Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.

Wu P, Moon JY, Daghlas I, Franco G, Porneala BC, Ahmadizar F, Richardson TG, Isaksen JL, Hindy G, Yao J, Sitlani CM, Raffield LM, Yanek LR, Feitosa MF, Cuadrat RRC, Qi Q, Arfan Ikram M, Ellervik C, Ericson U, Goodarzi MO, Brody JA, Lange L, Mercader JM, Vaidya D, An P, Schulze MB, Masana L, Ghanbari M, Olesen MS, Cai J, Guo X, Floyd JS, Jäger S, Province MA, Kalyani RR, Psaty BM, Orho-Melander M, Ridker PM, Kanters JK, Uitterlinden A, Davey Smith G, Gill D, Kaplan RC, Kavousi M, Raghavan S, Chasman DI, Rotter JI, Meigs JB, Florez JC, Dupuis J, Liu CT, Merino J. Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol. Diabetes Care. 2022 Jan 1; 45(1):232-240.

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Abstract:

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (ß = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.