Cholesterol Absorption Inhibitors
Ezetimibe is a selective cholesterol absorption inhibitor that blocks the absorption of dietary cholesterol and delivery of intestinal cholesterol to the liver resulting in up-regulation of hepatic LDL receptors and enhanced clearance of LDL particles from the circulation. Statins and ezetimibe taken together potentiate the LDL reduction. This reduction in LDL-C has been documented between 10–40 percent. The variable response is likely due to differences in the amount of residual functional LDL receptor activity, with those patients with no receptor activity (receptor negative) having limited response to drugs that work through mechanisms involving LDL receptor up-regulation. In one report, ezetimibe added an extra 15 % reduction in LDL levels when added to rosuvastatin 40 mg.29 Despite the added effect of ezetimibe, many patients require further LDL lowering therapy, including bile acid sequestrants, to achieve therapeutic goals.
Bile Acid Sequestrants
Bile acid sequestrants bind cholesterol in the gut thereby enhancing cholesterol excretion and reducing the enterohepatic circulation of bile acids and biliary cholesterol. The reduction in bile acids leads to a compensatory increase in conversion of cholesterol to bile acids, up-regulating expression of hepatic LDL receptors and consequently increasing hepatic removal of LDL particles from the circulation.30 Bile acid sequestrants, specifically colesevelam (the newest in its class), have been shown to reduce LDL-C levels alone and more significantly when used in combination with ezetimibe and statins. The combination of these drugs was proven to be safe and well tolerated.31–33 In FH, bile acid sequestrants are considered second line therapy after treatment with statins and ezetimibe.34
Niacin
In patients with FH, niacin is considered an alternative agent for patients after treatment with statins, ezetimibe and bile acid sequestrants. It can be used to further intensify therapy or as replacement when statins are not tolerated.3,35 Its beneficial effects on the lipid profile include increasing HDL-C by 15-30 %, lowering triglycerides up to 35 % and lowering LDL-C about 20 percent.36 Despite these favourable effects, two recent studies showed lack of clinical significance in terms of cardiovascular outcomes. It should be noted however that these two studies were not designed specifically to address the benefit of niacin as adjunct therapy for patients with FH. The recent Atherosclerosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact of Global Health Outcomes (AIM-HIGH) study showed that despite a significant increase in HDL, niacin did not reduce cardiovascular events compared to placebo when added to simvastatin.37 Similar results were demonstrated in the Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial in which more than 20,000 patients with known vascular disease were randomised to placebo or niacin in addition to statin or statin/ezetimibe therapy. The trial was stopped prematurely since niacin did not further reduce the risk of the composite endpoint and was found to increase the incidence of nonfatal serious side effects.38
Newly FDA Approved Agents, Mipomersen and Lomitapide
In the last year, two new drugs have been approved by the US Food and Drug Administration (FDA) as adjunct therapy for FH: mipomersen (an apolipoprotein-B [apoB] synthesis inhibitor) (Kynamro–Genzyme) and lomitapide (a microsomal transfer protein inhibitor) (Juxtapid– Aegerion).39 These agents interfere with the production and secretion of apoB-containing lipoproteins respectively, independent of the LDL receptor. These agents are used after statins, cholesterol absorption inhibitors and bile acid sequestrants have been considered.
Mipomersen
Mipomersen is an antisense molecule targeting the messenger ribonucleic acid (mRNA) that encodes apoB-100 produced by the liver. ApoB-100 is the main structural protein of LDL, and its precursor, VLDL. Mipomersen has been tested in four populations: 1) HoFH, 2) HeFH with coronary artery disease, 3) Patients with severe hypercholesterolaemia and 4) Patients at high risk for CAD with hypercholesterolaemia.40–43 All trials were phase 3, randomised, double blind, placebo-controlled and multicentre studies. Mipomersen demonstrated statistically significant reductions in LDL and apoB as a single drug or in combination with statins and other agents.40–45 It is administered weekly by subcutaneous injection with rapid absorption and distribution to tissues. The most common adverse effects observed in clinical studies were erythema or pain at the injection site, which were self-limited, flu-like symptoms and transient elevations in CRP at the beginning of the injections, with no other inflammatory marker elevations. Elevations in hepatic transaminases were less common, largely reversible with no other liver function tests abnormalities or clinical implications. Increase in liver fat was also observed, however it stabilised after a year of treatment. In combination with statin, mipomersen showed a LDL reduction of approximately 25 percent.40,46
Lomitapide
Lomitapide binds and inhibits the microsomal triglyceride transfer protein (MTTP). MTTP is critical in the synthesis of cholesterol particles, transferring triglycerides onto apo B in the hepatocyte to form VLDL and in the enterocyte to form chylomicrons.47 Lomitapide is given orally in doses of 5–50 mg daily and is rapidly absorbed with a significant first pass effect in the liver. It is metabolised by CYP3A4 and therefore has the potential for drug interactions with commonly prescribed medications. Ketoconazole can significantly increase levels of lomitapide while simvastatin and warfarin are both increased in concentration when coadministered with lomitapide.48 Gastrointestinal intolerance is the most common adverse effect with patients reporting diarrhoea, nausea and flatulence. These side effects can be ameliorated by slow dose uptitration and adherence to a low fat diet. Vitamin E deficiency is a potential adverse effect. Given patients with FH have higher baseline levels of vitamin E, treatment with lomitapide often results in a normal vitamin level.46
Similar to mipomersen, lomitapide can asymptomatically increase serum transaminases in some patients with no changes in bilirubin and alkaline phosphatase. Transaminase elevations appear to be reversible and transient. Mild increases in liver fat content have been observed and could potentially be counteracted by following a low fat diet.49 The long-term consequences of this induced hepatosteatosis remain unclear and will require future investigation.
Mipomersen and lomitapide were approved with an enclosed warning describing the risk of hepatotoxicity. Due to the overall risk profile, these medications are available only through the restricted Kynamro/ Juxtapid Risk Evaluation and Mitigation Strategy (REMS) Program. Only certified health care providers can prescribe the medicines and only certified pharmacies may dispense them. Risks considered, mipomersen and lomitapide should be considered as adjunctive therapy to diet and cholesterol-lowering drugs in adults with homozygous FH to further reduce plasma LDL cholesterol, particularly if lipoprotein apheresis (LA) is not available.50