HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
Open accessAbstract
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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Mendelian randomisation studies of variants mimicking statins, ezetimibe, or PCSK9 inhibitors suggest that lifelong LDL cholesterol lowering, by any mechanism, is linked to higher diabetes risk.
“mendelian randomisation studies 8,[19][20][21] of genetic polymorphisms that mimic the effects of statins, ezetimibe, or PCSK9 inhibitors suggest that lifelong reductions in LDL cholesterol, irrespective of the mechanism, are associated with an increased risk of diabetes.”
Myopathy is the most clinically relevant adverse effect of statins, and interaction with concomitant drug therapy is an important risk factor.
“Myopathy is the most clinically relevant adverse effect of statins. Among the risk factors for myopathy, it is particularly important that interaction with concomitant drug therapy is considered (see below).”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [234]
In rhabdomyolysis, creatine kinase levels are elevated by at least 10 times and often at least 40 times the upper limit of normal.
“In rhabdomyolysis, creatine kinase (CK) levels are elevated by ≥ 10 times, and often ≥40 times, the upper limit of normal (ULN) [234].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [234]
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- Authors
- Swerdlow, D. I., Preiss, D., Kuchenbaecker, K. B., Holmes, M. V., Engmann, J. E. L., Shah, T., Sofat, R., Stender, S., Johnson, P. C. D., Scott, R. A., Leusink, M., Verweij, N., Sharp, S. J., Guo, Y., Giambartolomei, C., Chung, C., Peasey, A., Amuzu, A., Li, K., Palmen, J., Howard, P., Cooper, J. A., Drenos, F., Li, Y. R., Lowe, G., Gallacher, J., Stewart, M. C. W., Tzoulaki, I., Buxbaum, S. G., van der A, D. L., Forouhi, N. G., Onland-Moret, N. C., van der Schouw, Y. T., Schnabel, R. B., Hubacek, J. A., Kubinova, R., Baceviciene, M., Tamosiunas, A., Pajak, A., Topor-Madry, R., Stepaniak, U., Malyutina, S., Baldassarre, D., Sennblad, B., Tremoli, E., de Faire, U., Veglia, F., Ford, I., Jukema, J. W., Westendorp, R. G. J., de Borst, G. J., de Jong, P. A., Algra, A., Spiering, W., der Zee, A. H. M.-V., Klungel, O. H., de Boer, A., Doevendans, P. A., Eaton, C. B., Robinson, J. G., Duggan, D., Kjekshus, J., Downs, J. R., Gotto, A. M., Keech, A. C., Marchioli, R., Tognoni, G., Sever, P. S., Poulter, N. R., Waters, D. D., Pedersen, T. R., Amarenco, P., Nakamura, H., McMurray, J. J. V., Lewsey, J. D., Chasman, D. I., Ridker, P. M., Maggioni, A. P., Tavazzi, L., Ray, K. K., Seshasai, S. R. K., Manson, J. E., Price, J. F., Whincup, P. H., Morris, R. W., Lawlor, D. A., Smith, G. D., Ben-Shlomo, Y., Schreiner, P. J., Fornage, M., Siscovick, D. S., Cushman, M., Kumari, M., Wareham, N. J., Verschuren, W. M. M., Redline, S., Patel, S. R., Whittaker, J. C., Hamsten, A., Delaney, J. A., Dale, C., Gaunt, T. R., Wong, A., Kuh, D., Hardy, R., Kathiresan, S., Castillo, B. A., van der Harst, P., Brunner, E. J., Tybjaerg-Hansen, A., Marmot, M. G., Krauss, R. M., Tsai, M., Coresh, J., Hoogeveen, R. C., Psaty, B. M., Lange, L. A., Hakonarson, H., Dudbridge, F., Humphries, S. E., Talmud, P. J., Kivimäki, M., Timpson, N. J., Langenberg, C., Asselbergs, F. W., Voevoda, M., Bobak, M., Pikhart, H., Wilson, J. G., Reiner, A. P., Keating, B. J., Hingorani, A. D., & Sattar, N.
