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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. 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. 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 (β = 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). 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. © 2021 by the American Diabetes Association.


Peitao Wu, Jee-Young Moon, Iyas Daghlas, Giulianini Franco, Bianca C Porneala, Fariba Ahmadizar, Tom G Richardson, Jonas L Isaksen, Georgy Hindy, Jie Yao, Colleen M Sitlani, Laura M Raffield, Lisa R Yanek, Mary F Feitosa, Rafael R C Cuadrat, Qibin Qi, M Arfan Ikram, Christina Ellervik, Ulrika Ericson, Mark O Goodarzi, Jennifer A Brody, Leslie Lange, Josep M Mercader, Dhananjay Vaidya, Ping An, Matthias B Schulze, Lluis Masana, Mohsen Ghanbari, Morten S Olesen, Jianwen Cai, Xiuqing Guo, James S Floyd, Susanne Jäger, Michael A Province, Rita R Kalyani, Bruce M Psaty, Marju Orho-Melander, Paul M Ridker, Jørgen K Kanters, Andre Uitterlinden, George Davey Smith, Dipender Gill, Robert C Kaplan, Maryam Kavousi, Sridharan Raghavan, Daniel I Chasman, Jerome I Rotter, James B Meigs, Jose C Florez, Josée Dupuis, Ching-Ti Liu, Jordi Merino. Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol. Diabetes care. 2022 Jan 01;45(1):232-240

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PMID: 34789503

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