l-carnitine, a friend or foe for cardiovascular disease? A Mendelian randomization study

BACKGROUND: l-carnitine is emerging as an item of interest for cardiovascular disease (CVD) prevention and treatment, but controversy exists. To examine the effectiveness and safety of l-carnitine, we assessed how genetically different levels of l-carnitine are associated with CVD risk and its risk factors. Given higher CVD incidence and l-carnitine in men, we also examined sex-specific associations. METHODS: We used Mendelian randomization to obtain unconfounded estimates. Specifically, we used genetic variants to predict l-carnitine, and obtained their associations with coronary artery disease (CAD), ischemic stroke, heart failure, and atrial fibrillation, as well as CVD risk factors (type 2 diabetes, glucose, HbA1c, insulin, lipid profile, blood pressure and body mass index) in large consortia and established cohorts, as well as sex-specific association in the UK Biobank. We obtained the Wald estimates (genetic association with CVD and its risk factors divided by the genetic association with l-carnitine) and combined them using inverse variance weighting. In sensitivity analysis, we used different analysis methods robust to pleiotropy and replicated using an l-carnitine isoform, acetyl-carnitine. RESULTS: Genetically predicted l-carnitine was nominally associated with higher risk of CAD overall (OR 1.07 per standard deviation (SD) increase in l-carnitine, 95% CI 1.02 to 1.11) and in men (OR 1.09, 95% CI 1.02 to 1.16) but had a null association in women (OR 1.00, 95% CI 0.92 to 1.09). These associations were also robust to different methods and evident for acetyl-carnitine. CONCLUSIONS: Our findings do not support a beneficial association of l-carnitine with CVD and its risk factors but suggest potential harm. l-carnitine may also exert a sex-specific role in CAD. Consideration of the possible sex disparity and exploration of the underlying pathways would be worthwhile. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12916-022-02477-z.