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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
- Swerdlow, Daniel I;
- Preiss, David;
- Kuchenbaecker, Karoline B;
- Holmes, Michael V;
- Engmann, Jorgen EL;
- Shah, Tina;
- Sofat, Reecha;
- Stender, Stefan;
- Johnson, Paul CD;
- Scott, Robert A;
- Leusink, Maarten;
- Verweij, Niek;
- Sharp, Stephen J;
- Guo, Yiran;
- Giambartolomei, Claudia;
- Chung, Christina;
- Peasey, Anne;
- Amuzu, Antoinette;
- Li, KaWah;
- Palmen, Jutta;
- Howard, Philip;
- Cooper, Jackie A;
- Drenos, Fotios;
- Li, Yun R;
- Lowe, Gordon;
- Gallacher, John;
- Stewart, Marlene CW;
- Tzoulaki, Ioanna;
- Buxbaum, Sarah G;
- van der A, Daphne L;
- Forouhi, Nita G;
- Onland-Moret, N Charlotte;
- van der Schouw, Yvonne T;
- Schnabel, Renate B;
- Hubacek, Jaroslav A;
- Kubinova, Ruzena;
- Baceviciene, Migle;
- Tamosiunas, Abdonas;
- Pajak, Andrzej;
- Topor-Madry, Romanvan;
- Stepaniak, Urszula;
- Malyutina, Sofia;
- Baldassarre, Damiano;
- Sennblad, Bengt;
- Tremoli, Elena;
- de Faire, Ulf;
- Veglia, Fabrizio;
- Ford, Ian;
- Jukema, J Wouter;
- Westendorp, Rudi GJ;
- de Borst, Gert Jan;
- de Jong, Pim A;
- Algra, Ale;
- Spiering, Wilko;
- der Zee, Anke H Maitland-van;
- Klungel, Olaf H;
- de Boer, Anthonius;
- Doevendans, Pieter A;
- Eaton, Charles B;
- Robinson, Jennifer G;
- Duggan, David;
- DIAGRAM Consortium, MAGIC Consortium;
- Kjekshus, John;
- Downs, John R;
- Gotto, Antonio M;
- Keech, Anthony C;
- Marchioli, Roberto;
- Tognoni, Gianni;
- Sever, Peter S;
- Poulter, Neil R;
- Waters, David D;
- Pedersen, Terje R;
- Amarenco, Pierre;
- Nakamura, Haruo;
- McMurray, John JV;
- Lewsey, James D;
- Chasman, Daniel I;
- Ridker, Paul M;
- Maggioni, Aldo P;
- Tavazzi, Luigi;
- Ray, Kausik K;
- Seshasai, Sreenivasa Rao Kondapally;
- Manson, JoAnn E;
- Price, Jackie F;
- Whincup, Peter H;
- Morris, Richard W;
- Lawlor, Debbie A;
- Smith, George Davey;
- Ben-Shlomo, Yoav;
- Schreiner, Pamela J;
- Fornage, Myriam;
- Siscovick, David S;
- Cushman, Mary;
- Kumari, Meena;
- Wareham, Nick J;
- Verschuren, WM Monique;
- Redline, Susan;
- Patel, Sanjay R;
- Whittaker, John C;
- Hamsten, Anders;
- Delaney, Joseph A;
- Dale, Caroline;
- Gaunt, Tom R;
- Wong, Andrew;
- Kuh, Diana;
- Hardy, Rebecca;
- Kathiresan, Sekar;
- Castillo, Berta A;
- van der Harst, Pim;
- Brunner, Eric J;
- Tybjaerg-Hansen, Anne;
- Marmot, Michael G;
- Krauss, Ronald M;
- Tsai, Michael;
- Coresh, Josef;
- Hoogeveen, Ronald C;
- Psaty, Bruce M;
- Lange, Leslie A;
- Hakonarson, Hakon;
- Dudbridge, Frank;
- Humphries, Steve E;
- Talmud, Philippa J;
- Kivimäki, Mika;
- Timpson, Nicholas J;
- Langenberg, Claudia;
- Asselbergs, Folkert W;
- Voevoda, Mikhail;
- Bobak, Martin;
- Pikhart, Hynek;
- Wilson, James G;
- Reiner, Alex P;
- Keating, Brendan J;
- Hingorani, Aroon D;
- Sattar, Naveed
Published Web Location
https://doi.org/10.1016/s0140-6736(14)61183-1Abstract
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.Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.