Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol
Year: 2021
Type: article
Study design: Observational Study
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 (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). 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.
Source: Diabetes Care
DOI: 10.2337/dc21-1284
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 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
Institutions: Boston University, Albert Einstein College of Medicine, Broad Institute, Massachusetts General Hospital, Brigham and Women's Hospital, Harvard University, Erasmus MC, University of Bristol, University of Copenhagen, Lund University, Skåne University Hospital, The Lundquist Institute, Harbor–UCLA Medical Center, University of Washington, University of North Carolina at Chapel Hill, Johns Hopkins University, Johns Hopkins Medicine, Washington University in St. Louis, German Center for Diabetes Research, German Institute of Human Nutrition, Region Zealand, Cedars-Sinai Medical Center, University of Colorado Anschutz, University of Potsdam, Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas, Institut de Recerca Biomèdica Catalunya Sud, Hospital Universitari Sant Joan de Reus, Universitat Rovira i Virgili, Copenhagen University Hospital, Rigshospitalet, Danish National Research Foundation, University of London, St George's, University of London, St George’s University Hospitals NHS Foundation Trust, Imperial College London, Fred Hutch Cancer Center, VA Eastern Colorado Health Care System, University of Colorado Denver
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Diabetes Association, U.S. Department of Veterans Affairs, Yale University, National Institute for Health and Care Research, British Heart Foundation, Imperial College London, European Commission, University of Bristol, Novo Nordisk, Shionogi, National Institutes of Health, Horizon 2020 Framework Programme, Medical Research Council, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences
Awards: G1017378214, TOPMed Omics of Cardiovascular Disease in Diabetes, Hunger genes, food choices, and metabolic responses: implications for obesity and type 2 diabetes, Research Excellence (round 3), G1653514516, G1801186217, G2033544460, G2538597952, G2651529389, G3345895242, G5095704568, G5573126869, CHARGE consortium: omics discovery for CVD and aging phenotypes, G6075306088, Rare Sequence Variation and Diabetes Quantitative Traits, G6329715174, Interplay between genetic determinants of glycaemia, type 2 diabetes and cardiovascular disease in interaction with dietary and lifestyle factors, North Carolina Translational and Clinical Science Institute (NC TraCS) KL2, Mendelian randomization to hypothesis-free causal inference, G6902144918, G7990456425, G8502142660, G8512683158, HISPANIC COMMUNITY HEALTH STUDY-268065233, G9000079831, G9000323435, TOPMed Omics of Type 2 Diabetes and Quantitative Traits, Development of Polygenic Risk Scores for Diabetes and Complications across the Life-Span in Populations of Multiple Ancestries, Washington University Nutrition Obesity Research Center, Mentoring Investigators on the Clinical Translation of Cardiometabolic Genetic Discoveries, The Genetic Epidemiology of Heart, Lung, and Blood Traits Training Grant (GenHLB), NYR-Diabetes Research Center (NYR-DRC), Boston Area Nutrition Obesity Research Center (NORC), New York Regional Center for Diabetes Translation Research
OpenAlex ID: W3213204823