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

Swerdlow, DI; Preiss, D; Kuchenbaecker, KB; Holmes, MV; Engmann, JE; Shah, T; Sofat, R; Stender, S; Johnson, PC; Scott, RA; +126 more...Leusink, M; Verweij, N; Sharp, SJ; Guo, Y; Giambartolomei, C; Chung, C; Peasey, A; Amuzu, A; Li, K; Palmen, J; Howard, P; Cooper, JA; Drenos, F; Li, YR; Lowe, G; Gallacher, J; Stewart, MC; Tzoulaki, I; Buxbaum, SG; van der A, DL; Forouhi, NG; Onland-Moret, NC; van der Schouw, YT; Schnabel, RB; Hubacek, JA; 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, JW; Westendorp, RG; de Borst, GJ; de Jong, PA; Algra, A; Spiering, W; Maitland-van der Zee, AH; Klungel, OH; de Boer, A; Doevendans, PA; Eaton, CB; Robinson, JG; Duggan, D; DIAGRAM Consortium; MAGIC Consortium; InterAct Consortium; Kjekshus, J; Downs, JR; Gotto, AM; Keech, AC; Marchioli, R; Tognoni, G; Sever, PS; Poulter, NR; Waters, DD; Pedersen, TR; Amarenco, P; Nakamura, H; McMurray, JJ; Lewsey, JD; Chasman, DI; Ridker, PM; Maggioni, AP; Tavazzi, L; Ray, KK; Seshasai, SRK; Manson, JE; Price, JF; Whincup, PH; Morris, RW; Lawlor, DA; Smith, GD; Ben-Shlomo, Y; Schreiner, PJ; Fornage, M; Siscovick, DS; Cushman, M; Kumari, M; Wareham, NJ; Verschuren, WM; Redline, S; Patel, SR; Whittaker, JC; Hamsten, A; Delaney, JA; Dale, C; Gaunt, TR; Wong, A; Kuh, D; Hardy, R; Kathiresan, S; Castillo, BA; van der Harst, P; Brunner, EJ; Tybjaerg-Hansen, A; Marmot, MG; Krauss, RM; Tsai, M; Coresh, J; Hoogeveen, RC; Psaty, BM; Lange, LA; Hakonarson, H; Dudbridge, F

; Humphries, SE; Talmud, PJ; Kivimäki, M; Timpson, NJ; Langenberg, C; Asselbergs, FW; Voevoda, M; Bobak, M; Pikhart, H; Wilson, JG; Reiner, AP; Keating, BJ; Hingorani, AD; Sattar, N and (2014) HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet, 385 (9965). pp. 351-361. ISSN 0140-6736 DOI: 10.1016/S0140-6736(14)61183-1

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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.