Author, as appears in the article.: Wu P; Moon JY; Daghlas I; Franco G; Porneala BC; Ahmadizar F; Richardson TG; Isaksen JL; Hindy G; Yao J; Sitlani CM; Raffield LM; Yanek LR; Feitosa MF; Cuadrat RRC; Qi Q; Ikram MA; Ellervik C; Ericson U; Goodarzi MO; Brody JA; Lange L; Mercader JM; Vaidya D; An P; Schulze MB; Masana L; Ghanbari M; Olesen MS; Cai J; Guo X; Floyd JS; Jager S; Province MA; Kalyani RR; Psaty BM; Orho-Melander M; Ridker PM; Kanters JK; Uitterlinden A; Smith GD; Gill D; Kaplan RC; Kavousi M; Raghavan S; Chasman DI; Rotter JI; Meigs JB; Florez JC; Dupuis J; Liu CT; Merino J

Department: Medicina i Cirurgia

URV's Author/s: Masana Marín, Luis

Keywords: Density-lipoprotein cholesterol 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: 2023-02-19

Papper version: info:eu-repo/semantics/acceptedVersion

Link to the original source: https://diabetesjournals.org/care/article-abstract/45/1/232/138981/Obesity-Partially-Mediates-the-Diabetogenic-Effect?redirectedFrom=fulltext

Licence document URL: http://repositori.urv.cat/ca/proteccio-de-dades/

Papper original source: Diabetes Care. 45 (1): 232-240

APA: Wu P; Moon JY; Daghlas I; Franco G; Porneala BC; Ahmadizar F; Richardson TG; Isaksen JL; Hindy G; Yao J; Sitlani CM; Raffield LM; Yanek LR; Feitosa MF (2022). Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol. Diabetes Care, 45(1), 232-240. DOI: 10.2337/dc21-1284

Article's DOI: 10.2337/dc21-1284

Entity: Universitat Rovira i Virgili

Journal publication year: 2022

Publication Type: Journal Publications