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

Table 1 Summary of major biomarkers of residual risk and their clinical relevance

Major biomarkers	Clinical relevance
Non-HDL-C/apoB	Superior to LDL-C in predicting residual ASCVD risk; elevated levels increase all-cause mortality and MI risk (Copenhagen, Danish registry, meta-analysis); stable non-fasting lipid target for better risk stratification
Lp(a)	Independent predictor of residual CVD risk in statin-treated patients; elevated ≥ 50 mg/dL increases events by 31%-43%; genetically determined via LPA variants; recommended once-in-lifetime testing (ESC/EAS, NLA)
TRLs/RC	Elevated TRLs, TG, and RC increase residual CVD risk independent of LDL-C; TRLs promote foam-cell formation, inflammation, and atherogenesis; RC > 29 mg/dL raises CVD risk by 20%-43% (PESA, MESA, KP-REACH)
HDL dysfunction/HDL-C-related ratio	HDL dysfunction impairs cholesterol efflux, NO production, and anti-inflammatory effects. Ratios such as apoA1/apoB, TG/HDL-C, and non-HDL-C/HDL-C predict ACS, CAD progression, and mortality, offering superior prognostic value over HDL-C alone
hsCRP/IL-6/NLRP3 inflammasome	Elevated hsCRP (> 2 mg/L) predicts higher CVD risk and mortality. The NLRP3-IL-1β-IL-6 axis drives vascular inflammation; IL-6 serves as a biomarker of residual inflammatory risk and therapeutic target for anti-inflammatory intervention

HDL-C: High-density lipoprotein cholesterol; apoB: Apolipoprotein B; LDL-C: Low-density lipoprotein cholesterol; ASCVD: Atherosclerotic cardiovascular disease; MI: Myocardial infarction; Lp(a): Lipoprotein(a); CVD: Cardiovascular disease; LPA: Lipoprotein(a) gene; ESC: European Society of Cardiology; EAS: European Atherosclerosis Society; NLA:National Lipid Association; TRLs: Triglyceride-rich lipoproteins; RC: Remnant cholesterol; PESA: Progression of early subclinical atherosclerosis; MESA: Multi-ethnic study of atherosclerosis; KP-REACH: Kaiser permanente regional examination of atherosclerosis, cardiometabolic health, and heart disease; HDL: High-density lipoprotein; NO: Nitric oxide; apoA1: Apolipoprotein A1; TG: Triglycerides; ACS: Acute coronary syndrome; CAD: Coronary artery disease; hsCRP: High-sensitivity C-reactive protein; NLRP3: NOD-like receptor pyrin domain-containing protein 3; IL: Interleukin.

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.

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.