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

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 PalmenPhilip 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, Romanvan 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

Research output: Contribution to journalArticlepeer-review

340 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)351-361
Number of pages11
JournalThe Lancet
Volume385
Issue number9965
DOIs
StatePublished - Jan 24 2015

Bibliographical note

Funding Information:
DIS is supported by a Medical Research Council (MRC) Doctoral Training Award and a grant from the Rosetrees Trust. MVH is supported by a MRC Population Health Scientist Fellowship ( G0802432 ). JELE is supported by grants from the National Institutes of Health (NIH) and the MRC. RS has been supported by a British Heart Foundation (Schillingford) Clinical Training Fellowship ( FS/07/011 ). SS is supported by the Danish MRC ( grant no. 10-083788 ), the Research Fund at Rigshospitalet, Copenhagen University Hospital, and Chief Physician Johan Boserup and Lise Boserup's Fund. CC and APe are supported by grants from the Wellcome Trust ( 064947/Z/01/Z and 081081/Z/06/Z ), a grant from the National Institute on Aging ( 1R01 AG23522-01 ), and a grant from MacArthur Foundation. SGB was supported by an award from the National Institute on Minority Health and Health Disparities of the NIH ( award number P20MD006899 ). NGF is supported by a grant from the MRC. JAH is supported by the project (Ministry of Health, Czech Republic) for the development of research organisation 00023001 (IKEM, Prague, Czech Republic). APa is supported by grants from the Wellcome Trust ( 064947/Z/01/Z and 081081/Z/06/Z ) and National Institute on Aging ( 1R01 AG23522-01 ). BS is supported by the Magnus Bergvall Foundation and the Foundation for Old Servants. RGJW is supported by the National Institute for Healthy Ageing ( Grant 05060810 ). JFP is supported by the British Heart Foundation; Chest, Heart and Stroke Scotland; the Wellcome Trust; and the MRC. DAL, GDS, and NJT work in a unit that receives funding from the MRC and University of Bristol. EJB's research is supported by a British Heart Foundation programme grant ( RG/13/2/30098 ) and the MooDFOOD Collaborative Project ( FP7 grant 613598 ). RMK is supported by the NIH ( grant NIH U19 HL065797 ). SEH and PJT are supported by the British Heart Foundation ( BHF RG 08/008, PG/07/133/24260 ), MRC, and NIH ( grant NHLBI 33014 ). MKi is supported by the National Institute on Aging ( AG034454 ); the MRC ( K013351 ); the National Heart, Lung and Blood Institute ( HL036310 ); and the Academy of Finland. NJT is supported by the MRC ( grant G0600705 ). FWA is supported by a clinical fellowship from the Netherlands Organisation for Health Research and Development ( ZonMw grant 90700342 ). ADH is supported by University College London NIHR Biomedical Research Centre. NS's research is supported by the British Heart Foundation, Diabetes UK, and the EU/EFPIA Innovative Medicines Initiative Joint Undertaking ( EMIF grant 115372 ). We thank Merck and Novartis for contributing data to the statin trials analysis. Details of grants or other support for included studies are provided in the appendix .

Funding Information:
JWJ has received research grants from and was speaker at CME-accredited meetings sponsored by Astellas, Anthera, AstraZeneca, Bayer, Biotronik, Boston Scientific, Correvio, Daiichi Sankyo, Lilly, Genzyme, Medtronic, Merck-Schering-Plough, Pfizer, Orbus Neich, Novartis, Roche, Servier, Sanofi Aventis, the Netherlands Heart Foundation, the Interuniversity Cardiology Institute of the Netherlands, and the European Community Framework KP7 Programme. JGR's institution has received grants for her work from Amgen, Daiichi Sankyo, Esperion, GlaxoSmithKline, Merck, Genentech/Hoffmann-La Roche, and Zinfandel/Takeda. AMG has received funds for board membership of Aegerion, Arisaph, DuPont, VascuVis, and Vatera; consultancy for Janssen, Kowa, Merck, and Roche; and manuscript preparation for AstraZeneca. ACK has received funds in the form of grants to his institution, consultancy fees, and travel support from Bristol-Myers Squibb; consultancy fees from AstraZeneca, Merck, Novartis, and Pfizer; grants paid to his institution from AstraZeneca, Merck, Novartis, and Pfizer; and fees for speaking engagements from AstraZeneca, Merck, Novartis, and Pfizer. RM has received funds for speaking engagements from Ferrer, Pronova BioPharma, Sigma-Tau, and Societa Prodotti Antibiotica; his institution has received funds from Sigma-Tau, Societa Prodotti Antibiotica, GlaxoSmithKline, Novartis, Amgen, Pronova BioPharma, and General Electric. PSS has received consultancy fees from Pfizer and Servier, fees for speaking engagements from Pfizer and Servier, and fees for development of educational presentations from Pfizer; his institution has received funds for his work from Pfizer and Servier. NRP has received fees for speaking engagements from Pfizer and fees for production of books from Servier; his institution has received grants from Pfizer and the Hypertension Trust. DDW has received consultancy fees from Merck-Schering Plough and Pfizer, and fees for speaking engagements from Pfizer. TRP has received consultancy fees, grants, and fees for speaking engagements from Merck; and fees for speaking engagements from AstraZeneca, Roche, and Amgen. PA has received funds for board membership, consultancy, grants, speaking engagements, and the development of educational presentations from Pfizer. JJVM has received reimbursement for travel from AstraZeneca, and his institution has received funds from AstraZeneca. LT's institution has received funds for his work from the ANMCO Foundation. KKR has received fees for advisory board membership from Pfizer; for involvement in trial management and advisory boards from Roche; for speaking engagements and advisory board membership from MSD; for speaking engagements, advisory board membership, and trial involvement from AstraZeneca; for advisory board membership and trial involvement from Sanofi; for advisory board membership from Aegerion, Regeneron, and Abbott; for speaking engagements from Menarini, Novo Nordisk, and theHeart.org ; for trial involvement and steering committee membership from GlaxoSmithKline; and for advisory board membership from Novartis. JEM is a co-inventor on a patent held by the Brigham and Women's Hospital that relates to inflammatory biomarkers in diabetes prediction. JCW is an employee of and holds stock in GlaxoSmithKline. RMK has received funds for advisory board membership from Merck, consultancy fees from Celera and Genentech, and grants from Quest Diagnostics, and his institution receives funds resulting from a patent related to diagnostic use of a HMGCR spliced isoform. RCH has received funds for board membership of Liposcience, for speaking engagements for Denka Seiken, and in the form of grants to his institution from Merck/Schering-Plough, Diadexus, and Denka Seiken. All other authors declare no competing interests.

Publisher Copyright:
© 2015 Swerdlow et al. Open Access article distributed under the terms of CC BY.

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