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Photo: KG Pressfoto

Marju Orho-Melander

Professor

Photo: KG Pressfoto

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol

Author

  • P Wu
  • George Hindy
  • Ulrika Ericson
  • Marju Orho-Melander
  • Jordi Merino

Summary, in English

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. © 2021 by the American Diabetes Association.

Department/s

  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease
  • EpiHealth: Epidemiology for Health
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2022

Language

English

Pages

232-240

Publication/Series

Diabetes Care

Volume

45

Issue

1

Document type

Journal article

Publisher

American Diabetes Association

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Cardiovascular Research - Hypertension
  • Diabetes - Cardiovascular Disease

ISBN/ISSN/Other

  • ISSN: 1935-5548