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

Abstract

Atherosclerotic is one of the leading causes of death worldwide. Although lowering low-density lipoprotein cholesterol (LDL-C) levels reduces cardiovascular risk, studies have shown that even when LDL-C is well controlled, patients may still develop atherosclerotic cardiovascular disease, a phenomenon known as residual risk. This review synthesizes current research on the definition, pathogenesis, and therapeutic strategies of residual risk, aiming to provide a theoretical basis for future advances in its diagnosis and management. Evidence derived exclusively from human clinical trials, cohort studies, and meta-analyses is summarized, excluding data from animal or in vitro experiments to maintain clinical relevance. We focus on lipid and inflammatory biomarkers beyond LDL-C, including non-high-density lipoprotein (HDL) cholesterol, apolipoprotein B, lipoprotein(a), triglycerides, triglyceride-rich lipoproteins, HDL dysfunction, and systemic inflammatory markers. Therapeutic interventions encompassing lifestyle modification, lipid-lowering agents, anti-inflammatory therapies, and novel gene-silencing approaches are reviewed. Evidence indicates that in patients receiving statin therapy, non-HDL-cholesterol and apolipoprotein B provide superior assessment of residual risk compared with LDL-C. Lipoprotein(a) remains predictive of cardiovascular events even when LDL-C levels are well controlled, while elevated triglycerides and triglyceride-rich lipoproteins consistently associate with higher cardiovascular risk. Inflammatory biomarkers such as high-sensitivity C-reactive protein and interleukin-6 serve as indicators of residual inflammatory risk. Persistent residual risk despite LDL-C control underscores the need for integrated, multi-target strategies to achieve comprehensive cardiovascular protection.

Key Words: Atherosclerosis; Cardiovascular disease; Inflammation; Lipid metabolism; Lipoprotein(a); Residual risk; Statins; Triglycerides

Core Tip: Residual cardiovascular risk remains in patients receiving statin therapy despite well-controlled low-density lipoprotein cholesterol. Key contributors include non-high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), triglycerides, and persistent inflammation marked by high-sensitivity C-reactive protein and interleukin-6. Comprehensive strategies combining novel lipid-lowering therapies, anti-inflammatory treatments, lifestyle modification, and gene-silencing approaches are essential to effectively reduce residual risk and improve long-term cardiovascular outcomes.

INTRODUCTION

Atherosclerotic cardiovascular disease (ASCVD) encompasses clinical syndromes rooted in atherosclerosis (AS), including coronary artery disease (CAD), ischemic stroke, and peripheral artery disease. According to the China Cardiovascular Health and Disease Report 2024, the incidence of cardiovascular disease (CVD) in China has shown a marked upward trend, increasing from 5.30 million cases (447.81 per 100000) in 1990 to 12.34 million cases (867.65 per 100000) in 2019[1]. Similarly, in the European Union, CVD remains the leading cause of death, with approximately 12.7 million new cases annually and over 4 million deaths each year[2]. These regional data collectively highlight the global burden and continuing rise of CVD worldwide.

Low-density lipoprotein (LDL) cholesterol (LDL-C) has long been established as a traditional surrogate marker for assessing CVD risk and remains one of the most used endpoints in clinical trials. Statins are foundational lipid-lowering therapies that have proven effective in both primary and secondary prevention of ASCVD. Clinical studies have consistently demonstrated that reducing LDL-C significantly decreases the risk of coronary heart disease. However, the overall CVD risk reduction achieved through lipid-lowering therapy is generally less than 30%, even with aggressive LDL-C lowering strategies[3].

Moreover, a growing body of clinical evidence has shown that some patients continue to experience cardiovascular events despite achieving LDL-C levels below 70 mg/dL. This phenomenon, known as residual risk, has become a central concern in contemporary CVD prevention research[4]. The Treating to New Targets study, a clinical trial involving stable CAD patients with baseline LDL-C levels above 130 mg/dL, randomized participants to receive either 10 mg or 80 mg of atorvastatin daily for approximately 5 years. Subsequent analyses revealed that LDL-C was less robust as a predictor of cardiovascular outcomes than other emerging biomarkers such as apolipoprotein B (apoB) and non-high-density lipoprotein (HDL) cholesterol (HDL-C), suggesting a need to re-evaluate the over-reliance on LDL-C for cardiovascular risk assessment[3].

In response, increasing attention has been directed toward non-LDL-C lipid markers and inflammatory biomarkers, including triglycerides (TG), triglyceride-rich lipoproteins (TRLs), lipoprotein(a) [Lp(a)], and C-reactive protein (CRP), which have been shown to be closely associated with residual cardiovascular risk[4]. Despite their growing clinical relevance, current guidelines still do not generally recommend these markers as first-line therapeutic targets[3].

