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

Abstract

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.

• Authors: 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, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, 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
• Journal: Lancet (London, England) (Lancet) Vol. 385 Issue 9965 Pg. 351-61 (Jan 24 2015) ISSN: 1474-547X [Electronic] England
• PMID: 25262344 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Swerdlow et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Cholesterol, HDL
• Cholesterol, LDL
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• HMGCR protein, human
• Hydroxymethylglutaryl CoA Reductases

Topics

• Aged
• Body Mass Index
• Body Weight (genetics)
• Cholesterol, HDL (metabolism)
• Cholesterol, LDL (metabolism)
• Diabetes Mellitus, Type 2 (genetics)
• Female
• Genetic Testing
• Humans
• Hydroxymethylglutaryl CoA Reductases (genetics)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (adverse effects)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)
• Randomized Controlled Trials as Topic
• Risk Factors