Hypolipaemic nutraceutics: red yeast rice and Armolipid, berberine and bergamot.

INTRODUCTION: Increased serum cholesterol levels constitute one of the main risk factors for cardiovascular diseases. Statins are a major method for reducing the levels which also lower the risk of cardiovascular events. However, these valuable drugs cannot be used in all patients who need them due to contraindications and intolerance. In such cases, help can be sought from nutraceutics that reduce the serum cholesterol concentration. Since there are numerous products of this type available at drugstores, registered as supplements, there seems to be a need to demonstrate their effectiveness in preventing cardiovascular diseases induced by atherosclerosis. In literature, increasingly more attention is drawn to red yeast rice, Armolipid, berberine and bergamot. BRIEF DESCRIPTION: This article presents knowledge about these nutraceutics based on clinical studies and expert statements relating to their use. The results of clinical studies and metaanalyses have shown that nutraceutics with cholesterol lowering properties, red yeast rice and Armolipid are the most favourable for reducing cardiovascular events. However, the evidence of benefits of berberine and bergamot is not so conclusive. CONCLUSIONS: Red yeast rice products and Armolipid may be used as an alternative treatment in statin intolerant patients, especially in combination with ezetimibe. These nutraceutics can be also considered, as an adjunct to diet therapy in primary prevention of cardiovascular diseases in patients with mild and moderate hypercholesterolaemia. The opinion of experts on berberine and bergamot is ambiguous.

How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors.

There is a strong evidence that more marked lowering of low-density lipoprotein cholesterol (LDL-C) leads to progressively lower risk of cardiovascular disease (CVD) events. The evidence on validity of this hypothesis comes from epidemiological, genetic and clinical studies. The hypothesis "the lower the better" has been recently strongly supported by the results of secondary prevention trials with PCSK9 inhibitors. The combination of PCSK9 inhibitors and statins has resulted in achieving extremely low LDL-C levels with additional reduction of CVD events in secondary prevention. However, despite large clinical benefits, the safety of aggressive LDL-C lowering should be always taken into consideration, and there is still an ongoing discussion on whether very low LDL-C might result in some non-CVD adverse events. However, based on the available knowledge, so far the serious adverse events associated with achieving of very low LDL-C levels or intensive drug therapy have not been noted. These positive clinical effects were reflected in current ESC/EAS Guidelines (2019) for dyslipidaemia management. The experts strongly recommended the LDL-C lowering to levels that have been achieved in trials of PCSK9 inhibitors. In this state of the art review, we aimed to finally justify the critical need for LDL-C reduction to very low levels in secondary prevention patients in order to be as low as possible, as early as possible, and preferably lifelong.

Current state-of-the-art knowledge on the role of omega-3 fatty acids in the prevention of cardiovascular disease.

INTRODUCTION: Polyunsaturated n-3 fatty acid preparations containing eicosapentaenoic acid (EPA) and docosahexanaenoic acid (DHA), or EPA only, have long been recommended in the management of hypertriglyceridaemia, especially when severe (triglyceride levels ≥500 mg/dL), at the dose of 2-4 g/d, mostly for the prevention of acute pancreatitis. MATERIAL AND METHODS: The presented article reviews clinical trials and their metaanalyses which evaluated the effect of n-3 fatty acids on cardiovascular disease risk, and regulatory agencies' and cardiac societies' positions regarding their use. RESULTS: The findings indicate that only EPA is effective. Particular clinical benefit (25% reduction of cardiovascular events) was observed in the recently published REDUCE-IT trial which evaluated EPA (icosapent ethyl) at the dose of 4 g/d for 4.9 years (median), compared to placebo, in hypertriglycerydaemic patients at high or very high cardiovascular risk. This positive effect has been reflected in the expert opinions which recommend eicosapent ethyl (4 g/d) in patients similar to those participating in the REDUCE-IT trial. Additional data in favour of the above position have been provided by the EVAPORATE trial results which showed reduced progression of coronary atherosclerosis with EPA at the dose of 4 g/d. CONCLUSIONS: The clinical studies and metaanalyses strongly point out that only EPA (icosapent ethyl), especially at dose of 4 g/d, is effective in reducing cardiovascular events in very high and high risk patients with hypertriglyceridemia. The use of EPA + DHA preparations in doses up to 1 g/d does not prevent recurrent cardiovascular events.

The association between the insertion/deletion polymorphism of the angiotensin converting enzyme gene and hypertension, as well as environmental, biochemical and anthropometric factors.

