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

  • Author(s): 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, Roman;
  • 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;
  • Maitland-van der Zee, Anke H;
  • Klungel, Olaf H;
  • de Boer, Anthonius;
  • Doevendans, Pieter A;
  • Eaton, Charles B;
  • Robinson, Jennifer G;
  • Duggan, David;
  • DIAGRAM Consortium;
  • MAGIC Consortium;
  • InterAct 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;
  • 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
  • et al.
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.

Funding

The funding sources are cited at the end of the paper.

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