You are here
HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.
Wednesday,2015-10-14 14:39 America/Los_Angeles — zdrager
| Title | HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. |
| Publication Type | Journal Article |
| Year of Publication | 2015 |
| Authors | Swerdlow, DI, Preiss, D, Kuchenbaecker, KB, Holmes, MV, Engmann, JEL, Shah, T, Sofat, R, Stender, S, Johnson, PCD, Scott, RA, Leusink, M, Verweij, N, Sharp, SJ, Guo, Y, Giambartolomei, C, Chung, C, Peasey, A, Amuzu, A, Li, KW, Palmen, J, Howard, P, Cooper, JA, Drenos, F, Li, YR, Lowe, G, Gallacher, J, Stewart, MCW, Tzoulaki, I, Buxbaum, SG, van der A, DL, Forouhi, NG, Onland-Moret, CN, 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, J Jukema, W, Westendorp, RGJ, de Borst, GJan, de Jong, PA, Algra, A, Spiering, W, van der Zee, AHMaitland, Klungel, OH, de Boer, A, Doevendans, PA, Eaton, CB, Robinson, JG, Duggan, D, 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, JJV, Lewsey, JD, Chasman, DI, Ridker, PM, Maggioni, AP, Tavazzi, L, Ray, KK, Seshasai, SRao Kondap, Manson, JAE, 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, WMMonique, 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, Kivimaki, M, Timpson, NJ, Langenberg, C, Asselbergs, FW, Voevoda, M, Bobak, M, Pikhart, H, Wilson, JG, Reiner, AP, Keating, BJ, Hingorani, AD, Sattar, N |
| Corporate/Institutional Authors | DIAGRAM Consortium, MAGIC Consortium,, InterAct Consortium |
| Journal | Lancet |
| Volume | 385 |
| Issue | 9965 |
| Pagination | 351-61 |
| Date Published | 2015 Jan 24 |
| ISSN | 1474-547X |
| Keywords | Aged, Body Mass Index, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Factors |
| Abstract | <p><b>BACKGROUND: </b>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.</p><p><b>METHODS: </b>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.</p><p><b>FINDINGS: </b>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).</p><p><b>INTERPRETATION: </b>The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.</p><p><b>FUNDING: </b>The funding sources are cited at the end of the paper.</p> |
| DOI | 10.1016/S0140-6736(14)61183-1 |
| Alternate Journal | Lancet |
| PubMed ID | 25262344 |
| PubMed Central ID | PMC4322187 |
| Grant List | 064947/Z/01/Z / / Wellcome Trust / United Kingdom 081081/Z/06/Z / / Wellcome Trust / United Kingdom 1R01 AG23522-01 / AG / NIA NIH HHS / United States 81081/Z/06/Z / / Wellcome Trust / United Kingdom AG034454 / AG / NIA NIH HHS / United States FS/07/011 / / British Heart Foundation / United Kingdom G0500877 / / Medical Research Council / United Kingdom G0600705 / / Medical Research Council / United Kingdom G0802432 / / Medical Research Council / United Kingdom HL036310 / HL / NHLBI NIH HHS / United States K013351 / / Medical Research Council / United Kingdom MC_U106179471 / / Medical Research Council / United Kingdom MC_UP_A100_1003 / / Medical Research Council / United Kingdom MC_UU_12013/1 / / Medical Research Council / United Kingdom MC_UU_12013/3 / / Medical Research Council / United Kingdom MC_UU_12013/5 / / Medical Research Council / United Kingdom MC_UU_12013/8 / / Medical Research Council / United Kingdom MC_UU_12015/1 / / Medical Research Council / United Kingdom MC_UU_12015/5 / / Medical Research Council / United Kingdom MC_UU_12019/1 / / Medical Research Council / United Kingdom MR/K006215/1 / / Medical Research Council / United Kingdom MR/K006584/1 / / Medical Research Council / United Kingdom MR/K013351/1 / / Medical Research Council / United Kingdom P20 MD006899 / MD / NIMHD NIH HHS / United States P20MD006899 / MD / NIMHD NIH HHS / United States PG/07/133/24260 / / British Heart Foundation / United Kingdom PG/11/63/29011 / / British Heart Foundation / United Kingdom PG/13/66/30442 / / British Heart Foundation / United Kingdom RG 08/008 / / British Heart Foundation / United Kingdom RG/10/12/28456 / / British Heart Foundation / United Kingdom RG/13/2/30098 / / British Heart Foundation / United Kingdom RG/13/2/30098 / / British Heart Foundation / United Kingdom U19 HL065797 / HL / NHLBI NIH HHS / United States UM1 CA182913 / CA / NCI NIH HHS / United States |