Microsomal triglyceride transfer protein inhibitor (lomitapide) efficacy in the treatment of patients with homozygous familial hypercholesterolaemia.

AIMS: The aim of this study was to evaluate the effect of microsomal triglyceride transfer protein inhibitor (lomitapide) in patients with homozygous familial hypercholesterolaemia. METHODS AND RESULTS: In 12 homozygous familial hypercholesterolaemia patients treated with lipid-lowering drugs ± biweekly lipoprotein apheresis sessions (nine patients), daily lomitapide was added. The lipid profile (total cholesterol, low-density lipoprotein cholesterol, triglycerides, high-density lipoprotein cholesterol) before and after lomitapide treatment was evaluated. The follow-up period with lomitapide treatment was 3-24 months (13.8 ± 7.9). The median baseline low-density lipoprotein cholesterol level was 900 mg/dl (348-1070), after lipid-lowering drugs therapy was 383.5 mg/dl (214-866) and after lipid-lowering drugs + time-averaged level was 288 mg/dl (183.7-716.6). The addition of lomitapide lowered low-density lipoprotein cholesterol levels further by 56.8% compared to lipid-lowering drugs alone (mean reduction 262, 95% confidence interval (105.5-418.7), p = 0.005) and by 54% (mean reduction 182.9, 95% confidence interval (-342 - -23), p = 0.031) comparing to lipid-lowering drugs + lipoprotein apheresis (time-averaged level). The time-averaged level of low-density lipoprotein cholesterol in lipid-lowering drugs + lipoprotein apheresis patients compared with lipid-lowering drugs + lomitapide was 54% in favour of lomitapide (p = 0.031). CONCLUSIONS: Treatment with lomitapide in homozygous familial hypercholesterolaemia patients has a beneficial effect with a constant decrease of low-density lipoprotein cholesterol by 57% compared with classical lipid-lowering therapy and by 54% compared with classical lipid-lowering therapy and time-averaged level of low-density lipoprotein cholesterol.

Microsomal transfer protein inhibitors, new approach for treatment of familial hypercholesterolemia, review of the literature, original findings, and clinical significance.

The genetic causes of cholesterol metabolism disorders usually lead to premature atherosclerosis. The most well recognized genetically caused hypercholesterolemia is familial hypercholesterolemia. Although the disease is well known, as the discovery of low-density lipoprotein receptor, the classical treatment with lipid-lowering drugs (statins, fibrates, ezetimibe, colesevelam) is still not adequate and new options are seeking. This review is an attempt to analyze the microsomal transfer protein (MTP) inhibitors as a new approach for treatment of familial hypercholesterolemia, to reviews the literature according to MTP inhibitors and finally to provide original findings.

Severe/Extreme Hypertriglyceridemia and LDL Apheretic Treatment: Review of the Literature, Original Findings.

Hypertriglyceridemia (HTG) is a feature of numerous metabolic disorders including dyslipidemias, metabolic syndrome, and diabetes mellitus type 2 and can increase the risk of premature coronary artery disease. HTG may also be due to genetic factors (called primary HTG) and particularly the severe/extreme HTG (SEHTG), which is a usually rare genetic disorder. Even rarer are secondary cases of SEHTG caused by autoimmune disease. This review considers the causes of SEHTG, and their management including treatment with low density lipoprotein apheresis and analyzes the original findings.

Changes in Lipids and Lipoproteins after Selective LDL Apheresis (7-Year Experience).

Background. The aim of the study was to investigate the changes in plasma lipids and lipoproteins and the cardiovascular events after selective LDL apheresis. Methods and Results. Two pediatric patients with familial hypercholesterolemia aged 11 and 13 years and 19 dyslipidemic adults aged 41 ± 14 years underwent direct adsorption of lipoproteins (DALI) sessions. The mean follow-up period was 47 ± 23 months. The total cholesterol (TC) values before and after treatment were 8.2 ± 2.2 and 3.1 ± 1.6 mmol/l (318 ± 86 and 122 ± 62 mg/dL), respectively. The interval mean of TC was 6.9 ± 1.9 mmol/l (268 ± 75 mg/dL). The LDL cholesterol concentrations before and after treatment were 6.6 ± 2.1 and 1.7 ± 1.1 mmol/l, (256 ± 82 mg/dL and 65 ± 41 mg/dL), respectively. The percentage of acute LDL cholesterol reduction was 75 ± 11%. Cardiovascular events were observed in seven patients. The average annual event rate was 5.51%. Conclusion. LDL apheresis is a very important therapeutic tool in managing patients at high risk for premature CAD or with aggressive CAD, despite adequate medical treatment.

