Background: People with type 2 diabetes mellitus (T2D) have preclinical cardiac and vascular dysfunction associated with low cardiorespiratory fitness (CRF). This is especially concerning because CRF is a powerful predictor of cardiovascular mortality, a primary issue in T2D management. Glucagon-like pepetide-1 (GLP-1) augments cardiovascular function and our previous data in rodents demonstrate that potentiating the GLP-1 signal with a dipeptidyl peptidase-4 (DPP4) inhibitor augments CRF. Lacking are pharmacological treatments which can target T2D-specific physiological barriers to exercise to potentially permit adaptations necessary to improve CRF and thereby health outcomes in people with T2D. We therefore hypothesized that administration of a DPP4-inhibitor (sitagliptin) would improve CRF in adults with T2D.
Methods and results: Thirty-eight participants (64 ± 1 years; mean ± SE) with T2D were randomized in a double-blinded study to receive 100 mg/day sitagliptin, 2 mg/day glimepiride, or placebo for 3 months after baseline measurements. Fasting glucose decreased with both glimepiride and sitagliptin compared with placebo (P = 0.002). CRF did not change in any group (Placebo: Pre: 15.4 ± 0.9 vs. Post: 16.1 ± 1.1 ml/kg/min vs. Glimepiride: 18.5 ± 1.0 vs. 17.7 ± 1.2 ml/kg/min vs. Sitagliptin: 19.1 ± 1.2 vs. 18.3 ± 1.1 ml/kg/min; P = 0.3). Sitagliptin improved measures of cardiac diastolic function, however, measures of vascular function did not change with any treatment.
Conclusions: Three months of sitagliptin improved diastolic cardiac function, however, CRF did not change. These data suggest that targeting the physiological contributors to CRF with sitagliptin alone is not an adequate strategy to improve CRF in people with T2D.
Clinical trials registration: www.clinicaltrials.gov NCT01951339.
Keywords: Cardiovascular diseases; Diabetes mellitus; Exercise; Glucagon-like peptide-1; Mitochondria.
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