Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy.

OBJECTIVE: High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator-activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS: A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non-HDL-C level lowering at week 12. RESULTS: Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non-HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations. CONCLUSIONS: Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.

Frequencies of four ATP-binding cassette transporter G8 polymorphisms in patients with ischemic vascular diseases.

ATP-binding cassette transporter G8 (ABCG8) was found to participate in plant sterol and cholesterol (CHOL) transport; however, the potential associations of ABCG8 genetic variants and ischemic vascular diseases are largely unknown. Determinations of allele frequencies of four common ABCG8 polymorphisms (D19H, Y54C, T400K, and A632V) were carried out in 241 unrelated patients with ischemic stroke, 148 patients with coronary heart disease, and 191 blood donors (controls). Allele frequencies of the investigated polymorphisms in patient groups showed no significant differences compared with controls. There was a tendency toward reduced 54YY-genotype frequency among male patients with stroke. On stratification by age at disease onset, male patients with stroke under the age of 50 (n = 62) showed significantly reduced 54YY-frequency compared with male controls (n = 92; 24.2% vs. 41.3%; odds ratio: 0.45 [95% confidence intervals: 0.22-0.93]; p = 0.038). No such associations were found among women. In healthy controls, CHOL levels of individuals with the 54YY genotype (n = 71; median: 4.51 mM, 25th-75th percentiles: 4.19-5.43) were significantly reduced compared with 54YC and 54CC individuals combined (n = 120; median: 4.95 mM, 25th-75th percentiles: 4.42-5.88, p = 0.009). Further, we identified a new ABCG8-variant, T401S, in a control subject. In conclusion, ABCG8 54YY-genotype may be a potential protecting factor against ischemic stroke in young men and may influence plasma CHOL levels.

[Thoughts about the results of the "IDEAL" study]. / Gondolatok az IDEAL vizsgálat eredményei kapcsán.

INTRODUCTION: Evidences and guidelines suggest that more intensive lowering of LDL-cholesterol will provide further benefit in coronary artery disease. AIM AND METHOD: In the IDEAL study patients with previous myocardial infarction were randomly assigned to receive 80 mg of atorvastatin (n = 4439) or 20-40 mg simvastatin (n = 4449). The median follow-up was 4.8 years. The objective was to compare the effects of two strategies of lipid lowering therapy. RESULTS: During treatment mean LDL-cholesterol levels were 2.7 mmol/l in the simvastatin group and 2.1 mmol/l in the atorvastatin group. A major coronary event occurred in 463 (10.4%) simvastatin patients and in 411 (9.3%) atorvastatin patients (p = 0.07). Death from any cause occurred 374 (8.4%) in the simvastatin group and 366 (8.2%) in the atorvastatin group (p = 0.81). Nonfatal acute myocardial infarction occurred 321 (7.2%) and 267 (6.0%) in the two groups (p = 0.02). Patients in the atorvastatin group had higher rates of drug discontinuation due to non-serious adverse events; transaminase elevation resulted in 43 (1.0%) versus 5 (0.1%) withdrawals (p <0.001). CONCLUSION: Patients with high risk or very high risk may benefit from intensive lowering of LDL-cholesterol without an increase of adverse reaction but try to find the ideal statin and dose of statin.

[New strategy in the treatment of hypertension: inhibition of renin-angiotensin-aldosterone system with renin inhibitor]. / A hypertonia kezelésének új megközelítése: a renin-angiotenzin-aldoszteron rendszer gátlás renininhibitorral.

In the Hungarian population, there is also a growing number of patients with hypertension. In order to prevent the target organ's damage or in order to slow down the process, it is indispensable to reach the therapeutic target blood pressure. An opportunity for reducing the cardiovascular morbidity and mortality is the inhibition of the renin-angiotensin-aldosterone system. So far, we have had three large families, the angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone antagonists, to our disposal. The above are the key molecules for the hypertension treatment, but their application is accompanied by plasma renin level elevations, and thus, increase of plasma renin activation. The protection against increased plasma renin activation is helped by the renin inhibitors. Several decades were needed for their clinical introduction, till a non-peptide, safety medicament was successfully produced, which can be administered orally in small once-per-day doses. Their most promising representative is aliskiren. Still an open question is the mapping of the advantage of the angiotensin-converting enzyme inhibitor and angiotensin receptor blockers combination with aliskiren. The morbidity and mortality investigations are still missing and we curiously await them.

