Statin Intolerance in Clinical Practice.

PURPOSE OF REVIEW: In our pilot study, we aimed to determine how many patients with the statin intolerance history referred to the specialized center for the diagnostics and treatment of lipoprotein metabolism disorders really suffer from a complete statin intolerance. The purpose of the study was to prove that complete statin intolerance is overestimated and overdiagnosed, and with the detailed knowledge of the issue and patient approach, it is possible to find an appropriate statin treatment for the most of patients. RECENT FINDINGS: With the increasing number of statin users worldwide, the issue of statin intolerance has been a frequently discussed topic in recent years. There are many factors that play a role in the manifestation of statin intolerance (predisposing factors as age, sex, and some diseases), genetic factors leading to a different metabolism, drug-drug interactions, psychological reasons, and the negative influence of the mass media. However, it is estimated that true complete statin intolerance, defined by an intolerance of at least three statins at their usual lowest daily doses, occurs in approximately 3-6% of all statin users. In our pilot study, we conducted a retrospective analysis of 300 patients who were referred to the Center of Preventive Cardiology with a history of statin intolerance. During the follow-up treatment, 222 patients (74%) were able to use some statin (rosu-, atorva-, simva-, fluvastatin), and in 21% of the cases (63 patient), the target values according their CV risk level were even achieved. Only 78 patients (26%) were confirmed as being complete statin intolerant following a thorough therapeutic effort. The most tolerated statin was rosuvastatin.

Strong Association between APOA5 Gene Polymorphisms and Hypertriglyceridaemic Episodes.

Plasma triglyceride (TG) levels represent a significant risk factor of cardiovascular and total mortality. Concentrations of TG in the plasma depend, to a large extent, on the genetic background, and the apolipoprotein A5 (APOA5) gene seems to be one of the most powerful players in the plasma TG metabolism regulation. In total, we analysed three tagging APOA5 (rs964184 rs662799, rs3135506) SNPs in 209 patients with plasma TG levels over 10 mmol/l (HTG) on at least one occasion and in 379 treatment-naïve controls (NTG) with plasma TG values within the normal range. Minor alleles of all three analysed APOA5 polymorphisms significantly (all P < 0.0001) increased the risk of hypertriglyceridaemia. The most significant association (P < 0.0000001) was observed for the rs964184 polymorphism, where the minor GG homozygotes had the odds ratio (OR, 95% CI) for hypertriglyceridaemia development 21.30 (8.09-56.07, P < 0.000001) in comparison with the major CC allele homozygotes. Carriers of at least one minor allele at rs3135506 had OR (95% CI) 4.19 (2.75-6.40); (P < 0.000005) for HTG development and similarly, carriers of a minor allele at rs662799 had OR (95% CI) 3.07 (2.00-4.72) (P < 0.0001). The cumulative presence of risk alleles (unweighted gene score) significantly differed between patients with episodes of high TG and controls at P < 0.0000001. There were 73 % of subjects without any of the risk alleles among the controls and 46 % in the patients. In contrast, the controls just included 3 % of subjects with score 3 and more in comparison with 18 % in HTG patients. We conclude that common APOA5 variants are very important genetic determinants of episodic hypertriglyceridaemia in the Czech population with a high potential to be applied in personalized medicine.

Familial hypercholesterolemia in the Czech Republic: more than 17 years of systematic screening within the MedPed project.

Familial hypercholesterolemia (FH) is the most common autosomal dominant disorder. It is characterized by a decrease in LDL cholesterol catabolism and an early clinical manifestation of atherosclerotic vessel damage. The aim of the MedPed (Make early diagnosis to Prevent early deaths) project is an early diagnosis of FH patients in order to profit from early treatment and prevent cardiovascular events. Till November 30, 2016 The Czech National MedPed Database has registered 7,001 FH patients from 5,223 different families that is 17.4 % of expected patients in the Czech Republic considering 1:250 FH prevalence. The improvement in diagnostic accuracy, patient cooperation and above all familial cascade screening is enabled by FH mutation detection using the modern technology of next-generation sequencing. FH still remain undiagnosed even though the Czech Republic is one of the most successful countries with respect to FH detection. The opportunities of international collaboration and experience sharing within international programs (e.g. EAS FHSC, ScreenPro FH etc.) will improve the detection of FH patients in the future and enable even more accessible and accurate genetic diagnostics.

