STRUGGLE FOR. Italian-Polish-Spanish-Uzbek-Vietnamese Expert Forum Position Paper 2023 for better control of classical modifiable risk factors in clinical practice.

The progress in pharmacotherapy that has been made in recent years, including the introduction of very effective and safe lipid-lowering and antihypertensive drugs, has not yet translated into the expected universal control of blood pressure, lipid disorders and diabetes. In the STRUGGLE FOR Italian- -Polish-Spanish-Uzbek-Vietnamese Expert Forum Position Paper 2023, experts from five countries recounted several points about the paradigms of cardiological and cardiometabolic care for better control of classical modifiable risk factors in the year 2023. It is believed herein, that the need to intensify treatment, actively search for patients with cardiovascular risk factors, especially with arterial hypertension, hypercholesterolemia and diabetes, should go hand in hand with the implementation of the latest therapy, based on single pill combinations including proven, effective antihypertensive, lipid-lowering and antidiabetic molecules, many of which are listed in the present document. There is a need to use both new technological concepts, completely new drugs, as well as novel treatment concepts such as metabolic treatment in coronary artery disease, try to intensify the fight against smoking in every way, including the available range of drugs and procedures reducing the harm. This approach will provide substantially better control of the underlying cardiovascular risk factors in countries as varied as Italy, Poland, Spain, Uzbekistan and Vietnam.

TIMES TO ACT. Italian-Spanish-Polish-Uzbek Expert Forum Position Paper 2022. Dyslipidemia and arterial hypertension: The two most important and modifiable risk factors in clinical practice.

Hypertension and lipid disorders are two of the main cardiovascular risk factors. Both risk factors - if detected early enough - can be controlled and treated with modern, effective drugs, devoid of significant side effects, available in four countries as different as Italy, Spain, Poland, and Uzbekistan. The aim herein, was to develop this TIMES TO ACT consensus to raise the awareness of the available options of the modern and intensified dyslipidemia and arterial hypertension treatments. The subsequent paragraphs involves consensus and discussion of the deleterious effects of COVID-19 in the cardiovascular field, the high prevalence of hypertension and lipid disorders in our countries and the most important reasons for poor control of these two factors. Subsequently proposed, are currently the most efficient and safe therapeutic options in treating dyslipidemia and arterial hypertension, focusing on the benefits of single-pill combination (SPCs) in both conditions. An accelerated algorithm is proposed to start the treatment with a PCSK9 inhibitor, if the target low-density-lipoprotein values have not been reached. As most patients with hypertension and lipid disorders present with multiple comorbidities, discussed are the possibilities of using new SPCs, combining modern drugs from different therapeutic groups, which mode of action does not confirm the "class effect". We believe our consensus strongly advocates the need to search for patients with cardiovascular risk factors and intensify their lipid-lowering and antihypertensive treatment based on SPCs will improve the control of these two basic cardiovascular risk factors in Italy, Spain, Poland and Uzbekistan.

Can metformin stabilize PCSK9 level in stable coronary artery disease patients treated with statins?

INTRODUCTION: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as an important marker of cardiovascular risk and a new target for therapeutic interventions. We aimed to study the influence of metformin on the level of circulating PCSK9 in patients with stable coronary artery disease (SCAD) and type 2 diabetes (T2DM) or metabolic syndrome (MetS), receiving moderate doses of statins used in routine clinical practice. MATERIAL AND METHODS: The study included 80 patients with T2DM or MetS receiving rosuvastatin for at least three months prior the study. MetS was diagnosed based on the Global Consensus Definition of the International Diabetes Federation (IDF). Serum level of PCSK9 was measured with an ELISA kit. RESULTS: Patients with T2DM or MetS, who took part in the research, were divided into 2 groups - those who received metformin prior the main study (21 patients - 1st group) and patients who did not (59 patients - 2nd group). Addition of metformin to the 3-month statin therapy of the 2nd group patients, divided into subgroup A (n = 27) with the addition of metformin and subgroup B (n = 29) without one, did not significantly affect the level of lipids. However, the level of circulating PCSK9 in subgroup A patients decreased, compared to subgroup B (p < 0.01). At the same time, ongoing metformin and rosuvastatin therapy in the 1st group patients was not accompanied by a further decrease of the PCSK9 level. CONCLUSIONS: The addition of metformin to ongoing rosuvastatin therapy did not significantly affect serum lipid levels, but stabilized the level of circulating PCSK9, compared with the group without metformin treatment.

Burden of familial heterozygous hypercholesterolemia in Uzbekistan: Time is muscle.