[Selection of statin considering the HDL cholesterol level]. / Statinválasztás a HDL-koleszterinszint tükrében.

Low HDL cholesterol level is an independent risk factor in the cardivascular diseases and the therapeutic aim is to increase this. In high risk patients (cardiovascular disease-, diabetic- or metabolic syndrome patients), the target value of HDL cholesterol is more than 1,0 mmol/l in males and 1,3 mmol/l in females. The PPARalpha receptor activity has an expressed impact on the HDL cholesterol metabolism. It has been proved that in addition to fibrates, statins also influence its functioning. Simvastatin, as compared to atorvastatin, increases the HDL cholesterol level in a better way which positive effect has also been proved by the clinical trials. On choosing a therapy the optimisation of the HDL cholesterol level is also important in addition to achieving an LDL cholesterol target value.

The methylenetetrahydrofolate reductase gene polymorphism (C677T) is associated with increased cardiovascular mortality in Hungary.

The gene for methylenetetrahydrofolate reductase (MTHFR) has two different alleles (C and T), where the T is associated with decreased enzyme activity, hyperhomocysteinaemia, and increased risk for thromboembolism in coronary heart disease (CHD). The study was conducted using a sample of 378 Hungarian newborn infants: 96 control subjects (age: 59.9+/-8.6 years) with chest pain and 315 CHD patients (61.4+/-7.5 years). All adult subjects had undergone coronary angiography. It can be concluded that the carriers of T allele with CHD died earlier due to myocardial infarction and the C allele with lower homocysteine level may provide protection against fatal coronary artery occlusion.

[Public health control of hyperhomocysteinemia and its consequences]. / A hyperhomocysteinaemia és következményeinek népegészségügyi szintú korlátozása.

The etiological role of hyperhomocysteinemia in the origin of neural-tube defects was proved, therefore a mandatory flour folic acid fortification program was introduced in the USA since January 1, 1998. In Hungary one kind of breads was fortified with folic acid, vitamin B12 and vitamin B6. The Hungarian randomised controlled trials of periconceptional folic acid containing micronutrient-combination supplementation also indicated a reduction in the occurrence of congenital cardiovascular malformations, urinary tract's defects and congenital limb deficiencies and these findings were confirmed by US teams. Recent studies showed a positive association between cardiovascular diseases and hyperhomocysteinemia as well, thus it is considered as an independent etiological factor in the pathogenesis of ischemic heart diseases, stroke, deep vein thrombosis, in addition of vascular diseases in the placenta during pregnancy. Other studies showed that hyperhomocysteinemia is more prevalent in demented patients and in persons with impaired cognitive performance. Some association was also found between hyperhomocysteinemia and cancers (e.g. colon). There is strong evidence that four vitamins B, such as vitamin B11 (folate-folic acid), vitamin B12, B2 and B6 can reduce the level of serum homocysteine and subsequently neural-tube defects. In addition the results of intervention studies indicated a protective effect of folic acid and other vitamins B for some other congenital abnormalities, cardiovascular diseases, senile dementia and cancers. The flour fortification with these water-soluble vitamins B is appropriate for an effective public health program for the primary prevention of these hyperhomocysteinemia-related disorders. There is no real risk for side effects on the basis of available US, Canadian and Hungarian experiences. In conclusion an urgent task is to introduce a mandatory flour fortification program in Hungary.

Postprandial triglyceride levels in familial combined hyperlipidemia. The role of apolipoprotein E and lipoprotein lipase polymorphisms.

