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 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

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

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

Lancet. 2015 Jan 24;385(9965):351-61. doi: 10.1016/S0140-6736(14)61183-1. Epub 2014 Sep 24.

Authors

Daniel I Swerdlow¹, David Preiss², Karoline B Kuchenbaecker³, Michael V Holmes⁴, Jorgen E L Engmann⁴, Tina Shah⁴, Reecha Sofat⁵, Stefan Stender⁶, Paul C D Johnson⁷, Robert A Scott⁸, Maarten Leusink⁹, Niek Verweij¹⁰, Stephen J Sharp⁸, Yiran Guo¹¹, Claudia Giambartolomei¹², Christina Chung¹³, Anne Peasey¹³, Antoinette Amuzu¹⁴, KaWah Li¹⁵, Jutta Palmen¹⁵, Philip Howard¹⁵, Jackie A Cooper¹⁵, Fotios Drenos¹⁵, Yun R Li¹¹, Gordon Lowe¹⁶, John Gallacher¹⁷, Marlene C W Stewart¹⁸, Ioanna Tzoulaki¹⁹, Sarah G Buxbaum²⁰, Daphne L van der A²¹, Nita G Forouhi⁸, N Charlotte Onland-Moret²², Yvonne T van der Schouw²², Renate B Schnabel²³, Jaroslav A Hubacek²⁴, Ruzena Kubinova²⁵, Migle Baceviciene²⁶, Abdonas Tamosiunas²⁷, Andrzej Pajak²⁸, Roman Topor-Madry²⁸, Urszula Stepaniak²⁸, Sofia Malyutina²⁹, Damiano Baldassarre³⁰, Bengt Sennblad³¹, Elena Tremoli³⁰, Ulf de Faire³², Fabrizio Veglia³³, Ian Ford⁷, J Wouter Jukema³⁴, Rudi G J Westendorp³⁵, Gert Jan de Borst³⁶, Pim A de Jong³⁷, Ale Algra³⁸, Wilko Spiering³⁹, Anke H Maitland-van der Zee⁹, Olaf H Klungel⁹, Anthonius de Boer⁹, Pieter A Doevendans⁴⁰, Charles B Eaton⁴¹, Jennifer G Robinson⁴², David Duggan⁴³; DIAGRAM Consortium; MAGIC Consortium; InterAct Consortium; John Kjekshus⁴⁴, John R Downs⁴⁵, Antonio M Gotto⁴⁶, Anthony C Keech⁴⁷, Roberto Marchioli⁴⁸, Gianni Tognoni⁴⁹, Peter S Sever⁵⁰, Neil R Poulter⁵⁰, David D Waters⁵¹, Terje R Pedersen⁵², Pierre Amarenco⁵³, Haruo Nakamura⁵⁴, John J V McMurray⁵⁵, James D Lewsey⁵⁶, Daniel I Chasman⁵⁷, Paul M Ridker⁵⁷, Aldo P Maggioni⁵⁸, Luigi Tavazzi⁵⁹, Kausik K Ray⁶⁰, Sreenivasa Rao Kondapally Seshasai⁶⁰, JoAnn E Manson⁵⁷, Jackie F Price¹⁸, Peter H Whincup⁶¹, Richard W Morris⁶², Debbie A Lawlor⁶³, George Davey Smith⁶³, Yoav Ben-Shlomo⁶⁴, Pamela J Schreiner⁶⁵, Myriam Fornage⁶⁶, David S Siscovick⁶⁷, Mary Cushman⁶⁸, Meena Kumari¹³, Nick J Wareham⁸, W M Monique Verschuren²¹, Susan Redline⁶⁹, Sanjay R Patel⁷⁰, John C Whittaker⁷¹, Anders Hamsten⁷², Joseph A Delaney⁷³, Caroline Dale⁷⁴, Tom R Gaunt⁷⁵, Andrew Wong⁷⁶, Diana Kuh⁷⁶, Rebecca Hardy⁷⁶, Sekar Kathiresan⁷⁷, Berta A Castillo¹¹, Pim van der Harst¹⁰, Eric J Brunner¹³, Anne Tybjaerg-Hansen⁶, Michael G Marmot¹³, Ronald M Krauss⁷⁸, Michael Tsai⁷⁹, Josef Coresh⁸⁰, Ronald C Hoogeveen⁸¹, Bruce M Psaty⁶⁷, Leslie A Lange⁸², Hakon Hakonarson¹¹, Frank Dudbridge¹⁴, Steve E Humphries¹⁵, Philippa J Talmud¹⁵, Mika Kivimäki¹³, Nicholas J Timpson⁶³, Claudia Langenberg⁸, Folkert W Asselbergs⁸³, Mikhail Voevoda⁸⁴, Martin Bobak¹³, Hynek Pikhart¹³, James G Wilson⁸⁵, Alex P Reiner⁸⁶, Brendan J Keating¹¹, Aroon D Hingorani⁴, Naveed Sattar⁵⁵

