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.

ANMCO Research Center Florence Italy

Atherosclerosis Research Unit Department of Medicine Solna Karolinska Institutet Stockholm Sweden

Atherosclerosis Research Unit Department of Medicine Solna Karolinska Institutet Stockholm Sweden; Science for Life Laboratory Karolinska Institutet Stockholm Sweden

Baylor College of Medicine Department of Medicine Division of Atherosclerosis and Vascular Medicine Houston TX USA

BHF Glasgow Cardiovascular Research Centre University of Glasgow Glasgow UK

Biostatistics Unit Milan Italy

Brigham and Women's Hospital Harvard Medical School Boston MA USA

Cardiac and Cell Sciences Research Institute London UK

Cardiology Division Massachusetts General Hospital Boston MA USA; Program in Medical and Population Genetics Broad Institute Cambridge MA USA

Cardiovascular Health Research Unit of the Department of Medicine Department of Epidemiology and Department of Health Services University of Washington Seattle WA USA

Center for Applied Genomics Abramson Research Center The Children's Hospital of Philadelphia Philadelphia PA USA

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

Centre for Cardiovascular Genetics University College London London UK

Centre for Experimental Medicine Institute of Clinical and Experimental Medicine Prague Czech Republic

Centre for Population Health Sciences University of Edinburgh Edinburgh UK

Centre for Preventative Medicine Oslo University Hospital Rikshospitalet University of Oslo Oslo Norway

Children's Hospital Oakland Research Institute Oakland CA USA

Denis Diderot University Paris France

Department of Cardiology Division of Heart and Lungs University Medical Center Utrecht Utrecht Netherlands

Department of Cardiology Leiden University Medical Center Leiden Netherlands

Department of Cardiology Oslo University Hospital Rikshospitalet University of Oslo Oslo Norway

Department of Clinical Biochemistry Rigshospitalet Copenhagen University Hospital Copenhagen Denmark

Department of Clinical Pharmacology and Epidemiology Consorzio Mario NegriSud Santa Maria Imbaro Chieti Italy

Department of Epidemiology and Biostatistics Imperial College London London UK

Department of Epidemiology and Population Studies Institute of Public Health Faculty of Health Sciences Jagiellonian University Medical College Krakow Poland

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA

Department of Epidemiology University of Washington Seattle WA USA

Department of Genetics University of North Carolina School of Medicine at Chapel Hill Chapel Hill NC USA

Department of Gerontology and Geriatrics Leiden University Medical Center Leiden Netherlands

Department of Medicine University of California San Francisco CA USA

Department of Medicine University of Texas Health Science Centre San Antonio TX USA; VERDICT South Texas Veterans Health Care System San Antonio TX USA

Department of Non Communicable Disease Epidemiology London UK

Department of Physiology and Biophysics University of Mississippi Medical Center Jackson MS USA

Department of Primary Care and Public Health Cardiff University Medical School Cardiff University Cardiff UK

Department of Radiology University Medical Center Utrecht Utrecht Netherlands

Department of Vascular Medicine University Medical Center Utrecht Utrecht Netherlands

Department of Vascular Surgery University Medical Center Utrecht Utrecht Netherlands

Departments of Medicine and Pathology University of Vermont Colchester VT USA

Dipartimento di Scienze Farmacologiche e Biomolecolari Università di Milano Milan Italy; Centro Cardiologico Monzino IRCCS Milan Milan Italy

Division of Cardiovascular Epidemiology Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Division of Pharmacoepidemiology and Clinical Pharmacology Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University Utrecht Netherlands

Division of Preventive Medicine Boston MA USA

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle WA USA

Division of Sleep Medicine Boston MA USA

GlaxoSmithKline Stevenage UK

Hematology and Oncology Therapeutic Delivery Unit Quintiles Milan Italy

Institute of Cardiology Kaunas Lithuania

Institute of Cardiovascular and Medical Sciences University of Glasgow Glasgow UK

Institute of Health and Wellbeing University of Glasgow Glasgow UK

Institute of Internal and Preventive Medicine Siberian Branch of Russian Academy of Medical Sciences Novosibirsk Russia

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

Institute of Molecular Medicine and Human Genetics Center University of Texas Health Science Center at Houston Houston TX USA

International Centre for Circulatory Health Imperial College London London UK

Jackson State University Jackson MS USA

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht Netherlands

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

Lithuanian University of Health Sciences Kaunas Lithuania

London School of Hygiene and Tropical Medicine London UK

Maria Cecilia Hospital GVM Care and Research E S Health Science Foundation Cotignola Italy

Memorial Hospital of Rhode Island RI USA

Mitsukoshi Health and Welfare Foundation Tokyo Japan

MRC Epidemiology Unit University of Cambridge School of Clinical Medicine Institute of Metabolic Science Cambridge Biomedical Campus Cambridge UK

MRC Integrative Epidemiology Unit University of Bristol Bristol UK

MRC Integrative Epidemiology Unit University of Bristol Bristol UK; School of Social and Community Medicine University of Bristol Bristol UK

MRCUnit for Lifelong Health and Ageing Institute of Epidemiology and Health Care University College London London UK

National Institute for Public Health and the Environment Bilthoven Netherlands

National Institute of Public Health Prague Czech Republic

NHMRC Clinical Trials Centre University of Sydney Sydney NSW Australia

Robertson Centre for Biostatistics University of Glasgow Glasgow UK

School of Public Health Minneapolis MN USA

School of Social and Community Medicine University of Bristol Bristol UK

St George's University of London London UK

Translational Genomics Research Institute Phoenix AZ USA

UCL Department of Medicine University College London London UK

UCL Department of Primary Care and Population Health University College London London UK

UCL Genetics Institute University College London London UK

UCL Institute of Cardiovascular Science and Farr Institute University College London London UK

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

UCL Research Department of Epidemiology and Public Health University College London London UK

University Heart Center Hamburg Department of General and Interventional Cardiology Hamburg Germany

University of Groningen University Medical Centre Groningen Department of Cardiology Groningen Netherlands

University of Iowa IA USA

University of Minnesota Minneapolis MN USA

Weill Cornell Medical College New York NY USA

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