{"doi":"10.2337/dc21-1284","title":"Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol","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.","journal":"Diabetes Care","year":2021,"id":172079,"datarank":0.6999242914095436,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.20554876150889417,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.20554876150889417,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":13,"citers_with_citation_signal":8,"citers_with_endowment":8,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9617,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.16826305"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":218544,"name":"Jee‐Young Moon","orcid":"0000-0001-9218-8335","position":1,"is_corresponding":false},{"id":302169,"name":"Iyas Daghlas","orcid":"0000-0001-8735-284X","position":2,"is_corresponding":false},{"id":243636,"name":"Franco Giulianini","orcid":null,"position":3,"is_corresponding":false},{"id":514446,"name":"Bianca Porneala","orcid":"0009-0001-5762-379X","position":4,"is_corresponding":false},{"id":681552,"name":"Fariba Ahmadizar","orcid":"0000-0002-6261-9445","position":5,"is_corresponding":false},{"id":240623,"name":"Tom G. 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