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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: Evidence from genetic analysis and randomised trials

Swerdlow, DI and Preiss, D and Kuchenbaecker, KB and Holmes, MV and Engmann, JEL and Shah, T and Sofat, R and Stender, S and Johnson, PCD and Scott, RA and Leusink, M and Verweij, N and Sharp, SJ and Guo, Y and Giambartolomei, C and Chung, C and Peasey, A and Amuzu, A and Li, K and Palmen, J and Howard, P and Cooper, JA and Drenos, F and Li, YR and Lowe, G and Gallacher, J and Stewart, MCW and Tzoulaki, I and Buxbaum, SG and Van Der A, DL and Forouhi, NG and Onland-Moret, NC and Van Der Schouw, YT and Schnabel, RB and Hubacek, JA and Kubinova, R and Baceviciene, M and Tamosiunas, A and Pajak, A and Topor-Madry, R and Stepaniak, U and Malyutina, S and Baldassarre, D and Sennblad, B and Tremoli, E and De Faire, U and Veglia, F and Ford, I and Jukema, JW and Westendorp, RGJ and De Borst, GJ and De Jong, PA and Algra, A and Spiering, W and Der Zee, AHMV and Klungel, OH and De Boer, A and Doevendans, PA and Eaton, CB and Robinson, JG and Duggan, D and Kjekshus, J and Downs, JR and Gotto, AM and Keech, AC and Marchioli, R and Tognoni, G and Sever, PS and Poulter, NR and Waters, DD and Pedersen, TR and Amarenco, P and Nakamura, H and McMurray, JJV and Lewsey, JD and Chasman, DI and Ridker, PM and Maggioni, AP and Tavazzi, L and Ray, KK and Seshasai, SRK and Manson, JE and Price, JF and Whincup, PH and Morris, RW and Lawlor, DA and Smith, GD and Ben-Shlomo, Y and Schreiner, PJ and Fornage, M and Siscovick, DS and Cushman, M and Kumari, M and Wareham, NJ and Verschuren, WMM and Redline, S and Patel, SR and Whittaker, JC and Hamsten, A and Delaney, JA (2015) 'HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: Evidence from genetic analysis and randomised trials.' The Lancet, 385 (9965). 351 - 361. ISSN 0140-6736

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Abstract

© 2015 Swerdlow et al. Open Access article distributed under the terms of CC BY. 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. Funding The funding sources are cited at the end of the paper.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Divisions: Faculty of Social Sciences > Institute for Social and Economic Research
Depositing User: Jim Jamieson
Date Deposited: 06 Feb 2015 13:56
Last Modified: 01 May 2019 00:15
URI: http://repository.essex.ac.uk/id/eprint/12670

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