_______________________________________ Hyperlipidemias and Atherosclerotic Cardiovascular Disease
Advances in pharmacologic research have provided new molecular insights on lipid metabolism, and translational knowledge is being applied to the development of novel therapies including squalene synthase inhibitors (e.g., lapaquistat), new generation cholesterol absorption inhibitors, ATP-binding cassette transporter activators/cholesterol excretion stimulators, a new generation of nicotinic acid analogs, microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides against Apo B-100 (e.g., mipomersen), and PCSK9, a serine protease synthesized in the liver, being investigated for its regulatory effect on LDL receptors [56; 202; 203; 204; 205; 206]. Squalene synthase modulates the first committed step of hepatic cholesterol biosynthesis. Its inhibition results in a reduction in cholesterol synthesis in the liver and upregulation of the LDL receptor. Inhibition of squalene synthase activity occurs downstream from HMG-CoA reductase inhibited by statins. Theoretically, squalene synthase inhibitors reduce LDL cholesterol without causing the myopathy side effect seen with upstream inhibition of HMG-CoA. As of 2013, only one synthase inhibitor, lapaquistat (TAK-475), has undergone extensive development in clinical trials as a monotherapy; however, two cases of severe liver enzyme elevations among more than 5,100 study participants exposed to the drug resulted in termination of the development program [207; 208]. New-generation cholesterol absorption inhibitors (e.g., AVE5530) share some mechanistic properties with ezetimibe, a NPC1L1 transporter inhibitor. However, rather than being partially absorbed in the intestine, they remain in the lumen where they can exert their pharmacologic actions more effectively than ezetimibe. As a result, these agents can inhibit cholesterol absorption for up to 24 hours [209]. These drugs have been subjected to clinical trials. To date, four trials have been terminated and one completed, with results not yet available [210]. The process of cholesterol being transported back into the intestinal tract by selective transporters, such as the ATP- binding cassette transporters, has also been a target for potential treatments [55]. A new generation of drugs that is able to stimulate the ATP-binding cassette transporter and promote cholesterol elimination by enterocytes is being investigated [56]. The discovery of a G protein-coupled receptor for nicotinic acid has provided new insights on its lipid-lowering properties. This has raised the possibility of developing selective agonists that will not share its flush-inducing side effects [165; 203]. Microsomal triglyceride transfer protein catalyzes the assembly of cholesterol, triglycerides, and Apo B-100. Microsomal triglyceride transfer protein inhibitors (e.g., AEGR-733, lomitapide) inhibit intestinal assembly of chylomicrons and hepatic synthesis of VLDL, consequently lowering LDL. Initial clinical results showed a dose-dependent reduction of LDL
by 19% to 30% when administered alone, or by 46% when administered in combination with ezetimibe [211]. Research is ongoing [212; 213]. Antisense oligonucleotides (e.g., mipomersen) are single- stranded DNA that bind to matching mRNA and induce its selective degradation. Pre-clinical studies and small clinical trials have shown a 30% to 50% reduction in LDL with the use of these agents. Increases in transaminases and injection site reactions have been observed, and larger clinical trials are being conducted [210; 214]. Downregulation of the LDL receptor by PCSK9 is one regulatory mechanism that controls plasma LDL cholesterol concentrations. Studies have demonstrated that the PCSK9 enzyme binds to the hepatic LDL receptor and promotes its degradation, which in turn decreases LDL uptake and increases plasma LDL cholesterol levels. However, PCSK9 may have much broader roles than initially thought. For example, when human PCSK9 is injected into LDL receptor-deficient mice, it is still rapidly cleared by the liver, suggesting that it is physiologically also cleared by receptors other than the LDL receptor [215; 216; 217; 218]. PCSK9 inhibitors are monoclonal antibodies that inactivate the PCSK9 enzyme and promote clearance of LDL from the circulation. Administration of PCSK9 inhibitors can reduce serum LDL cholesterol by 60% [235]. In 2015, the FDA approved two PCSK9 inhibitors, alirocumab and evolocumab, to be used in conjunction with diet and statin therapy to reduce LDL cholesterol. To date, clinical trials of PCSK9 inhibitor therapy as an adjunct to statins have been conducted for secondary prevention of ASCVD in high-risk patients [235]. The demonstrated benefit is modest, the cost relatively high, and the long-term safety not yet well-established. As noted, one important factor accounting for residual risk despite optimal conventional therapy is the inherited predisposition to elevated levels of lipoprotein(a). The most important genetic variants affecting lipoprotein(a) levels involve the gene LPA , which encodes apolipoprotein(a). The level of circulating lipoprotein(a) is determined by the rate of apolipoprotein(a) synthesis by the liver. New approaches to treatment of patients with this disorder target production of apolipoprotein(a) in the liver by using antisense oligonucleotides and RNA interference to silence gene LPA activity, down-regulate production, and lower the level of lipoprotein(a) [248]. Three small interfering RNAs (siRNAs)—lpasiran, lepodisiran, and zerlasiran—have been reported to reduce lipoprotein(a) levels by more than 90%. These agents are administered subcutaneously, achieve maximum effect in 30 to 60 days and duration of effect lasting six months to one year. In a phase 2, placebo-adjusted trial, 320 persons with elevated lipoprotein(a) (median baseline level of 254 nmol per liter) were randomized to receive lepodisiran in a dose of 16 mg, 96 mg, or 400 mg. In the cohort who received the 400-mg dose, lepodisiran
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