**Conflicts of interest**

None.

By using anti-resistin antibodies, studies have shown an increase in LDL receptors in obese

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].

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

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

Over the last several years, the role of cholesterol-lowering agents in reducing cardiovascular disease and mortality has been further established. Statin therapy remains the cornerstone of lipid-lowering therapy; however, in patients already on maximal dose of statins or intolerant to statins with residual CV risk, other options are also available. As evidenced by the recent bench to bedside development of a new drug class (PCSK9), the emergence of drugs to specifically target a population, in this case, familial hypercholesterolemia, the national call for precision medicine is on the horizon. By continuing to scientifically probe biologic mechanisms in preclinical models related to cholesterol perturbation, drug development and

translation to human clinical studies marks a bright and promising future.

individuals [145].

92 Cholesterol Lowering Therapies and Drugs

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

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

**4.8. Lipoprotein-associated phospholipase A2**

inhibitor, darapladib, failed to show any CV benefit [152].

atherosclerosis [149].

**5. Conclusion**
