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Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

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posted on 17.11.2021, 22:54 authored by 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
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.


Dr. Wu, Dr. Liu, and Dr. Dupuis were partially supported by the National Institutes of Health (U01 DK078616). Dr. Meigs was supported by the National Institutes of Health 5UM1 DK078616-13 and R01 HL151855. Dr. Florez was partially supported by National Institutes of Health (HHSN268201300001I / N01-HC-65233). Dr. Gill is supported by the British Heart Foundation Centre of Research Excellence (RE/18/4/34215) at Imperial College and a National Institute for Health Research Clinical Lectureship (CL-2020-16-001) at St. George's, University of London. Dr. Merino was partially supported by American Diabetes Association grant #7-21-JDFM-005, the National Institutes of Health (DK40561), and the European Commission (H2020-MSCA-IF- 2015-703787). Dr. Raffield was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant KL2TR002490 and by T32HL129982. Dr. Mercader is supported by American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068. Dr. Olesen was supported by The Hallas-Møller Emerging Investigator Novo Nordisk (NNF17OC0031204). Funding support for participating cohorts is provided in the eMethods in the supplement. Dr. Davey Smith works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol MC_UU_00011/1.