ScreenPro FH: from the Czech MedPed to international collaboration. ScreenPro FH is a participating project of the EAS-FHCS.

This article describes the evolution of our understanding of familial hypercholesterolemia (FH) in the Central, Eastern, and Southern Europe (CESE) region, and the dissemination of this understanding to other countries. Using the ScreenPro FH project as an example, we would like to illustrate the progression from national objectives, to regional networking and, finally, to international collaboration via the Familial Hypercholesterolemia Studies Collaboration (FHSC) project under the leadership of the European Atherosclerosis Society (EAS). It is essential to improve our ability to diagnose FH. In this regard, the EAS and its FHSC project must be commended for their educational and organizational activities which, above all, are dedicated to the creation of a global FH patient registry. In the CESE region, FH diagnostics and treatment situation are markedly different than in Western Europe or North America. Since the Czech MedPed project (Make Early Diagnoses to Prevent Early Deaths in Medical Pedigrees) has been so successful (with results not only comparable to, but, for some parameters, even surpassing the results of many Western countries) we decided to apply the Czech experience to the CESE region. Thus, the ScreenPro FH project was created. The aim of ScreenPro FH is to create a specialist network in the CESE region. The primary objective of the ScreenPro FH project was to dramatically reduce the number of premature deaths due to clinical complications of atherosclerosis in FH patients. At present, ScreenPro FH comprises 18 member countries with a total population of 500,000,000; which, in terms of the FH population, represents 1-2 million patients.

Gene variants at FTO, 9p21, and 2q36.3 are age-independently associated with myocardial infarction in Czech men.

AIM: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in developed countries. This study aimed to confirm the effect of common putative CVD-associated gene variants (FTO rs17817449, KIF6 rs20455, 9p21 rs10757274 and 2q36.3 rs2943634) on CVD manifestation, and determine whether this effect differs between younger (< 50 years) and older CVD patients. METHODS: 1191 controls and 1889 MI patients were analyzed. All participants were Caucasian Czech males aged <65 years (532 were <50 years) who were examined at cardiology clinics in Prague, Czech Republic. Variants of FTO, 9p21, 2q36.3, and KIF-6 were genotyped using PCR-RFLP or TaqMan assay. RESULTS: Variants of FTO (OR 1.48; 95% CI, 1.19-1.84 in a TT vs. GG comparison, p=0.0005); 9p21 (OR 1.74; 95% CI, 1.41-2.14 in an AA vs. GG comparison, p=0.0001); and 2q36.3 (OR 1.34; 95%CI, 1.09-1.65 in an AA vs. +C comparison, p=0.006) were significantly associated with MI in the male Czech population. In contrast, genotype frequencies of KIF-6 (rs20455) were the same in patients and controls (P=1.00). Nearly identical results were observed when a subset of young MI patients (N=532, aged <50 years) was analyzed. CONCLUSION: We confirmed the importance of determining FTO, 9p21, and 2q36.3 variants as part of the genetic determination of MI risk in the Czech male population.

Treatment of hypertriglyceridemia: a review of current options.

Hypertriglyceridemia is an important marker of increased levels of highly atherogenic remnant-like particles. The importance of lowering plasma levels of triglycerides (TG) has been called into question many times, but currently it is considered an integral part of residual cardiovascular risk reduction strategies. Lifestyle changes (improved diet and increased physical activity) are effective TG lowering measures. Pharmacological treatment usually starts with statins, although associated TG reductions are typically modest. Fibrates are currently the drugs of choice for hyperTG, frequently in combination with statins. Niacin and omega-3 fatty acids improve control of triglyceride levels when the above measures are inadequately effective. Some novel therapies including anti-sense oligonucleotides and inhibitors of microsomal triglyceride transfer protein have shown significant TG lowering efficacy. The current approach to the management of hypertriglyceridemia is based on lifestyle changes and, usually, drug combinations (statin and fibrate and/or omega-3 fatty acids or niacin).

Statin-associated myopathy: from genetic predisposition to clinical management.

