Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

Peitao Wu¹, Jee-Young Moon², Iyas Daghlas^{3

4}, Giulianini Franco⁵, Bianca C Porneala⁶, Fariba Ahmadizar⁷, Tom G Richardson^{8

9}, Jonas L Isaksen¹⁰, Georgy Hindy¹¹, Jie Yao¹², Colleen M Sitlani¹³, Laura M Raffield¹⁴, Lisa R Yanek¹⁵, Mary F Feitosa¹⁶, Rafael R C Cuadrat^{17

18}, Qibin Qi², M Arfan Ikram⁷, Christina Ellervik^{19

20}, Ulrika Ericson¹¹, Mark O Goodarzi²¹, Jennifer A Brody¹³, Leslie Lange²², Josep M Mercader^{4

23

24}, Dhananjay Vaidya¹⁵, Ping An¹⁶, Matthias B Schulze^{17

18

25}, Lluis Masana^{26

27}, Mohsen Ghanbari⁷, Morten S Olesen^{28

29}, Jianwen Cai³⁰, Xiuqing Guo¹², James S Floyd^{13

31}, Susanne Jäger^{17

18}, Michael A Province¹⁶, Rita R Kalyani¹⁵, Bruce M Psaty^{13

31

32}, Marju Orho-Melander¹¹, Paul M Ridker^{5

24}, Jørgen K Kanters¹⁰, Andre Uitterlinden^{7

33}, George Davey Smith⁸, Dipender Gill^{9

34

35

36}, Robert C Kaplan^{2

37}, Maryam Kavousi⁷, Sridharan Raghavan^{38

39}, Daniel I Chasman^{3

4}, Jerome I Rotter¹², James B Meigs^{4

6

24}, Jose C Florez^{4

23

24}, Josée Dupuis¹, Ching-Ti Liu¹, Jordi Merino^{4

23

24

26}

Affiliations

¹ 1Department of Biostatistics, Boston University School of Public Health, Boston, MA.
² 2Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
³ 3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
⁴ 4Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
⁵ 5Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
⁶ 6Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
⁷ 7Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁸ 8MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K.
⁹ 9Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, U.K.
¹⁰ 10Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹ 11Department of Clinical Sciences, Skåne University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
¹² 12Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
¹³ 13Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
¹⁴ 14Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹⁵ 15Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
¹⁶ 16Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO.
¹⁷ 17Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
¹⁸ 18German Center for Diabetes Research, Neuherberg, Germany.
¹⁹ 19Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
²⁰ 20Department of Research, Region Zealand, Sorø, Denmark.
²¹ 21Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
²² 22Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
²³ 23Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
²⁴ 24Department of Medicine, Harvard Medical School, Boston, MA.
²⁵ 25Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
²⁶ 26Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Rovira i Virgil University, IISPV, Reus, Spain.
²⁷ 27Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
²⁸ 28Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
²⁹ 29Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³⁰ 30Collaborative Studies Coordinating Center, Department of Biostatistics, The University of North Carolina at Chapel Hill, NC.
³¹ 31Department of Epidemiology, University of Washington, Seattle, WA.
³² 32Department of Health Services, University of Washington, Seattle, WA.
³³ 33Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁴ 34Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K.
³⁵ 35Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, London, U.K.
³⁶ 36Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, U.K.
³⁷ 37Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle WA.
³⁸ 38Department of Veterans Affairs Medical Center, Eastern Colorado Health Care System, Denver, CO.
³⁹ 39Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Denver, CO.

PMID: 34789503
PMCID: PMC8753762
DOI: 10.2337/dc21-1284

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

Peitao Wu et al. Diabetes Care. 2022.

. 2022 Jan 1;45(1):232-240.

doi: 10.2337/dc21-1284.

Authors

Affiliations

¹ 1Department of Biostatistics, Boston University School of Public Health, Boston, MA.
² 2Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY.
³ 3Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
⁴ 4Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA.
⁵ 5Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
⁶ 6Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA.
⁷ 7Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
⁸ 8MRC Integrative Epidemiology Unit, Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, U.K.
⁹ 9Novo Nordisk Research Centre Oxford, Old Road Campus, Oxford, U.K.
¹⁰ 10Laboratory of Experimental Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹ 11Department of Clinical Sciences, Skåne University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden.
¹² 12Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA.
¹³ 13Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA.
¹⁴ 14Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC.
¹⁵ 15Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
¹⁶ 16Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO.
¹⁷ 17Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
¹⁸ 18German Center for Diabetes Research, Neuherberg, Germany.
¹⁹ 19Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
²⁰ 20Department of Research, Region Zealand, Sorø, Denmark.
²¹ 21Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA.
²² 22Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO.
²³ 23Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.
²⁴ 24Department of Medicine, Harvard Medical School, Boston, MA.
²⁵ 25Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
²⁶ 26Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Rovira i Virgil University, IISPV, Reus, Spain.
²⁷ 27Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
²⁸ 28Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
²⁹ 29Laboratory for Molecular Cardiology, Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
³⁰ 30Collaborative Studies Coordinating Center, Department of Biostatistics, The University of North Carolina at Chapel Hill, NC.
³¹ 31Department of Epidemiology, University of Washington, Seattle, WA.
³² 32Department of Health Services, University of Washington, Seattle, WA.
³³ 33Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁴ 34Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, U.K.
³⁵ 35Clinical Pharmacology and Therapeutics Section, Institute of Medical and Biomedical Education and Institute for Infection and Immunity, St George's, University of London, London, U.K.
³⁶ 36Clinical Pharmacology Group, Pharmacy and Medicines Directorate, St George's University Hospitals NHS Foundation Trust, London, U.K.
³⁷ 37Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle WA.
³⁸ 38Department of Veterans Affairs Medical Center, Eastern Colorado Health Care System, Denver, CO.
³⁹ 39Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado School of Medicine, Denver, CO.

PMID: 34789503
PMCID: PMC8753762
DOI: 10.2337/dc21-1284

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.

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Figures

**Figure 1**
Direct acyclic graph to illustrate total, direct, and indirect effects of LDLc on type 2 diabetes risk. Directed acyclic graphs demonstrating the hypothesized direction for the total effect of lower LDLc on increased odds of type 2 diabetes (T2D) (A) and the hypothesized direction for the effect of lower LDL-c on increased BMI (B), which may partially mediate the effect of lowering LDLc on T2D risk.

**Figure 2**
MR estimates for the total, indirect, and direct effect of a genetically predicted low LDLc on type 2 diabetes risk. Forest plot of univariable and multivariable MR estimates for the total, indirect, and direct effect of a genetically driven low LDLc on type 2 diabetes risk from summary-level (A) and individual-level (B) analyses. The indirect effect was calculated with the products of the coefficient method (research design and methods). The direct effect was obtained with multivariable MR (research design and methods). Estimates for genetically predicted LDLc analyses were oriented to reflect the effect of a 1-SD decrease in LDLc on the outcome. We used β-coefficients to report estimated effect sizes in the figure due to the inclusion of binary and continuous outcomes, but in the main text we elected to provide ORs (=exp(β)) for binary outcomes, as these are easier to interpret than the β-coefficients. LDLc adj BMI, LDLc adjusted for BMI; T2D, type 2 diabetes.

See this image and copyright information in PMC

References

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Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

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Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

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