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

Table 3 Comparison of lipid and inflammation targeting residual risk management strategies

Aspect	Lipid targeting strategies	Inflammation targeting strategies
Primary pathophysiology addressed	Persistent atherogenic lipoproteins despite LDL-C control (non-HDL-C, apoB, Lp(a), TG/TRLs, HDL dysfunction)	Chronic vascular inflammation and immune activation (NLRP3 inflammasome → IL-1β → IL-6 → hsCRP axis)
Representative biomarkers	Non-HDL-C, apoB, Lp(a), TG, TRL, HDL-C, apoA1/apoB ratio	hsCRP, IL-1β, IL-6, fibrinogen, serum amyloid A
Key therapeutic agents	Statins, ezetimibe, PCSK9 inhibitors, siRNA (inclisiran), ASO (pelacarsen), fibrates, icosapent ethyl (EPA), ANGPTL3 inhibitors	Colchicine, canakinumab (anti-IL-1β), ziltivekimab (anti-IL-6), bempedoic acid, lifestyle modification
Mechanisms of action	Reduce circulating atherogenic particles, inhibit cholesterol synthesis, promote LDLR recycling	Inhibit inflammasome activation and interleukin signalling latestto suppress vascular inflammation
Major clinical trials	TNT, ODYSSEY, ORION-11, REDUCE-IT, OCEAN(a)-DOSE, EVAPORATE	CANTOS (canakinumab), COLCOT and LoDoCo-MI (colchicine), ziltivekimab phase 2 RCT
Clinical outcomes	↓ LDL-C, ↓ TG, ↓ Lp(a), ↓ MACE in high-risk statin-treated patients	↓ hsCRP, ↓ IL-6, ↓ MACE independent of lipid lowering
Limitations	Lp(a) reduction limited with conventional therapy; high cost of novel agents	Infection risk (IL-1β blockade), cost, limited indication, tolerability
Regulatory approval status	Statins, PCSK9 inhibitors, IPE, fibrates approved; siRNA/ASO in late-phase trials	Colchicine FDA-approved (2023); others under clinical evaluation
Synergistic approach	Combining lipid-lowering and anti-inflammatory therapies provides additive benefit	Dual targeting of lipid and inflammation reduces residual cardiovascular risk

LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; apoB: Apolipoprotein B; Lp(a): Lipoprotein(a); TG: Triglycerides; TRLs: Triglyceride-rich lipoproteins; HDL: High-density lipoprotein; NLRP3: NOD-like receptor pyrin domain-containing protein 3; IL: Interleukin; hsCRP: High-sensitivity C-reactive protein; apoA1: Apolipoprotein A1; PCSK9: Proprotein convertase subtilisin/kexin type 9; siRNA: Small interfering RNA; ASO: Antisense oligonucleotide; EPA: Eicosapentaenoic acid; ANGPTL3: Angiopoietin-like protein 3; LDLR: Low-density lipoprotein receptor; TNT: Treating to new targets trial; ODYSSEY: Evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab; ORION-11: Trial to evaluate the effect of inclisiran on low-density lipoprotein cholesterol in subjects with atherosclerotic cardiovascular disease or atherosclerotic cardiovascular disease risk equivalents; REDUCE-IT: Reduction of cardiovascular events with icosapent ethyl–intervention trial; OCEAN(a)-DOSE: Olpasiran trials of cardiovascular events and lipoprotein(a) lowering - dose finding study; EVAPORATE: Effect of vascepa on improving coronary atherosclerosis in people with high triglycerides trial; CANTOS: Canakinumab anti-inflammatory thrombosis outcomes study; COLCOT: Colchicine cardiovascular outcomes trial; LoDoCo-MI: Low-dose colchicine after myocardial infarction trial; RCT: Randomized controlled trial; MACE: Major adverse cardiovascular events; FDA: Food and drug administration; IPE: Icosapent ethyl.