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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
DI. Swerdlow, D. Preiss, KB. Kuchenbaecker, MV. Holmes, JE. Engmann, T. Shah, R. Sofat, S. Stender, PC. Johnson, RA. Scott, M. Leusink, N. Verweij, SJ. Sharp, Y. Guo, C. Giambartolomei, C. Chung, A. Peasey, A. Amuzu, K. Li, J. Palmen, P. Howard,...
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, metaanalýza, Research Support, N.I.H., Extramural, práce podpořená grantem
NLK
ProQuest Central
od 1992-01-04 do Před 3 měsíci
Nursing & Allied Health Database (ProQuest)
od 1992-01-04 do Před 3 měsíci
Health & Medicine (ProQuest)
od 1992-01-04 do Před 3 měsíci
Family Health Database (ProQuest)
od 1992-01-04 do Před 3 měsíci
Psychology Database (ProQuest)
od 1992-01-04 do Před 3 měsíci
Health Management Database (ProQuest)
od 1992-01-04 do Před 3 měsíci
Public Health Database (ProQuest)
od 1992-01-04 do Před 3 měsíci
- MeSH
- diabetes mellitus 2. typu genetika MeSH
- genetické testování MeSH
- HDL-cholesterol metabolismus MeSH
- hydroxymethylglutaryl-CoA-reduktasy genetika MeSH
- index tělesné hmotnosti MeSH
- jednonukleotidový polymorfismus genetika MeSH
- LDL-cholesterol metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- randomizované kontrolované studie jako téma MeSH
- rizikové faktory MeSH
- senioři MeSH
- statiny škodlivé účinky MeSH
- tělesná hmotnost genetika MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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
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
Centre for Cardiovascular Genetics University College London London UK
Centre for Population Health Sciences University of Edinburgh Edinburgh UK
Centro Cardiologico Monzino IRCCS Milan Milan Italy
Children's Hospital Oakland Research Institute Oakland CA USA
Denis Diderot University Paris France
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 Epidemiology and Biostatistics Imperial College London London UK
Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore MD USA
Department of Epidemiology University of Washington Seattle WA 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
Department of Neurology and Neurosurgery University Medical Center Utrecht Utrecht Netherlands
Department of Non Communicable Disease Epidemiology London UK
Department of Physiology and Biophysics University of Mississippi Medical Center Jackson MS USA
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
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
Durrer Center for Cardiogenetic Research ICIN Netherlands Heart Institute Utrecht Netherlands
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
International Centre for Circulatory Health Imperial College London London UK
Jackson State University Jackson MS USA
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 Integrative Epidemiology Unit University of Bristol Bristol 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
Program in Medical and Population Genetics Broad Institute Cambridge MA USA
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
Science for Life Laboratory Karolinska Institutet Stockholm Sweden
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 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 Minnesota Minneapolis MN USA
VERDICT South Texas Veterans Health Care System San Antonio TX USA
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- $a Swerdlow, Daniel I $u UCL Institute of Cardiovascular Science and Farr Institute, University College London, London, UK. Electronic address: d.swerdlow@ucl.ac.uk.
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- $a HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials / $c DI. Swerdlow, D. Preiss, KB. Kuchenbaecker, MV. Holmes, JE. Engmann, T. Shah, R. Sofat, S. Stender, PC. Johnson, RA. Scott, M. Leusink, N. Verweij, SJ. Sharp, Y. Guo, C. Giambartolomei, C. Chung, A. Peasey, A. Amuzu, K. Li, J. Palmen, P. Howard, JA. Cooper, F. Drenos, YR. Li, G. Lowe, J. Gallacher, MC. Stewart, I. Tzoulaki, SG. Buxbaum, DL. van der A, NG. Forouhi, NC. Onland-Moret, YT. van der Schouw, RB. Schnabel, JA. Hubacek, R. Kubinova, M. Baceviciene, A. Tamosiunas, A. Pajak, R. Topor-Madry, U. Stepaniak, S. Malyutina, D. Baldassarre, B. Sennblad, E. Tremoli, U. de Faire, F. Veglia, I. Ford, JW. Jukema, RG. Westendorp, GJ. de Borst, PA. de Jong, A. Algra, W. Spiering, AH. Maitland-van der Zee, OH. Klungel, A. de