Metformin for walking impairment in peripheral artery disease: The PERMET Randomized Clinical Trial.

BACKGROUND: Metformin is a widely available and inexpensive first line therapy for diabetes mellitus. Pleiotropic effects of metformin that improve endothelial function, reduce oxidative stress, and increase AMPK and eNOS abundance may improve walking performance in people with lower extremity peripheral artery disease (PAD) who do not have diabetes mellitus. OBJECTIVE: In a randomized clinical trial, we tested the hypothesis that six months of metformin would significantly improve walking performance, compared to placebo, in people with PAD without diabetes mellitus. METHODS: Eligible participants were randomized (double-blinded) to either metformin or placebo for six months at four U.S. centers. Metformin or placebo was titrated from 500 mgs to 2,000 mgs daily as tolerated in a blinded fashion. The primary outcome was change in 6-minute walk distance at 6-month follow-up. Pre-specified analyses adjusted for recruitment site and the baseline value of each outcome measure. RESULTS: 202 participants with PAD were randomized and 178 (88%) completed 6-month follow-up. Mean age was 69.6±8.4, 27.7% were female, and 39.1% were black. Mean ankle brachial index (ABI) was 0.64 and mean BMI was 28.6 kg/m2. There were no effects of metformin, compared to placebo, on 6-minute walk or any secondary outcomes at 6-month follow-up (Table). Most common adverse effects were indigestion/stomach upset (64.9% for metformin and 40.6% for placebo) and headache (37.2% for metformin and 49.5% placebo). CONCLUSIONS: These results do not support metformin to improve walking performance in people with PAD.