학술논문
Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.
Document Type
article
Author
Wu, Peitao; Moon, Jee-Young; Daghlas, Iyas; Franco, Giulianini; Porneala, Bianca; Ahmadizar, Fariba; Richardson, Tom; Isaksen, Jonas; Hindy, Georgy; Yao, Jie; Sitlani, Colleen; Raffield, Laura; Yanek, Lisa; Feitosa, Mary; Cuadrat, Rafael; Qi, Qibin; Arfan Ikram, M; Ellervik, Christina; Ericson, Ulrika; Goodarzi, Mark; Brody, Jennifer; Lange, Leslie; Mercader, Josep; Vaidya, Dhananjay; An, Ping; Schulze, Matthias; Masana, Lluis; Ghanbari, Mohsen; Olesen, Morten; Cai, Jianwen; Guo, Xiuqing; Floyd, James; Jäger, Susanne; Province, Michael; Kalyani, Rita; Psaty, Bruce; Orho-Melander, Marju; Ridker, Paul; Kanters, Jørgen; Uitterlinden, Andre; Davey Smith, George; Gill, Dipender; Kaplan, Robert; Kavousi, Maryam; Raghavan, Sridharan; Chasman, Daniel; Rotter, Jerome; Meigs, James; Florez, Jose; Dupuis, Josée; Liu, Ching-Ti; Merino, Jordi
Source
Diabetes reviews (Alexandria, Va.). 45(1)
Subject
Language
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.