This article summarizes recent clinical evidence on the residual risk that persists following statin therapy, including its core mechanisms, diagnostic and risk associations, and corresponding therapeutic strategies, thereby providing a theoretical basis for precise clinical prevention and treatment.

NON-HDL-C

Core mechanisms

Non-HDL-C represents the total concentration of atherogenic lipoproteins, including LDL-C, TRLs, and Lp(a). In statin-treated patients with well-controlled LDL-C levels, non-HDL-C remains an independent predictor of residual cardiovascular risk[5]. Accumulating evidence indicates that non-HDL-C is a stronger predictor of ASCVD risk than LDL-C, particularly among individuals with metabolic disorders, type 2 diabetes, or obesity[6].

The Copenhagen General Population Study, which followed 13015 statin-treated individuals over a median of 8 years, reported that elevated apoB and non-HDL-C levels were significantly associated with higher risks of all-cause mortality (ACM) and myocardial infarction (MI), whereas elevated LDL-C was not. Participants with high apoB but low LDL-C showed a 21% higher risk of ACM and a 49% higher risk of MI; when both apoB and non-HDL-C were elevated while LDL-C remained normal, these risks increased to 23% and 82%, respectively[7].

Further evidence from a Danish registry including 42057 statin-treated patients with ischemic heart disease demonstrated that non-HDL-C levels above the 75^th percentile were significantly associated with increased ASCVD events, irrespective of diabetes status. This association persisted even when LDL-C levels met target ranges, underscoring the value of non–HDL-C monitoring for identifying high-risk individuals who may benefit from intensified therapy[8].

A meta-analysis of 38153 statin-treated patients from 8 randomized trials (n = 62154) showed that non-HDL-C correlated more strongly with cardiovascular events than LDL-C (hazard ratio = 1.16 vs 1.13, P = 0.002) and apoB (P = 0.02), supporting its use as a superior therapeutic target compared with LDL-C[9].

Collectively, these findings reinforce that non-HDL-C and apoB are valuable markers for evaluating residual cardiovascular risk among statin-treated patients. Integrating these parameters into clinical practice could improve risk stratification and inform more effective dyslipidemia management strategies.

Diagnosis and risk associations

Recent studies indicate that a non-HDL-C/apoB ratio < 1.4 serves as an independent risk factor for long-term ACM and cardiovascular mortality. This ratio may reflect the quantity of cholesterol-depleted forms of atherogenic lipoprotein particles, thereby suggesting residual risk not fully captured by conventional lipid parameters (e.g., non-HDL-C or apoB alone). Hence, monitoring this ratio may improve identification of individuals with persistent residual risk despite optimal lipid profiles[10].

Furthermore, another study found that an elevated non-HDL-C/HDL-C ratio significantly increased the 1-year risk of stroke recurrence in elderly patients (age > 65 years) with non-disabling ischemic cerebrovascular events. The optimal range for the non-HDL-C/HDL-C ratio should not exceed the second quartile (Q2: 2.256-2.939). Maintaining this ratio within the appropriate range in elderly non-disabling ischemic cerebrovascular events patients may help reduce their 1-year stroke recurrence risk[11].

Additionally, when evaluating non-fasting lipid target attainment in CAD patients, non-HDL-C has demonstrated greater stability than LDL-C. If LDL-C is used to assess postprandial lipid target attainment, lower non-fasting reference thresholds may need to be established[12].

Therapeutic strategies

A randomized single-blind crossover trial involving 12 sedentary but otherwise healthy young adults found that compared with uninterrupted sitting for 6.5 hours following aerobic exercise, interrupting sitting every hour with 4 minutes of walking (total 24 minutes) significantly reduced the post-meal non-HDL-C incremental area under the curve over 7 hours by 36.07 mg × hour/dL (P = 0.030). This reduction was marginally greater than that achieved by an alternative protocol of 8-minute walking breaks every 2 hours (reduction 33.02 mg × hour/dL, P = 0.044), suggesting that more frequent, shorter walking breaks may be more effective in lowering post-prandial non-HDL-C levels in sedentary young adults[13].

A 20-year prospective cohort study of 1988 Greek adults demonstrated that baseline adherence to the Mediterranean diet was associated with an 8% reduction in 20-year CVD risk [each 1-point increase in MedDietScore; highest adherence group vs lowest group: Relative risk (RR) = 0.56; 95% confidence interval (CI): 0.32-0.97]. Participants with consistently high adherence to the Mediterranean diet showed a significantly lower incidence of CVD compared to those with low adherence (9.4% vs 63.3%, P < 0.001). The protective effects may be partially mediated through anti-inflammatory mechanisms [e.g., reduction of high-sensitivity CRP (hsCRP)], regulation of uric acid metabolism, and improvement of renal function[14].

