Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

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. GoodarziJennifer 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 Jager, 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)232-240
Number of pages9
JournalDiabetes Care
Volume45
Issue number1
DOIs
Publication statusPublished - Jan 2022

Bibliographical 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-Møller 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?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:
© 2021 by the American Diabetes Association.

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