Statin-associated myopathy (SAM) represents a broad spectrum of disorders from insignificant myalgia to fatal rhabdomyolysis. Its frequency ranges from 1-5 % in clinical trials to 15-20 % in everyday clinical practice. To a large extent, these variations can be explained by the definition used. Thus, we propose a scoring system to classify statin-induced myopathy according to clinical and biochemical criteria as 1) possible, 2) probable or 3) definite. The etiology of this disorder remains poorly understood. Most probably, an underlying genetic cause is necessary for overt SAM to develop. Variants in a few gene groups that encode proteins involved in: i) statin metabolism and distribution (e.g. membrane transporters and enzymes; OATP1B1, ABCA1, MRP, CYP3A4), ii) coenzyme Q10 production (e.g. COQ10A and B), iii) energy metabolism of muscle tissue (e.g. PYGM, GAA, CPT2) and several others have been proposed as candidates which can predispose to SAM. Pharmacological properties of individual statin molecules (e.g. lipophilicity, excretion pathways) and patients´ characteristics influence the likelihood of SAM development. This review summarizes current data as well as our own results.

Biomarkers of cardiometabolic risk in obese/overweight children: effect of lifestyle intervention.

Obesity is a strong cardiometabolic (CM) risk factor in children. We tested potential CM risk in obese/overweight children and the effect of an intensive lifestyle intervention using newer CM markers: atherogenic index of plasma AIP [Log(TG/HDL-C)], apoB/apoAI ratio and a marker of insulin resistance HOMA-IR. The participants (194 girls, 115 boys, average age 13) were enrolled in an intensive, one-month, inpatient weight reduction program. The program consisted of individualised dietary changes and the exercise program comprised aerobic and resistance training. Anthropometrical and biochemical parameters in plasma and CM risk biomarkers - (AIP, apoB/apoAI ratio and HOMA-IR) were examined before and after the intervention. AIP and HOMA-IR significantly correlated with BMI while apoB/apoAI ratio did not. Only AIP and HOMA-IR showed systematic increases according to the level of obesity by BMI quartiles. Lifestyle intervention significantly improved anthropometrical and biochemical values and the biomarkers too. The response of lipid parameters to the intervention was considerably higher in boys than in girls. The children were stratified into three risk categories according to AIP, where 13.8 % of boys and 5.3 % of girls fell into high risk category. The monitored biomarkers may complement each other in the prognosis of CM risk. AIP was strongly related to obesity and to lipid and glycid metabolism, while the relationship of the apoB/apoAI ratio to obesity and glycid metabolism was not significant. The obese children benefited from the intensive lifestyle intervention which improved the anthropometrical and biochemical parameters and CM risk biomarkers.

Rosiglitazone influences the expression of leukocyte adhesion molecules and CD14 receptor in type 2 diabetes mellitus patients.

Diabetes mellitus is associated with increased inflammatory response, which may contribute to atherosclerosis progression. Experimental results demonstrated anti-inflammatory activity of glitazones; their effect on leukocyte adhesion molecules has not been studied to date. We therefore studied the effect of rosiglitazone treatment on leukocyte surface expression of adhesion molecules in patients with type 2 diabetes mellitus and compared our results with findings in healthy subjects. 33 subjects with type 2 diabetes and 32 healthy controls were included; patients were examined at baseline and after 5 months of rosiglitazone treatment (4 mg/d). Leukocyte expression of adhesion molecules LFA-1, CD18 and ICAM-1 was quantified using flow cytometry; in addition, CD14 (lipopolysaccharide receptor) expression was analyzed as a marker of nonspecific immunity. The expression of examined molecules at baseline was higher in patients compared to controls. Despite only mild decrease in blood glucose, rosiglitazone treatment induced substantial decrease of CD18 and CD14 expression and borderline decrease of LFA-1 and ICAM-1 expression (on monocytes only). We thus observed improvement in the expression of leukocyte inflammatory markers after rosiglitazone treatment. This effect is supposed to be mediated by direct effect of rosiglitazone on PPAR-gamma receptors on leukocytes.

FTO and MC4R gene variants determine BMI changes in children after intensive lifestyle intervention.

