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

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

doi:10.1016/s0140-6736(14)61183-1

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

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

362 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Lancet
Vol/bind	385
Udgave nummer	9965
Sider (fra-til)	351-361
Antal sider	11
ISSN	0140-6736
DOI	https://doi.org/10.1016/s0140-6736(14)61183-1
Status	Udgivet - 24 jan. 2015

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10.1016/s0140-6736(14)61183-1

http://www.thelancet.com/article/S0140673614611831/pdfLicens: CC BY

Citationsformater

Swerdlow, D. I., Preiss, D., Kuchenbaecker, K. B., Holmes, M. V., Engmann, J. E. L., Shah, T., Sofat, R., Stender, S., Johnson, P. C. D., Scott, R. A., Leusink, M., Verweij, N., Sharp, S. J., Guo, Y., Giambartolomei, C., Chung, C., Peasey, A., Amuzu, A., Li, K., ... Sattar, N. (2015). HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet, 385(9965), 351-361. https://doi.org/10.1016/s0140-6736(14)61183-1

Swerdlow, DI, Preiss, D, Kuchenbaecker, KB, Holmes, MV, Engmann, JEL, Shah, T, Sofat, R, Stender, S, Johnson, PCD, Scott, RA, Leusink, M, Verweij, N, Sharp, SJ, Guo, Y, Giambartolomei, C, Chung, C, Peasey, A, Amuzu, A, Li, K, Palmen, J, Howard, P, Cooper, JA, Drenos, F, Li, YR, Lowe, G, Gallacher, J, Stewart, MCW, Tzoulaki, I, Buxbaum, SG, van der A, DL, Forouhi, NG, Onland-Moret, NC, van der Schouw, YT, Schnabel, RB, Hubacek, JA, Kubinova, R, Baceviciene, M, Tamosiunas, A, Pajak, A, Topor-Madry, R, Stepaniak, U, Malyutina, S, Baldassarre, D, Sennblad, B, Tremoli, E, de Faire, U, Veglia, F, Ford, I, Jukema, JW, Westendorp, RGJ, de Borst, GJ, de Jong, PA, Algra, A, Spiering, W, Maitland-van der Zee, AH, Klungel, OH, de Boer, A, Doevendans, PA, Eaton, CB, Robinson, JG, Duggan, D, Kjekshus, J, Downs, JR, Gotto, AM, Keech, AC, Marchioli, R, Tognoni, G, Sever, PS, Poulter, NR, Waters, DD, Pedersen, TR, Amarenco, P, Nakamura, H, McMurray, JJV, Lewsey, JD, Chasman, DI, Ridker, PM, Maggioni, AP, Tavazzi, L, Ray, KK, Seshasai, SRK, Manson, JE, Price, JF, Whincup, PH, Morris, RW, Lawlor, DA, Smith, GD, Ben-Shlomo, Y, Schreiner, PJ, Fornage, M, Siscovick, DS, Cushman, M, Kumari, M, Wareham, NJ, Verschuren, WMM, Redline, S, Patel, SR, Whittaker, JC, Hamsten, A, Delaney, JA, Dale, C, Gaunt, TR, Wong, A, Kuh, D, Hardy, R, Kathiresan, S, Castillo, BA, van der Harst, P, Brunner, EJ, Tybjaerg-Hansen, A, Marmot, MG, Krauss, RM, Tsai, M, Coresh, J, Hoogeveen, RC, Psaty, BM, Lange, LA, Hakonarson, H, Dudbridge, F, Humphries, SE, Talmud, PJ, Kivimäki, M, Timpson, NJ, Langenberg, C, Asselbergs, FW, Voevoda, M, Bobak, M, Pikhart, H, Wilson, JG, Reiner, AP, Keating, BJ, Hingorani, AD & Sattar, N 2015, 'HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials', Lancet, bind 385, nr. 9965, s. 351-361. https://doi.org/10.1016/s0140-6736(14)61183-1

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

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.",

keywords = "Aged, Body Mass Index, Body Weight, Cholesterol, HDL, Cholesterol, LDL, Diabetes Mellitus, Type 2, Female, Genetic Testing, Humans, Hydroxymethylglutaryl CoA Reductases, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Risk Factors",

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

year = "2015",

month = jan,

day = "24",

doi = "10.1016/s0140-6736(14)61183-1",

language = "English",

volume = "385",

pages = "351--361",

journal = "Lancet",

issn = "0140-6736",

publisher = "TheLancet Publishing Group",

number = "9965",

}

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

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

SN - 0140-6736

VL - 385

SP - 351

EP - 361

JO - Lancet

JF - Lancet

IS - 9965

ER -

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

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