The DIRECT-PLUS randomized controlled trial further supported the benefits of the Green Mediterranean diet (Green-MED), which includes additional daily intake of 28 g of walnuts, green tea, and the aquatic plant Mankai. In a sample of 294 individuals with abdominal obesity or dyslipidemia, the Green-MED group exhibited more pronounced improvements in cardiometabolic risk parameters and gut microbiota composition compared to the standard MED group. Notable microbial shifts included increased abundance of Prevotella species, decreased abundance of Bifidobacterium species, enhanced microbial pathways for branched-chain amino acid (BCAA) catabolism, and suppressed pathways for BCAA biosynthesis. These microbiota changes, along with increased plant-based food intake and reduced meat consumption, were associated with progressive reductions in body weight, blood lipids, and glucose levels. Importantly, microbial alterations partially mediated the relationship between dietary adherence and cardiometabolic risk improvement. These results suggest that the Green-MED diet may optimize metabolic health interventions by specifically modulating gut microbial composition and BCAA metabolic pathways[15].

Lp(a)

Core mechanisms: Lp(a) is a distinct lipoprotein particle synthesized by the liver (Figure 1), structurally composed of a LDL-like core covalently linked via a disulfide bond to apolipoprotein(a) [apo(a)]. The LDL-like particle is rich in cholesteryl esters and anchored by apolipoprotein B-100, whereas apo(a) contains multiple kringle IV (KIV) repeats, particularly KIV type 2. The number of KIV type 2 repeats, determined by the LPA gene, is inversely correlated with plasma Lp(a) concentrations [fewer repeats correspond to higher Lp(a) levels]. Notably, Lp(a) concentrations exhibit considerable interethnic variation[16].

Figure 1 Structural features of lipoprotein(a). Apo(a): Apolipoprotein(a); KIV: Kringles type IV; ApoB-100: Apolipoprotein B-100.

Lp(a) exerts its pathogenic effects mainly through prothrombotic and proatherogenic mechanisms. Lp(a) promotes thrombosis through both coagulation and fibrinolytic pathways[17]. Due to the high structural homology between apo(a) and plasminogen and the presence of a lysine-binding site on apo(a), Lp(a) interferes with plasminogen receptor interaction and its conversion to plasmin, thereby disrupting fibrinolysis and promoting thrombus formation[18]. In addition, Lp(a) alters fibrin clot architecture, resulting in reduced permeability and increased resistance to lysis[19]. It can also stimulate the expression of plasminogen activator inhibitor-1, a key inhibitor of fibrinolysis, which consequently suppresses tissue-type plasminogen activator-induced plasmin generation. Furthermore, by binding to and inhibiting tissue factor (TF) pathway inhibitor - an endogenous inhibitor of TF-mediated coagulation - Lp(a) enhances TF activity. When endothelial cells are damaged, the exposure of TF to the bloodstream activates the extrinsic coagulation pathway[19,20]. Although Lp(a) contributes significantly to arterial thrombosis, genetic studies have not confirmed a causal association between elevated Lp(a) levels and venous thromboembolism risk[21].

Lp(a) can penetrate and accumulate within the arterial intima, where it contributes to foam cell formation and atherosclerotic plaque development. It activates endothelial cells to secrete pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha, as well as adhesion molecules like intercellular adhesion molecule-1. Moreover, Lp(a) promotes monocyte activation and induces pro-inflammatory responses in vascular smooth muscle cells, thereby facilitating the progression of AS[22].

Lp(a) also serves as a carrier of oxidized phospholipids (OxPLs), which play a pivotal role in vascular inflammation. OxPLs promote smooth muscle cell proliferation, foam cell formation, and the release of pro-inflammatory mediators[23]. Schnitzler et al[24] further demonstrated that Lp(a)-associated OxPLs induce cytokine and chemokine secretion, enhancing monocyte adhesion and migration and thereby amplifying vascular inflammation. The pro-inflammatory effects of OxPLs are crucial in the initiation and progression of AS.

Collectively, due to its unique structure and biochemical properties, apo(a) endows Lp(a) with a combination of atherogenic, thrombogenic, and pro-inflammatory characteristics. Beyond the harmful effects of LDL-C, Lp(a) confers additional vascular risk, positioning it as a “triple threat” in the initiation and progression of CVD[25,26].

Diagnosis and risk association: A meta-analysis based on individual participant data from seven randomized controlled trials (n = 29069) demonstrated that elevated Lp(a) is an independent predictor of residual cardiovascular risk in patients with established CVD. While statin therapy significantly reduced LDL-C levels by 39%, it did not affect Lp(a) concentrations. At baseline, Lp(a) levels ≥ 30 mg/dL (compared with < 15 mg/dL) were associated with an 11% increased risk of cardiovascular events (HR = 1.11; 95%CI: 1.00-1.22). This risk increased to 31% for individuals with Lp(a) ≥ 50 mg/dL (HR = 1.31; 95%CI: 1.08-1.58). During treatment, Lp(a) levels ≥ 50 mg/dL remained associated with a 43% higher risk of events (HR = 1.43; 95%CI: 1.15-1.76). These findings suggest that Lp(a) may serve as a dynamic biomarker for monitoring residual risk in statin-treated populations and provide crucial evidence to support clinical trials targeting Lp(a) reduction for improved cardiovascular outcomes[27].

The European Society of Cardiology (ESC) and the European AS Society (EAS) recommend that all individuals should have their Lp(a) levels measured at least once in their lifetime, particularly those with a family history of premature CVD or individuals diagnosed with heterozygous familial hypercholesterolemia[28]. It is important to note that plasma Lp(a) concentrations are predominantly genetically determined, with over 90% of interindividual variability attributable to variations in the LPA gene, including single nucleotide polymorphisms such as rs10455872 and rs3798220. These genetic variants are also independently associated with increased risk of CVD and aortic valve stenosis[29].

Furthermore, the National Lipid Association in its latest scientific statement recommends that for individuals with moderate or borderline cardiovascular risk, Lp(a) concentrations exceeding 50 mg/dL should prompt reassessment of their overall cardiovascular risk profile[30].

Therapeutic strategies

Currently, there is a lack of targeted and widely available pharmacological interventions specifically designed to lower Lp(a) concentrations. Consequently, in individuals with elevated Lp(a) levels, early and intensive management of conventional ASCVD risk factors remains the cornerstone of preventive therapy.

Two proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, including the fully human monoclonal antibodies evolocumab and alirocumab, have been the first agents demonstrated to significantly reduce circulating Lp(a) levels. Meta-analytic data indicate an average reduction of approximately 26.7% (mean reduction 26.7%, 95%CI: -29.5% to -23.9%). However, inter-study heterogeneity in treatment response has been observed, attributable to differences in comparator therapies and treatment duration[31].

A prespecified subgroup analysis from the ODYSSEY outcomes trial assessed the long-term efficacy of alirocumab in post ACS patients revealed that alirocumab conferred incremental clinical benefit in reducing major adverse cardiovascular events (MACE) only among those with at least modestly elevated baseline Lp(a) levels (greater than the median level of 13.7 mg/dL), particularly in the context of optimal LDL-C control < 70 mg/dL[32].

Inclisiran, a chemically synthesized small interfering RNA (siRNA) targeting hepatic PCSK9 mRNA, has recently gained regulatory approval in China. It achieves sustained LDL-C reductions via RNA interference, comparable to those observed with PCSK9 monoclonal antibodies[33]. A significant reduction in Lp(a) was observed in a pre-specified subgroup of the ORION-11 trial, comprising 203 high-risk patients with LDL-C ≥ 2.6 mmol/L despite maximally tolerated statin therapy. This “primary prevention cohort” included individuals with familial hypercholesterolemia, type 2 diabetes mellitus, or ≥ 20% 10-year cardiovascular risk. Baseline median (interquartile range) Lp(a) was 40 (17-148) nmol/L in the inclisiran group (n = 98) and 27 (14-138) nmol/L in the placebo group (n = 105). At day 540, the placebo-corrected reduction was 28.5%. Time-adjusted absolute changes were -12.5 nmol/L (inclisiran) vs +5.5 nmol/L (placebo), with a least-squares difference of -18.1 nmol/L (95%CI: -24.3 to -11.8; P < 0.0001). The marked Lp(a) rise in the placebo group (+ 16.8%) may have amplified the observed effect[34].

In contrast, lipoprotein apheresis an extracorporeal therapeutic modality offers immediate and profound reductions in both LDL-C and Lp(a) levels, typically exceeding 60% per session. Lipoprotein apheresis has been shown to significantly attenuate the incidence of recurrent MACE in high-risk individuals with refractory hyperlipoproteinemia(a), particularly in those with progressive ASCVD despite maximally tolerated lipid-lowering therapy[35].

Pelacarsen, the most extensively studied antisense oligonucleotide (ASO) currently under development for Lp(a) reduction, exerts its therapeutic effect by selectively inhibiting hepatic synthesis of apo(a). It has emerged as a promising strategy for effectively lowering circulating Lp(a) levels[36]. In a randomized controlled trial, subcutaneous administration of Pelacarsen at varying doses and intervals resulted in up to an 80% reduction in plasma Lp(a) concentrations[37].

siRNAs, a class of double-stranded RNA molecules, function by binding to the mRNA of the LPA gene and silencing its expression via a mechanism analogous to ASOs, thereby reducing Lp(a) biosynthesis at the post-transcriptional level[38]. Olpasiran, an siRNA targeting LPA mRNA, demonstrated profound Lp(a) lowering efficacy (up to 98% in individuals with baseline levels > 30 mg/dL) in preclinical and early phase clinical studies, with no major adverse events reported[39]. The phase 2 randomized controlled trial OCEAN(a) DOSE evaluated the efficacy of Olpasiran in 281 patients with established ASCVD and elevated Lp(a) levels (> 65 mg/dL). Participants received subcutaneous Olpasiran at doses of 10 mg, 75 mg, or 225 mg every 12 weeks, or 225 mg every 24 weeks. Results demonstrated dose dependent reductions in Lp(a) of 70.5%, 97.4%, 101.1%, and 100.5%, respectively[40].