Affiliations

¹ UCL Institute of Cardiovascular Science and Farr Institute, University College London, London, UK. Electronic address: d.swerdlow@ucl.ac.uk.
² BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK. Electronic address: david.preiss@glasgow.ac.uk.
³ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Department of Surgery, Division of Transplantation, and Clinical Epidemiology Unit, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ UCL Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
⁵ UCL Department of Medicine, University College London, London, UK.
⁶ Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁷ Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK.
⁸ MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
⁹ Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands.
¹⁰ University of Groningen, University Medical Centre Groningen, Department of Cardiology, Groningen, Netherlands.
¹¹ Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
¹² UCL Genetics Institute, University College London, London, UK.
¹³ UCL Research Department of Epidemiology and Public Health, University College London, London, UK.
¹⁴ London School of Hygiene & Tropical Medicine, London, UK.
¹⁵ Centre for Cardiovascular Genetics, University College London, London, UK.
¹⁶ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
¹⁷ Department of Primary Care and Public Health, Cardiff University Medical School, Cardiff University, Cardiff, UK.
¹⁸ Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK.
¹⁹ Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
²⁰ Jackson State University, Jackson, MS, USA.
²¹ National Institute for Public Health and the Environment, Bilthoven, Netherlands.
²² Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands.
²³ University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany.
²⁴ Centre for Experimental Medicine, Institute of Clinical and Experimental Medicine, Prague, Czech Republic.
²⁵ National Institute of Public Health, Prague, Czech Republic.
²⁶ Lithuanian University of Health Sciences, Kaunas, Lithuania.
²⁷ Institute of Cardiology, Kaunas, Lithuania.
²⁸ Department of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland.
²⁹ Institute of Internal and Preventive Medicine, Siberian Branch of Russian Academy of Medical Sciences, Novosibirsk, Russia.
³⁰ Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy; Centro Cardiologico Monzino IRCCS Milan, Milan, Italy.
³¹ Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
³² Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
³³ Biostatistics Unit, Milan, Italy.
³⁴ Department of Cardiology, Leiden University Medical Center, Leiden, Netherlands.
³⁵ Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, Netherlands.
³⁶ Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, Netherlands.
³⁷ Department of Radiology, University Medical Center Utrecht, Utrecht, Netherlands.
³⁸ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, Netherlands; Department of Neurology and Neurosurgery, University Medical Center Utrecht, Utrecht, Netherlands.
³⁹ Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, Netherlands.
⁴⁰ Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands.
⁴¹ Memorial Hospital of Rhode Island, RI, USA.
⁴² University of Iowa, IA, USA.
⁴³ Translational Genomics Research Institute, Phoenix, AZ, USA.
⁴⁴ Department of Cardiology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
⁴⁵ Department of Medicine, University of Texas Health Science Centre, San Antonio, TX, USA; VERDICT, South Texas Veterans Health Care System, San Antonio, TX, USA.
⁴⁶ Weill Cornell Medical College, New York, NY, USA.
⁴⁷ NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia.
⁴⁸ Hematology and Oncology Therapeutic Delivery Unit, Quintiles, Milan, Italy.
⁴⁹ Department of Clinical Pharmacology and Epidemiology, Consorzio Mario NegriSud, Santa Maria Imbaro, Chieti, Italy.
⁵⁰ International Centre for Circulatory Health, Imperial College London, London, UK.
⁵¹ Department of Medicine, University of California, San Francisco, CA, USA.
⁵² Centre for Preventative Medicine, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway.
⁵³ Denis Diderot University, Paris, France.
⁵⁴ Mitsukoshi Health and Welfare Foundation, Tokyo, Japan.
⁵⁵ BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
⁵⁶ Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK.
⁵⁷ Division of Preventive Medicine, Boston, MA, USA.
⁵⁸ ANMCO Research Center, Florence, Italy.
⁵⁹ Maria Cecilia Hospital, GVM Care and Research, E.S. Health Science Foundation, Cotignola (RA), Italy.
⁶⁰ Cardiac and Cell Sciences Research Institute, London, UK.
⁶¹ St George's University of London, London, UK.
⁶² UCL Department of Primary Care and Population Health, University College London, London, UK.
⁶³ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK; School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁶⁴ School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁶⁵ School of Public Health, Minneapolis, MN, USA.
⁶⁶ Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁶⁷ Cardiovascular Health Research Unit of the Department of Medicine, Department of Epidemiology, and Department of Health Services, University of Washington, Seattle, WA, USA.
⁶⁸ Departments of Medicine and Pathology, University of Vermont, Colchester, VT, USA.
⁶⁹ Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁷⁰ Division of Sleep Medicine, Boston, MA, USA.
⁷¹ GlaxoSmithKline, Stevenage, UK.
⁷² Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
⁷³ Department of Epidemiology, University of Washington, Seattle, WA, USA.
⁷⁴ Department of Non-Communicable Disease Epidemiology, London, UK.
⁷⁵ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
⁷⁶ MRCUnit for Lifelong Health and Ageing, Institute of Epidemiology and Health Care, University College London, London, UK.
⁷⁷ Cardiology Division, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.
⁷⁸ Children's Hospital Oakland Research Institute, Oakland, CA USA.
⁷⁹ University of Minnesota, Minneapolis, MN, USA.
⁸⁰ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁸¹ Baylor College of Medicine, Department of Medicine, Division of Atherosclerosis and Vascular Medicine, Houston, TX, USA.
⁸² Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, USA.
⁸³ UCL Institute of Cardiovascular Science and Farr Institute, University College London, London, UK; Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands; Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, Netherlands.
⁸⁴ Institute of Internal and Preventive Medicine, Siberian Branch of Russian Academy of Medical Sciences, Novosibirsk, Russia; Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Medical Sciences, Novosibirsk, Russia.
⁸⁵ Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
⁸⁶ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding