Details

Autor(en) / Beteiligte

• Swerdlow, Daniel I, Dr
• Preiss, David, Dr
• Holmes, Michael V, PhD
• Shah, Tina, PhD
• Sofat, Reecha, MD
• Johnson, Paul C D, PhD
• Verweij, Niek, MD
• Sharp, Stephen J, MSc
• Giambartolomei, Claudia, MSc
• Chung, Christina, MSc
• Peasey, Anne, PhD
• Amuzu, Antoinette, MSc
• Li, KaWah, MSc
• Cooper, Jackie A, MSc
• Drenos, Fotios, PhD
• Li, Yun R, BSc
• Lowe, Gordon, Prof
• Gallacher, John, PhD
• Stewart, Marlene C W, PhD
• Tzoulaki, Ioanna, PhD
• van der A, Daphne L, PhD
• Forouhi, Nita G, MRCP
• Onland-Moret, N Charlotte, PhD
• Schnabel, Renate B, MD
• Hubacek, Jaroslav A, PhD
• Kubinova, Ruzena, MD
• Baceviciene, Migle, MD
• Tamosiunas, Abdonas, Prof
• Topor-Madry, Romanvan, MD
• Stepaniak, Urszula, PhD
• Malyutina, Sofia, Prof
• Baldassarre, Damiano, PhD
• Sennblad, Bengt, PhD
• Tremoli, Elena, Prof
• Veglia, Fabrizio, PhD
• Ford, Ian, Prof
• Westendorp, Rudi G J, Prof
• Algra, Ale, Prof
• der Zee, Anke H Maitland-van, PhD
• Eaton, Charles B, Prof
• Robinson, Jennifer G, Prof
• Duggan, David, PhD
• Downs, John R, MD
• Gotto, Antonio M, MD
• Keech, Anthony C, MD
• Marchioli, Roberto, MD
• Tognoni, Gianni, MD
• Sever, Peter S, Prof
• Waters, David D, MD
• Pedersen, Terje R, MD
• Nakamura, Haruo, MD
• McMurray, John J V, Prof
• Lewsey, James D, PhD
• Chasman, Daniel I, PhD
• Ridker, Paul M, MD
• Maggioni, Aldo P, Prof
• Tavazzi, Luigi, Prof
• Manson, JoAnn E, Prof
• Price, Jackie F, MD
• Whincup, Peter H, Prof
• Morris, Richard W, Prof
• Lawlor, Debbie A, Prof
• Ben-Shlomo, Yoav, Prof
• Schreiner, Pamela J, Prof
• Fornage, Myriam, Prof
• Siscovick, David S, Prof
• Cushman, Mary, MD
• Kumari, Meena, PhD
• Verschuren, W M Monique, PhD
• Redline, Susan, Prof
• Patel, Sanjay R, MD
• Whittaker, John C, Prof
• Hamsten, Anders, Prof
• Delaney, Joseph A, PhD
• Dale, Caroline, PhD
• Gaunt, Tom R, PhD
• Wong, Andrew, PhD
• Hardy, Rebecca, Prof
• Kathiresan, Sekar, MD
• Castillo, Berta A, PhD
• van der Harst, Pim, Prof
• Brunner, Eric J, Prof
• Tybjaerg-Hansen, Anne, Prof
• Krauss, Ronald M, MD
• Tsai, Michael, Prof
• Coresh, Josef, Prof
• Psaty, Bruce M, Prof
• Hakonarson, Hakon, Prof
• Dudbridge, Frank, PhD
• Humphries, Steve E, Prof
• Timpson, Nicholas J, PhD
• Langenberg, Claudia, MD
• Asselbergs, Folkert W, MD
• Voevoda, Mikhail, Prof
• Bobak, Martin, Prof
• Pikhart, Hynek, PhD
• Reiner, Alex P, Prof
• Keating, Brendan J, PhD
• Hingorani, Aroon D, Prof
• Sattar, Naveed, Prof

Titel

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

Ist Teil von

• The Lancet (British edition), 2015-01, Vol.385 (9965), p.351-361

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2015

Quelle

MEDLINE

Beschreibungen/Notizen

• Summary 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.