BACKGROUND: Arterial hypertension is caused by environmental factors and genetic predisposition. OBJECTIVE: The aim of this study was to assess the association between the angiotensin converting enzyme (ACE) gene variants and environmental factors, biochemical and anthropometric parameters and the incidence of hypertension. MATERIAL AND METHODS: A total of 73 patients, aged 24 to 68, with Body Mass Index (BMI) above 25 kg/m2 took part in this study. Nutrient intake was assessed with a diet based on consumption records. The ACE gene insertion/deletion (I/D) polymorphism was determined by the polymerase chain reaction (PCR) method. RESULTS: Normal pressure predominated in persons with genotype II (59.1%), whereas hypertension in persons with genotype ID (55.2%). The frequency of the D allele was 5% higher in the hypertensive group (53% vs. 48%), but this difference was not statistically significant. The percentage of patients who consumed alcohol and smoked cigarettes in the D allele group was higher than in the I allele group. People with the D allele had lower vitamin D intake and higher copper intake than carriers of the allele I. The highest vitamin D intake was found in people with genotype II, and the differences were significant compared to patients with ID genotype. People with the D allele consumed more carbohydrates and less protein than those with the I allele, but these differences were not statistically significant. CONCLUSIONS: Hypertensive subjects were more frequent DD and ID genotypes, whereas normotensive subjects - the II genotype. People with the D allele had lower vitamin D and protein intake, while the carbohydrate and copper intake was higher than those with the I allele. The group with the D allele had a higher percentage of smokers and alcohol drinkers. Our studies have shown a relationship between environmental and genetic factors and hypertension, but more research is needed.

What do we know about the role of lipoprotein(a) in atherogenesis 57 years after its discovery?

Elevated circulating concentrations of lipoprotein(a) [Lp(a)] is strongly associated with increased risk of atherosclerotic cardiovascular disease (CVD) and degenerative aortic stenosis. This relationship was first observed in prospective observational studies, and the causal relationship was confirmed in genetic studies. Everybody should have their Lp(a) concentration measured once in their lifetime. CVD risk is elevated when Lp(a) concentrations are high i.e. > 50 mg/dL (≥100 mmol/L). Extremely high Lp(a) levels >180 mg/dL (≥430 mmol/L) are associated with CVD risk similar to that conferred by familial hypercholesterolemia. Elevated Lp(a) level was previously treated with niacin, which exerts a potent Lp(a)-lowering effect. However, niacin is currently not recommended because, despite the improvement in lipid profile, no improvements on clinical outcomes have been observed. Furthermore, niacin use has been associated with severe adverse effects. Post hoc analyses of clinical trials with proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors have shown that these drugs exert clinical benefits by lowering Lp(a), independent of their potent reduction of low-density lipoprotein cholesterol (LDL-C). It is not yet known whether PCSK9 inhibitors will be of clinical use in patients with elevated Lp(a). Apheresis is a very effective approach to Lp(a) reduction, which reduces CVD risk but is invasive and time-consuming and is thus reserved for patients with very high Lp(a) levels and progressive CVD. Studies are ongoing on the practical application of genetic approaches to therapy, including antisense oligonucleotides against apolipoprotein(a) and small interfering RNA (siRNA) technology, to reduce the synthesis of Lp(a).

Landmark studies in coronary heart disease epidemiology. The Framingham Heart Study after 70 years and the Seven Countries Study after 60 years.

This year we celebrate anniversaries of two prospective studies that have contributed most to our understanding of the epi-demiology of coronary heart disease (CHD): the Framingham Heart Study (FHS) and the Seven Countries Study (SCS). The FHS was initiated 70 years ago and is continued in the subsequent generations using new research opportunities, including evaluation of the risk factors for chronic non-cardiovascular diseases. The SCS is now finished because the original study population are mostly deceased, and the study did not continue in the children and grandchildren of the participants. The FHS allowed identification of factors predisposing to CHD, which were referred to as "risk factors" for the first time. Based on the FHS findings, a multivariate model of the 10-year CHD risk was developed, known as the Framingham Heart Score. In addition, criteria of heart failure and risk factors for atrial fibrillation were defined. The SCS provided the first evidence for an association between nutrition and CHD and laid the foundations for recommending the Mediterranean diet for cardio-vascular disease prevention.

Clinical management of heterozygous familial hypercholesterolemia in a Polish outpatient metabolic clinic: a retrospective observational study.

INTRODUCTION: There are currently no reports available from a Polish clinical practice on heterozygous familial hypercholesterolemia (HeFH) management. The aim of this study was to test the efficacy of HeFH hypolipidemic treatment in a Polish outpatient metabolic clinic according to treatment targets outlined in the European Atherosclerosis Society (EAS) and European Society of Cardiology (ESC) guidelines. MATERIAL AND METHODS: This retrospective, observational study was performed on HeFH patients who attended their routine follow-up visits in the metabolic outpatient clinic in the period between April and September 2016. According to EAS/ESC guidelines, the goal and intensity of therapy were assigned individually for every patient based on cardiovascular (CV) risk (high or very high). The treatment target was achievement of low-density lipoprotein cholesterol (LDL-C) levels < 1.8 mmol/l for very high CV risk patients and < 2.6 mmol/l for high CV risk patients. A ≥ 50% decrease in LDL-C over the observation period was an additional outcome measure. RESULTS: In the overall group of 222 HeFH patients (mean age: 55.2 ±16.2 years, 72% women), LDL-C levels decreased on average by 52.6% (p < 0.001). More than half of the patients were treated with the maximum tolerated dose of statins. A total of 25.2% of patients attained target levels of LDL-C and 55.9% attained a ≥ 50% reduction in its concentration. Despite therapy, significantly elevated post-follow-up levels of LDL-C (> 4.1 mmol/l) remained in 14% of all patients. CONCLUSIONS: Hypolipidemic therapy according to EAS/ESC guidelines was suboptimal for a significant number of HeFH patients. Additional clinical management should be considered.

How do we know that statins are diabetogenic, and why? Is it an important issue in the clinical practice?

There is no doubt nowadays that statins exert a diabetogenic action. The evidence comes from observational studies, ran-domised trials, and meta-analyses. The relationship between statin use and new-onset type 2 diabetes is associated with statin potency and dose. It seems also to be stronger if the lowering effect is stronger and the low-density lipoprotein cholesterol level achieved is lower. The mechanisms underlying the development of diabetes in statin-treated patients are not completely understood. Generally, the increased insulin resistance and decreased insulin secretion are taken into account. However, it should be kept in mind that the cardiovascular risk reduction effect of statins outweighs the harm related to diabetes induc-tion. The patients at risk of diabetes development should be monitored with regard to the parameters of glucose metabolism. The introduction of preventive lifestyle modifications to prevent diabetes is recommended. New-onset diabetes should be managed according to the guidelines.

Nutrition and lifestyle in patients pharmacologically treated due to hypertension.

BACKGROUND: Proper nutrition and physical activity are together an important way of non-pharmacological treatment of arterial hypertension. The aim of the study was to answer the question whether patients with hypertension use non-pharmacological methods of hypertension treatment. METHODS: The study included a group of 280 patients aged 18-85, suffering from hypertension. In the study, 10 nutritional and non-nutritional factors affecting the treatment of hypertension were analyzed. Data regarding the diet were collected by a method of 24-h recall. Basic anthropometric measurements (body weight, body height, waist and hip circumference) were taken, as well as threefold measurement of blood pressure. The data were statistically analyzed. RESULTS: The average value of blood pressure was 131.2 ± 15.5/82.9 ± 10.5 mm Hg. Approximately 90% of the respondents had abnormal body weight, i.e. excessive weight or obesity. Abdominal obesity according to waist hip ratio assessment was diagnosed in 87% of women and 66% of men; according to the measurement of waist circumference, it was diagnosed in 140 (81%) women and 88 (81%) men. Among the ingredients with antihypertensive effect, the sodium intake was 4,417.8 ± 2,052.7 mg/d, which when converted to salt is on average 11 g/d, potassium: 3,808.5 ± 1,265.7 mg/d, calcium: 724.6 ± 413.7 mg/d, and magnesium: 383.9 ± 139.3 mg/d. One in 5 (18%) people declared smoking. Only 5% of subjects reported high level of physical activity. CONCLUSIONS: In persons with diagnosed hypertension, vast majority of patients did not implement non-pharmacological hypertension treatment.

[Severe hypercholesterolaemia--when to use the proprotein convertase subtilisin-kexin type 9 protease inhibitors (PCSK9 inhibitors)? Polish Society of Cardiology experts' group statement]. / Ciezka hipercholesterolemia - kiedy stosowac inhibitory proproteinowej konwertazy subtilizyny/kexiny 9 (inhibitory PCSK9)? Stanowisko grupy ekspertów Polskiego Towarzystwa Kardiologicznego.

