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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.* ; Daphne, L.v.d.A.* ; Forouhi, N.G.* ; Onland-Moret, N.C.* ; van der Schouw, Y.T.* ; Schnabel, R.B.* ; Hubácek, J.A.* ; Kubínová, R.* ; Baceviciene, M.* ; Tamosiunas, A.* ; Pajak, A.* ; Topor-Madry, R.* ; Stepaniak, U.* ; Malyutina, S.A.* ; 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.* ; Maitland-van der Zee, A.H.* ; 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.E.* ; 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.* ; Kivimaeki, 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.* ; DIAGRAM Consortium (Grallert, H. ; Gieger, C. ; Klopp, N. ; Illig, T. ; Müller-Nurasyid, M. ; Peters, A.) ; MAGIC Consortium (Meisinger, C. ; Thorand, B. ; Wichmann, H.-E.) ; InterAct Consortium

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

Lancet 385, 351-361 (2015)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
Keywords High-dose Atorvastatin; Body-mass Index; Statin Therapy; Mendelian Randomization; Association Analyses; Ldl Cholesterol; Metaanalysis; Risk; Prevention; Disease
Reviewing status