I. Vakalyuk, N. Virstyuk

Ivano-Frankivsk National Medical University

Introduction. Today, dyslipidemia is considered one of the main risk factors for atherosclerosis and, as a consequence, cardiovascular disease [1]. In turn, it is indisputable, that the liver plays a leading role in the pathogenesis of atherogenic dyslipidemia and at the same time serves as the “target organ”, which leads to the non-alcoholic fatty liver disease (NAFLD) [7, 12]. Moreover, NAFLD is considered an additional component of the metabolic syndrome, as it is associated with its major manifestations – abdominal obesity, type 2 diabetes, secondary atherogenic dyslipidemia [9]. In addition, non-alcoholic fatty hepatosis and non-alcoholic steatohepatitis are the direct factors of cardiovascular risk regardless of the serum cholesterol of low density lipoprotein (LDL cholesterol) content [3, 14]. It has been established that the overall mortality rate of patients with NAFLD is primarily due to an increase in the proportion of cardiovascular mortality [11, 12].

Therefore, the most appropriate treatment for dyslipidaemia is statin therapy, which provides not only a decrease in serum LDL cholesterol and triglyceride (TG) levels, an increase in high-density lipoprotein cholesterol (HDL cholesterol), but also positively affects the state of the endothelium due to its pleiotropic effects [2]. The randomized trials (GREACE, REVERSAL, ASTEROID) identified the efficacy and safety of atorvastatin and rosuvastatin by stabilizing or reducing atherosclerotic plaques in coronary arteries [8, 11]. However, it is known that hypolipidemic agents can negatively affect the liver. In addition, the presence of atherogenic dyslipidemia also leads to a disruption of liver function [4].

Thus, the search for an adequate hypolipidemic treatment is still important, which would combine sufficient effectiveness in the correction of dyslipidemia, taking into account the stage of NAFLD and the individual tolerance of drugs in patients with stable coronary heart disease (CHD) with a comorbid NAFLD.

The purpose of the study was to evaluate the effectiveness of the effect of average-dose statin therapy on lipid profile in patients with stable coronary heart disease combined with nonalcoholic fatty liver disease in the stage of steatosis.

Material and methods. After obtaining a written consent for conducting a comprehensive survey in accordance with the principles of the Helsinki Declaration of Human Rights, the Council of Europe Convention on Human Rights and Biomedicine and relevant laws of Ukraine, in a randomized manner with pre-stratification, in the presence of a stable CHD of the II or III functional classes after more than 3 months of acute coronary syndrome, with NAFLD, 249 patients (81 women, 168 men, aged 54.2 ± 5.3 years) who were screened and treated on the basis of the regional clinical cardiologic dispensary and Ivano-Frankivsk central city clinical hospital were observed.

Diagnosis of stable CHD was verified in accordance with the order of the Ministry of Health of Ukraine # 152 from 02.03.2016 “Unified clinical protocol of primary, secondary (specialized) and tertiary (highly specialized) medical care: stable ischemic heart disease” [1]. Diagnosis of NAFLD was established in accordance with the order of the Ministry of Health of Ukraine # 826 from 06.11.2014 “Unified clinical protocol of primary, secondary (specialized) medical aid: non-alcoholic steatohepatitis” [6], Adapted clinical guidelines “Non-alcoholic fatty liver disease” [5], according to the recommendations of the European Association for the Study of Liver (EASL), the European Association for the Study of Diabetes (EASD), the European Association for the Study of Obesity (EASO) [10].

Lipid profile was tested using standard laboratory techniques. The content of plasma total cholesterol, TG and HDL cholesterol was determined by a photocolorimetric method modified by Karl T. Libermann – H. Burchard using reagent kits “Vital”, Russia. The content of cholesterol LDL was determined using the William Friedewald formula: LDL cholesterol = total cholesterol – (HDL cholesterol + TG / 2.2) [13].

According to the results of a detailed clinical-laboratory and instrumental examination, all patients stratified depending on the presence of NAFLD into two groups: 160 patients without NAFLD (Group I) and 89 patients with NAFLD in the stage of steatosis (Group II). The control group consisted of 20 practically healthy persons, comparable by gender and age.

All, those involved into the study, complied with the recommendations for lifestyle modification, namely diet therapy and the individual regimen of increasing physical activity, depending on the period after an acute coronary syndrome and physical activity tolerance, as well as, according to clinical protocols, standard treatment, which included β-adrenoblockers, prolonged-release nitrates, calcium antagonists, angiotensin-converting enzyme inhibitors or sartans (if necessary), antiagregants and statins. Depending on the intended hypolipidemic drug and its dose, the patients of each group were distributed to the appropriate subgroups. In particular, among patients of Group I, the following groups were isolated: subgroup IA (n = 98) – patients who received rosuvastatin at a dose of 20.0 mg / day orally; subgroup IB (n = 62) – patients who received atorvastatin at a dose of 40.0 mg / day orally. Accordingly, among the patients of Groyp II, the following groups were isolated: subgroup IIA (n = 38) – patients who received rosuvastatin at a dose of 20.0 mg / day orally; subgroup IIB (n = 34) – patients who received atorvastatin at a dose of 40.0 mg / day orally; subgroup of IIC (n = 17) – patients who received atorvastatin at a dose of 20.0 mg / day orally.