The severe hypercholesterolaemia can be recognised when low density lipoprotein cholesterol (LDL-C) serum levels are equal to or above 5 mmol/L (≥ 190 mg/dL). The prevalence of LDL-C ≥ 5 mmol/L is 3.8% in Polish population aged 18-79 years. Among these adults there are patients with familial hypercholesterolaemia (FH). According to meta-analysis of 6 Polish population surveys prevalence of heterozygous FH (HeFH) diagnosed using Dutch Lipid Clinic criteria is 0.4% (95% Cl 0.28-0.53%) in men and women aged 20-74 years, i.e. one in every 250 people. As HeFH is a wellknown cause of premature coronary heart disease the rigorous treatment targets for LDL-C have been established in clinical guidelines. Their achievements, even with a high dose of high efficacy statin therapy is difficult or even impossible. New strong hypolipidaemic drugs i.e. PCSK9 inhibitors have been initiated against this chalange. Both drugs, evolocumab and alirocumab, have been extensively studied in numerous phase 2 and phase 3 trials. Fewer studies with bococizumab are available until now. The PCSK9 inhibitors, as monotherapy as well in combination with statins were associated with mean LDL-C reduction about 60%. It means that the majority of patients (70-90%) with severe hypercholesterolaemia (including HeFH), treated with statins, after addition of PCSK9 inhibitors were able to achieve an LDL-C < 2.5 mmol/L (< 100 mg/dL) or < 1.8 mmol/L (< 70 mg/dL) level. Another group of patients who may benefit from PCSK9 inhibitors include those who need lipid lowering therapy, but who are statin intolerant, especially because of statin-associated muscle symptoms (SAMS). In our statement we have accepted the diagnosis of SAMS proposed recently by European Atherosclerosis Society. Today the longest clinical trial with evolocumab (11 months) was the open OSLER study, and with alirocumab ODYSSEY LONG TERM (78 weeks). In the first one the reduction of cardiovascular events by 53% (95% Cl 22-72%) was observed, and in the second one by 48% (10-69%). Neurocognitive events were reported more frequently with both drugs than with placebo. This adverse effect will be the subject of observation in ongoing studies. We still await the results of 4 ongoing large placebo controlled phase 3 trials investigating whether PCSK9 inhibitors on background of statin therapy reduce cardiovascular events. Meanwhile evolocumab, as well as alirocumab have been accepted to use in clinical practice by European Medicine Agency. In this situation the experts of Polish Society of Cardiology have prepared the statement on the use PCSK9 inhibitors with indication in the first place for HeFH patients, statin intolerant and those at high risk who are not able to reach LDL-C target level with a high potent high dose statin.

The HDL paradox: what does it mean and how to manage low serum HDL cholesterol level?

The topic of this article is an important practical lipidologic issue, along with familial hypercholesterolaemia and severe hypertriglyceridaemia which have also been recently reviewed in the Polish literature. In this paper, we attempted to summarise current scientific evidence and views on the complex role of HDL in atherogenesis, as well as therapeutic recommendations in patients with low HDL-C level. In summary, it should be noted that the available evidence does not indicate that HDL are not antiatherogenic lipoproteins but rather directs our attention towards their functionality and dysfunctionality accompanying numerous pathologic conditions associated with inflammation. It may be hoped that effective methods to increase the number of functional HDL in the plasma will be developed in future studies, translating to a reduction in CV events and thus deserving a place in clinical practice guidelines.

Management of severe hypertriglyceridaemia.

Diagnostic approach to and management of SHTG are not always straightforward and specialist knowledge is required, particularly with the expected increase in the rates of SHTG associated with obesity and diabetes epidemics. We hope that this article will prove helpful for physicians caring for such patients. Their management may be guided by our recommendations that are shown in Table 2.

Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum.

Heterozygous familial hypercholesterolemia (HFH) affects on average 1 in 500 individuals in European countries, and it is estimated that HeFH in Poland may affect more than 80,000 people. Cardiovascular mortality in individuals with FH between 20 and 39 years of age is 100 times higher than in the general population. HFH is a relatively common lipid disorder, but usually still remaining undiagnosed and untreated. A very high risk of cardiovascular diseases and a shortened lifespan in patients with this condition require early diagnosis and intensive treatment. The aim of the position paper was to present the importance and scale of this problem in Poland, which has not been raised enough so far, as well as the recommendations of diagnosis, treatment and prevention methods.