Year: 2021
Type: other
Abstract: Objective: Low-density lipoprotein 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 body mass index (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: One-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12, 95% confidence interval (CI) 1.01, 1.24) and BMI (b=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). Conclusion: 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 amongst individuals taking LDLc lowering medications.
Authors: 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 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
Institution: Massachusetts General Hospital
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4226208731