The hypolipidemic efficacy of average-dose of statin therapy was evaluated after 3 and 6 months of treatment compared to indicator of blood lipid profile before treatment. The statistical processing of the obtained results was carried out by software Microsoft Excel spreadsheet processor “Statistica” v. 10.0 StatSoft, USA. The estimation of the probability of the difference in mean values was carried out using the Student’s paired t-test. Average values were given in the form (M ± m), where M was the average value of the indicator, m – the standard error of the mean. The results were considered statistically significant when the value of p < 0.05.

Results and discussion. It was established that the violation of lipid metabolism in the examined patients with stable CHD corresponded to the dyslipidemia of type IIb by Fredrickson. Moreover, in the presence of NAFLD, changes of the blood lipid profile were more significant than in the absence of it. In particular, the serum total cholesterol level in patients of Group I was higher by 14.9% compared with the control (p < 0.05), (Table 1). In turn, in Group II, this indicator was by 49.4% higher vs. control group (p < 0.05), (Table 2).

Table 1

Dynamics of the indicators of blood lipid profile under the influence of hypolipidemic treatment in patients with stable coronary heart disease without non-alcoholic fatty liver disease (n; М ± m; р)

Table 2

Dynamics of the indicators of blood lipid profile under the influence of hypolipidemic treatment in patients with stable coronary heart disease, combined with NAFLD in the stage of steatosis (n; М ± m; р)

Instead, the content of TG exceeded its value in the control group in 1.6 times (Group I) and 2.3 times (Group II) respectively (p < 0.05). In turn, the LDL cholesterol level in patients Group I was higher by 29.3% while simultaneously reducing the HDL cholesterol level by 13.0% compared with the corresponding indices in control group (p < 0.05). In patients of Group II the LDL cholesterol level was by 2.4 times higher than in the control group (p < 0.05).

Instead, the HDL cholesterol level in patients of Group II was lower by 25.2% compared to the corresponding index in healthy control group (p < 0.05). The described disorders of the blood lipid profile caused the appropriate changes in the coefficient of atherogeny. In particular, if in patients of Group I this index was by 1.4 times higher than that of the control group, then in Group II – was by 2.4 times higher compared to corresponding its value in the healthy control group (p < 0.05).

The study of the dynamics of blood lipid profile for three months of treatment in patients of Group I has established the advantage of the hypolipidemic effect of rosuvastatin at a dose 20.0 mg / day compared to atorvastatin at a dose 40.0 mg / day. In patients of Group IA after 3 months of curare recorded elimination of dislipidemic disorders, which was characterized by a decrease in blood total cholesterol level by 14.7% (p < 0.05), TG – by 16.8% (p < 0.05), LDL cholesterol by 23.6% (p < 0.05) and an increase of HDL cholesterol by 8.4% (p > 0.05) compared with those indexes before treatment, which achieved a target its levels of 86 (87.8 %) cases.

Moreover, a stable hypolipidemic effect in patients Group I was maintained throughout the all observation and treatment period. In patients of Group IB, the achievement of a significant positive dynamics of changes in blood lipid profile was observed at the 6th month of treatment in 51 (82.3%) cases, with a decrease of total cholesterol level by 13.1% (p < 0.05), TG – by 16.3% (p < 0.05), LDL cholesterol – by 22.7% (p < 0.05) with a simultaneous increase of HDL cholesterol by 9.3% (p > 0.05) compared with its indexes before treatment. Negative influence of the studied statin therapy in patients of Group IA and Group IB on the liver functional state was not detected.

Evaluating the hypolipidemic effect of the statins appointment in moderate therapeutic doses for patients with stable CHD, combined with NAFLD in the stage of steatosis, after 3 months of treatment, it was found that the achievement of the target reference values of the blood lipid profile was in patients who received rosuvastatin at a dose of 20.0 mg / day.

Instead, the use of atorvastatin at a dose of 20.0-40.0 mg / day in patients of Group II did not result the clinically significant changes in blood lipid profile at the third month of treatment. In particular, the serum total cholesterol and TG levels after 3 months of treatment in patients of Group IIA decreased by 33.2% and 41.7% compared with the pre-treatment levels (p < 0.05), respectively. Instead, in Group IIB, these indicators decreased by 18.8% and 23.5% compared to their values before treatment (p < 0.05), respectively. In Group IIC, the dynamics of reduction in serum total cholesterol and TG levels was the least significant and was 7.4% and 8.7% compared to their basal level (p > 0.05), respectively.