OBJECTIVES: This study aimed to determine whether there is a relationship between common FTO (rs17817449) and MC4R (rs17782313) gene variants and body mass reduction or weight loss after a one-month lifestyle intervention in overweight/obese children. DESIGN AND METHODS: We genotyped 357 unrelated non-diabetic Czech children (age 13.7 ± 4.9 years, average BMI at baseline 30.8 ± 4.6 kg/m(2)). Biochemical and anthropometrical measurements were performed before and after 4 weeks of lifestyle interventions (comprising a reduction in energy intake to the age-matched optimum and a supervised exercise program consisting of 5 exercise units per day, 50 min each). RESULTS: The mean weight loss achieved was 6.2 ± 2.1 kg (P<0.001). Significant associations were found between a BMI decrease and the FTO and MC4R variants. Carriers of the FTO GG genotype and/or MC4R CC genotype lost significantly more body weight compared to noncarriers (P<0.0009 for BMI and P<0.002 for body weight). These differences remained significant following adjustment for sex, age and baseline values (P=0.004 for BMI and P=0.01 for body weight). CONCLUSIONS: FTO and MC4R gene variants modify the impact of an intensive lifestyle intervention on BMI decrease in overweight/obese children. Carriers of the FTO GG genotype and MC4R CC genotype benefit significantly more from the lifestyle intervention.

Impact of variants within seven candidate genes on statin treatment efficacy.

Statins are the most commonly used drugs in patients with dyslipidemia. Among the patients, a significant inter-individual variability with supposed strong genetic background in statin treatment efficacy has been observed. Genome wide screenings detected variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes that are among the candidates potentially modifying response to statins. Ten variants (SNPs) within these genes (rs599838, rs646776, rs16996148, rs693, rs515135, rs4420638, rs12654264, rs6511720, rs6235, rs11206510) were analyzed in 895 (46 % men, average age 60.3+/-13.1 years) patients with dyslipidemia treated with equipotent doses of statins (~90 % on simvastatin or atorvastatin, doses 10 or 20 mg) and selected 672 normolipidemic controls (40 % men, average age 46.5 years). Lipid parameters were available prior to the treatment and after 12 weeks of therapy. Statin treatment resulted in a significant decrease of both total cholesterol (7.00+/-1.53-->5.15+/-1.17 mmol/l, P<0.0001) and triglycerides (2.03+/-1.01-->1.65+/-1.23 mmol/l, P<0.0005). Rs599838 variant was not detected in first analyzed 284 patients. After adjustment for multiple testing, there was no significant association between individual SNPs and statin treatment efficacy. Only the rs4420638 (APOE/C1/C4 gene cluster) G allele carriers seem to show more profitable change of HDL cholesterol (P=0.007 without and P=0.06 after adjustment). Results demonstrated that, although associated with plasma TC and LDL cholesterol per se, variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes do not modify therapeutic response to statins.

[An anaesthesiologist's perspective on requirements for pre-surgery examinations]. / Pozadavky na predoperacní vysetrení z pohledu anesteziologa.

A preoperative check-up remains still an issue. The preoperative check-up should thoroughly evaluate an actual state of patients health, an anticipated perioperative course should be taken into account. An internist should closely collaborate not only with a surgeon, but with an anaesthesiologist as well. As guidelines cover this topic only sparsely, different approach might result either in excess or in insufficient examinations. Therefore an anaesthesia department should have its own guidelines available that would cover required preoperative check-ups considering expected operation. These guidelines should be then sent to the internist. Preoperative check-up should be done with an adequate margin before the operation, the internist should deliver a complete report including executed laboratory check-ups and consultations with specialists.

Therapeutic equivalence of the generic and the reference atorvastatin in patients with increased coronary risk.

