Effectiveness and safety of PCSK9 inhibitor therapy in patients with familial hypercholesterolemia within a therapeutic program in Poland: Preliminary multicenter data.

BACKGROUND: In Poland, treatment with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has become available free of charge in a therapeutic program. Assessed herein, is the efficacy and safety of alirocumab and evolocumab in patients with heterozygous familial hypercholesterolemia (FH). METHODS: Data of 55 adult FH patients who participated in the program were analyzed upon meeting the criteria established by the Ministry of Health (low density lipoprotein cholesterol [LDL-C] above 160 mg/dL on max. tolerated statin dose and ezetimib). The efficacy of PCSK9 inhibitors in reducing LDL-C with drug administration every 2 weeks was assessed after 3 months and 1 year of therapy. A safety profile evaluation was performed at each visit. 48 patients completed the 3-month and 21 for the 1-year observation periods (34 patients treated with alirokumab and 14 with evolocumab). RESULTS: The mean concentration of direct-measured LDL-C decreased from the initial level of 215.1 ± 74.5 mg/dL to 75.3 ± 64.1 mg/dL, i.e., by 65 ± 14% following 3 months of treatment. This effect was stable in 1-year observation (77.7 ± 72.8 mg/dL). Adverse effects were flu-like symptoms (13.0%), injection site reactions (11.1%), fatigue (5.6%) and musculoskeletal symptoms (5.6%). Seven patients failed to complete the 3-month treatment period due to side effects or non-compliance, and 1 patient failed to complete the 1-year treatment due to myalgia. CONCLUSIONS: This study confirmed high effectiveness of PCSK9 inhibitors in reducing LDL-C levels in patients with FH. Due to restrictive inclusion criteria with LDL-C threshold level > 160 mg/dL (> 4.1 mmol/L) required for participation in the therapeutic program, a relatively small number of FH patients were eligible for treatment.

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.

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.

Prevalence, diagnosis, and treatment of familial hypercholesterolaemia in outpatient practices in Poland.

BACKGROUND: Familial hypercholesterolaemia (FH) is the most common genetic disease leading to premature atherosclerosis. AIM: The aim of the study was to evaluate the prevalence, diagnosis, and treatment of FH in outpatient practices in Poland. METHODS: The study included a representative sample of 147 primary care physicians, cardiologists, and diabetologists caring for 2812 adult patients with hypercholesterolaemia and low-density lipoprotein cholesterol (LDL-C) level > 1.8 mmol/L, who were treated with statins or did not receive statins due to intolerance or contraindications. The physicians declared whether they diagnosed FH in the study group. In addition, we evaluated the Dutch Lipid Clinic Network (DLCN) diagnostic criteria for FH in all patients. The results were weighted and extrapolated to the general outpatient population in Poland. Treatment and its effectiveness were also evaluated. RESULTS: FH6+ score by the DLCN criteria was found in 3.6% of the study group, which translates by extrapolation to 136,300 adult patients with FH in Poland. Among patients with FH6+, this diagnosis was correctly made by physicians in 25% of cases and was not established in 75% of cases. Only 32.8% of patients received high statin doses. High LDL-C levels were found in a large proportion of patients, including levels ≥ 5.0 mmol/L in 42.7% of patients and ≥ 4.1 mmol/L in 59.7% of patients. CONCLUSIONS: Familial hypercholesterolaemia is inadequately diagnosed and treated in Poland, which calls for a radical im-provement of pre- and postgraduate education in this regard.

[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.

Prevalence of lipid abnormalities in Poland. The NATPOL 2011 survey.

BACKGROUND: Poland represents a country of high cardiovascular (CV) risk. The association between lipid abnormalities and increased CV risk is well established. Therefore, it is important to monitor the prevalence and control of dyslipidaemia. AIM: To evaluate serum lipids concentrations as well as the prevalence, awareness, and control of lipid abnormalities in a representative sample of adults in Poland. METHODS: In 2011, in a national cross-sectional survey blood samples were collected from 1168 males and 1245 females, aged 18-79 years, for measurement of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG) in blood serum. Low density lipoprotein cholesterol (LDL-C) was calculated using Friedewald's formula. RESULTS: Mean serum TC concentration was 197.1 mg/dL (95% CI 193.8-200.4) in males (M) and 198.6 mg/dL (95% CI 195.7-201.5) in females (F). Levels of LDL-C were 123.6 mg/dL (120.9-126.2) and 123.7 mg/dL (121.4-126.1), HDL-C - 45.8 mg/dL (44.7-47.0) and 54.1 mg/dL (53.1-55.1), TG - 140.9 mg/dL (133.0-148.8) and 104.0 mg/dL (99.8-108.2) for males and females, respectively. TC ≥ 190 mg/dL was found in 54.3% subjects (M 54.3%; F 54.4%). After adding patients on lipid-lowering treatment, hypercholesterolaemia was present in 61.1% of adults (M 60.8%; F 61.3%). LDL-C ≥ 115 mg/dL was detected in 57.8% of all subjects (M 58.3%; F 57.3%), while HDL-C < 40 mg/dL in 35.2% of males and < 45 mg/dL in 22% of females TG ≥ 150 mg/dL was found in 21.1% of subjects (M 28.4%; F 14.0%). The highest prevalence of elevated TC and LDL-C levels was present in the age group of 40-59-year-olds. Of those with hypercholesterolaemia 58.7% (M 61.5%, F 56.0%) were not aware of the condition; 22.0% (M 21.0%, F 24.5%) were aware but were not being treated; 8.1% (M 7.7%, F 8.5%) were treated but with TC ≥ 190 mg/dL; and only 10.9% (M 10.7%, F 11.0%) were being treated with TC < 190 mg/dL. CONCLUSIONS: The prevalence of dyslipidaemia in Poland continues to be high--over 60% of adults have hypercholesterolaemia, and control remains poor. The results of the NATPOL 2011 survey call for urgent preventive measures.

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.