Boer, PA. Doevendans, CB. Eaton, JG. Robinson, D. Duggan, . , . , . , J. Kjekshus, JR. Downs, AM. Gotto, AC. Keech, R. Marchioli, G. Tognoni, PS. Sever, NR. Poulter, DD. Waters, TR. Pedersen, P. Amarenco, H. Nakamura, JJ. McMurray, JD. Lewsey, DI. Chasman, PM. Ridker, AP. Maggioni, L. Tavazzi, KK. Ray, SR. Seshasai, JE. Manson, JF. Price, PH. Whincup, RW. Morris, DA. Lawlor, GD. Smith, Y. Ben-Shlomo, PJ. Schreiner, M. Fornage, DS. Siscovick, M. Cushman, M. Kumari, NJ. Wareham, WM. Verschuren, S. Redline, SR. Patel, JC. Whittaker, A. Hamsten, JA. Delaney, C. Dale, TR. Gaunt, A. Wong, D. Kuh, R. Hardy, S. Kathiresan, BA. Castillo, P. van der Harst, EJ. Brunner, A. Tybjaerg-Hansen, MG. Marmot, RM. Krauss, M. Tsai, J. Coresh, RC. Hoogeveen, BM. Psaty, LA. Lange, H. Hakonarson, F. Dudbridge, SE. Humphries, PJ. Talmud, M. Kivimäki, NJ. Timpson, C. Langenberg, FW. Asselbergs, M. Voevoda, M. Bobak, H. Pikhart, JG. Wilson, AP. Reiner, BJ. Keating, AD. Hingorani, N. Sattar,
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- $a 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.
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- 700 1_
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- $a Siscovick, David S $u Cardiovascular Health Research Unit of the Department of Medicine, Department of Epidemiology, and Department of Health Services, University of Washington, Seattle, WA, USA.
- 700 1_
- $a Cushman, Mary $u Departments of Medicine and Pathology, University of Vermont, Colchester, VT, USA.
- 700 1_
- $a Kumari, Meena $u UCL Research Department of Epidemiology and Public Health, University College London, London, UK.
- 700 1_
- $a Wareham, Nick J $u MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.
- 700 1_
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- 700 1_
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- 700 1_
- $a Patel, Sanjay R $u Division of Sleep Medicine, Boston, MA, USA.
- 700 1_
- $a Whittaker, John C $u GlaxoSmithKline, Stevenage, UK.
- 700 1_
- $a Hamsten, Anders $u Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
- 700 1_
- $a Delaney, Joseph A $u Department of Epidemiology, University of Washington, Seattle, WA, USA.
- 700 1_
- $a Dale, Caroline $u Department of Non-Communicable Disease Epidemiology, London, UK.
- 700 1_
- $a Gaunt, Tom R $u MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
- 700 1_
- $a Wong, Andrew $u MRCUnit for Lifelong Health and Ageing, Institute of Epidemiology and Health Care, University College London, London, UK.
- 700 1_
- $a Kuh, Diana $u MRCUnit for Lifelong Health and Ageing, Institute of Epidemiology and Health Care, University College London, London, UK.
- 700 1_
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- 700 1_
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- 700 1_
- $a Castillo, Berta A $u Center for Applied Genomics, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- 700 1_
- $a van der Harst, Pim $u University of Groningen, University Medical Centre Groningen, Department of Cardiology, Groningen, Netherlands.
- 700 1_
- $a Brunner, Eric J $u UCL Research Department of Epidemiology and Public Health, University College London, London, UK.
- 700 1_
- $a Tybjaerg-Hansen, Anne $u Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- 700 1_
- $a Marmot, Michael G $u UCL Research Department of Epidemiology and Public Health, University College London, London, UK.
- 700 1_
- $a Krauss, Ronald M $u Children's Hospital Oakland Research Institute, Oakland, CA USA.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Dudbridge, Frank $u London School of Hygiene & Tropical Medicine, London, UK.
- 700 1_
- $a Humphries, Steve E $u Centre for Cardiovascular Genetics, University College London, London, UK.
- 700 1_
- $a Talmud, Philippa J $u Centre for Cardiovascular Genetics, University College London, London, UK.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Voevoda, Mikhail $u 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.
- 700 1_
- $a Bobak, Martin $u UCL Research Department of Epidemiology and Public Health, University College London, London, UK.
- 700 1_
- $a Pikhart, Hynek $u UCL Research Department of Epidemiology and Public Health, University College London, London, UK.
- 700 1_
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- 700 1_
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- 700 1_
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- 700 1_
- $a Hingorani, Aroon D $u UCL Institute of Cardiovascular Science and Farr Institute, University College London, London, UK.
- 700 1_
- $a Sattar, Naveed $u BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
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