AIM: Generic drugs are more and more frequently used instead of originators. However, uncertainty exists with respect to therapeutic equivalence of generic product with originator one. Therefore, in this study efficacy and safety of generic atorvastatin was compared to reference product. In patients with increased low density lipoprotein cholesterol (LDL-C) levels of cholesterol and changes of total coronary risk were followed. METHODS: A randomized, double-blind, multicenter parallel study was carried out in 22 centers. The study included 148 subjects with LDL-C higher than 3 mmol/L and increased coronary risk (>9.5% in 10 years calculated according to PROCAM algorithm). After a four-week placebo run-in period, patients were randomly assigned to receive the generic or the reference atorvastatin for 12 weeks. The initial dose of the drugs was 10 mg or 20 mg depending on the baseline LDL-C value. After six weeks the dose was increased to 20 mg or 40 mg in patients who had not reached the target LDL-C value of 2.99 mmol/L. RESULTS: Altogether 117 patients have been analysed in the per-protocol analysis. The GA was proven to be equally effective to the reference product as shown by the significantly equal reduction in LDL-C (GA: 37.8%, RA: 38.4%, P=NS) using the non-inferiority statistical analysis. Also other lipid parameters were significantly lowered by both drugs with the exception of HDL-C. Both drugs significantly reduced absolute coronary risk by 13% and 13.3% for the generic and the reference atorvastatin, respectively. Systolic blood pressure was also significantly reduced by approximately 10 mmHg in both study groups. Both products had similar adverse events profile. No cases of therapy withdrawal due to safety were recorded. CONCLUSION: Both the generic and the reference atorvastatin were equally effective in correcting the lipid profile and reducing calculated absolute coronary risk in patients with hyperlipidemia and increased coronary risk. Both treatments were equally well tolerated.

[Dyslipidemia and obesity 2011. Similarities and differences]. / Dyslipidemie a obezita 2011. Jak spolu souvisejí a v cem se lisí.

We shall open our overview of issues related to obesity and hyperlipoproteinemia (HLP) or dyslipidemia with a notoriously known truth (that some are still reluctant to accept): HLP/DLP is not obesity. It is certainly not possible to put an equal sign between subcutaneous fat and the level of plasma lipids and lipoproteins. On the other hand, it is obvious that there is a number of connecting links between HLP/DLP and obesity. These associations on one side and differences on the other are the focus of this review paper. (1) HLP/DLP as well as obesity represent a group of high incidence metabolic diseases (gradually evolving from epidemic to pandemic) that affect several tens of percent of inhabitants. (2) Both HLP/DLP and obesity often occur concurrently, often as a result of unhealthy lifestyle. However, genetic factors are also been studies and it is possible that mutual predispositions for the development of both diseases will be identified. At present, it is only possible to conclude that obesity worsens lipid metabolism in genetically-determined HLP. (3) Both these metabolic diseases represent a risk factor for other pathologies, cardiovascular diseases are the most important common complication of both conditions (central type of obesity only). Concurrent presence of HDL/DLP and obesity is often linked to other diagnoses, such as type 2 diabetes mellitus (DM2T), hypertension, pro-coagulation or pro-inflammatory states; all as part of so called metabolic syndrome. (4) Patients with metabolic syndrome and, mainly, central obesity usually have typical dyslipidemia with reduced HDL-cholesterol (HDL-C) and sometimes hypertriglyceridaemia. Current treatment of HDL/DLP aims to first impact on the primary aim, i.e. LDL-cholesterol (LDL-C), and than influence HDL-C. (5) It seems that the therapeutic efforts in HLP/DLP and obesity will go in the same direction. I will skip the trivial (and difficult to accept by patients) dietary changes. Pharmacotherapy, however, (very scarce with respect to obesity) may bring positive effects on lipids and BMI. Metformin used to be considered as a drug that could improve lipid profile and lead to body weight reduction. Even though larger studies did not provide an unambiguous evidence for this, metformin keeps its position as a first line oral antidiabetic (not only) in patients with T2DM, HLP and obesity. Positive effect on lipids, mainly HDL-C is reported with pioglitazone. This drug, unlike other glitazones, does not bring body weight reduction but at least does not have a negative effect. Other antidiabetics with a positive effect on lipids and body weight include incretins, liraglutid in particular. Liraglutid importantly decreases triglyceride levels and has anorectic effect. Furthermore, metabolic effects of bariatric surgery should not be overlooked. Bariatric surgery brings weight reduction as well as it improves lipid profile and compensation of diabetes mellitus (DM). It should be mentioned here that bariatric surgery has been used for the treatment of HLP as early as 1980s. The results of the 25-year follow up within the POSCH study (ideal bypass indicated for HLP), presented in 2010, confirm a decrease in overall as well as cardiovascular mortality in an operated group, even though patients who did not undergo surgery were significantly more frequently treated with statins.

