New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins

Abstract

Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance but the large clinical phase 3 trial (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabe- Tes [PROMINENT]) was recently stopped due to the underperformance from interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.

Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia

“…Beyond the abovementioned drugs, other therapeutics have been attempted to lower LDL-C with different targets which include inclisiran, bempedoic acid, lomitapide, mipomersen, etc. [70]. But most studies of new lipid lowering treatment were the result on the top of www.e-enm.org 583 statin therapies and still have very narrow indication for extremely high risk population such as homozygous familial hypercholesterolemia.…”

Bempedoic acid: new evidence and recommendations on use

“…An interesting analysis performed on individuals with loss of function of acetyCoA lyase and 3hydroxy-3-methylglutaryl-coenzyme A reductase, imitating effects of statins and bempedoic acid, showed an association between a decrease in levels of LDL cholesterol and reduction of CVD risk [29,30].…”

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review

“…The treatment of F-HTG focuses on the reduction of low-density lipoprotein (LDL) cholesterol levels, followed by management of non–high-density lipoprotein cholesterol levels; this can be achieved by changes in lifestyle and dietary modifications [ 126 ] or by the administration of statins such as Atorvastatin, Lovastatin, Fluvastatin, Pravastatin Rosuvastatin and Simvastatin [ 127 ]. Fibrates [ 128 ], Niacin [ 129 ] and Fish oil [ 126 , 130 , 131 ], The development of alternatives to statins, which include Evinacumab, the angiotensin-like 2 monoclonal antibody [ 132 ], which has shown adequate safety in trials [ 133 ]. The resurgence of approval for monoclonal antibody treatments for rare disorders [ 134 ] and gene therapy in animal models [ 135 ] will set the direction for the advancement of therapeutics for the management of this emerging disorder.…”