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; DIAGRAM Consortium; MAGIC Consortium; InterAct Consortium; Jackie F Price

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, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium, Jackie F Price

Research output: Contribution to journal › Article › peer-review

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
Pages (from-to)	351-361
Number of pages	11
Journal	The Lancet
Volume	385
Issue number	9965
Early online date	24 Sep 2014
DOIs	https://doi.org/10.1016/S0140-6736(14)61183-1
Publication status	Published - 24 Jan 2015

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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight
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http://www.sciencedirect.com/science/article/pii/S0140673614611831#

Inflammation, glucocorticoids abd microvascular disease in the aetiology of cognitive impairment in type 2 diabetes
Price, D.
MRC
1/06/06 → 30/11/11
Project: Research

Jackie Price
- Deanery of Molecular, Genetic and Population Health Sciences - Personal Chair of Molecular Epidemiology
- Usher Institute
- Centre for Global Health Research
Person: Academic: Research Active

Cite this

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., ... Price, J. F. (2015). HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. The Lancet, 385(9965), 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.",

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 {DIAGRAM Consortium} and {MAGIC Consortium} and {InterAct Consortium} and Price, {Jackie F}",

year = "2015",

month = jan,

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

language = "English",

volume = "385",

pages = "351--361",

journal = "The Lancet",

issn = "0140-6736",

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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, DIAGRAM Consortium, MAGIC Consortium, InterAct Consortium & Price, JF 2015, 'HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials', The Lancet, vol. 385, no. 9965, pp. 351-361. https://doi.org/10.1016/S0140-6736(14)61183-1

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, 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 - DIAGRAM Consortium

AU - MAGIC Consortium

AU - InterAct Consortium

AU - Price, Jackie F

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.

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

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

M3 - Article

C2 - 25262344

VL - 385

SP - 351

EP - 361

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9965

ER -

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

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Inflammation, glucocorticoids abd microvascular disease in the aetiology of cognitive impairment in type 2 diabetes

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