Evaluating the impact of AMPK activation, a target of metformin, on risk of cardiovascular diseases and cancer in the UK Biobank: a Mendelian randomisation study

Whether metformin reduces cardiovascular or cancer risk is unclear owing to concerns over immortal time bias and confounding in observational studies. This study evaluated the effect of AMP-activated protein kinase (AMPK), the target of metformin, on risk of cardiovascular disease and cancer.This is a Mendelian randomisation design, using AMPK, the pharmacological target of metformin, to infer the AMPK pathway-dependent effects of metformin on risk of cardiovascular disease and cancer in participants of white British ancestry in the UK Biobank.A total of 391,199 participants were included (mean age 56.9 years; 54.1% women), including 26,690 cases of type 2 diabetes, 38,098 cases of coronary artery disease and 80,941 cases of overall cancer. Genetically predicted reduction in HbA1c (%) instrumented by AMPK variants was associated with a 61% reduction in risk of type 2 diabetes (OR 0.39; 95% CI 0.20, 0.78; p = 7.69 × 10-3), a 53% decrease in the risk of coronary artery disease (OR 0.47; 95% CI 0.26, 0.84; p = 0.01) and a 44% decrease in the risk of overall cancer (OR 0.56; 95% CI 0.36, 0.85; p = 7.23 × 10-3). Results were similar using median or quartiles of AMPK score, with dose-response effects (p for trend = 4.18 × 10-3 for type 2 diabetes, 4.37 × 10-3 for coronary artery disease and 4.04 × 10-3 for overall cancer).This study provides some genetic evidence that AMPK activation by metformin may protect against cardiovascular disease and cancer, which needs to be confirmed by randomised controlled trials.