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

Lancet (London, England) (2014-09-30)
Daniel I Swerdlow, David Preiss, Karoline B Kuchenbaecker, Michael V Holmes, Jorgen E L Engmann, Tina Shah, Reecha Sofat, Stefan Stender, Paul C D Johnson, Robert A Scott, Maarten Leusink, Niek Verweij, Stephen J Sharp, Yiran Guo, Claudia Giambartolomei, Christina Chung, Anne Peasey, Antoinette Amuzu, KaWah Li, Jutta Palmen, Philip Howard, Jackie A Cooper, Fotios Drenos, Yun R Li, Gordon Lowe, John Gallacher, Marlene C W Stewart, Ioanna Tzoulaki, Sarah G Buxbaum, Daphne L van der A, Nita G Forouhi, N Charlotte Onland-Moret, Yvonne T van der Schouw, Renate B Schnabel, Jaroslav A Hubacek, Ruzena Kubinova, Migle Baceviciene, Abdonas Tamosiunas, Andrzej Pajak, Roman Topor-Madry, Urszula Stepaniak, Sofia Malyutina, Damiano Baldassarre, Bengt Sennblad, Elena Tremoli, Ulf de Faire, Fabrizio Veglia, Ian Ford, J Wouter Jukema, Rudi G J Westendorp, Gert Jan de Borst, Pim A de Jong, Ale Algra, Wilko Spiering, Anke H Maitland-van der Zee, Olaf H Klungel, Anthonius de Boer, Pieter A Doevendans, Charles B Eaton, Jennifer G Robinson, David Duggan, John Kjekshus, John R Downs, Antonio M Gotto, Anthony C Keech, Roberto Marchioli, Gianni Tognoni, Peter S Sever, Neil R Poulter, David D Waters, Terje R Pedersen, Pierre Amarenco, Haruo Nakamura, John J V McMurray, James D Lewsey, Daniel I Chasman, Paul M Ridker, Aldo P Maggioni, Luigi Tavazzi, Kausik K Ray, Sreenivasa Rao Kondapally Seshasai, JoAnn E Manson, Jackie F Price, Peter H Whincup, Richard W Morris, Debbie A Lawlor, George Davey Smith, Yoav Ben-Shlomo, Pamela J Schreiner, Myriam Fornage, David S Siscovick, Mary Cushman, Meena Kumari, Nick J Wareham, W M Monique Verschuren, Susan Redline, Sanjay R Patel, John C Whittaker, Anders Hamsten, Joseph A Delaney, Caroline Dale, Tom R Gaunt, Andrew Wong, Diana Kuh, Rebecca Hardy, Sekar Kathiresan, Berta A Castillo, Pim van der Harst, Eric J Brunner, Anne Tybjaerg-Hansen, Michael G Marmot, Ronald M Krauss, Michael Tsai, Josef Coresh, Ronald C Hoogeveen, Bruce M Psaty, Leslie A Lange, Hakon Hakonarson, Frank Dudbridge, Steve E Humphries, Philippa J Talmud, Mika Kivimäki, Nicholas J Timpson, Claudia Langenberg, Folkert W Asselbergs, Mikhail Voevoda, Martin Bobak, Hynek Pikhart, James G Wilson, Alex P Reiner, Brendan J Keating, Aroon D Hingorani, Naveed Sattar
ABSTRACT

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. 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. 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). The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition. The funding sources are cited at the end of the paper.

MATERIALS
Product Number
Brand
Product Description

SAFC
Cholesterol, Plant-Derived, SyntheChol®, NF, Ph. Eur., JP
Supelco
Cholesterol, Pharmaceutical Secondary Standard; Certified Reference Material
SAFC
Cholesterol, from sheep wool, Controlled origin, meets USP/NF testing specifications
Sigma-Aldrich
SyntheChol® NS0 Supplement, 500 ×, synthetic cholesterol, animal component-free, aqueous solution, sterile-filtered, suitable for cell culture
Supelco
Cholesterol solution, certified reference material, 10 mg/mL in chloroform
Sigma-Aldrich
Cholesterol, powder, BioReagent, suitable for cell culture, ≥99%
Sigma-Aldrich
Cholesterol, from sheep wool, ≥92.5% (GC), powder
Sigma-Aldrich
Cholesterol, Sigma Grade, ≥99%
Sigma-Aldrich
Cholesterol, tested according to Ph. Eur.