Due to its unique molecular structure and strong genetic determination, Lp(a) has become a critical therapeutic target for addressing residual cardiovascular risk. While conventional lipid lowering therapies exert minimal influence on Lp(a), emerging gene-silencing technologies such as ASOs and siRNAs offer transformative potential. Further studies are warranted to assess the impact of these novel agents on hard cardiovascular outcomes and to refine Lp(a) guided precision prevention and treatment strategies.

TG AND TRLS

Core mechanisms

TRLs are apoB-containing particles synthesized by enterocytes and hepatocytes, with TG constituting their core lipid component. During intravascular metabolism, TRLs are progressively hydrolyzed by lipoprotein lipase (LPL), generating remnant lipoproteins enriched in remnant cholesterol (RC). Elevated plasma TRLs and TG promote small dense LDL-C formation via cholesteryl ester transfer protein-mediated lipid exchange and enhance renal clearance of small dense HDL, ultimately reducing circulating HDL-C levels[41].

LPL plays a central role in RC catabolism, and loss-of-function mutations in the LPL gene (Asp9Asn and Asn291Ser) are associated with increased RC concentrations. LPL activity is tightly regulated by modulators: Inhibitory factors include apoC-III and angiopoietin-like protein 3 (ANGPTL3), ANGPTL4, and ANGPTL8, whereas activators include apolipoprotein A (apoA)-V, apoC-II, LMF1, and GPIHBP1[42].

Due to their small particle size (< 70 nm), remnant lipoproteins can readily penetrate the arterial endothelium and are taken up by macrophages and smooth muscle cells, promoting foam cell formation. These particles can further induce endothelial dysfunction by stimulating proinflammatory cytokines (e.g., tumor necrosis factor-alpha, IL-1β), impairing endothelium-dependent vasodilation, and exacerbating oxidative stress, thereby accelerating AS initiation and progression[43]. Moreover, RC may contribute to chronic low-grade vascular inflammation and enhance thrombotic propensity, amplifying atherogenesis[44].

Diagnosis and risk association

Elevated TG reflects an increase in TRLs and their remnants which are consistently associated with residual cardiovascular risk. In the PESA study involving over 3000 asymptomatic individuals, fasting TG > 150 mg/dL was associated with a 35% higher risk of non-coronary subclinical AS, independent of LDL-C levels[45].

Similarly, the retrospective KP-REACH study from Kaiser Permanente Northern California included 373389 primary and 97832 secondary prevention patients. The study found that TG > 150 mg/dL was associated with a 4%-14% increased risk of cardiovascular events, even among statin-treated individuals[46].

Regarding RC, longitudinal data from the MESA study (6720 participants) demonstrated that RC > 29.1 mg/dL conferred a 20% higher CVD risk, increasing to 43% when elevated RC coexisted with high-sensitivity CRP (hsCRP) > 2 mg/L[47]. Large-scale studies have further confirmed that elevated RC is significantly associated with increased coronary heart disease (CHD), MI, and stroke risk, independent of LDL-C[48].

Therapeutic strategies

Current American College of Cardiology (ACC)/American Heart Association (AHA) and ESC/EAS guidelines recommend lifestyle modification and statin therapy as first-line interventions for mild to moderate hypertriglyceridemia (HTG) (TG 150-499 mg/dL). ω-3 fatty acids such as icosapent ethyl (IPE) are reserved as secondary options to optimize TG control. Intensive lifestyle interventions combined with pharmacotherapy, including statins, ω-3 ethyl esters, IPE, and fibrates, are required for severe HTG (ACC/AHA: TG > 500 mg/dL per; ESC/EAS: TG > 880 mg/dL) to mitigate cardiovascular risk and prevent acute pancreatitis[49,28].

In China, the National Medical Products Administration has approved prescription-grade ω-3 fatty acid ethyl ester formulations, including products containing both eicosapentaenoic acid (EPA) and docosahexaenoic acid, and IPE, the EPA-only ethyl ester of EPA at 2-4 g/day for severe HTG (TG ≥ 496 mg/dL) management[33]. The REDUCE-IT trial (8179 statin-treated patients with CVD or type 2 diabetes plus additional risk factors, baseline TG 135-499 mg/dL, LDL-C 41-100 mg/dL) showed that 4 g/day IPE reduced the composite endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, unstable angina, or revascularization) by 25% over 4.9 years[50].

