Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis

Abstract

Background-—Subclinical myocardial injury, as measured by high-sensitivity cardiac troponin T (hsTnT), and myocardial stress, as measured by N-terminal pro-B-type natriuretic peptide (NT-proBNP), are related to glycemic control in patients with type 2 diabetes mellitus, and are strong predictors of adverse cardiovascular outcomes. We sought to determine whether antihyperglycemic therapy improves measures of myocardial injury and myocardial stress in patients with type 2 diabetes mellitus. Methods and Results-—We randomized, in a 292 factorial fashion, 438 patients with type 2 diabetes mellitus to insulin glargine, metformin, the combination, or placebo and measured changes in NT-proBNP and hsTnT after 12 weeks of therapy. At baseline, the median (Q1–Q3) plasma concentration was 35.4 (15.7–86.3) ng/L for NT-proBNP and 6.7 (4.6–10.1) ng/L for hsTnT. The adjusted (95% confidence interval) change in NT-proBNP concentration was 20.7% (7.9–35.0) in the insulin arm compared with 0.13% (10.8 to 12.5) in the no-insulin arm (P=0.03 for comparison). These changes were not related to changes in fasting or postprandial glucose, glycated hemoglobin, weight, blood pressure, or inflammation. In the metformin arm, the adjusted change in NT-proBNP was 7.8% (3.7 to 20.7) compared with 13.0% (0.72–26.8) in the no-metformin arm (P=0.58). No significant changes in hsTnT concentrations were observed for any of the treatment arms. Conclusions-—Insulin glargine was associated with a significant 20.7% increase in NT-proBNP, a marker of myocardial stress, after 12 weeks of therapy. No change in hsTnT, a marker of myocardial injury, was observed. The changes were independent of substantial improvements in glucose control. Clinical Trial Registration-—URL: Http://www.clinicaltrials.gov. Unique identifier: NCT00366301. (J Am Heart Assoc. 2017;6: E007268. DOI: 10.1161/JAHA.117.007268.).