Metformin Fails to Improve Walking Performance in Peripheral Artery Disease: Results of the PERMET Randomized Trial

Introduction: The Quest for Functional Improvement in PAD

Lower extremity peripheral artery disease (PAD) remains a significant global health burden, characterized by atherosclerotic narrowing of the arteries supplying the legs. Beyond the risk of major adverse cardiovascular and limb events, the hallmark of PAD is functional impairment. Patients frequently experience claudication or asymptomatic walking limitations that lead to a sedentary lifestyle, muscle atrophy, and a precipitous decline in quality of life. Despite the prevalence of the condition, pharmacological options to improve walking performance are remarkably limited. Currently, only cilostazol is FDA-approved for symptomatic improvement, yet its use is often curtailed by side effects such as headache and palpitations, and its efficacy is modest at best.

Against this backdrop, researchers have looked toward repurposed therapies. Metformin, a cornerstone in the management of type 2 diabetes, emerged as a promising candidate. Beyond its glucose-lowering effects, metformin exhibits pleiotropic properties that are theoretically beneficial in the context of PAD. These include the activation of AMP-activated protein kinase (AMPK), reduction of oxidative stress, and the potential stimulation of endothelial nitric oxide synthase (eNOS). The PERMET (Metformin to Improve Walking Performance in Lower Extremity Peripheral Artery Disease) randomized clinical trial was designed to rigorously test whether these mechanistic potentials could translate into tangible clinical benefits for patients with PAD who do not have diabetes.