HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. / Swerdlow, Daniel I; Preiss, David; Kuchenbaecker, Karoline B; Holmes, Michael V; Engmann, Jorgen E L; Shah, Tina; Sofat, Reecha; Stender, Stefan; Johnson, Paul C D; 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 C W; 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 G J; 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; 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 J V; 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, W M 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; DIAGRAM Consortium.
in: LANCET, Jahrgang 385, Nr. 9965, 24.01.2015, S. 351-361.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: 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 G J
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
AU - DIAGRAM Consortium
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/genetics
KW - Cholesterol, HDL/metabolism
KW - Cholesterol, LDL/metabolism
KW - Diabetes Mellitus, Type 2/genetics
KW - Female
KW - Genetic Testing
KW - Humans
KW - Hydroxymethylglutaryl CoA Reductases/genetics
KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide/genetics
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 - SCORING: Journal article
C2 - 25262344
VL - 385
SP - 351
EP - 361
JO - LANCET
JF - LANCET
SN - 0140-6736
IS - 9965
ER -