Author, as appears in the article.: Wu, Peitao; Moon, Jee-Young; Daghlas, Iyas; Franco, Giulianini; Porneala, Bianca C; Ahmadizar, Fariba; Richardson, Tom G; Isaksen, Jonas L; Hindy, Georgy; Yao, Jie; Sitlani, Colleen M; Raffield, Laura M; Yanek, Lisa R; Feitosa, Mary F; Cuadrat, Rafael R C; Qi, Qibin; Ikram, M Arfan; Ellervik, Christina; Ericson, Ulrika; Goodarzi, Mark O; Brody, Jennifer A; Lange, Leslie; Mercader, Josep M; Vaidya, Dhananjay; An, Ping; Schulze, Matthias B; Masana, Lluis; Ghanbari, Mohsen; Olesen, Morten S; Cai, Jianwen; Guo, Xiuqing; Floyd, James S; Jaeger, Susanne; Province, Michael A; Kalyani, Rita R; Psaty, Bruce M; Orho-Melander, Marju; Ridker, Paul M; Kanters, Jorgen K; Uitterlinden, Andre; Smith, George Davey; Gill, Dipender; Kaplan, Robert C; Kavousi, Maryam; Raghavan, Sridharan; Chasman, Daniel, I; Rotter, Jerome, I; Meigs, James B; Florez, Jose C; Dupuis, Josee; Liu, Ching-Ti; Merino, Jordi
Department: Medicina i Cirurgia
URV's Author/s: Masana Marín, Luis / MERINO RIBAS, JORDI
Keywords: Risk factors Obesity Mendelian randomization analysis Humans Genome-wide association study Diabetes mellitus, type 2 Density-lipoprotein cholesterol Cholesterol, ldl risk pcsk9 mendelian randomization instruments genome-wide association genetic-variants bias
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.
Thematic Areas: Saúde coletiva Odontología Nutrição Medicina iii Medicina ii Medicina i Internal medicine Interdisciplinar General medicine Engenharias iv Enfermagem Endocrinology, diabetes and metabolism Endocrinology & metabolism Ciências biológicas ii Ciências biológicas i Biotecnología Antropologia / arqueologia Advanced and specialized nursing
licence for use: https://creativecommons.org/licenses/by/3.0/es/
Author's mail: luis.masana@urv.cat
Author identifier: 0000-0002-0789-4954
Record's date: 2025-02-19
Paper version: info:eu-repo/semantics/acceptedVersion
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Paper original source: Diabetes Care. 45 (1): 232-240
APA: Wu, Peitao; Moon, Jee-Young; Daghlas, Iyas; Franco, Giulianini; Porneala, Bianca C; Ahmadizar, Fariba; Richardson, Tom G; Isaksen, Jonas L; Hindy, Geo (2022). Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol. Diabetes Care, 45(1), 232-240. DOI: 10.2337/dc21-1284
Entity: Universitat Rovira i Virgili
Journal publication year: 2022
Publication Type: Journal Publications
Repositori URV