significant (HR 1.14; 95 percent CI 0.97-1.34)."

Meanwhile, results from the ARTS-HF trial, also presented Aug. 31, found finerenone was no more effective than the currently approved mineralocorticoid receptor antagonist eplerenone in reducing the heart failure biomarker N-terminal pro-B-type natriuretic peptide [NT-proBNP] in patients with heart failure and type-2 diabetes and/or chronic kidney disease. The study randomized 1,055 patients into six groups, one group receiving eplerenone, and the other five receiving different doses of finerenone for 90 days.

Study investigators noted that dosing of all medications was up-titrated through the study period with the eplerenone group starting at 25 mg every other day, increasing to 25 mg daily on day 30, with up-titration to 50 mg daily by day 60. The finerenone groups started with 2.5 mg, 5 mg, 7.5 mg, 10 mg or 15 mg daily, 5mg, 10mg, 15mg, 20mg and 20 mg, respectively on day 30, provided that blood potassium remained at or below 5.0 mmol/L. By day 90, a similar percentage of patients in each group had achieved the primary endpoint of more than a 30 percent decrease in plasma NT-proBNP.

"While finerenone was not superior for the primary outcome of our study, it was more effective than eplerenone for the secondary composite endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening heart failure," said Gerasimos Filippatos, MD, from Athens University Hospital Attikon in Greece. Filippatos added that he and fellow investigators were "somewhat surprised" by a striking reduction in cardiovascular events, especially mortality in the finerenone 10-20 mg group, which appears to be the optimal dose. "Preclinical studies have shown that finerenone provides greater cardiac protection and has different binding to the receptor than eplerenone and this could be the mechanism for more pronounced organ protection that could explain better outcome," he said. "If confirmed in further, adequately powered, large scale prospective, randomized studies, this could have important public health and health cost implications"

Keywords: ESC Congress, Angina, Unstable, Biomarkers, Diabetes Mellitus, Type 2, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases, Dipeptidyl-Peptidase IV Inhibitors, Follow-Up Studies, Heart Failure, Hospitalization, Mineralocorticoid Receptor Antagonists, Myocardial Infarction, Natriuretic Peptide, Brain, Peptide Fragments, Pyrazines, Public Health, Renal Insufficiency, Chronic, Stroke, Spironolactone, Triazoles

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