BACKGROUND AND AIMS: We aimed to assess the disease burden and to study the molecular genetic characteristics of heterozygous familial hypercholesterolemia (HeFH) patients within the Uzbek population to develop a program of early disease detection and effective treatment measures. METHODS: 201 patients were included in the study, of whom 57 with chronic stable coronary artery disease (SCAD) and HeFH, and 144 with SCAD without HeFH belonging to the control group, and divided into two subgroups: A, statin free before the study (n = 63) and B (n = 81), who took statin outpatiently. We applied the Dutch Lipid Clinic Network Criteria (DLCN) to diagnose HeFH. Serum level of PCSK-9 was measured with the ELISA Kit. The genetic typing at PCSK9 E670G (rs505151) polymorphism was performed with the PCR-RFLP method. RESULTS: Underestimation of early lipid studies and inadequate treatment in HeHF patients within the Uzbek population are accompanied by a 1.8-time increase of more frequent history of myocardial infarction (p < 0.05), a 3-time stroke (p < 0.05) and 2-time percutaneous coronary intervention (p < 0.05). The study of genotypes and alleles of PCSK9 E670G (rs505151) polymorphism allowed to state that сarriage of the «damaging ¼â€¯allele G in SCAD and HeHF patients was 2 times higher (11.4%), than in non HeHF (6.0%) and 3 times (3.0%) than in healthy ones, but the differences were not significant. Herewith, G-carriership is accompanied by a higher incidence of myocardial infarction (p < 0.05) and stroke (p < 0.05), coronary artery bypass grafting in anamnesis (p < 0.001), and number of plaques in carotids (p < 0.05). In group I of SCAD patients with HeFH, 18 (31.6%) cases of diabetes mellitus were observed, which did not exceed their number in group II (48, 33.3%). However, most of them were carriers of the G allele (82.0%, p < 0.001). Despite treatment with rosuvastatin 20-40 mg/day, in HeHF patients after 3 months, the level of total cholesterol (p < 0.001) and LDL-C (p < 0.001) was significantly higher than in the control group. CONCLUSIONS: Improvement of early diagnosis of FH, including genetic confirmation, and preventional high-intensity statin therapy or a combination of statins with ezetimibe to achieve the target level of LDL-C, is the closest tactical objective for prevention of MACE within the Uzbek population.

Personalized rosuvastatin therapy in problem patients with partial statin intolerance.

INTRODUCTION: The aim was to study the pharmacogenetic determinants of switching simvastatin-intolerant ethnic Uzbek patients with coronary artery disease (CAD) to rosuvastatin treatment. MATERIAL AND METHODS: The study included 50 patients with CAD, who demonstrated statin-induced adverse liver symptoms, accompanied by an elevation in transaminase level (3-fold or more in 37 cases) or statin-induced adverse muscle symptoms, accompanied by elevations in serum (CK > 3 times above the upper limit of normal (ULN)) in simvastatin treatment with a dose of 10-20 mg/day. The control group consisted of 50 patients without side effects. Patients were genotyped for polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes CYP3A5(6986A>G), CYP2C9(430C>T), CYP2C9(1075A>C), and hepatic influx and efflux transporters SLCO1B1(521T>C) and BCRP(ABCG2, 421C>A) by means of the PCR-RFLP method. RESULTS: When the 50 patients of the case group were switched to the starting rosuvastatin dose of 5 mg, intolerance symptoms were not observed in 29 (58%) versus 21 with adverse symptoms. In this case-control study, the groups differed significantly only in the prevalence of the *3/*3 genotype CYP3A5 (OR = 5.25; 95% CI: 1.6-17.8; p = 0.014). CONCLUSIONS: In a considerable proportion of ethnic Uzbek patients with CAD and simvastatin intolerance symptoms, serious side effects when switching to a starting dose of rosuvastatin were not observed, and it should be noted that in most cases (72.4%) this phenomenon was observed among the carriers of *3/*3 genotype of the CYP3A5 (6986A> G) gene.

Simvastatin intolerance genetic determinants: some features in ethnic Uzbek patients with coronary artery disease.

INTRODUCTION: The objective is to study the influence of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) gene polymorphisms on the development of simvastatin intolerance in ethnic Uzbek patients with coronary artery disease (CAD). MATERIAL AND METHODS: The case group contained 50 patients with clinical simvastatin-induced intolerance symptoms; the control group contained 50 patients without side-effects. Genotyping was performed by means of the PCR-RFLP method. RESULTS: Among 37 patients with simvastatin-induced liver symptoms the *3/*3 genotype of the CYP3A5 gene (p = 0.0001) and variant genotype of the CA BCRP gene were observed more frequently than in the control group (p = 0.0001). However, when the 13 patients who had statin-associated muscle symptoms (SAMS) were compared with the control group (n = 50), it was found that in the case group the 3*/3* genotype of the CYP3A5 gene (OR = 8.6; 95% CI: 2.1-34.1; p = 0.003) and C allele carriers of the gene polymorphism SLCO1B1 (OR = 3.54; 95% CI: 1.35-9.27; Χ2 = 5.7; p = 0.017) were predominant. CONCLUSIONS: The *3/*3 genotype of the CYP3A5 (6986A>G) gene and CA genotype of the BCRP (ABCG2, 421C>A) gene were associated with simvastatin-induced liver symptoms in ethnic Uzbek CAD patients, whereas in patients with simvastatin-associated muscle symptoms (SAMS), the combination of *3/*3 genotype of CYP3A5 (6986A> G) and carriage of the C allele of the SLCO1B1 gene polymorphism was predominant.