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; Romanvan Topor-Madry; Urszula Stepaniak; Sofia Malyutina; Damiano Baldassarre; Bengt Sennblad; Elena Tremoli; Ulf de Faire; Fabrizio Veglia; Ian Ford; J Wouter Jukema; Anne Tybjaerg-Hansen; DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium

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, Romanvan Topor-Madry, Urszula Stepaniak, Sofia Malyutina, Damiano Baldassarre, Bengt Sennblad, Elena Tremoli, Ulf de Faire, Fabrizio Veglia, Ian Ford, J Wouter Jukema, Anne Tybjaerg-Hansen, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium

Department of Clinical Biochemistry

538 Citations (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.

Original language	English
Journal	Lancet
Volume	385
Issue number	9965
Pages (from-to)	e351-61
ISSN	0140-6736
DOIs	https://doi.org/10.1016/S0140-6736(14)61183-1
Publication status	Published - 2015

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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., ... DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium (2015). HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet, 385(9965), e351-61. 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, Tybjaerg-Hansen, A & DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium 2015, 'HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials', Lancet, vol. 385, no. 9965, pp. e351-61. https://doi.org/10.1016/S0140-6736(14)61183-1

@article{b587ddc7707a4fb2a89a70c944396559,

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.",

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 Romanvan 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 Anne Tybjaerg-Hansen and {DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium}",

year = "2015",

doi = "10.1016/S0140-6736(14)61183-1",

language = "English",

volume = "385",

pages = "e351--61",

journal = "Lancet",

issn = "0140-6736",

publisher = "The/Lancet 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, Romanvan

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 - Tybjaerg-Hansen, Anne

AU - DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium

PY - 2015

Y1 - 2015

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.

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 - e351-61

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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