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 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 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; Sofi A. 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 Kivimaeki; 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; MAGIC Consortium

doi:10.1016/S0140-6736(14)61183-1

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

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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, …

The Lancet (British edition), Vol.385(9965), pp.351-361

01/24/2015

DOI: 10.1016/S0140-6736(14)61183-1

PMCID: PMC4322187

PMID: 25262344

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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.

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Title: Subtitle: HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
Creators: Daniel I. Swerdlow - University College London
David Preiss - University of Glasgow
Karoline B. Kuchenbaecker - University of Cambridge
Michael V. Holmes - University College London
Jorgen E. L. Engmann - Farr Institute
Tina Shah - University College London
Reecha Sofat - University College London
Stefan Stender - Utrecht University
Paul C. D. Johnson - University of Glasgow
Robert A. Scott - University of Cambridge
Maarten Leusink - University of Pennsylvania
Niek Verweij - University of Groningen
Stephen J. Sharp - University of Cambridge
Yiran Guo - University of London
Claudia Giambartolomei - University College London
Christina Chung - University College London
Anne Peasey - University College London
Antoinette Amuzu - University of Edinburgh
Kawah Li - University of London
Jutta Palmen - University College London
Philip Howard - University College London
Jackie A. Cooper - University College London
Fotios Drenos - University College London
Yun R. Li - Children's Hospital of Philadelphia
Gordon Lowe - University of Glasgow
John Gallacher - Imperial College London
Marlene C. W. Stewart - Imperial College London
Ioanna Tzoulaki - Jackson State University
Sarah G. Buxbaum - Utrecht University
Daphne Van der A - National Institute for Public Health and the Environment
Nita G. Forouhi - University of Groningen
N. Charlotte Onland-Moret - Utrecht University
Yvonne T. van der Schouw - Utrecht University
Renate B. Schnabel - Universität Hamburg
Jaroslav A. Hubacek - Institute of Clinical and Experimental Medicine
Ruzena Kubinova - National Institute of Public Health
Migle Baceviciene - Lithuanian University of Health Sciences
Abdonas Tamosiunas - Russian Academy of Sciences
Andrzej Pajak - Karolinska Institutet
Roman Topor-Madry - Jagiellonian University
Urszula Stepaniak - Karolinska Institutet
Sofi A. Malyutina - Research Institute of Physiology and Fundamental Medicine of the Siberian Branch of the Russian Academy of Medical Sciences
Damiano Baldassarre - Translational Genomics Research Institute
Bengt Sennblad - Leiden University
Elena Tremoli - Translational Genomics Research Institute
Ulf de Faire - Memorial Hospital of Rhode Island
Fabrizio Veglia - University of Iowa
Ian Ford - University of Glasgow
J. Wouter Jukema - University of Oslo
Rudi G. J. Westendorp - University of Oslo
Gert Jan de Borst - Utrecht University
Pim A. de Jong - Utrecht University
Ale Algra - Utrecht University
Wilko Spiering - Utrecht University
Anke H. Maitland-van der Zee - Univ Utrecht, Fac Sci, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht Inst Pharmaceut Sci, Utrecht, Netherlands
Olaf H. Klungel - University of Pennsylvania
Anthonius de Boer - University of Pennsylvania
Pieter A. Doevendans - Utrecht University
Charles B. Eaton - The University of Texas at San Antonio
Jennifer G. Robinson - University of Iowa
David Duggan - Cornell University
John Kjekshus - The University of Sydney
John R. Downs - The University of Texas at San Antonio
Antonio M. Gotto - Weill Cornell Medicine
Anthony C. Keech - The University of Sydney
Roberto Marchioli - Quintiles, Hematol & Oncol Therapeut Delivery Unit, Milan, Italy
Gianni Tognoni - Harvard University
Peter S. Sever - University of London
Neil R. Poulter - University of London
David D. Waters - University of California, San Francisco
Terje R. Pedersen - University of Oslo
Pierre Amarenco - Université Paris Cité
Haruo Nakamura - Mitsukoshi Hlth & Welf Fdn, Tokyo, Japan
John J. V. McMurray - University of Glasgow
James D. Lewsey - University of Cambridge
Daniel I. Chasman - St George's, University of London
Paul M. Ridker - Brigham and Women's Hospital
Aldo P. Maggioni - University of Minnesota
Luigi Tavazzi - University of Minnesota
Kausik K. Ray - The University of Texas Health Science Center at Houston
Sreenivasa Rao Kondapally Seshasai - The University of Texas Health Science Center at Houston
Joann E. Manson - St George's, University of London
Jackie F. Price - Imperial College London
Peter H. Whincup - University of Washington
Richard W. Morris - University College London
Debbie A. Lawlor - University of Vermont
George Davey Smith - University of Vermont
Yoav Ben-Shlomo - University of Vermont
Pamela J. Schreiner - University of Minnesota