[Comprehensive management of cardiovascular risk. Focusing on telmisartan]. / Komplexní lécba kardiovaskulárního rizika. Zamereno na telmisartan.

Cardiovascular diseases (CVD) represent a significant health problem in all countries world-wide and in the developed world, including the Czech Republic, in particular. The underlying cause in the majority of CVD patients is atherosclerosis and its complications, respectively. The present paper focuses on prevention and timely treatment of atherosclerosis. Management should be comprehensive and should target the risk factors (RF). Hypertension, hyperlipoproteinaemia and dyslipidemia (HLP and DLP), type 2 diabetes mellitus (T2DM), visceral fat obesity and cigarette smoking are the dominating RFs. Even though all RFs have to be managed simultaneously and it is not possible to focus on just one of them, for the sake of clarity, this paper discusses hypertension and the use of telmisartan, a representative of one the most up-to-date group of antihypertensives. There is a growing evidence that it is not always just a reduction of a specific risk that is important but also the mode of treatment. For example, to reduce a CV risk in a patient with hypertension but also, for example, with metabolic syndrome, it is more beneficial to treat the patient with rennin-angiotensin system (RAS) blocking agents, possibly in a combination with calcium channels antagonists, than to use "traditional" (older) treatment approach with a combination of a beta/blocker and diuretic. Among the RAS-modifying agents, ACE inhibitors and sartans are the most widely used. Among sartans, telmisartan is very well-tolerated and has evidence from a large interventional study for its effect on reducing the CV risk.

[Hyperlipoproteinaemia and dyslipoproteinaemia II. Therapy: non-pharmacological and pharmacological approaches]. / Hyperlipoproteinemie a dyslipoproteinemie II. Terapie: Nefarmakologická a farmakologická lécba.

At present, literally no one disputes hyperlipoproteinaemia and dyslipidemia (HLP and DLP) treatment as a rational therapeutic approach in the prevention of cardiovascular diseases (CVD). This approach is in line with the current principles of evidence-based medicine (EBM) and is sufficiently evidenced particularly by the results of large intervention studies. Nevertheless! When the results of the recent studies are critically appraised, these by no means are (mostly, there, obviously, are exceptions) as conclusive as the studies conducted in 1980s and 1990s. Consequently, positive results are being sought in subanalyses, subgroup evaluations and multiple-study metaanalyses. This paper is not intended as a critique of new drugs. These certainly are developed to be safe, effective and well-tolerated. However, the newer studies suffer from a range of issues: the populations studied are already very well managed, it is not possible to compare against placebo and sometimes, let us be honest, the trial design itself is problematic (often it is an uncritical effort to treat as wide as possible range of patients as well as new groups of patients who might not be suitable for the given treatment). Certainly, we should not start disputing the well-evidenced hypotheses and seek alternatives to the long-established arguments and approaches as a consequence to some less convincing studies. We must not overlook the most robust results of statin studies as well as 'positive' studies with other hypolipidemics. There is no doubt that the effect ofstatins on LDL-cholesterol represents a significant move towards cardiovascular disease prevention. Despite this, we currently recognise with increased intensity that this very effective and well-evidenced treatment has its limits and that a high proportion of patients dies or are faced with cardiovascular diseases even though they are treated with a correct dose ofa statin and a target LDL-C level is achieved. This remaining risk (represents more than 50% ofevents) has been termed 'RESIDUAL RISK'. The issue of residual risk is crucial in patients with type 2 diabetes mellitus (DM2T) or in all patients with HDL-C-low DLP. As was repeatedly emphasised, a statin will be a cornerstone of pharmacological treatment of a DLP. However, a question arises what to combine it with. The most convincing data exist for niacin (combination of niacin with laropiprant minimising the incidence of unwanted flushes). We surely should not marginalize other hypolipidemics used mainly in combinations: resin and ezetimibe to treat LDL-C, niacin, fibrates and possibly omega-3-fatty acids to manage the residual risk (HDL and TG). Last but not least we should not forget non-pharmacological treatment as the pivotal treatment approach in all patients.

