HMG-CoA reductase inhibition, type 2 diabetes and body weight: evidence from genetic analysis and randomised trials
Title / First name / Init. / Surname / Preferred qualification(s) / AffiliationDr / Daniel / I / Swerdlow* / MBBS, PhD / UCL Institute of Cardiovascular Science, UCL, London, UK
Dr / David / Preiss* / MD, PhD / BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
Ms / Karoline / B / Kuchenbaecker / Dipl.-Psych., MSc / Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Dr / Michael / V / Holmes / MD, PhD, MSc / 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 19103
UCL Institute of Cardiovascular Science, UCL, London, UK
Mr / Jorgen / EL / Engmann / MSc BSc / Research Department of Epidemiology & Public Health, UCL, London, UK
Dr / Tina / Shah / PhD / Research Department of Epidemiology & Public Health, UCL, London, UK
Dr / Reecha / Sofat / MD, PhD / Research Department of Epidemiology & Public Health, UCL, London, UK
Dr / Stefan / Stender / MD, PhD / Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
Dr / Paul / CD / Johnson / PhD / Robertson Centre for Biostatistics, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK
Dr / Robert / A / Scott / PhD / MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
Mr / Maarten / Leusink / MSc / Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
Mr / Niek / Verweij / University of Groningen, University Medical Centre Groningen, Department of Cardiology, Groningen, the Netherlands
Mr / Stephen / J / Sharp / MSc / MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
Dr / Yiran / Guo / PhD / Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Ms / Claudia / Giambartolomei / MSc / UCL Genetics Institute, UCL, London, UK
Ms / Christina / Chung / MSc / UCL Department of Epidemiology and Public Health
Dr / Anne / Peasey / PhD / UCL Department of Epidemiology and Public Health
Ms / Antoinette / Amuzu / MSc / London School of Hygiene & Tropical Medicine, Keppel Street, London, UK
Ms / KaWah / Li / MSc / Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK
Ms / Jutta / Palmen / MSc / Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK
Mr / Philip / Howard / MSc / Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK
Ms / Jackie / A / Cooper / MSc / Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK
Dr / Fotios / Drenos / PhD / Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK
Ms / Yun / R / Li / BSc / Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Professor / Gordon / Lowe / DSc / Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
Dr / John / Gallacher / Department of Primary Care and Public Health, Cardiff University Medical School, Cardiff University, Cardiff, Wales
Dr / Marlene / CW / Stewart / PhD / Centre for Population Health Sciences, University of Edinburgh, Edinburgh, UK
Dr / Ioanna / Tzoulaki / PhD / Department pf Epidemiology and Biostatistics, Imperial College London, London, UK
Dr / Sarah / G / Buxbaum / PhD / Jackson State University, Jackson, MS, USA
Dr / Daphne / L / van der A / PhD / National Institute for Public Health and the Environment, Bilthoven, the Netherlands
Dr / Nita / G / Forouhi / MRCP, PhD, FFPH / MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
Dr / N Charlotte / Onland-Moret / PhD / Julius Center for Health Sciences and Primary Care, UMC Utrecht
Professor / Yvonne / T / van der Schouw / PhD / Julius Center for Health Sciences and Primary Care, UMC Utrecht
Dr / Renate / B / Schnabel / MD, MSc / University Heart Center Hamburg, Department of General and Interventional Cardiology, Hamburg, Germany
Dr / Jaroslav / A / Hubacek / PhD / Centre for Experimental Medicine,Institute of Clinical and Experimental Medicine, Prague, Czech Republic
Dr / Ruzena / Kubinova / MD / National Institute of Public Health, Prague, Czech Republic
Dr / Migle / Baceviciene / MD, PhD / Lithuanian University of Health Sciences, Kaunas, Lithuania
Professor / Abdonas / Tamosiunas / MD, PhD / Lithuanian University of Health Sciences, Institute of Cardiology, Kaunas, Lithuania
Prof / Andrzej / Pajak / MD, PhD / Department of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
Dr / Roman / Topor-Madry / MD, PhD / Department of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
Dr / Urszula / Stepaniak / PhD / Department of Epidemiology and Population Studies, Institute of Public Health, Faculty of Health Sciences, Jagiellonian University Medical College, Krakow, Poland
Professor / Sofia / Malyutina / MD, PhD / Institute of Internal and Preventive Medicine, Siberian Branch of Russian Academy of Medical Sciences, Novosibirsk, Russia