- Affiliations
- Farr Institute (GB)
- University of Glasgow (GB)
- University of Cambridge (GB)
- University College London (GB)
- Copenhagen University Hospital (DK)
- Utrecht University (NL)
- University Medical Center Groningen (NL)
- Children's Hospital of Philadelphia (US)
- London School of Hygiene & Tropical Medicine (GB)
- Cardiff University (GB)
- University of Edinburgh (GB)
- Imperial College London (GB)
- Jackson State University (US)
- Institute of Clinical and Experimental Medicine (CZ)
- Jagiellonian University (PL)
- University of Milan (IT)
- Science for Life Laboratory (SE)
- Leiden University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Memorial Hospital of Rhode Island (US)
- University of Iowa (US)
- Translational Genomics Research Institute (US)
- Oslo University Hospital (NO)
- The University of Texas at San Antonio Health Science Center (US)
- Weill Cornell Medicine (US)
- The University of Sydney (AU)
- IQVIA (United Kingdom) (GB)
- University of California, San Francisco (US)
- Université Paris Diderot (FR)
- Mitsukoshi Health and Welfare Foundation (JP)
- Associazione Nazionale Medici Cardiologi Ospedalieri (IT)
- Maria Cecilia Hospital (IT)
- St George's, University of London (GB)
- University of Bristol (GB)
- University of Minnesota (US)
- The University of Texas Health Science Center at Houston (US)
- University of Washington (US)
- University of Vermont (US)
- National Institute for Public Health and the Environment (NL)
- Brigham and Women's Hospital (US)
- GlaxoSmithKline (United Kingdom) (GB)
- Karolinska Institutet (SE)
- MRC Unit for Lifelong Health and Ageing (GB)
- Broad Institute (US)
- Johns Hopkins University (US)
- University of North Carolina at Chapel Hill (US)
- Institute of Cytology and Genetics (RU)
- University of Mississippi Medical Center (US)
- Fred Hutch Cancer Center (US)
- Corresponding author
- Swerdlow, Daniel I
- Preiss, David
- ORCID
- Swerdlow, Daniel I
- Preiss, David
- Kuchenbaecker, Karoline B
- Holmes, Michael V
- Engmann, Jorgen E L
- Shah, Tina
- Sofat, Reecha
- Stender, Stefan
- Johnson, Paul C D
- Scott, Robert A
- Verweij, Niek
- Sharp, Stephen J
- Guo, Yiran
- Giambartolomei, Claudia
- Chung, Christina
- Peasey, Anne
- Cooper, Jackie A
- Drenos, Fotios
- Lowe, Gordon
- Gallacher, John
- Stewart, Marlene C W
- Tzoulaki, Ioanna
- Buxbaum, Sarah G
- Forouhi, Nita G
- Schnabel, Renate B
- Hubacek, Jaroslav A
- Stepaniak, Urszula
- Malyutina, Sofia
- Baldassarre, Damiano
- Sennblad, Bengt
- Tremoli, Elena
- Veglia, Fabrizio
- Ford, Ian
- Jukema, J Wouter
- Westendorp, Rudi G J
- Algra, Ale
- Spiering, Wilko
- Klungel, Olaf H
- Doevendans, Pieter A
- Robinson, Jennifer G
- Duggan, David
- Kjekshus, John
- Gotto, Antonio M
- Keech, Anthony C
- Marchioli, Roberto
- Sever, Peter S
- Poulter, Neil R
- Waters, David D
- Pedersen, Terje R
- Amarenco, Pierre
- McMurray, John J V
- Chasman, Daniel I
- Ridker, Paul M
- Maggioni, Aldo P
- Tavazzi, Luigi
- Ray, Kausik K
- Seshasai, Sreenivasa Rao Kondapally
- Manson, JoAnn E
- Price, Jackie F
- Whincup, Peter H
- Morris, Richard W
- Lawlor, Debbie A
- Smith, George Davey
- Schreiner, Pamela J
- Fornage, Myriam
- Siscovick, David S
- Cushman, Mary
- Verschuren, W M Monique
- Redline, Susan
- Patel, Sanjay R
- Whittaker, John C
- Hamsten, Anders
- Delaney, Joseph A
- Dale, Caroline
- Gaunt, Tom R
- Wong, Andrew
- Kuh, Diana
- Hardy, Rebecca
- Kathiresan, Sekar
- Brunner, Eric J
- Marmot, Michael G
- Krauss, Ronald M
- Tsai, Michael
- Coresh, Josef
- Psaty, Bruce M
- Lange, Leslie A
- Hakonarson, Hakon
- Dudbridge, Frank
- Humphries, Steve E
- Talmud, Philippa J
- Timpson, Nicholas J
- Langenberg, Claudia
- Asselbergs, Folkert W
- Voevoda, Mikhail
- Pikhart, Hynek
- Wilson, James G
- Reiner, Alex P
- Keating, Brendan J
- Hingorani, Aroon D
- Sattar, Naveed
- Venue
- The Lancet
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 385
- Issue
- 9965
- Pages
- 351-361
- ISSN
- 0099-5355 (ISSN-L)
- 0140-6736
- PMC
- PMC4322187
- OpenAlex
- W2097510503
- Cited by
- 680
- References
- 50
- Citations by year
- 2026: 16 · 2025: 41 · 2024: 59 · 2023: 44 · 2022: 56 · 2021: 62 · 2020: 45 · 2019: 61 · 2018: 58 · 2017: 73 · 2016: 84 · 2015: 70 · 2014: 8
- FWCI
- 14.79
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Lancet (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- eScholarship (California Digital Library) (submittedVersion, public-domain)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Research Bank (Australian Catholic University) (submittedVersion, cc-by)
- Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- Lithuanian University of Health Sciences (submittedVersion, cc-by)
- Site cant be reached (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Bristol Research (University of Bristol) (submittedVersion, cc-by)
- Rivm (National Institute for Public Health and the Environment) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, cc-by)
- Apollo (cc-by)
- Funders
- ZonMw (90700342)
- Rosetrees Trust (G0802432)
- Seventh Framework Programme (613598, U19 HL065797)
- National Institute on Minority Health and Health Disparities (P20MD006899)
- Chest Heart and Stroke Scotland (RG/13/2/30098)
- Gentofte Hospital
- Medical Research Council
- Magnus Bergvalls Stiftelse
- Diabetes UK
- University College London Hospitals Biomedical Research Centre
- Stiftelsen för Gamla Tjänarinnor
- British Heart Foundation (FS/07/011, RG 08/008, PG/07/133/24260, K013351, NHLBI 33014, AG034454)
- National Institutes of Health
- John D. and Catherine T. MacArthur Foundation
- National Institute on Aging (1R01 AG23522-01)
- Wellcome Trust (081081/Z/06/Z, 064947/Z/01/Z)
- National Heart and Lung Institute (HL036310)
- Academy of Finland (G0600705)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- statins, HMG-CoA reductase inhibition, type 2 diabetes, body weight, LDL cholesterol, single nucleotide polymorphisms, waist circumference, plasma insulin, plasma glucose, genetic proxies, randomised trials, weight gain, diabetes risk
- MeSH terms
- Aged, Body Weight, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Risk Factors, Body Mass Index, Randomized Controlled Trials as Topic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Polymorphism, Single Nucleotide
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