期刊
LANCET
卷 385, 期 9965, 页码 351-361出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/S0140-6736(14)61183-1
关键词
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资金
- Medical Research Council (MRC) Doctoral Training Award
- Rosetrees Trust
- MRC Population Health Scientist Fellowship [G0802432]
- National Institutes of Health (NIH)
- British Heart Foundation (Schillingford) Clinical Training Fellowship [FS/07/011]
- Danish MRC [10-083788]
- Research Fund at Rigshospitalet
- Copenhagen University Hospital
- Chief Physician Johan Boserup and Lise Boserup's Fund
- Wellcome Trust [064947/Z/01/Z, 081081/Z/06/Z]
- National Institute on Aging [1R01 AG23522-01, AG034454]
- MacArthur Foundation
- National Institute on Minority Health
- Health Disparities of the NIH [P20MD006899]
- MRC [K013351, G0600705]
- Ministry of Health, Czech Republic [00023001]
- Magnus Bergvall Foundation
- Foundation for Old Servants
- National Institute for Healthy Ageing [05060810]
- British Heart Foundation
- Chest, Heart and Stroke Scotland
- Wellcome Trust
- British Heart Foundation [RG/13/2/30098]
- MooDFOOD Collaborative Project (FP7) [613598]
- NIH [NIH U19 HL065797, NHLBI 33014]
- British Heart Foundation (BHF) [RG 08/008, PG/07/133/24260]
- EMIF [115372]
- National Heart, Lung and Blood Institute [HL036310]
- Academy of Finland
- Netherlands Organisation for Health Research and Development (ZonMw grant) [90700342]
- University College London NIHR Biomedical Research Centre
- Diabetes UK
- ESRC [ES/F02679X/1] Funding Source: UKRI
- MRC [G1000616, G0601647, MR/K013351/1, MR/K006215/1, MC_UP_A100_1003, G0500877, MC_UU_12019/1, MC_UU_12013/1, MC_UU_12013/3, G0802432, G0701830, MC_UU_12015/5, MC_UU_12013/5, MC_UU_12013/8, G0600705, G0902037, MC_UU_12015/1] Funding Source: UKRI
- British Heart Foundation [PG/13/66/30442, RG/08/013/25942, RG/10/12/28456, RG/08/008/25291, RG/13/2/30098, RG/07/008/23674, RG/13/16/30528] Funding Source: researchfish
- Economic and Social Research Council [ES/F02679X/1] Funding Source: researchfish
- Medical Research Council [G0100222, MR/K006215/1, G0902037, MC_PC_13048, G1000616, MC_UU_12013/8, G0601647, G8802774, MC_PC_13046, G0500877, MR/K006584/1, MC_UU_12019/1, MC_UU_12015/5, G0802432, MR/K013351/1, MC_UP_A100_1003, MC_U106179471, MC_UU_12013/1, MC_UU_12015/1, MC_UU_12013/5, MC_UU_12013/3, G0701830, G19/35, G0600705] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0513-10059, NF-SI-0512-10135] Funding Source: researchfish
Background Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target. Methods We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis. Findings Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0.06 mmol/L (95% CI 0.05-0.07) lower LDL cholesterol and higher body weight (0.30 kg, 0.18-0.43), waist circumference (0.32 cm, 0.16-0.47), plasma insulin concentration (1.62%, 0.53-2.72), and plasma glucose concentration (0.23%, 0.02-0.44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1.02, 95% CI 1.00-1.05); the rs12916-T allele association was consistent (1.06, 1.03-1.09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0.92 mmol/L (95% CI 0.18-1.67) at 1-year of follow-up, increased bodyweight by 0.24 kg (95% CI 0.10-0.38 in all trials; 0.33 kg, 95% CI 0.24-0.42 in placebo or standard care controlled trials and 0.15 kg, 95% CI 0.39 to 0.08 in intensive-dose vs moderate-dose trials) at a mean of 4. 2 years (range 1.9-6.7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1.12, 95% CI 1.06-1.18 in all trials; 1.11, 95% CI 1.03-1. 20 in placebo or standard care controlled trials and 1.12, 95% CI 1.04-1. 22 in intensive-dose vs moderate dose trials). Interpretation The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
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