TY - JOUR
T1 - HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.
JF - Lancet
Y1 - 2015
A1 - Swerdlow, Daniel I
A1 - Preiss, David
A1 - Kuchenbaecker, Karoline B
A1 - Holmes, Michael V
A1 - Engmann, Jorgen E L
A1 - Shah, Tina
A1 - Sofat, Reecha
A1 - Stender, Stefan
A1 - Johnson, Paul C D
A1 - Scott, Robert A
A1 - Leusink, Maarten
A1 - Verweij, Niek
A1 - Sharp, Stephen J
A1 - Guo, Yiran
A1 - Giambartolomei, Claudia
A1 - Chung, Christina
A1 - Peasey, Anne
A1 - Amuzu, Antoinette
A1 - Li, KaWah
A1 - Palmen, Jutta
A1 - Howard, Philip
A1 - Cooper, Jackie A
A1 - Drenos, Fotios
A1 - Li, Yun R
A1 - Lowe, Gordon
A1 - Gallacher, John
A1 - Stewart, Marlene C W
A1 - Tzoulaki, Ioanna
A1 - Buxbaum, Sarah G
A1 - van der A, Daphne L
A1 - Forouhi, Nita G
A1 - Onland-Moret, N Charlotte
A1 - van der Schouw, Yvonne T
A1 - Schnabel, Renate B
A1 - Hubacek, Jaroslav A
A1 - Kubinova, Ruzena
A1 - Baceviciene, Migle
A1 - Tamosiunas, Abdonas
A1 - Pajak, Andrzej
A1 - Topor-Madry, Roman
A1 - Stepaniak, Urszula
A1 - Malyutina, Sofia
A1 - Baldassarre, Damiano
A1 - Sennblad, Bengt
A1 - Tremoli, Elena
A1 - de Faire, Ulf
A1 - Veglia, Fabrizio
A1 - Ford, Ian
A1 - Jukema, J Wouter
A1 - Westendorp, Rudi G J
A1 - de Borst, Gert Jan
A1 - de Jong, Pim A
A1 - Algra, Ale
A1 - Spiering, Wilko
A1 - Maitland-van der Zee, Anke H
A1 - Klungel, Olaf H
A1 - de Boer, Anthonius
A1 - Doevendans, Pieter A
A1 - Eaton, Charles B
A1 - Robinson, Jennifer G
A1 - Duggan, David
A1 - Kjekshus, John
A1 - Downs, John R
A1 - Gotto, Antonio M
A1 - Keech, Anthony C
A1 - Marchioli, Roberto
A1 - Tognoni, Gianni
A1 - Sever, Peter S
A1 - Poulter, Neil R
A1 - Waters, David D
A1 - Pedersen, Terje R
A1 - Amarenco, Pierre
A1 - Nakamura, Haruo
A1 - McMurray, John J V
A1 - Lewsey, James D
A1 - Chasman, Daniel I
A1 - Ridker, Paul M
A1 - Maggioni, Aldo P
A1 - Tavazzi, Luigi
A1 - Ray, Kausik K
A1 - Seshasai, Sreenivasa Rao Kondapally
A1 - Manson, JoAnn E
A1 - Price, Jackie F
A1 - Whincup, Peter H
A1 - Morris, Richard W
A1 - Lawlor, Debbie A
A1 - Smith, George Davey
A1 - Ben-Shlomo, Yoav
A1 - Schreiner, Pamela J
A1 - Fornage, Myriam
A1 - Siscovick, David S
A1 - Cushman, Mary
A1 - Kumari, Meena
A1 - Wareham, Nick J
A1 - Verschuren, W M Monique
A1 - Redline, Susan
A1 - Patel, Sanjay R
A1 - Whittaker, John C
A1 - Hamsten, Anders
A1 - Delaney, Joseph A
A1 - Dale, Caroline
A1 - Gaunt, Tom R
A1 - Wong, Andrew
A1 - Kuh, Diana
A1 - Hardy, Rebecca
A1 - Kathiresan, Sekar
A1 - Castillo, Berta A
A1 - van der Harst, Pim
A1 - Brunner, Eric J
A1 - Tybjaerg-Hansen, Anne
A1 - Marmot, Michael G
A1 - Krauss, Ronald M
A1 - Tsai, Michael
A1 - Coresh, Josef
A1 - Hoogeveen, Ronald C
A1 - Psaty, Bruce M
A1 - Lange, Leslie A
A1 - Hakonarson, Hakon
A1 - Dudbridge, Frank
A1 - Humphries, Steve E
A1 - Talmud, Philippa J
A1 - Kivimaki, Mika
A1 - Timpson, Nicholas J
A1 - Langenberg, Claudia
A1 - Asselbergs, Folkert W
A1 - Voevoda, Mikhail
A1 - Bobak, Martin
A1 - Pikhart, Hynek
A1 - Wilson, James G
A1 - Reiner, Alex P
A1 - Keating, Brendan J
A1 - Hingorani, Aroon D
A1 - Sattar, Naveed
KW - Aged
KW - Body Mass Index
KW - Body Weight
KW - Cholesterol, HDL
KW - Cholesterol, LDL
KW - Diabetes Mellitus, Type 2
KW - Female
KW - Genetic Testing
KW - Humans
KW - Hydroxymethylglutaryl CoA Reductases
KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide
KW - Randomized Controlled Trials as Topic
KW - Risk Factors
AB - **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.

VL - 385
IS - 9965
U1 - http://www.ncbi.nlm.nih.gov/pubmed/25262344?dopt=Abstract
ER -