[Hyperlipoproteinaemia and dyslipoproteinaemia I. Classification, diagnostics, cardiovascular, cardiometabolic and residual risk]. / Hyperlipoproteinemie a dyslipoproteinemie I. Klasifikace, diagnostika, kardiovaskulární, kardiometabolické a reziduální riziko.

Cardiovascular diseases remain the most important cause of death worldwide. The situation in the Czech Republic is one of the best when compared to the other countries of the former socialist block; on the other hand, we significantly lack behind when the comparison is made to south and southwest European countries. The concept of risk factors (RF) and multifactorial character of atherosclerosis as the main cause of cardiovascular diseases (CVD) is fully accepted at present. Hyperlipoproteinaemia (HLP) and dyslipidemia (DLP) are a group of high incidence metabolic diseases characterised by increased levels of lipids and lipoproteins in plasma or, in case of DLP, by unsuitable, atherogenic composition of lipids and lipoproteins in plasma. HLP and DLP are among the most important RF for the development of CVD. Mainly LDL-cholesterol (LDL-C) is perceived as a very important risk factor; successful reduction of LDL-C is linked to a reduction in cardiovascular risk. Even when LDL-C is decreased and the so-called "target values" achieved, patients are still at risk ofa CV event. This remnant risk is the so called "residual risk". The most important "rival" to LDL-cholesterol among the risk factors is the metabolic syndrome, or rather the DLP associated with the metabolic syndrome, characterised from the perspective of DLP by low levels of HDL-cholesterol and increased triglycerides with concurrent occurrence of "small dense LDL". The issue of heterogeneity and atherogenicity oflipoprotein particles in general then becomes topical. Lipoprotein (a)--Lp(a) is another important lipid risk factor that is getting a significant attention.

Efficacy and safety of extended-release niacin/laropiprant plus statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia.

BACKGROUND: Co-administration of niacin with statin offers the potential for additional lipid management and cardiovascular risk reduction. However, niacin is underutilised because of the side effects of flushing, mediated primarily by prostaglandin D(2) (PGD(2)). A combination tablet containing extended-release niacin and laropiprant (ERN/LRPT), a PGD(2) receptor (DP1) antagonist, offers improved tolerability. This study assessed the efficacy and safety of ERN/LRPT added to statin vs. doubling the dose of statin in patients with primary hypercholesterolaemia or mixed dyslipidaemia who were not at their National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol (LDL-C) goal based on their coronary heart disease risk category (high, moderate or low). METHODS: After a 2- to 6-week run-in statin (simvastatin 10 or 20 mg or atorvastatin 10 mg) period, 1216 patients were randomised equally to one of two treatment groups in a double-blind fashion: group 1 received ERN/LRPT (1 g) plus the run-in statin dose and advanced to ERN/LRPT (2 g) after 4 weeks for an additional 8 weeks, with no adjustments to the run-in statin dose; group 2 received simvastatin or atorvastatin at twice their run-in statin dose and remained on this stable dose for 12 weeks. RESULTS: ERN/LRPT added to statin (pooled across statin and statin dose) significantly improved key lipid parameters vs. the doubled statin dose (pooled): the between-treatment group difference in least squares mean per cent change [95% confidence interval (CI)] from baseline to week 12 in LDL-C (primary end-point) was -4.5% (-7.7, -1.3) and in high-density lipoprotein cholesterol (HDL-C) was 15.6% (13.4, 17.9) and in median per cent change for triglyceride (TG) was -15.4% (-19.2, -11.7). Treatment-related adverse experiences (AEs) related to flushing, pruritis, rash, gastrointestinal upset and elevations in liver transaminases and fasting serum glucose occurred more frequently with ERN/LRPT added to statin vs. statin dose doubled. CONCLUSIONS: The addition of ERN/LRPT to ongoing statin treatment produced significantly improved lipid-modifying benefits on LDL-C, HDL-C and TG and all other lipid parameters compared with doubling the statin dose in patients with primary hypercholesterolaemia or mixed dyslipidaemia. The types of AEs that occurred at a greater frequency in the ERN/LRPT group were those typically associated with niacin.