Wu P, Moon JY, Daghlas I, et al. - In this study, the diabetogenic impact of lowering LDL cholesterol (LDLc) was shown to be partially mediated by increased BMI.

• A modest increase in body weight and type 2 diabetes risk has been seen with LDLc-lowering drugs, but the extent to which the diabetogenic impact of lowering LDLc is mediated via elevated BMI is not known.

• This topic was addressed in this summary-level univariable and multivariable Mendelian randomization (MR) analyses of 921,908 participants.

• Univariable MR analyses revealed elevated type 2 diabetes odds (odds ratio [OR] 1.12) and BMI (β = 0.07 SD units) in relation to a 1-SD reduction in genetically predicted LDLc.

• In multivariable MR analysis, evidence of an indirect impact of lowering LDLc on type 2 diabetes via BMI (OR 1.04) was obtained with a proportion mediated of 38% of the total impact.

• In individual-level MR analyses, the indirect impact of decreasing LDLc on type 2 diabetes through BMI was corroborated with an estimated proportion mediated of 8%.