Residual risk in atherosclerotic cardiovascular disease after statin therapy: Clinical mechanisms and management strategies

Table 2 Current and emerging therapeutic strategies

Drug/intervention	Class	Core mechanism targeted	Primary target/molecular pathway	Effect on lipid/inflammatory marker	Key clinical trial(s)
Lifestyle modification (walking, mediterranean diet)	Behavioural intervention	Atherogenic lipoprotein metabolism, inflammation	Improves lipid metabolism and endothelial function	↓ Non-HDL-C, ↓ hsCRP, improved gut microbiota	Crossover trial (n = 12); ATTICA; DIRECT-PLUS
PCSK9 inhibitors (evolocumab, alirocumab)	Monoclonal antibody	Lp(a) mediated thrombosis, LDL-C accumulation	Inhibits PCSK9, prevents LDLR degradation	↓ LDL-C (about 60%)	ODYSSEY outcomes; FOURIER
				↓ Lp(a) (about 27%)
Inclisiran	siRNA	LDL-C and Lp(a) elevation	Silences hepatic PCSK9 mRNA	↓ LDL-C	ORION-11
				↓ Lp(a) (about 28.5%)
LA	Extracorporeal therapy	Lp(a) and apo B driven atherothrombosis	Physical removal of apoB containing particles	↓ LDL-C and Lp(a) ≥ 60% per session	Observational cohort studies
Pelacarsen	ASO	Lp(a) mediated atherosclerosis	Inhibits hepatic apo(a) synthesis	↓ Lp(a) up to 80%	Phase 2 RCT
Olpasiran	siRNA	Lp(a) mediated atherothrombosis	Silences LPA mRNA	↓ Lp(a) up to 98%	OCEAN(a)-DOSE
Icosapent ethyl	ω-3 fatty acid derivative	TG rich lipoproteins, inflammation	Lowers TRLs, reduces oxidative stress	↓ TG (25%-45%)	REDUCE-IT; EVAPORATE
				↓ MACE (25%)
Fibrates (fenofibrate, bezafibrate)	PPAR-α agonist	TG accumulation, HDL dysfunction	Enhances TG catabolism, raises HDL-C	↓ TG (30%-50%), ↑ HDL-C (10%)	FIELD; ACCORD-Lipid
Volanesorsen/olezarsen	ASO	apoC-III-mediated LPL inhibition	Inhibits apoC-III mRNA to enhance LPL activity	↓ TG (40%-77%), ↓ apoC-III (40%-84%)	Phase 1/2 RCTs
ARO-APOC3	siRNA	apoC-III-mediated TG retention	Silences apoC-III mRNA	↓ TG up to 90%, ↑ LPL activity	Phase 1/2a
Evinacumab	Monoclonal antibody	ANGPTL3-mediated LPL inhibition	Inhibits ANGPTL3, enhances LPL and EL activity	↓ TRLs, ↓ apoB, ↓ apoC-III	ELIPSE-HoFH (phase 3)
Colchicine	Anti-inflammatory agent	NLRP3 inflammasome activation	Inhibits microtubule polymerization and IL-1β signalling	↓ hsCRP, ↓ IL-6, ↓ MACE (HR 0.77)	COLCOT; LoDoCo2; COLCHICINE-PCI
Canakinumab	Monoclonal antibody	IL-1β–mediated inflammation	Neutralizes IL-1β signaling	↓ hsCRP, ↓ IL-6, ↓ MACE, no lipid change	CANTOS
Bempedoic acid	ACL inhibitor	Cholesterol synthesis and inflammation	Inhibits ATP-citrate lyase	↓ hsCRP by 23%, ↓ LDL-C	CLEAR outcomes
Ziltivekimab	Anti-IL-6 monoclonal antibody	IL-6-driven inflammation	Blocks IL-6 receptor signalling	↓ hsCRP (66%-88%), ↓ fibrinogen, ↓ Lp(a)	RESCUE (phase 2)

HDL-C: High-density lipoprotein cholesterol; hsCRP: High-sensitivity C-reactive protein; PCSK9: Proprotein convertase subtilisin/kexin type 9; Lp(a): Lipoprotein(a); LA: Lipoprotein apheresis; apo B: Apolipoprotein B; LDL-C: Low-density lipoprotein cholesterol; ASO: Antisense oligonucleotide; RCT: Randomized controlled trial; siRNA: Small interfering RNA; LPA: Lipoprotein(a) gene; IPE: Icosapent ethyl; TRLs: Triglyceride-rich lipoproteins; PPAR-α: Peroxisome proliferator-activated receptor-alpha; TG: Triglycerides; MACE: Major adverse cardiovascular events; LPL: Lipoprotein lipase; apoC: Apolipoprotein C; ARO-APOC3: Antisense RNA oligonucleotide targeting apolipoprotein C-III; ANGPTL3: Angiopoietin-like protein 3; EL: Endothelial lipase; NLRP3: NOD-like receptor pyrin domain-containing protein 3; hsCRP: High-sensitivity C-reactive protein; HR: Hazard ratio; IL: Interleukin; ACL: ATP-citrate lyase.