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Gene inhibition with statin therapy increased body weight, risk for type 2 diabetes
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Genetic analysis conducted by an international group of researchers demonstrates that the increased risk for type 2 diabetes observed with statin therapy can be partially explained by inhibition of the intended drug target, according to research published in The Lancet.
Using 43 genetic studies, Daniel I. Swerdlow, PhD, of the Institute of Cardiovascular Science and Farr Institute, University College London, and researchers from other institutions examined single nucleotide polymorphisms (SNPs) in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene.
“Both statin treatment in randomized trials and carriage of common SNPs in the HMGCR gene in population studies were associated with body weight gain and higher risk of type 2 diabetes,” the researchers wrote. “Body weight gain is physiologically linked to insulin resistance and is one of the strongest risk factors for type 2 diabetes, which might partly explain the higher risk of type 2 diabetes in statin-treated patients.”
The scientists reviewed data for up to 223,463 individuals; two SNPs — rs17238484 for the main analysis and rs12916 for a subsidiary analysis — served as proxies for HMGCR inhibition by statins. The researchers explored the variants in relation to: plasma lipid, glucose and insulin concentrations; body weight; waist circumference; and prevalent and incident type 2 diabetes.
Meta-analysis was used to pool study-specific effect estimates per copy of each LDL-lowering allele. The investigators compared these findings with a meta-analysis of new-onset type 2 diabetes and body weight change data collected from randomized trials of statin drugs. The effects of statins in each randomized trial were evaluated through meta-analysis.
On average, with every additional rs17238484-G allele, LDL cholesterol dropped by 0.06 mmol/L (95% CI, 0.05-0.07) body weight increased 0.3 kg (95% CI, 0.18-0.43), waist circumference increased 0.32 cm (95% CI, 0.16-0.47), plasma insulin concentration increased 1.62% (95% CI, 0.53-2.72) and plasma glucose concentration increased 0.23% (95% CI, 0.02-0.44). Similar effects on LDL cholesterol, body weight and waist circumference were seen with the rs12916 SNP.
Every additional rs17238484-G allele appeared to be associated with increased type 2 diabetes risk (OR=1.02; 95% CI, 1-1.05). The rs12916-T allele association remained consistent (OR=1.06; 95% CI, 1.03-1.09).
In 129,170 individuals in randomized trials, 1-year follow up showed statins reduced LDL cholesterol by 0.92 mmol/L (95% CI, 0.18-1.67).
Statin therapy increased body weight, at a mean of 4.2 years, by an average of 0.24 kg (95% CI, 0.1-0.38) in all trials, with an increase of 0.33 kg (95% CI, 0.24-0.42) in placebo or standard care controlled trials but a decrease of 0.15 kg (95% CI, –0.39 to 0.08) in trials comparing intensive and moderate doses.
Treatment increased new-onset type 2 diabetes risk in all trials (OR=1.12; 95% CI, 1.06-1.18), with similar rates in placebo or standard care controlled trials (OR=1.11; 95% CI, 1.03-1.2) and in trials comparing intensive and moderate doses (OR=1.12; 95% CI, 1.04-1.22).
“Our results, including the new finding of increased body weight with statin treatment, suggest lifestyle interventions such as body weight optimization, healthy diet and adequate physical activity should be emphasized as important adjuncts to prevention of cardiovascular disease with statin treatment to attenuate risks of type 2 diabetes,” the researchers wrote.
Disclosure: Please see study for full list of disclosures.
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