EVAPORATE and other studies revealed IPE’s pleiotropic benefits, including plaque regression, improved endothelial function, and reduced vascular inflammation[51]. IPE is indicated for CVD risk reduction in HTG patients, especially ASCVD or high-risk individuals with residual HTG despite statin therapy.

Fibrates markedly lower TG and modestly increase HDL-C, mainly used in severe HTG. Common agents include fenofibrate, bezafibrate, and gemfibrozil, although gemfibrozil is contraindicated with statins[33].

Emerging therapies targeting TG metabolism, such as apoC-III and ANGPTL3 inhibitors, aim to reduce residual cardiovascular risk. ApoC-III impairs TRL clearance by inhibiting LPL and hepatic lipase activity[52]. ASO and siRNA therapies targeting apoC-III mRNA have been developed. Volanesorsen, an apoC-III-targeted ASO, produced dose-dependent reductions in apoC-III (40%-84%) and TG (38%-72%) in clinical trials involving severe HTG and familial chylomicronemia syndrome (FCS) patients (100-300 mg weekly SC). However, platelet monitoring is required due to thrombocytopenia risk. Olezarsen, another apoC-III ASO, demonstrated improved tolerability with TG reductions of 42%-77% in a phase 1/2a randomized controlled trial (RCT)[53,54]. ARO-APOC3, an siRNA therapy suppressing apoC-III expression, enhanced LPL activity and achieved remarkable apoC-III/TG reductions (FCS: 98%/91%; non-FCS: 96%/90%) in a phase 1/2a RCT[55,56].

ANGPTL3 inhibitors represent another novel approach. ANGPTL3 modulates TRL clearance via LPL and endothelial lipase regulation[57]. Evinacumab, a monoclonal antibody against ANGPTL3, significantly reduced TRLs, apoB, and apoC-III in severe HTG, hypercholesterolemia, and homozygous familial hypercholesterolemia populations[58,59]. Currently approved in the United States and Europe as adjunctive therapy for homozygous familial hypercholesterolemia patients ≥ 12 years old, evinacumab remains limited to LDL-C-lowering indications[60]. Further randomized controlled trials are needed to evaluate apoC-III and ANGPTL3 inhibitors’ effects on TRL-related cardiovascular outcomes and their role in mitigating residual cardiovascular risk.

HDL DYSFUNCTION

Core mechanisms

HDL may lose its protective functions or even acquire detrimental properties during the progression of CHD. HDL dysfunction manifests as impaired capacities in multiple processes, including macrophage cholesterol efflux stimulation, LDL oxidation inhibition, apoptosis regulation, nitric oxide (NO) production, and suppression of endothelial expression of monocyte chemoattractant protein-1 and vascular cell adhesion molecules. Systematic studies on the structure-function relationship of HDL in patients with CHD and diabetes reveal that distinct functional properties of HDL are not intercorrelated but determined by specific molecular characteristics[61].

Notably, HDL from patients with CHD or chronic kidney disease inhibits rather than promotes NO production. Mechanistically, when HDL interacts with the lectin-like oxidized LDL receptor or toll-like receptors (TLR) TLR2/TLR4, it induces phosphorylation of endothelial NO synthase at inhibitory sites rather than activation sites. This shift toward harmful receptor-binding behavior arises from abnormal accumulation of OxPLs, apoA-I, serum amyloid A, or symmetric dimethylarginine[62,63]. From a functional perspective, HDL-C is not a direct pathogenic factor in ASCVD. The pleiotropic functions of HDL are predominantly mediated by the entire particle or its specific components (rather than cholesterol content). Furthermore, low HDL-C levels are strongly associated with elevated TGRLs. Thus, reduced HDL-C is generally considered an indirect marker of increased TGRLs, reflecting heightened ASCVD risk[64].

The apoA-I, the primary protein component of HDL, exerts diverse biological functions. Although epidemiological studies demonstrate an inverse correlation between apoA-I levels and ASCVD risk, but Mendelian randomization analyses fail to establish a causal relationship between apoA-I and cardiovascular outcomes. This suggests that apoA-I levels may merely serve as an indirect indicator of HDL functionality[65].

The functional heterogeneity of HDL is further influenced by its dynamic protein and lipid composition. For instance, HDL particles containing apoE or apoC-I exhibit enhanced anti-atherogenic properties, whereas serum amyloid A-enriched HDL is associated with increased mortality in CHD patients[66]. However, it remains unclear whether these compositional changes directly drive HDL dysfunction or indirectly reflect systemic inflammation. In summary, HDL-C levels are not causative in ASCVD pathogenesis, their role in CVD likely mirrors abnormalities in other lipoproteins or inflammatory states.