The serum LDL cholesterol level at the third month of treatment decreased by 57.7% (Group IIA), (p <0.05); by 26.0% (Group IIB), (p < 0.05) and by 10.0% (Group IIC), (p > 0.05) compared with their values before treatment, respectively. In turn, the HDL cholesterol level increased by 21.7% (Group IIA) (p < 0.05); by 17.4% (Group ІІB) (p < 0.05) and by 6.5% (Group IIC) (p > 0.05) compared to their levels before treatment, respectively. The described changes of the blood lipid profile during a three-month of treatment caused a corresponding decrease in atherogeny coefficient. However, in patients of Group IIA this index decreased by 2.1 times compared to its initial value (p < 0.05); in Group IIB – decreased by 1.6 times compared to its value in patients before treatment (p < 0.05), then in Group IIC – it was only a tendency to decrease (by 1.2 times compared with its value before treatment, p > 0.05).

After 6 months of treatment, the advantage of rosuvastatin at a dose of 20.0 mg / day vs. atorvastatin at a dose 20.0-40.0 mg / day in the stability and duration of the hypolipidemic effect was detected, which is confirmed by the achievement of the target values in patients of Group IIA in 32 (84,2%) cases. Instead, a comparative analysis of the efficacy of atorvastatin at a dose 40.0 mg / day vs. atorvastatin at a dose 20.0 mg / day detected a more pronounced positive dynamics of changes in lipid profile in patients of group IIB. In particular, in patients of group IIB, the decrease of serum total cholesterol level by 32.9% compared to its level before treatment (p < 0.05) and by 17.4% compared to its level after 3 months of treatment (p <0.05) was observed.

Instead, in Group IIC the change of this indicator was less significant and was characterized by a decrease by 17.9% compared with its level before treatment (p < 0.05) and by 11.4% compared to its value after 3 months of treatment (p < 0, 05). In turn, the serum TG level in patients of Group ІІB and Group IIC decreased by 42.6% and by 22.8%, compared to their rates in these patients before treatment (p < 0.05), that was by 24.9% and by 15.5% less compared to the corresponding indicators after 3 months of treatment (p < 0.05). Serum LDL cholesterol level have been more significantly reduced in patients of Group IIB, that was lower on 55.3% vs. is level before treatment and on 39.6% vs. its level after 3 months of treatment (p < 0.05). This was accompanied by an increase of HDL cholesterol content in patients of Group ІІB by 23.9% compared with its level before treatment (p < 0.05) and by 5.6% – compared to the corresponding value after 3 months of treatment (p > 0.05). In turn, in patients of group IIC serum LDL cholesterol level decreased by 25.7% compared to its value before treatment (p < 0.05) and by 17.4% – compared to its level after 3 months of treatment (p < 0.05). To the same, the content of HDL cholesterol in patients of Group IIC increased by 15.2% (p < 0.05) and by 8.2% (p > 0.05), compared with its level before treatment and after three months of treatment, respectively.

As a result of a blood lipid profile changes under the treatment coefficient of atherogeny decreased by 53.4% compared to its level before treatment and by 27.4% compared its value after 3 months of curation (p < 0.05). Instead, in patients of group IIC this indicator decreased by 33.5% and by 21.7%, compared to its initial value and the level after 3 months of treatment (p < 0.05), respectively.

Conclusions. The efficacy of hypolipidemic treatment depends on the presence of non-alcoholic fatty liver disease, the selected statin, its dosage, and the duration of administration. In patients with stable coronary heart disease, it is reasonable to appoint a long-term statin therapy in order to provide the most effective and steady control of the blood lipid profile, especially under combined duration with non-alcoholic fatty liver disease in the stage of steatosis.

The use of rosuvastatin at a dose of 20.0 mg / day determines achievement of target levels of lipid profile after 3 months of treatment in 86 (87.8%) cases with a preserved hypolipidemic effect for 6 months compared to atorvastatin at a dose of 40 mg / day, accompanied by the achievement of the desired indicators in 51 (82.3%) cases only at the 6th month of treatment in patients with stable coronary heart disease without non-alcoholic fatty liver disease. In patients with stable coronary heart disease combined with nonalcoholic fatty liver disease in the stage of steatosis, the reliable advantage is the continued use of rosuvastatin at a dose of 20.0 mg / day compared to taking atorvastatin at a dose of 20.0-40.0 mg / day, which is manifested by a decrease of serum low-density lipoprotein cholesterol level by 57.7% after 3 months of treatment and achievement of a stable target levels of the blood lipid profile for 6 months of observation in 32 (84.2%) cases.

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