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HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials
- Source :
- The Lancet, 385(9965), 351-361. ELSEVIER SCIENCE INC, 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, Palmen, J, Howard, P, Cooper, J A, Drenos, F, Li, Y R, Lowe, G, Gallacher, J, Stewart, M C W, Tzoulaki, I, Buxbaum, S G, van der A, D L, Forouhi, N G, Onland-Moret, N C, van der Schouw, Y T, Schnabel, R B, Hubacek, J A, 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, J W & Price, J F 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, Lancet, 385(9965), 351-361, The Lancet. Lancet Publishing Group, The Lancet, 385(9965), 351. Elsevier Limited, Lancet
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
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.
- Subjects :
- Male
STATIN THERAPY
Type 2 diabetes
030204 cardiovascular system & hematology
Gastroenterology
DISEASE
Body Mass Index
chemistry.chemical_compound
0302 clinical medicine
Risk Factors
Medicine
HIGH-DOSE ATORVASTATIN
Randomized Controlled Trials as Topic
RISK
0303 health sciences
MAGIC Consortium
Articles
11 Medical And Health Sciences
General Medicine
Middle Aged
3. Good health
MENDELIAN RANDOMIZATION
Female
Life Sciences & Biomedicine
medicine.medical_specialty
Statin
medicine.drug_class
DIAGRAM Consortium
Placebo
Polymorphism, Single Nucleotide
03 medical and health sciences
Medicine, General & Internal
General & Internal Medicine
Internal medicine
Diabetes mellitus
Humans
Genetic Testing
METAANALYSIS
Aged
030304 developmental biology
Science & Technology
business.industry
Cholesterol
Body Weight
Cholesterol, HDL
Type 2 Diabetes Mellitus
Cholesterol, LDL
Odds ratio
InterAct Consortium
medicine.disease
R1
PREVENTION
BODY-MASS INDEX
Endocrinology
Diabetes Mellitus, Type 2
chemistry
Hydroxymethylglutaryl CoA Reductases
Hydroxymethylglutaryl-CoA Reductase Inhibitors
LDL CHOLESTEROL
business
ASSOCIATION ANALYSES
Body mass index
Subjects
Details
- ISSN :
- 01406736
- Volume :
- 385
- Database :
- OpenAIRE
- Journal :
- The Lancet
- Accession number :
- edsair.doi.dedup.....8065559ebe25091fd4c6ea7cd5388558