The effect of apolipoprotein E genotype and polymorphisms of lipoprotein lipase gene on plasma postprandial triglyceride levels in familial combined hyperlipidemic subjects and their relatives have not been sufficiently studied. This study included sixteen familial combined hyperlipidemic parents (G1): age: 52 +/- 9 years with total-cholesterol: 7.2 +/- 1.7 mmol/L, fasting triglycerides: 2.8 +/- 1.4 mmol/L and sixteen children (G2) (twelve were normolipidemic): of age: 22 +/- 5 years with total-cholesterol: 5.2 +/- 1.1 mmol/L, fasting triglycerides: 2.06 +/- 1.8 mmol/L and twelve normolipidemic, healthy controls. Blood samples were taken fasting and 2, 4, 6, 8, 10 hr postprandially after the standard fat rich test meal. We determined lipid parameters, apolipoprotein E and lipoprotein lipase HindIII and PvuII polymorphisms as well. The 6-hr critical postprandial triglyceride values were abnormal in both G1: 5.88 +/- 2.7 mmol/L and G2: 3.53 +/- 2.7 mmol/L (p <0.001), respectively, and differed significantly (p <0.001) from each other. The subjects of familial combined hyperlipidemic families with E4 allele in both generations exhibited significantly (p <0.001) higher and extended postprandial lipemia. We did not find significant effects of lipoprotein lipase HindIII or PvuII polymorphisms on the fasting lipid values alone, however in normolipidemic subjects from the same families the homozygosity of HindIII variation was associated with higher triglyceride postprandial peak (p <0.01). The main findings of our study are that i.) normolipidemic G2 subjects in familial combined hyperlipidemic families have already abnormal postprandial status, and ii.) the 6 h postprandial triglyceride values were correlated with fasting triglyceride levels, which showed association with the apolipoprotein E4 allele.

Association of plasma lipid levels with apolipoprotein E polymorphism in Type 2 diabetes.

OBJECTIVE: To evaluate the distribution of apolipoprotein E polymorphism in patients with Type 2 diabetes and their impact on plasma lipid levels. SUBJECTS: Unrelated Type 2 diabetic patients (n = 298) treated by diet and sulfonylurea and not receiving lipid-lowering regimens, elderly (n = 98) and young (n = 101)unrelated healthy control subjects in Hungary. METHODS: Apolipoprotein E genotypes were identified by PCR amplification and subsequent restriction endonuclease digestion. RESULTS: The distribution of the most frequent genotypes in the diabetes group was E2/3 8.7%, E3/3 78.2%, E3/4 12.8%, in the elderly group E2/3 9.2%, E3/3 78.6%, E3/4 12.2% and in the young group E2/3 11.9%, E3/3 62.4%, E3/4 24.8%. The frequencies of allele e4 in the diabetes and in the elderly control group were significantly lower than in the young control group (both P < 0.05). Associations were found between the e4 allele and increased triglyceride level in the diabetes group, the e2 allele and decreased total cholesterol and LDL-cholesterol levels both in the elderly and young control groups (both P < 0.01). CONCLUSION: The lower frequency of allele e4 in both the elderly and diabetes groups, may be explained by an increased morbidity and mortality in middle-aged carriers of apo e4 allele. The increased risk of e4 carriers in Type 2 diabetes may be partly mediated by a higher triglyceride level.

[Correlation of lipoprotein(a) and ischemic heart disease]. / A lipoprotein(a) és az ischaemiás szívbetegség kapcsolata.

Increased plasma levels of lipoprotein(a) [Lp(a)] have been considered an independent risk factor for coronary heart disease (CHD). A high concentration of Lp(a) contributes to atherothrombotic risk by multiple mechanisms that include impaired fibrinolysis and increased cholesterol deposition in the arterial wall. Its atherogenicity seems to be related to the similarity in structure with thrombohemostatic factors. The level of Lp(a) in plasma is genetically determined and appears to be unaffected by usual risk factors. There are few medications which have been shown to lower the plasma concentration of Lp(a), however, since these drugs all have multiple other effects their, use is not the choice of the therapy. According to the results of examinations, the best therapeutic option for increased plasma Lp(a) concentration is to lower the plasma level of LDL.