Pulse lineResearch With Heart Logo

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

TitleHMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials.
Publication TypeJournal Article
Year of Publication2015
AuthorsSwerdlow DI, Preiss D, Kuchenbaecker KB, et al.
Secondary AuthorsSattar N
Corporate AuthorsDIAGRAM Consortium, MAGIC Consortium, InterAct Consortium
JournalLancet
Volume385
Issue9965
Pagination351-61
Date Published2015 Jan 24
ISSN1474-547X
KeywordsAged, 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
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.

DOI10.1016/S0140-6736(14)61183-1
Alternate JournalLancet
PubMed ID25262344
PubMed Central IDPMC4322187
Grant List1R01 AG23522-01 / AG / NIA NIH HHS / United States
RG/13/2/30098 / / British Heart Foundation / United Kingdom
RG/08/008/25291 / / British Heart Foundation / United Kingdom
PG/13/66/30442 / / British Heart Foundation / United Kingdom
R01 HL036310 / HL / NHLBI NIH HHS / United States
MC_UP_A100_1003 / / Medical Research Council / United Kingdom
MR/K006215/1 / / Medical Research Council / United Kingdom
G19/35 / / Medical Research Council / United Kingdom
MC_UU_12013/3 / / Medical Research Council / United Kingdom
G0100222 / / Medical Research Council / United Kingdom
K013351 / / Medical Research Council / United Kingdom
MC_UU_12019/1 / / Medical Research Council / United Kingdom
G8802774 / / Medical Research Council / United Kingdom
RG/08/013/25942 / / British Heart Foundation / United Kingdom
G0902037 / / Medical Research Council / United Kingdom
R01 AG034454 / AG / NIA NIH HHS / United States
MC_UU_12015/1 / / Medical Research Council / United Kingdom
MC_U106179471 / / Medical Research Council / United Kingdom
G0500877 / / Medical Research Council / United Kingdom
FS/07/011 / / British Heart Foundation / United Kingdom
064947/Z/01/Z / / Wellcome Trust / United Kingdom
P20 MD006899 / MD / NIMHD NIH HHS / United States
R01 AG023522 / AG / NIA NIH HHS / United States
P20MD006899 / MD / NIMHD NIH HHS / United States
G1000616 / / Medical Research Council / United Kingdom
MC_UU_12013/1 / / Medical Research Council / United Kingdom
G0701830 / / Medical Research Council / United Kingdom
RG 08/008 / / British Heart Foundation / United Kingdom
HL036310 / HL / NHLBI NIH HHS / United States
UM1 CA182913 / CA / NCI NIH HHS / United States
81081/Z/06/Z / / Wellcome Trust / United Kingdom
G0802432 / / Medical Research Council / United Kingdom
MR/K006584/1 / / Medical Research Council / United Kingdom
MR/K013351/1 / / Medical Research Council / United Kingdom
MC_UU_12015/5 / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
PG/07/133/24260 / / British Heart Foundation / United Kingdom
U19 HL065797 / HL / NHLBI NIH HHS / United States
RG/13/16/30528 / / British Heart Foundation / United Kingdom
MC_UU_12013/5 / / Medical Research Council / United Kingdom
G0601647 / / Medical Research Council / United Kingdom
AG034454 / AG / NIA NIH HHS / United States
MC_UU_12013/8 / / Medical Research Council / United Kingdom
G0600705 / / Medical Research Council / United Kingdom
081081/Z/06/Z / / Wellcome Trust / United Kingdom
RG/07/008/23674 / / British Heart Foundation / United Kingdom
RG/10/12/28456 / / British Heart Foundation / United Kingdom