**4. Other potential therapy options**

Statins are the preferred therapy for most patients with dyslipidemia, especially those with elevated total cholesterol and LDL cholesterol. However, in patients on maximal tolerated statin dose with a persistently elevated LDL, other therapies may be considered. These include niacin, bile acid sequestrants, and ezetimibe. Not uncommonly, these additional agents may not be sufficient to "normalize" abnormal cholesterol profiles, especially in patients with severe hypercholesterolemia and familial cholesterol diseases. Therapeutic options in this group of patients, who remain "at risk" for CV events, include LDL apheresis, lomitapide, surgical options, and gene therapy. Preferably, this cohort of patients should be managed by a specialist.

#### **4.1. LDL apheresis**

LDL apheresis is a procedure that involves extracorporeal removal of circulating Apo Bcontaining lipoprotein (e.g., LDL, VLDL, and lipoprotein-a). Regimens include weekly or biweekly depending on the rate LDL returns to baseline after therapy [131].

The National Lipid Associated Expert Panel on familial hypercholesterolemia recommended LDL apheresis in those with FH if LDL targets are not achieved with maximal tolerated medical therapy. These targets include LDL of ≥300 mg/dL in those with functional homozygous or heterozygous FH, LDL of ≥200 mg/dL in those with functional heterozygous FH, and ≥2 risk factors or high lipoprotein-a (≥50 mg/dL), or LDL of ≥160 mg/dL in those established CAD, CV disease, or diabetes [132]. In the absence of statin therapy, LDL apheresis lowers LDL by 50– 75% acutely, by 30% after 6 months, and 38% after 18 months [133]. There are numerous studies showing benefit in outcomes such as myocardial infarction and reduction in arterial inflammation, but none have shown a survival benefit [134, 135]. Limitations to using LDL apheresis include patient burden, problems related to venous access, frequent long visits, and high costs [136].

#### **4.2. Lomitapide**

AIM-HIGH, ARBITER-2, and HPS2-THRIVE trials found no significant benefit of adding

Unfortunately, its use is limited by poor tolerability. The most common side effect is flushing, which occurs in the majority (up to 80%) of patients at standard recommended doses. Other notable side effects include paresthesia, pruritis, and nausea, each of which occurs in 20% of

All patients with an elevated LDL should be advised to attempt and undergo for therapeutic lifestyle changes. Therapeutic lifestyle changes involve weight loss (even in those who are only slightly overweight), exercise, and improvement in diet. Numerous studies have investigated and demonstrated the benefits of lifestyle modification. In the United Kingdom Lipid Clinics Program study, 2508 subjects who underwent diet modification experienced a 5–7% reduction in serum total and LDL cholesterol [128]. In the Lifestyle Heart Trial, 53 patients were randomized to either control diet (National Cholesterol Education Program-NCEP step 2 diet) or vegetarian therapy with exercise and relaxation therapy (intervention group). After 5 years of follow-up, the intervention group demonstrated a decrease in CV events (0.89 vs 2.25 events per patient) [129]. In the Lyon Diet Heart Study, 605 patients were randomized after a first myocardial infarction to either a Mediterranean diet or a control diet. After 4 years of followup, the Mediterranean diet group demonstrated lower rates of death and myocardial infarc-

Statins are the preferred therapy for most patients with dyslipidemia, especially those with elevated total cholesterol and LDL cholesterol. However, in patients on maximal tolerated statin dose with a persistently elevated LDL, other therapies may be considered. These include niacin, bile acid sequestrants, and ezetimibe. Not uncommonly, these additional agents may not be sufficient to "normalize" abnormal cholesterol profiles, especially in patients with severe hypercholesterolemia and familial cholesterol diseases. Therapeutic options in this group of patients, who remain "at risk" for CV events, include LDL apheresis, lomitapide, surgical options, and gene therapy. Preferably, this cohort of patients should be managed by a specialist.

