HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: Evidence from genetic analysis and randomised trials
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Publication date
2015-01-24
Authors
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.
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Article
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taverne
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.
Keywords
HIGH-DOSE ATORVASTATIN, BODY-MASS INDEX, STATIN THERAPY, MENDELIAN RANDOMIZATION, ASSOCIATION ANALYSES, LDL CHOLESTEROL, METAANALYSIS, RISK, PREVENTION, DISEASE, Taverne
Citation
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 2015, 'HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight : Evidence from genetic analysis and randomised trials', The Lancet, vol. 385, no. 9965, pp. 351-361. https://doi.org/10.1016/S0140-6736(14)61183-1