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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
  • 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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