LDL apheresis is a procedure that involves extracorporeal removal of circulating Apo Bcontaining lipoprotein (e.g., LDL, VLDL, and lipoprotein-a). Regimens include weekly or

The National Lipid Associated Expert Panel on familial hypercholesterolemia recommended LDL apheresis in those with FH if LDL targets are not achieved with maximal tolerated medical

biweekly depending on the rate LDL returns to baseline after therapy [131].

niacin to statin therapy [125–127].

90 Cholesterol Lowering Therapies and Drugs

patients at standard doses [120].

**3. Lifestyle modification**

**4. Other potential therapy options**

tion [130].

**4.1. LDL apheresis**

Lomitapide is a microsomal TG transfer protein inhibitor which inhibits the transfer of TG to Apo-B for the production of VLDL in the liver. However, lomitapide is metabolized by CYP3A4 and is also an inhibitor of CYP 3A4 and P-glycoprotein leading to numerous drug interactions. It was FDA approved in 2012 for use in patients with homozygous FH. It is used in addition to standard therapy, as well as other therapies such as LDL apheresis or liver transplantation. It has been shown to significantly decrease LDL (up to 50%) in a phase 3, open-label, nonrandomized, dose-escalating study [137].

#### **4.3. Mipomersen**

Mipomersen is an injected antisense oligonucleotide that inhibits the production of Apo-B. Mipomersen binds to the Apo-B mRNA, affects Apo-B production, and consequently reduces the levels of LDL, VLDL, and intermediate dense lipoprotein. It has been approved by FDA in 2013 for use in homozygous FH patients; however, it is not approved in Europe. It has been shown that mipomersen can significantly decrease LDL in those patients with homozygous FH (up to 25%) [138]. Similar findings were found in studies involving other populations, including those with heterozygous FH and have CAD, statin intolerant, and at high risk of CV disease, and in those without FH who have or are at high risk of CVD [139–143].

#### **4.4. Cholesteryl ester transfer protein inhibitors**

Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib, have shown to significantly increase in HDL and lower LDL; however, there are no studies showing clinical benefit. In fact, in the REALIZE trial, despite a significant reduction in LDL in the intervention group compared to placebo, there was a significant increase in CV events, hence limiting its clinical use [144].

#### **4.5. Anti-resistin antibodies**

Anti-resistin antibodies inhibit resistin function, an adipokine (protein derived from adipose tissue) that is increased in obese individuals and positively correlated with atherosclerosis. In *in vitro* studies, resistin can decrease LDL receptor expression and increase PCSK9 expression. By using anti-resistin antibodies, studies have shown an increase in LDL receptors in obese individuals [145].

#### **4.6. Small molecule regulator of lipid metabolism**

ETC-1002 is a small molecule regulator of carbohydrate and lipid metabolism. In a study of 177 subjects with LDL between 130 and 220 mg/dL not on statin therapy, patients were randomized to ETC-1002 (one of three different doses) or placebo. After 12 weeks of followup, treated subjects at the highest dose demonstrated a 27% decrease in LDL. There were no changes in TG or HDL. ETC-1002 also demonstrated a limited side effect profile [146, 147].

#### **4.7. Recombinant Apo-A-I milano**

Apo-A-I milano is a variant of the Apolipoprotein A-I (Apo-A-I). This variant leads to rapid mobilization of cholesterol with rapid regression of atherosclerosis. Subjects with Apo-A-I Milano have very low levels of HDL (10–30 mg/dL), longer survival, and reduced atherosclerosis compared to what is expected for their HDL levels [148]. Infusion of recombinant Apo-A-I milano (ETC-216) in an RCT was shown to lead to a significant regression of coronary atherosclerosis [149].

### **4.8. Lipoprotein-associated phospholipase A2**

Lipoprotein-associated phospholipase A2 is also known as platelet-activating factor acetylhydrolase. It is a protein with pro-inflammatory properties that co-travels with circulating LDL particles and is found abundantly in atherosclerotic plaques [150]. Lipoprotein-associated phospholipase A2 has been shown in a meta-analysis to significantly increase CHD and is an independent predictor of CHD and ischemic stroke [151]. However, in a large phase III randomized control trial (STABILITY trial), the lipoprotein-associated phospholipase A2 inhibitor, darapladib, failed to show any CV benefit [152].