Sex-associated effect of CETP and LPL polymorphisms on postprandial lipids in familial hypercholesterolaemia.

BACKGROUND: This study assessed the gender-specific influence of the cholesteryl ester transfer protein (TaqIB, I405V) and lipoprotein lipase (S447X) polymorphisms on the response to an oral fat tolerance test in heterozygotes for familial hypercholesterolaemia. METHODS: We selected and genotyped 80 men and postmenopausal women heterozygous for familial hypercholesterolaemia (main group) as well as 11 healthy control subjects. Patients were subgrouped based on their response to oral fat tolerance test. The oral fat tolerance test was defined as pathological when postprandial triglyceride concentration was higher than the highest triglyceride concentration observed in healthy subjects (220 mg/dl) at any time (2, 4, 6 or 8 h). RESULTS: In the pathological subgroup, men had significantly higher incremental area under the curve after oral fat tolerance test than postmenopausal women. Furthermore, multivariate analysis revealed a gender association of TaqIB and I405V influence on postprandial lipaemia in this subgroup. CONCLUSION: In conclusion, it seems that gender and TaqIB polymorphism of the cholesteryl ester transfer protein gene were both associated with the distribution of triglyceride values after oral fat tolerance test, only in subjects with a pathological response to oral fat tolerance test. Specifically, men carrying the B2 allele of the TaqIB polymorphism showed a higher postprandial triglyceride peak and a delayed return to basal values compared with women carrying B2. However, further investigations in larger populations are required to replicate and confirm these findings.

Apolipoprotein E gene polymorphism and obesity status in middle-aged men with coronary heart disease.

BACKGROUND: Apolipoprotein (apo) E polymorphism has been associated with coronary heart disease (CHD) and obesity. We aimed to determine whether apoE polymorphism is related to CHD in patients with different body mass index (BMI). PATIENTS AND METHODS: A total of 359 CHD men and 248 healthy controls with BMI <27 kg/m2 were genotyped for the apoE polymorphism. The CHD patients were divided into: normoweight (BMI: 24 +/- 1 kg/m2, n=98), overweight (BMI: 27 +/- 1 kg/m2, n=189) and obese (BMI: 32 +/- 2 kg/m2, n=72) groups. RESULTS: There was a significant difference in apoE genotype frequency between normoweight CHD patients and healthy controls (epsilon2epsilon2 + epsilon2epsilon3: 6% vs. 15%, p=0.029; epsilon3epsilon3: 83% vs. 70%, p=0.045, respectively). The apo epsilon3epsilon4 + epsilon4epsilon4 frequency was higher in obese compared with normoweight CHD patients (p=0.043). The severity of CHD was similar in all patients with CHD. CONCLUSION: Normoweight CHD patients, despite having a lower BMI and more favorable lipid profile, did not display any significant difference in CHD severity. This could be partially attributed to the lower frequency of the epsilon2 cardio-protective allele in normoweight CHD patients compared with normoweight healthy individuals.

Postprandial lipemia in hypertension.

OBJECTIVE: Many studies have shown that patients with coronary artery disease have an exaggerated rise and a delayed fall of plasma triglyceride (TG) concentration postprandially. We examined whether patients with essential hypertension have the same response to a fatty meal. METHODS: A fatty meal (350g per 2 m(2) body surface with 83.5% fat) was given to 25 patients with essential hypertension (H) and to 25 normotensives (N). The two groups were matched for age, body mass index, lipid profile, basal glucose and insulin concentrations, and an index of homeostasis model of insulin resistance (HOMA-IR). A quantitative insulin sensitivity check index (QUICKI) was calculated. Blood samples were taken at 0, 4, 6, and 8 hours after the fatty meal. Lipid variables were measured in all samples. Blood glucose and insulin levels were measured in the fasting state. RESULTS: Total and high density lipoprotein cholesterol, apolipoprotein A1 and B, lipoprotein (a), HOMA-IR and QUICKI did not differ significantly over time between the groups. The plasma TG concentration (mg/dL) increased significantly after fat loading in H (from 118 +/- 31 to 284 +/- 137 at 4 hours, 327 +/- 93 at 6 hours and 285 +/- 71 at 8 hours) compared to N group (from 105 +/- 29 to 150 +/- 38 at 4 hours, 148 +/- 40 at 6 hours and 115 +/- 34 at 8 hours), p = 0.001, p < 0.001 and p < 0.001, respectively. CONCLUSION: This study suggests that patients with hypertension have an exaggerated response and delayed clearance of plasma TG concentration after fat loading.