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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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
  • 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
  • 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

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.

OriginalsprogEngelsk
TidsskriftLancet
Vol/bind385
Udgave nummer9965
Sider (fra-til)351-361
Antal sider11
ISSN0140-6736
DOI
StatusUdgivet - 24 jan. 2015

ID: 135499785