Efficiency of combined antihypertensive pharmacotherapy in patients with arterial hypertension, combined with type 2 diabetes mellitus and non-alcoholic fatty liver disease
Authors: Lukonin I. A. , Skibitsky V. V. , Fendrikova A. V. , Pavlyuchenko I. I. , Lazarev K. Yu. , Kovalenko F. A. 
Published: November 2022

Background. Treatment of patients with arterial hypertension (AH) associated with type 2 diabetes mellitus (DM2) and non-alcoholic fatty liver disease (NAFLD) is a complex clinical challenge. The complementary and aggravating effect of these comorbidities often prevents the realization of the antihypertensive potential of the drugs used and their combinations, and therefore it is necessary to search for additional ways to intensify therapy.

Aim. To assess the efficiency of combined pharmacotherapy in patients with AH associated with DM2 and NAFLD, depending on the CYP2C9 gene polymorphism.

Materials and methods. The study included 68 patients with uncontrolled AH associated with DM2 and NAFLD (Fatty Liver Index (FLI) > 60) who received prior antihypertensive therapy. All subjects were prescribed a combination of azilsartan medoxomil with amlodipine at doses of 40/5 mg/day. The duration of therapy was 24 weeks. Those included in the study underwent control of office blood pressure (BP) at the initial visit, after 4, 8 and 24 weeks of treatment; 24-hour BP monitoring (ABPM) — initially and after 24 weeks. Venous blood samples were taken from patients, followed by DNA isolation from leukocytes by phenol- chloroform extraction. Determination of polymorphic variants of the CYP2C9 gene was carried out on an amplifier Rotor Gene — Q. The TaqMan method (allele discrimination) and a set of primers and probes were used.

Results. As a result of genetic testing, the following distribution of polymorphic variants of the CYP2C9 gene was revealed: *1/*1 was found in 73,5% of patients, *1/*2 in 14,7%, *1/*3 in 11,8%. It was shown that after 4 weeks of therapy with a polymorphic variant of the *1/*1 CYP2C9 gene, the achievement of the target level (TL) of BP was registered in 62% of patients, with polymorphisms *1/*2 and *1/*3 — in 30% and 25%. After increasing the dose of azilsartan medoxomil and amlodipine to 80/10 mg/day, respectively, and 8 weeks from the start of treatment in the *1/*1 group, the number of BP targets achieved increased to 88%, in the *1/*2 groups and *1/*3 — up to 60% and 62,5%. Antihypertensive therapy was intensified with prolonged release indapamide at a dose of 1,5 mg/day, and according to the results of 24 weeks of therapy, patients with a polymorphic variant of the CYP2C9 *1/*1 gene achieved the TLBP in 96% of cases, with *1/*2 and *1/*3 — In 90% and 87,5%, respectively. At the same time, in patients with polymorphism of the CYP2C9 gene *1/*1, *1/*2 and *1/*3, positive dynamics of all ABPM parameters was revealed. However, in the *1/*1 variant, more pronounced positive changes were observed in the systolic BP time index during the day and the diastolic BP time index during the day, and the diastolic BP time index at night.

Conclusions. As a result of a 24-week study, the majority of patients who had the polymorphic variant *1/*1 of the CYP2C9 gene showed a more pronounced efficacy of the studied combination of drugs. Patients with *1/*2 and *1/*3 polymorphisms often required triple therapy to achieve TLBP. At the same time, further studies are needed to study the dependence of the antihypertensive effects of drugs on polymorphisms of the corresponding genes, which may help identify groups of patients who need more intensive antihypertensive therapy already at the start of treatment.