Dr / Damiano / Baldassarre / PhD / Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy and Centro Cardiologico Monzino IRCCS Milan, Italy
Dr / Bengt / Sennblad / PhD / Atherosclerosis Research Unit, Department of Medicine Solna, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
Professor / Elena / Tremoli / PhD / Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano, Milan, Italy and Centro Cardiologico Monzino IRCCS Milan, Italy
Professor / Ulf / de Faire / MD PhD / Division of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Dr / Fabrizio / Veglia / PhD / Biostatistics Unit, Centro Cardiologio Cardiologico Monzino IRCCS, Milano, Italy
Professor / Ian / Ford / PhD / Robertson Centre for Biostatistics, University of Glasgow, Glasgow, UK
Professor / J Wouter / Jukema / MD / Dept of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
Professor / Rudi / GJ / Westendorp / MD, PhD / Department of Gerontology and Geriatrics , Leiden University Medical Center, The Netherlands
Dr / Gert Jan / de Borst / MD, PhD / Department of Vascular Surgery, University Medical Center, Utrecht, Netherlands
Dr / Pim / A / de Jong / MD, PhD / University Medical Center Utrecht, Department of Radiology
Professor / Ale / Algra / MD / Department of Neurology and Neurosurgery and Julius Center for Health Sciences and Primary Care, UMC Utrecht
Dr / Wilko / Spiering / PhD, MD / University Medical Center Utrecht, Department of Vascular Medicine, Utrecht, The Netherlands
Dr / Anke / H / Maitland-van der Zee / PharmD PhD / Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
Dr / Olaf / H / Klungel / PharmD PhD / Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
Professor / Anthonius / de Boer / MD, PhD / Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands
Professor / Pieter / A / Doevendans / MD, PhD / Dept of Cardiology; Division of heart and lungs; Universtity Medical Center Utrecht,The Netherlands
Professor / Charles / B / Eaton / MD, MS / Memorial Hospital of Rhode Island, Rhode Island, USA
Professor / Jennifer / G / Robinson / MD, MPH / University of Iowa, Iowa, USA
Dr / David / Duggan / PhD / Translational Genomics Research Institute, Phoenix, AZ 85004, USA
DIAGRAM / Consortium
MAGIC / Consortium
InterAct / Consortium
Professor / John / Kjekshus / MD, PhD / Department of Cardiology, Oslo University Hospital Rikshospitalet, University of Oslo, Oslo, Norway
Dr / John / R / Downs / MD / Department of Medicine, University of Texas Health Science Centre, San Antonio TX, and VERDICT, South Texas Veterans Health Care System, San Antonio, TX, USA
Dr / Antonio / M / Gotto / MD, DPhil / Weill Cornell Medical College, 1305 York Ave Y-805, New York, NY, USA
Dr / Anthony / C / Keech / MD, PhD / NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
Dr / Roberto / Marchioli / MD / Hematology/Oncology TDU, Quintiles, Milan, Italy
Dr / Gianni / Tognoni / MD / Department of Clinical Pharmacology and Epidemiology, Consorzio Mario NegriSud, Santa Maria Imbaro, Chieti, Italy
Professor / Peter / S / Sever / PhD, FRCP / International Centre for Circulatory Health, Imperial College London, 59,61 North Wharf Rd
London W2 1LA
Professor / Neil / R / Poulter / MBBS, FRCP, FMedSci / International Centre for Circulatory Health, Imperial College London, London, UK
Dr / David / D / Waters / MD / Department of Medicine, University of California, San Francisco, California, USA
Dr / Terje / R / Pedersen / MD, PhD / University of Oslo and Centre for Preventative Medicine, Oslo University Hospital, Ulleval, Oslo, Norway
Dr / Pierre / Amarenco / MD / Denis Diderot University, Paris, France
Dr / Haruo / Nakamura / MD / Mitsukoshi Health and Welfare Foundation, Tokyo, Japan
Professor / John / JV / McMurray / MD / BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
Dr / James / D / Lewsey / PhD / Institute of Health and Wellbeing, University of Glasgow, UK
Dr / Daniel / I / Chasman / PhD / Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Dr / Paul / M / Ridker / MD / Division of Preventive Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
Prof / Aldo / P / Maggioni / MD / ANMCO Research Center, Via La Marmora 34, 50121 Florence, Italy
Professor / Luigi / Tavazzi / MD / Maria Cecilia Hospital, GVM Care&Research- E.S. Health Science Foundation, Via Corriera, 1 48010 Cotignola (RA), Italy
Professor / Kausik / K / Ray / MD, MPhil / Cardiovascular Sciences Research Centre, St George’s University of London
Dr / Sreenivasa Rao / Kondapally Seshasai / MD, MRCP, PhD / Cardiovascular and Cell Sciences Research Institute, St George's, University of London
