Effects of the Antidiabetic Drug Metformin on Maximal Aerobic Capacity

Abstract

Metformin is a commonly prescribed antidiabetic drug that promotes normoglycemia mainly by decreasing liver glucose production. Metformin has been shown to inhibit Complex 1 of the electron transport system, reducing mitochondrial oxidative phosphorylation (OxPhos). Lower capacity for OxPhos is expected to constrain maximal aerobic capacity (VO2max). This impact on VO2max is clinically relevant given that the prediabetic and diabetic individuals prescribed metformin are also encouraged to be physically active. PURPOSE: To examine the effects of metformin on VO2max as well as maximal heart rate (HRmax) and ventilation (VEmax). METHODS: Using a randomized, counterbalanced, placebo-controlled design, 7 healthy, normoglycemic men and women (33.6 ± 3.9 yrs) underwent an initial VO2max test after at least 3 days stabilization at the typical clinical dose of metformin (2000 mg/day) or placebo (single-blind). Following at least 7 days of the alternate treatment, subjects underwent a second VO2max test. Each continuous exercise test was conducted on a cycle ergometer or treadmill and commenced at a low work rate with incremental increases in treadmill grade or ergometer resistance until a maximal voluntary effort was achieved. Gas exchange measurements were obtained continuously throughout the test by open-circuit spirometry. HR was measured by telemetry using a Polar monitor. RESULTS: After treatment with metformin, absolute (L/min−1) and relative (mL/kg−1/min−1) VO2max were consistently lower relative to placebo (−4.7 ± 1.6% and−4.6 ± 1.5%, respectively). In addition, HRmax (bpm−1) and VEmax (L/min−1) were lower after metformin treatment compared to placebo (−4.0 ± 0.8 and−7.7 ± 1.8%, respectively). Maximal work output achieved was the same across conditions and mean test duration was 15.2 ± 1.1 min−1 on placebo versus 14.5 ± 0.7 min−1 with metformin treatment. CONCLUSION: Treatment with metformin appears to lower VO2max, HRmax, and VEmax. We hypothesized that VO2max would be lower with metformin treatment due to reduced OxPhos from the inhibition of Complex 1. However, because HRmax was also lower with metformin, it is unclear whether the decrease in VO2max is a result of central or peripheral factors, or both. These findings may have clinical relevance given the millions of people who are prescribed metformin and also encouraged to be physically active. This study was supported by a grant from the American Diabetes Association.