TY - JOUR

T1 - HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight

T2 - evidence from genetic analysis and randomised trials

AU - Swerdlow, Daniel I

AU - Preiss, David

AU - Kuchenbaecker, Karoline B

AU - Holmes, Michael V

AU - Engmann, Jorgen E L

AU - Shah, Tina

AU - Sofat, Reecha

AU - Stender, Stefan

AU - Johnson, Paul C D

AU - Scott, Robert A

AU - Leusink, Maarten

AU - Verweij, Niek

AU - Sharp, Stephen J

AU - Guo, Yiran

AU - Giambartolomei, Claudia

AU - Chung, Christina

AU - Peasey, Anne

AU - Amuzu, Antoinette

AU - Li, KaWah

AU - Palmen, Jutta

AU - Howard, Philip

AU - Cooper, Jackie A

AU - Drenos, Fotios

AU - Li, Yun R

AU - Lowe, Gordon

AU - Gallacher, John

AU - Stewart, Marlene C W

AU - Tzoulaki, Ioanna

AU - Buxbaum, Sarah G

AU - van der A, Daphne L

AU - Forouhi, Nita G

AU - Onland-Moret, N Charlotte

AU - van der Schouw, Yvonne T

AU - Schnabel, Renate B

AU - Hubacek, Jaroslav A

AU - Kubinova, Ruzena

AU - Baceviciene, Migle

AU - Tamosiunas, Abdonas

AU - Pajak, Andrzej

AU - Topor-Madry, Roman

AU - Stepaniak, Urszula

AU - Malyutina, Sofia

AU - Baldassarre, Damiano

AU - Sennblad, Bengt

AU - Tremoli, Elena

AU - de Faire, Ulf

AU - Veglia, Fabrizio

AU - Ford, Ian

AU - Jukema, J Wouter

AU - Westendorp, Rudi GJ

AU - de Borst, Gert Jan

AU - de Jong, Pim A

AU - Algra, Ale

AU - Spiering, Wilko

AU - Maitland-van der Zee, Anke H

AU - Klungel, Olaf H

AU - de Boer, Anthonius

AU - Doevendans, Pieter A

AU - Eaton, Charles B

AU - Robinson, Jennifer G

AU - Duggan, David

AU - Kjekshus, John

AU - Downs, John R

AU - Gotto, Antonio M

AU - Keech, Anthony C

AU - Marchioli, Roberto

AU - Tognoni, Gianni

AU - Sever, Peter S

AU - Poulter, Neil R

AU - Waters, David D

AU - Pedersen, Terje R

AU - Amarenco, Pierre

AU - Nakamura, Haruo

AU - McMurray, John J V

AU - Lewsey, James D

AU - Chasman, Daniel I

AU - Ridker, Paul M

AU - Maggioni, Aldo P

AU - Tavazzi, Luigi

AU - Ray, Kausik K

AU - Seshasai, Sreenivasa Rao Kondapally

AU - Manson, JoAnn E

AU - Price, Jackie F

AU - Whincup, Peter H

AU - Morris, Richard W

AU - Lawlor, Debbie A

AU - Smith, George Davey

AU - Ben-Shlomo, Yoav

AU - Schreiner, Pamela J

AU - Fornage, Myriam

AU - Siscovick, David S

AU - Cushman, Mary

AU - Kumari, Meena

AU - Wareham, Nick J

AU - Verschuren, W M Monique

AU - Redline, Susan

AU - Patel, Sanjay R

AU - Whittaker, John C

AU - Hamsten, Anders

AU - Delaney, Joseph A

AU - Dale, Caroline

AU - Gaunt, Tom R

AU - Wong, Andrew

AU - Kuh, Diana

AU - Hardy, Rebecca

AU - Kathiresan, Sekar

AU - Castillo, Berta A

AU - van der Harst, Pim

AU - Brunner, Eric J

AU - Tybjaerg-Hansen, Anne

AU - Marmot, Michael G

AU - Krauss, Ronald M

AU - Tsai, Michael

AU - Coresh, Josef

AU - Hoogeveen, Ronald C

AU - Psaty, Bruce M

AU - Lange, Leslie A

AU - Hakonarson, Hakon

AU - Dudbridge, Frank

AU - Humphries, Steve E

AU - Talmud, Philippa J

AU - Kivimäki, Mika

AU - Timpson, Nicholas J

AU - Langenberg, Claudia

AU - Asselbergs, Folkert W

AU - Voevoda, Mikhail

AU - Bobak, Martin

AU - Pikhart, Hynek

AU - Wilson, James G

AU - Reiner, Alex P

AU - Keating, Brendan J

AU - Hingorani, Aroon D

AU - Sattar, Naveed

N1 - Copyright © 2015 Swerdlow et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.

PY - 2015/1/24

Y1 - 2015/1/24

N2 - 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.

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.

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

U2 - 10.1016/S0140-6736(14)61183-1

DO - 10.1016/S0140-6736(14)61183-1

M3 - Journal article

C2 - 25262344

VL - 385

SP - 351

EP - 361

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9965

ER -