Professor / JoAnn / E / Manson / MD, DrPH / Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
Dr / Jackie / F / Price / MD, FFPH / Centre for Population Health Sciences, University of Edinburgh
Professor / Peter / H / Whincup / MD, PhD / St George's University of London, London, UK
Professor / Richard / W / Morris / PhD / UCL Department of Primary Care & Population Health
Professor / Debbie / A / Lawlor / PhD / MRC Integrative Epidemiology Unit at the University of Bristol (IEU) and School of Social and Community Medicine, University of Bristol, Bristol, UK
Professor / George / Davey Smith / MD, PhD / MRC Integrative Epidemiology Unit at the University of Bristol (IEU) and School of Social and Community Medicine, University of Bristol, Bristol, UK
Professor / Yoav / Ben-Shlomo / MB BS, PhD / School of Social and Community Medicine, University of Bristol, Bristol, UK
Professor / Pamela / J / Schreiner / PhD / School of Public Health, University of Minnesota, Minneapolis, Minnesota, United States of America
Professor / Myriam / Fornage / PhD / Institute of Molecular Medicine and Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, TX, USA
Professor / David / S / Siskovick / MD, MPH / Cardiovascular Health Research Unit, Departments of Medicine and Epidemiology, University of Washington, Seattle, WA, USA
Dr / Mary / Cushman / MD, MSc / Departments of Medicine and Pathology, University of Vermont, 208 South Park Dr, Colchester, VT 05446 USA
Dr / Meena / Kumari / PhD / Research Department of Epidemiology & Public Health, UCL, London, UK
Professor / Nick / J / Wareham / MBBS, PhD / MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
Dr / W M Monique / Verschuren / PhD / National Institute for Public Health and the Environment, Bilthoven, the Netherlands, P.O. Box 1, 3720 BA Bilthoven, The Netherlands
Professor / Susan / Redline / MD, MPH / Harvard Medical School, Brigham and Women's Hospital, 221 Longwood Ave Boston MA 02115
Dr / Sanjay / R / Patel / MD, MS / Division of Sleep Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
Professor / John / C / Whittaker / PhD / GlaxoSmithKline
Professor / Anders / Hamsten / MD PhD FRCP / Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
Dr / Joseph / A / Delaney / PhD / Department of Epidemiology, University of Washington, USA
Dr / Caroline / Dale / BA, MSc, PhD / Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK
Dr / Tom / R / Gaunt / PhD / MRC Integrative Epidemiology Unit (IEU), University of Bristol, Bristol, UK
Dr / Andrew / Wong / PhD / MRC Unit for Lifelong Health & Ageing, Institute of Epidemiology and Health Care, University College London, UK
Professor / Diana / Kuh / PhD, FFPH / MRC Unit for Lifelong Health & Ageing, Institute of Epidemiology and Health Care, University College London, UK
Professor / Rebecca / Hardy / PhD / MRC Unit for Lifelong Health & Ageing, Institute of Epidemiology and Health Care, University College London, UK
Dr / Sekar / Kathiresan / MD / Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA;
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA; Cardiology Division, Massachusetts General Hospital, Boston, MA
Dr / Berta / A / Castillo / PhD / Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Professor / Pim / van der Harst / MD, PhD / Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Prof / Eric / J / Brunner / PhD, FFPH / Research Department of Epidemiology & Public Health, UCL, London, UK
Professor / Anne / Tybjaerg-Hansen / MD, DMSc / Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark
Professor Sir / Michael / G / Marmot / FRCP / Research Department of Epidemiology & Public Health, UCL, London, UK
Dr / Ronald / M / Krauss / MD / Children's Hospital Oakland Research Institute, Oakland, CA USA
Professor / Michael / Tsai / MD, PhD / University of Minnesota, Minneapolis, MS, USA
Professor / Josef / Coresh / MD, PhD, MHS / Department of Epidemiology, Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD, USA
Dr / Ronald / C / Hoogeveen / PhD / Baylor College of Medicine, Department of Medicine, Division of Atherosclerosis & Vascular Medicine, Houston, Texas 77030
Professor / Bruce / M / Psaty / MD, PhD, MPH / Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA,USA
Dr / Leslie / A / Lange / PhD / Department of Genetics, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, North Carolina 27514, USA
Professor / Hakon / Hakonarson / MD, PhD / Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Dr / Frank / Dudbridge / PhD / Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK
