Evaluation of the influence of genetic polymorphisms and clinical factors on torasemide dosing in patients with heart failure

Background. Heart failure (HF) is a significant problem in modern medicine. Loop diuretics are used in 80–90% of patients with HF, representing a long-established basis for symptomatic treatment. However, many complex and unresolved issues for evidence-based medicine regarding diuretic therapy in HF remain. Given the genetic polymorphism of proteins involved in the metabolism and transport of torasemide, a loop diuretic widely used in clinical practice, as well as the importance of optimal dosing of diuretic therapy in patients with HF, it is necessary to personalize treatment and identify factors influencing diuretic therapy.

Objective. Evaluation of the influence of clinical factors and polymorphisms of the CYP2C9*2 (rs1799853, c.430C>T, Arg144Cys), CYP2C9*3 (rs1057910, 1075A>C, Ile359Leu) and SLCO1B1*5 (rs4149056, c.521T>C, Val174Ala) genes on the dosing of torasemide in patients with HF.

Methods. The study included 68 patients hospitalized with HF who received torasemide as diuretic therapy. Therapy adjustment was performed during hospitalization based on clinical, laboratory and instrumental data. Allelic variants of the CYP2C9 and SLCO1B1 genes were determined by real-time PCR.

Results. The distribution of CYP2C9 gene genotypes in the study population was as follows: 52 (76.5%) patients had the CYP2C9*1/*1 genotype, 9 (13.2%) – CYP2C9*1/*2, 6 (8.8%) – CYP2C9*1/*3, 1 (1.5%) – CYP2C9*2/*2, and the distribution of SLCO1B1*5: 46 (67.6%) – TT, 16 (23.5%) – TC and 6 (8.8%) – CC. The frequency of alleles and genotypes of CYP2C9*2 (χ2=0.82; p=0.66), CYP2C9*3 (χ2=0.14; p=0.93) and SLCO1B1*5 (χ2=5.35; p=0.07) corresponded to the Hardy–Weinberg equation; 30 (44.1%) patients did not require dose adjustment of torasemide, 14 (20.6%) patients required dose increase, 6 (8.8%) patients required dose decrease, 5 (7.4%) patients required loop diuretic therapy discontinued, and 13 (19.1%) patients were replaced with furosemide. Comparison of diuretic therapy depending on CYP2C9 (p=0.879) and SLCO1B1 (p=0.297) genotypes revealed no statistically significant differences. The need to replace torasemide with furosemide was statistically significantly higher in patients with more severe manifestations of HF (p=0.002), renal failure (p=0.020) and polypharmacy (p=0.001). Progression of the HF stage increases the chances of increasing the dose of torasemide or replacing it with furosemide by 4.94 times (95% CI 1.92–12.69); an increase in serum creatinine by 1 μmol/l increases the chances of increasing the dose of torasemide or replacing it with furosemide by 1.02 times (95% CI 1.01–1.04).

Conclusion. Polymorphisms of the CYP2C9*2, CYP2C9*3 and SLCO1B1*5 genes did not demonstrate a statistically significant association with the features of torasemide dosing in patients with HF in the current study. The stage of HF and the serum creatinine level had a direct relationship with the probability of increasing the dose of torasemide or replacing it with furosemide.