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

By D. Swerdlow, D. Preiss, K. Kuchenbaecker, Michael Holmes, J. Engmann, T. Shah, R. Sofat, S. Stender, Paul C. D. Johnson, R. Scott and 123 more. The Lancet, 2015

671 citations recorded by the source corpus.

Summary 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.

Subfields: Endocrinology, Diabetes and Metabolism, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/05855c94a57a82f194a9c1191fd060436302d121

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Citations in the corpus

Developing medicines that mimic the natural successes of the human genome: lessons from NPC1L1, HMGCR, PCSK9, APOC3, and CETP. (2015, background): “(18) demonstrated that those harboring an LDLlowering allele at either of 2 HMGCR polymorphisms displayed higher body weight, increased fasting insulin, higher plasma glucose, and increased risk for type 2 diabetes.”
Statin Safety and Associated Adverse Events: A Scientific Statement From the American Heart Association (2019, methodology): “An analysis of study-level data from 20 major statin trials found no relationship between the length of those statin trials and the risk of newly diagnosed diabetes mellitus attributable to statin therapy.(114) Stopping statin treatment increases cardiovascular risk; therefore, statins should be con”
Interpretation of the evidence for the efficacy and safety of statin therapy. (2016, background): “Recently, it has been found that genetic variants that reduce the activity of HMGCoA reductase (which is analogous to inhibiting this enzyme with a statin) are associated with increased incidence of diabetes.(230) On the other hand, individuals with familial”
2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. (2016, background): “110,111 The long-ago dismissed association of statins and cataract formation has re-emerged from several cohort studies, most of which suggest a positive association.”