Professor / Steve / E / Humphries / PhD MRCpath MRCP FAMS / Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK
Professor / Philippa / J / Talmud / PhD, DSc / Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, 5 University Street, London WC1E 6JF, UK
Professor / Mika / Kivimaki / PhD / Research Department of Epidemiology & Public Health, UCL, London, UK
Dr / Nicholas / J / Timpson / PhD / MRC Integrative Epidemiology Unit at the University of Bristol (IEU) and School of Social and Community Medicine, University of Bristol, Bristol, UK
Dr / Claudia / Langenberg / MD PhD / MRC Epidemiology Unit, University of Cambridge, Institute of Metabolic Science, Box 285, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK
Professor / Folkert / W / Asselbergs / MD PhD / Department of Cardiology, Division Heart andLungs, University MedicalCentre Utrecht, Utrecht, The Netherlands; Durrer Center for Cardiogenetic Research,ICIN-Netherlands Heart Institute,Utrecht, The Netherlands; Institute of Cardiovascular Science, faculty ofPopulation Health Sciences,University College London, London, United Kingdom
Professor / Mikhail / Voevoda / MD, PhD / Institute of Internal and Preventive Medicine, Siberian Branch of Russian Academy of Medical Sciences, Novosibirsk, Russia. Institute of Internal Medicine with Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Science
Professor / Martin / Bobak / MD, PhD / Research Department of Epidemiology & Public Health, UCL, London, UK
Dr / Hynek / Pikhart / PhD / Research Department of Epidemiology & Public Health, UCL, London, UK
Professor / James / G / Wilson / MD / Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216 USA
Professor / Alex / P / Reiner / MD, MS / Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Dr / Brendan / J / Keating / PhD / Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
Professor / Aroon / D / Hingorani** / FRCP / Institute of Cardiovascular Science, UCL, London, UK
Professor / Naveed / Sattar** / FRCP / BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
* Joint first authors
** Joint senior authors
1
Abstract
Background: Statins increase risk of new-onset type 2 diabetes mellitus (T2D) but it is uncertain if this is a consequence ofinhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR).
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. In up to 223,463 individuals (43 studies), we examined associations of these variants with plasma lipid, glucose and insulin concentrations, weight, and prevalent and incident T2D. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. The findings were compared with a meta-analysis of new-onset T2D and weight change data from up to 20 major randomised statin cardiovascular end-point trials (n=129,170).
Results: Each additional rs17238484-G allele was associated with 0.06mmol/L lower LDL-cholesterol (95% confidence interval [CI] 0.05-0.07), and higher weight (0.30kg, 95% CI 0.18-0.43), waist circumference (0.32cm, 95% CI 0.16-0.47), plasma insulin concentration (1.62%, 95% CI 0.53-2.72), and plasma glucose (0.23%, 95% CI 0.02-0.44). The rs12916 SNP had similar effects on LDL-cholesterol, weight, and waist circumference. The rs17238484 G-allele that was associated with lower LDL-cholesterol was associated with higher T2D risk (odds ratio [OR] per allele 1.02, 95% CI 1.00-1.05); the rs12916 allele association was consistent (OR 1.06, 95% CI 1.03-1.09). Over 4.2 (range 1.9–6.7) years, statins lowered LDL-cholesterol by 0.92mmol/L (95% CI 0.18-1.67), increased body weight by 0.24kg (95% CI 0.10-0.38) (0.33kg, 95% CI 0.24-0.42, in placebo/standard care-controlled trials; -0.15kg, 95% CI -0.39-0.08 in intensive vs moderate dose trials) and increased odds of new-onset T2D (OR 1.12, 95% CI 1.06-1.18) (OR 1.11, 95% CI 1.03 to 1.20 in placebo/standard care-controlled trials; OR 1.12, 95% CI 1.04 to 1.22 in intensive vs moderate dose trials).
Conclusions: The increased T2D risk observed on statins is at least partially explained by an on-target effect of HMGCR inhibition.
Background
Statinsreduce low-density lipoprotein cholesterol (LDL-C) concentration by inhibiting3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR), leading to a proportionate reduction incardiovascular disease (CVD) risk1–4.Consequently, statins have become the most widely prescribed drugclass,with over 25% of US adults aged ≥45 years (30million individuals) receiving these drugs from 2005 to 20085, and an estimated 56 million may be eligible for statin therapy under new guidelines6.