Case report: The efficacy and safety of lomitapide in a homozygous familial hypercholesterolemic child.

We report for the first time the efficiency and safety of a 49-month compassionate use of the microsomal transfer protein inhibitor lomitapide in a child with homozygous familial hypercholesterolemia. On average, 20 mg of lomitapide caused a 37% reduction in low-density lipoprotein cholesterol levels on top of ezetimibe and atorvastatin. The drug was well tolerated with no changes in liver enzymes and occurrence of steatosis on hepatic ultrasound. The patient presented adequate growth and sexual maturation. Nonetheless, there was progression in either subclinical atherosclerotic carotid or aortic valve diseases. Further studies are necessary to test the impact and safety of lomitapide in children with homozygous familial hypercholesterolemia.

Investigational drugs in development for hypertriglyceridemia: a coming-of-age story.

Introduction: Elevated triglyceride (TG) level is a prevalent condition in the general population and in patients with cardiovascular (CV) risk even under statin therapy. Severe hypertriglyceridemia (HTG) puts patients at risk for acute pancreatitis. Several TG-lowering drugs failed in clinical trials, but subgroup analyses suggest that high-risk patients, such as those with atherogenic dyslipidemia or diabetes, benefit from TG lowering.Areas covered: We review advances for TG-lowering drugs in clinical development. These include selective PPARα modulators, omega-3 fatty acid formulations that have been approved for severe HTG, and inhibitors of apolipoprotein C-III, angiopoietin-like-3 or microsomal transfer protein. Lessons learned from the success of the phase 3 trial REDUCE-IT with high-dose icosapent ethyl are also reviewed.Expert opinion: We believe that TG-lowering therapies are coming of age as they will allow to treat patients with high CV risk and moderate HTG, including T2D subjects, as well as patients with severe HTG or even homozygous familial hypercholesterolemia, all of which being 'optimally' treated with a statin. More studies on the impact of therapy on quality of life in patients with severe HTG should be conducted with the help of patient registries.

Mipomersen and lomitapide: Two new drugs for the treatment of homozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is a disease associated with very high plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. It is difficult in these high risk patients, exposed lifelong to very high LDL-C, to reach target LDL-C concentrations, which require >50% LDL-C reduction, even when on maximally tolerated statin therapy and on apheresis if available. Therefore, there is an unmet need for new therapeutic options for these patients. In 2013 two new drugs were approved for the treatment of homozygous FH, namely the apolipoprotein B synthesis inhibitor mipomersen and the microsomal transfer protein inhibitor lomitapide. Objective of this narrative review is to discuss the available evidence on the safety and efficacy profile of these new drugs.

Clinical experience of lomitapide therapy in patients with homozygous familial hypercholesterolaemia.

The microsomal triglyceride transfer protein (MTP) inhibitor lomitapide is a licenced adjunct to a low-fat diet and other lipid-lowering medication, with or without low-density lipoprotein apheresis, for the treatment of adults with homozygous familial hypercholesterolaemia (HoFH). In a recently published phase 3 study, patients with HoFH received lomitapide in addition to maximally tolerated lipid-lowering therapy. Treatment with lomitapide resulted in a mean approximate 50% reduction in LDL-C levels after 26 weeks compared with baseline levels (p < 0.0001). This decrease in LDL-C was maintained at Weeks 56 and 78 (44% [p < 0.0001] and 38% [p = 0.0001], respectively). This paper offers clinical perspectives based on selected case histories of patients participating in the phase 3 lomitapide study. These cases provide illustrative examples of the efficacy of lomitapide, with or without apheresis, and show that the effective management of adverse effects can enable patients to remain on effective treatment.

MTP -493G/T gene polymorphism is associated with steatosis in hepatitis C-infected patients

The reduction of hepatic microsomal transfer protein (MTP) activity results in fatty liver, worsening hepatic steatosis and fibrosis in chronic hepatitis C (CHC). The G allele of the MTP gene promoter, -493G/T, has been associated with lower transcriptional activity than the T allele. We investigated this association with metabolic and histological variables in patients with CHC. A total of 174 untreated patients with CHC were genotyped for MTP -493G/T by direct sequencing using PCR. All patients were negative for markers of Wilson’s disease, hemochromatosis and autoimmune diseases and had current and past daily alcohol intake lower than 100 g/week. The sample distribution was in Hardy-Weinberg equilibrium. Among subjects with genotype 1, 56.8 percent of the patients with fibrosis grade 3+4 presented at least one G allele versus 34.3 percent of the patients with fibrosis grade 1+2 (OR = 1.8; 95 percentCI = 1.3-2.3). Logistic regression analysis with steatosis as the dependent variable identified genotypes GG+GT as independent protective factors against steatosis (OR = 0.4, 95 percentCI = 0.2-0.8; P = 0.01). The results suggest that the presence of the G allele of MTP -493G/T associated with lower hepatic MTP expression protects against steatosis in our CHC patients.