The impact of genetically proxied AMPK activation, the target of metformin, on functional outcome following ischemic stroke

Abstract

<div lang="en" class="abs"><p class="abs_header">Abstract</p><p><em>Background and Purpose:</em> We performed a two-sample Mendelian randomization (MR) analysis to evaluate the causal effect of genetically proxied AMP-activated protein kinase (AMPK) activation, which is the target of metformin, on functional outcome following ischemic stroke onset.</p><p><em>Methods:</em> A total of 44 AMPK-related variants associated with HbA1c (%) were used as instruments for AMPK activation. The primary outcome was the modified Rankin Scale (mRS) score at 3 months following the onset of ischemic stroke, evaluated as a dichotomous variable (3–6 vs. 0–2) and subsequently as an ordinal variable. Summary-level data for the 3-month mRS were obtained from the Genetics of Ischemic Stroke Functional Outcome network, including 6,165 patients with ischemic stroke. The inverse-variance weighted method was used to obtain causal estimates. The alternative MR methods were used for sensitivity analysis.</p><p><em>Results:</em> Genetically predicted AMPK activation was significantly associated with lower odds of poor functional outcome (mRS 3–6 vs. 0–2, odds ratio [OR]: 0.06, 95% confidence interval [CI]: 0.01–0.49, <em>P</em>=0.009). This association was maintained when 3-month mRS was analyzed as an ordinal variable. Similar results were observed in the sensitivity analyses, and there was no evidence of pleiotropy.</p><p><em>Conclusion:</em> This MR study provided evidence that AMPK activation by metformin may exert beneficial effects on functional outcome following ischemic stroke.</p></div>