Myriam Fornage - Broad Institute
David S. Siscovick - University of Washington
Mary Cushman - University of North Carolina at Chapel Hill
Meena Kumari - University College London
Nick J. Wareham - University of Cambridge
W. M. Monique Verschuren - Utrecht University
Susan Redline - Brigham and Women's Hospital
Sanjay R. Patel - University of Bristol
John C. Whittaker - GlaxoSmithKline (United Kingdom)
Anders Hamsten - Leiden University
Joseph A. Delaney - Johns Hopkins University
Caroline Dale - Cardiff University
Tom R. Gaunt - University of Washington
Andrew Wong - University College London
Diana Kuh - University College London
Rebecca Hardy - University College London
Sekar Kathiresan - Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA
Berta A. Castillo - University of London
Pim van der Harst - University of Groningen
Eric J. Brunner - University College London
Anne Tybjaerg-Hansen - University of Copenhagen
Michael G. Marmot - University College London
Ronald M. Krauss - University of Mississippi
Michael Tsai - Harvard University
Josef Coresh - Johns Hopkins University
Ronald C. Hoogeveen - Baylor College of Medicine
Bruce M. Psaty - University of Washington
Leslie A. Lange - University of North Carolina at Chapel Hill
Hakon Hakonarson - Children's Hospital of Philadelphia
Frank Dudbridge - London School of Hygiene & Tropical Medicine
Steve E. Humphries - University College London
Philippa J. Talmud - University College London
Mika Kivimaeki - UCL, UCL Res Dept Epidemiol & Publ Hlth, London, England
Nicholas J. Timpson - University of Bristol
Claudia Langenberg - University of Cambridge
Folkert W. Asselbergs - Farr Institute
Mikhail Voevoda - Institute of Cytology and Genetics
Martin Bobak - University College London
Hynek Pikhart - University College London
James G. Wilson - University of Mississippi
Alex P. Reiner - Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA
Brendan J. Keating - University of London
Aroon D. Hingorani - University College London
Naveed Sattar - University of Glasgow
MAGIC Consortium
Resource Type: Journal article
Publication Details: The Lancet (British edition), Vol.385(9965), pp.351-361
DOI: 10.1016/S0140-6736(14)61183-1
PMID: 25262344
PMCID: PMC4322187
NLM abbreviation: Lancet
ISSN: 0140-6736
eISSN: 1474-547X
Publisher: Elsevier
Number of pages: 11
Grant note: Chief Physician Johan Boserup and Lise Boserup's Fund Wellcome Trust; European Commission MC_UU_12015/5 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) ES/F02679X/1 / Economic and Social Research Council; UK Research & Innovation (UKRI); Economic & Social Research Council (ESRC) 05060810 / National Institute for Healthy Ageing Rosetrees Trust British Heart Foundation NIH U19 HL065797; NHLBI 33014 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA NF-SI-0513-10059 / National Institute for Health Research; National Institute for Health Research (NIHR) HL036310 / National Heart, Lung and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Academy of Finland R01AG023522 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) Copenhagen University Hospital K013351; G0600705 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) UM1CA182913 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) MacArthur Foundation Research Fund at Rigshospitalet 115372 / EMIF RG/13/16/30528 / British Heart Foundation P20MD006899 / National Institute on Minority Health and Health Disparities; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Minority Health & Health Disparities (NIMHD) Chest, Heart and Stroke Scotland Medical Research Council (MRC) Doctoral Training Award; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) 064947/Z/01/Z; 081081/Z/06/Z / Wellcome Trust; European Commission 00023001 / Ministry of Health, Czech Republic; Czech Republic Government 90700342 / Netherlands Organisation for Health Research and Development (ZonMw grant) R01HL036310 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 1R01 AG23522-01; AG034454 / National Institute on Aging; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) 613598 / MooDFOOD Collaborative Project (FP7) 10-083788 / Danish MRC; Danish Medical Research Council National Institute on Minority Health RG 08/008; PG/07/133/24260 / British Heart Foundation (BHF); British Heart Foundation Diabetes UK ES/F02679X/1 / ESRC; UK Research & Innovation (UKRI); Economic & Social Research Council (ESRC) FS/07/011 / British Heart Foundation (Schillingford) Clinical Training Fellowship University College London NIHR Biomedical Research Centre National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA RG/13/2/30098 / British Heart Foundation MC_UP_A100_1003 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC); European Commission G0802432 / MRC Population Health Scientist Fellowship; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) P20MD006899 / Health Disparities of the NIH Magnus Bergvall Foundation Foundation for Old Servants
Language: English
Date published: 01/24/2015
Academic Unit: Epidemiology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984364433702771

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