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

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

Swerdlow DI1, Preiss D2, Kuchenbaecker KB3, Holmes MV4, Engmann JE4, Shah T4, Sofat R5, Stender S6, Johnson PC7, Scott RA8, Leusink M9, Verweij N10, Sharp SJ8, Guo Y11, Giambartolomei C12, Chung C13, Peasey A13, Amuzu A14, Li K15, Palmen J15, Howard P15, Cooper JA15, Drenos F15, Li YR11, Lowe G16, Gallacher J17, Stewart MC18, Tzoulaki I19, Buxbaum SG20, van der A DL21, Forouhi NG8, Onland-Moret NC22, van der Schouw YT22, Schnabel RB23, Hubacek JA24, Kubinova R25, Baceviciene M26, Tamosiunas A27, Pajak A28, Topor-Madry R28, Stepaniak U28, Malyutina S29, Baldassarre D30, Sennblad B31, Tremoli E30, de Faire U32, Veglia F33, Ford I7, Jukema JW34, Westendorp RG35, de Borst GJ36, de Jong PA37, Algra A38, Spiering W39, Maitland-van der Zee AH9, Klungel OH9, de Boer A9, Doevendans PA40, Eaton CB41, Robinson JG42, Duggan D43; DIAGRAM Consortium; MAGIC Consortium; InterAct Consortium, Kjekshus J44, Downs JR45, Gotto AM46, Keech AC47, Marchioli R48, Tognoni G49, Sever PS50, Poulter NR50, Waters DD51, Pedersen TR52, Amarenco P53, Nakamura H54, McMurray JJ55, Lewsey JD56, Chasman DI57, Ridker PM57, Maggioni AP58, Tavazzi L59, Ray KK60, Seshasai SR60, Manson JE57, Price JF18, Whincup PH61, Morris RW62, Lawlor DA63, Smith GD63, Ben-Shlomo Y64, Schreiner PJ65, Fornage M66, Siscovick DS67, Cushman M68, Kumari M13, Wareham NJ8, Verschuren WM21, Redline S69, Patel SR70, Whittaker JC71, Hamsten A72, Delaney JA73, Dale C74, Gaunt TR75, Wong A76, Kuh D76, Hardy R76, Kathiresan S77, Castillo BA11, van der Harst P10, Brunner EJ13, Tybjaerg-Hansen A6, Marmot MG13, Krauss RM78, Tsai M79, Coresh J80, Hoogeveen RC81, Psaty BM67, Lange LA82, Hakonarson H11, Dudbridge F14, Humphries SE15, Talmud PJ15, Kivimäki M13, Timpson NJ63, Langenberg C8, Asselbergs FW83, Voevoda M84, Bobak M13, Pikhart H13, Wilson JG85, Reiner AP86, Keating BJ11, Hingorani AD4, Sattar N55.

Author information

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.

PMID:
25262344
PMCID:
PMC4322187
DOI:
10.1016/S0140-6736(14)61183-1
[Indexed for MEDLINE]
Free PMC Article

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