Diagnosis and risk association

A retrospective study of 81 patients undergoing continuous ambulatory peritoneal dialysis demonstrated a significant association between the apoA1/apoB ratio and acute coronary syndrome (ACS) risk. During follow-up, 34 patients (41.98%) developed ACS, showing significantly lower apoA1/apoB ratios compared to the non-ACS group (P < 0.01). Patients with apoA1/apoB ≥ 1.105 had a lower ACS incidence (33.33% vs 75.56%, P = 0.03). Cox regression analysis confirmed the apoA1/apoB ratio as an independent predictor of ACS (relative risk = 0.06; 95%CI: 0.00-0.77; P = 0.03), suggesting its utility in cardiovascular risk stratification for continuous ambulatory peritoneal dialysis patients[67].

A study of 355 patients with CAD, diabetes, hyperlipidaemia, hypertension, or metabolic syndrome identified the TG-to-HDL-C ratio as an independent predictor of adverse outcomes in stable CAD patients, with a significant correlation to coronary AS progression[68]. Additionally, a cohort study of 5679 CAD patients undergoing percutaneous coronary intervention (PCI) determined the optimal cutoff value of the white blood cell count-to-HDL-C ratio (WHR) as 8.25 via receiver operating characteristic curve analysis. Patients in the high WHR group exhibited significantly elevated long-term ACM (2-fold increase in ACS patients; 1.5-fold increase in stable CAD patients) and cardiac mortality. WHR independently predicted mortality (P < 0.05), underscoring its role as a biomarker of inflammation-lipid metabolic imbalance particularly valuable for postoperative risk stratification in ACS patients[69].

Emerging evidence further highlights the clinical utility of HDL-C-derived ratios. Wu et al[70] demonstrated an independent association between the remnant cholesterol/HDL-C ratio and coronary computed tomography-derived fractional flow reserve in patients with borderline coronary lesions[70]. Zhu et al[71] established the HDL-C-to-total cholesterol ratio as a robust predictor of repeat revascularization in diabetic patients post-PCI. Xie et al[72] reported that the non-HDL-C/HDL-C ratio outperformed LDL-C in predicting major adverse cardiovascular events (MACE) among non-ST-segment elevation ACS patients with chronic kidney disease[72]. Collectively, these HDL-C-related ratios demonstrate critical diagnostic and prognostic relevance in ASCVD.

Therapeutic strategies

A study of national-level athletes revealed that acute exhaustive exercise increases oxidized HDL lipid concentrations while reducing oxidized LDL lipid levels and the oxidized LDL lipid/oxidized HDL lipid ratio. These findings suggest HDL’s active role in scavenging lipid peroxides during physical exertion. However, the generalizability of these results to the broader population (particularly sedentary individuals or females) remains unverified[73].

Observational studies consistently demonstrate an inverse correlation between HDL-C levels and ASCVD risk. However, clinical trials targeting HDL-C elevation through pharmacological agents (e.g., niacin, fibrates, or cholesteryl ester transfer protein inhibitors) have failed to significantly reduce cardiovascular event rates. This discrepancy implies that merely raising HDL-C concentrations is insufficient for effective cardiovascular prevention[74].

INFLAMMATION AND OXIDATIVE STRESS

Core mechanisms

As shown in Figure 2, the mechanistic overview of residual cardiovascular risk involves lipid - and inflammation-related pathways that are independent of LDL. Systemic vascular inflammation plays a pivotal role in the progression and destabilization of CVD. In affected atherosclerotic lesions, the inflammatory cascade originates from tissue hypoxia and hemodynamic disturbances[75]. These triggers activate the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, which amplifies inflammatory responses through T-lymphocyte and macrophage-derived ILs, ultimately driving hepatic production hsCRP[76]. HsCRP is widely recognized as a robust predictor of CVD events[77].

Figure 2 Mechanistic overview of residual cardiovascular risk (low-density lipoprotein-independent lipid and inflammatory pathways). TRLs: Triglyceride-rich lipoproteins; LPL: Lipoprotein lipase; eNOS: Endothelial nitric oxide synthase; LDL: Low-density lipoprotein; Lp(a): Lipoprotein(a); HDLC: High-density lipoprotein cholesterol; Apo B: Apolipoprotein B; IL: Interleukin; TNF: Tumor necrosis factor; hsCRP: High-sensitivity C-reactive protein; LDL-C: Low-density lipoprotein-cholesterol.

A pooled analysis of 3 randomized controlled trials involving 31245 patients with established or high-risk CVD demonstrated significantly increased adjusted HR for CVD events (HR = 1.31; 95%CI: 1.20-1.43; P < 0.0001), CVD mortality (HR = 2.68; 95%CI: 2.22-3.23; P < 0.0001) and ACM (HR = 2.42; 95%CI: 2.12-2.77; P < 0.0001) when comparing the highest and lowest hsCRP quartiles. These findings solidify hsCRP’s status as the gold-standard inflammatory biomarker and underscore the necessity of anti-inflammatory therapies to mitigate residual cardiovascular risk[78].

