Table 3. Approved agents and agents in development to lower plasma concentrations of apoB lipoproteins and thereby reduce ASCVD events (Updated with permission from Keyes et al⁵).

Class	Specific drugs	Effects/indications	References
Therapies approved by the FDA to lower plasma LDLc levels and/or ASCVD event risk
Statins	Lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin	Reduce plasma LDLc levels and ASCVD events; FDA approved for both.
Anti-PCSK9 inhibitory monoclonal antibodies	Evolocumab, alirocumab	Lower plasma levels of LDLc to approximately 30 mg/dL and reduce ASCVD event risk. FDA approved for both effects.	80 81
Cholesterol absorption inhibitor	Ezetimibe	Approved for lowering LDLc; also shown to decrease ASCVD events in two key clinical trials (IMPROVE-IT and EWTOPIA 75), but not FDA approved for this indication.	82 83
Omega-3 fatty acid derivatives	Icosapent ethyl	Lowers plasma levels of triglycerides and apolipoprotein B; FDA approved for ASCVD event reduction in patients at a high ASCVD event risk with plasma triglyceride levels of ≥150 mg/dL.	117
Bile acid sequestrants	Cholestyramine, colestipol, colesevelam	Lower plasma LDLc concentrations and ASCVD event risk; but can have significant gastrointestinal side effects and can raise plasma concentrations of triglycerides.	118
ATP citrate lyase inhibitor	Bempedoic acid	FDA approved for LDLc lowering in heterozygous familial hypercholesterolaemia or established ASCVD. CLEAR Outcomes trial demonstrated decreased ASCVD events in statin-intolerant patients. Appears to have no effects in muscles. Available alone and in a fixed combination with ezetimibe.	40 119
siRNA against PCSK9 mRNA	Inclisiran	FDA approved for LDL lowering in heterozygous familial hypercholesterolaemia or established ASCVD; after two loading doses it is administered only twice per year, which may improve convenience and adherence.	120 122
Candidate therapies under investigation in dyslipoproteinaemias and ASCVD events
Antisense oligonucleotide against APOC3 mRNA	Volanesorsen	Approved in Europe for familial chylomicronaemia syndrome, which is a rare condition of extremely high plasma triglycerides. Approval was declined in the USA based on its risk–benefit ratio.	40 42
Antisense oligonucleotide targeting APOC3 mRNA:olezarsen	Olezarsen	Results of the phase II trial were published. Significant reductions in TG, apolipoprotein C-III, very-low-density lipoprotein cholesterol and non-HDLc were also seen, while LDLc levels changed minimally or increased with some doses. Phase III studies are currently ongoing with olezarsen in patients with familial chylomicronaemia syndrome or severe hypertriglyceridaemia.	42 123
siRNA inhibiting APOC3 mRNA	AROAPOC3	Reduced TG up to 90% in phase I trials; GalNAc-linked siRNA; phase IIItrials are ongoing.	124
Humanised monoclonal antibody against ANGPTL3	Evinacumab	FDA approved for homozygous familial hypercholesterolaemia, a rare syndrome of extremely high LDL levels; also under evaluation in more common circumstances.	125
Antisense oligonucleotide against LPA mRNA	Pelacarsen	Lowers Lp(a) levels in a dose-dependent manner in patients with elevated Lp(a) and clinically evident cardiovascular disease.	126 128
siRNAs against LPA mRNA	Olpasiran, lepodisiran, zerlasiran	Lower Lp(a) levels in a dose-dependent manner in patients with elevated Lp(a) and clinically evident cardiovascular disease.	126 130
Orally administered agent to block Lp(a) formation	Muvalaplin	Lowered plasma Lp(a) concentrations, as assessed by an intact lipoprotein(a) assay and by an apolipoprotein(a) assay.	131
Antisense oligonucleotide against sulfatase-2 mRNA	Unnamed	Restores normal postprandial clearance of C-TRLs via hepatic syndecan-1 in obese type 2 diabetic animals.	132

ASCVDatherosclerotic cardiovascular diseaseC-TRLcholesterol and triglyceride-rich lipoproteinFDAUS Food and Drug AdministrationHDLchigh-density lipoprotein cholesterolLDLlow-density lipoproteinLDLcLDL cholesterolLp(a)lipoprotein(a)TGtriglyceride