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.
HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight : evidence from genetic analysis and randomised trials / D.I. Swerdlow, D. Preiss, K.B. Kuchenbaecker, M.V. Holmes, J.E.L. Engmann, T. Shah, R. Sofat, S. Stender, P.C.D. Johnson, R.A. Scott, M. Leusink, N. Verweij, S.J. Sharp, Y. Guo, C. Giambartolomei, C. Chung, A. Peasey, A. Amuzu, K. Li, J. Palmen, P. Howard, J.A. Cooper, F. Drenos, Y.R. Li, G. Lowe, J. Gallacher, M.C.W. Stewart, I. Tzoulaki, S.G. Buxbaum, D.L. van der A, N.G. Forouhi, N.C. Onland Moret, Y.T. van der Schouw, R.B. Schnabel, J.A. 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, J.W. Jukema, R.G.J. Westendorp, G.J. de Borst, P.A. de Jong, A. Algra, W. Spiering, A.H.M. der Zee, O.H. Klungel, A. de Boer, P.A. Doevendans, C.B. Eaton, J.G. Robinson, D. Duggan, J. Kjekshus, J.R. Downs, A.M. Gotto, A.C. Keech, R. Marchioli, G. Tognoni, P.S. Sever, N.R. Poulter, D.D. Waters, T.R. Pedersen, P. Amarenco, H. Nakamura, J.J.V. Mcmurray, J.D. Lewsey, D.I. Chasman, P.M. Ridker, A.P. Maggioni, L. Tavazzi, K.K. Ray, S.R.K. Seshasai, J.E. Manson, J.F. Price, P.H. Whincup, R.W. Morris, D.A. Lawlor, G.D. Smith, Y. Ben Shlomo, P.J. Schreiner, M. Fornage, D.S. Siscovick, M. Cushman, M. Kumari, N.J. Wareham, W.M.M. Verschuren, S. Redline, S.R. Patel, J.C. Whittaker, A. Hamsten, J.A. Delaney, C. Dale, T.R. Gaunt, A. Wong, D. Kuh, R. Hardy, S. Kathiresan, B.A. Castillo, P. van der Harst, E.J. Brunner, A. Tybjaerg Hansen, M.G. Marmot, R.M. Krauss, M. Tsai, J. Coresh, R.C. Hoogeveen, B.M. Psaty, L.A. Lange, H. Hakonarson, F. Dudbridge, S.E. Humphries, P.J. Talmud, M. Kivimäki, N.J. Timpson, C. Langenberg, F.W. Asselbergs, M. Voevoda, M. Bobak, H. Pikhart, J.G. Wilson, A.P. Reiner, B.J. Keating, A.D. Hingorani, N. Sattar. - In: THE LANCET. - ISSN 0140-6736. - 385:9965(2015), pp. 351-361. [10.1016/S0140-6736(14)61183-1]
HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight : evidence from genetic analysis and randomised trials
D. Baldassarre;E. Tremoli;
2015
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.
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