@article{edf0a903114c491da27386473b6f6589,
title = "Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol",
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 (b 5 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 5 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 5 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.",
author = "Peitao Wu and Moon, {Jee Young} and Iyas Daghlas and Giulianini Franco and Porneala, {Bianca C.} and Fariba Ahmadizar and Richardson, {Tom G.} and Isaksen, {Jonas L.} and Georgy Hindy and Jie Yao and Sitlani, {Colleen M.} and Raffield, {Laura M.} and Yanek, {Lisa R.} and Feitosa, {Mary F.} and Cuadrat, {Rafael R.C.} and Qibin Qi and Ikram, {M. Arfan} and Christina Ellervik and Ulrika Ericson and Goodarzi, {Mark O.} and Brody, {Jennifer A.} and Leslie Lange and Mercader, {Josep M.} and Dhananjay Vaidya and Ping An and Schulze, {Matthias B.} and Lluis Masana and Mohsen Ghanbari and Olesen, {Morten S.} and Jianwen Cai and Xiuqing Guo and Floyd, {James S.} and Susanne Jager and Province, {Michael A.} and Kalyani, {Rita R.} and Psaty, {Bruce M.} and Marju Orho-Melander and Ridker, {Paul M.} and Kanters, {J{\o}rgen K.} and Andre Uitterlinden and Smith, {George Davey} and Dipender Gill and Kaplan, {Robert C.} and Maryam Kavousi and Sridharan Raghavan and Chasman, {Daniel I.} and Rotter, {Jerome I.} and Meigs, {James B.} and Florez, {Jose C.} and Jos{\'e}e Dupuis and Liu, {Ching Ti} and Jordi Merino",
note = "Funding Information: Acknowledgments. The authors thank geno mic consortia (GIANT and DIAGRAM) for access to their publicly available data as well as participants and staff of the UK Biobank and CHARGE cohorts for their valuable contributions. A complete list of acknowledgments for participating studies can be found in Supplementary Data. Funding. P.W., C.-T.L., and J.D. were partially supported by the National Institutes of Health (U01 DK078616). J.B.M. was supported by National Institutes of Health grants 5UM1 DK078616-13 and R01 HL151855. J.C.F. was partially supported by the National Institutes of Health (HHSN268201300001I/N01-HC-65233). D.G. 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. J.M. 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). L.M.R. was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant KL2TR002490 and by T32HL129982. J.M.M. is supported by American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068. M.S.O. was supported by the Hallas-M{\o}ller Emerging Investigator grant from the Novo Nordisk Foundation (NNF17OC0031204). Funding support for participating cohorts is provided in Supplementary Data. G.D.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1). Duality of Interest. T.G.R. and D.G. are employed part-time by Novo Nordisk outside of this work. D.G. has received consultancy fees from Policy Wisdom. J.S.F. has consulted for Shionogi Inc. B.M.P. serves on the Steering Committee of the Yale University Open Data Access (YODA) Project, funded by Johnson & Johnson. No other potential conflicts of interest relevant to this article were reported. Author Contributions. P.W., J.-Y.M., I.D., J.D., C.-T.L., and J.M. conceived the study design. P.W., J.-Y.M., I.D., J.I.R., J.B.M., and J.M. were involved in data collection. P.W., J.-Y.M., I.D., G.F., B.C.P. F.A., T.G.R., J.L.I., G.H., J.Y., C.M.S., L.M.R., L.R.Y., M.F.F., and R.R.C.C. provided statistical expertise. I.D., S.R., C.-T.L., and J.M. wrote the first draft of the manuscript. All authors contributed to the interpretation of the results and critical revision of the manuscript for important intellectual content and approved the final version of the manuscript. The corresponding authors attest that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. C.-T.L. and J.M. are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Funding Information: P.W., C.-T.L., and J.D. were partially supported by the National Institutes of Health (U01 DK078616). J.B.M. was supported by National Institutes of Health grants 5UM1 DK078616-13 and R01 HL151855. J.C.F. was partially supported by the National Institutes of Health (HHSN268201300001I/N01-HC-65233). D.G. 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. J.M. 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). L.M.R. was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant KL2TR002490 and by T32HL129982. J.M.M. is supported by American Diabetes Association Innovative and Clinical Translational Award 1-19-ICTS-068. M.S.O. was supported by the HallasM{\o}ller Emerging Investigator grant from the Novo Nordisk Foundation (NNF17OC0031204). Funding support for participating cohorts is provided in Supplementary Data. G.D.S. works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol (MC_UU_00011/1). Publisher Copyright: {\textcopyright} 2021 by the American Diabetes Association.",
year = "2022",
month = jan,
doi = "10.2337/dc21-1284",
language = "English (US)",
volume = "45",
pages = "232--240",
journal = "Diabetes care",
issn = "0149-5992",
publisher = "American Diabetes Association Inc.",
number = "1",
}