The NLRP3 inflammasome hsCRP axis operates through IL-mediated pathways, particularly IL-1β and IL-6 signaling. Activation of the NLRP3 inflammasome promotes IL-1β production, which subsequently induces IL-6 secretion. IL-6 then stimulates hepatic hsCRP synthesis, serving as a marker of systemic inflammation. Consequently, IL-6 acts not only as a central mediator within the inflammatory cascade but also as a potential biomarker of residual inflammatory risk[79].

Collectively, inflammation is integral to AS and CVD progression. Targeted inhibition of key inflammatory mediators such as NLRP3 inflammasome, IL-1β and IL-6 holds promise for developing novel therapies to reduce residual inflammatory risk and improve cardiovascular outcomes.

Diagnosis and risk association

The ACC/AHA guidelines identify hsCRP levels > 2 mg/L as a risk-enhancing factor in patients with intermediate cardiovascular risk[80]. Importantly, the NLRP3 inflammasome-hsCRP axis in CVD pathogenesis is mediated through IL-signaling pathways, particularly the IL-1β/IL-6 cascade. This mechanistic link supports the utility of IL-6 as an adjunctive inflammatory biomarker, enabling the identification and targeting of residual inflammatory risk in clinical practice[79]. Table 1 summarizes the major biomarkers of residual cardiovascular risk and their clinical relevance.

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.

Therapeutic strategies

As shown in Figure 3, lipid- and inflammation-targeting therapies can be integrated into a unified framework that addresses multiple pathways contributing to cardiovascular risk. Canakinumab is a monoclonal antibody targeting IL-1β evaluated in the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study. The trial demonstrated significant reduction in MACEs alongside decreased hsCRP and IL-6 levels without altering circulating lipid profiles, providing direct evidence for inflammation-targeted therapy. However, its clinical adoption remains limited due to increased infection-related mortality risk and high cost[81].

Figure 3 Integrated diagram of lipid and inflammation - targeting therapies. LDL: Low-density lipoprotein; PCSK9: Proprotein convertase subtilisin/kexin type 9; siRNA: Small interfering RNA; IL: Interleukin.

Colchicine is a traditional anti-inflammatory agent that has re-emerged as a potent therapeutic option for CVD. It suppresses NLRP3 inflammasome activation and IL-1β signalling through multiple mechanisms, such as disrupting microtubule polymerization to inhibit inflammasome assembly, reducing the release of pro-inflammatory cytokines (IL-1β, IL-18), and attenuating AS-related inflammation. The COLCOT trial (n = 4745 post-MI patients) showed 0.5 mg daily colchicine significantly reduced MACE risk (HR = 0.77; 95%CI: 0.61-0.96; P = 0.02)[82].

The COLCHICINE-PCI trial demonstrated preoperative colchicine suppressed post-PCI IL-6 and hsCRP elevation within 24 hours (P < 0.05)[83]. Pooled analysis of COLCOT and LoDoCo-MI trials revealed higher hsCRP control rates (≤ 1.0 mg/L) with colchicine (odds ratio = 1.64; 95%CI: 1.07-2.51; P = 0.024)[84]. A meta-analysis of 15 studies confirmed colchicine’s hsCRP-lowering effect (mean reduction: 0.36 mg/dL) and MACE risk reduction[85]. Based on this evidence, the United States Food and Drug Administration approved 0.5 mg daily colchicine in 2023 for ASCVD risk reduction[86].

Bempedoic acid is a non-statin lipid-lowering drug reduced hsCRP by 23.4% (95%CI: -32.6% to -14.2%; P < 0.05) in a meta-analysis (n = 3892), indicating anti-inflammatory properties[87]. While ziltivekimab, a humanized anti-IL-6 monoclonal antibody reduced hsCRP by 66.2%-87.8% (P < 0.0001) in a phase 2 RCT (n = 264) chronic kidney disease patients with hsCRP ≥ 2 mg/L), while lowering fibrinogen, serum amyloid A, and Lp(a)[88]. Despite multiple anti-inflammatory candidates under investigation, colchicine remains the only approved therapy for residual inflammatory risk management in CVD. Table 2 summarizes the current and emerging therapeutic strategies, highlighting their mechanisms of action and clinical relevance in residual cardiovascular risk reduction. As summarized in Table 3, lipid- and inflammation-targeting strategies differ in their mechanisms, therapeutic targets, and clinical evidence supporting residual risk reduction.

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.

CONCLUSION

Residual cardiovascular risk remains a critical challenge in achieving comprehensive prevention and management of atherosclerotic events. Deciphering the core mechanisms by which residual risk factors drive plaque progression is essential for developing precision clinical strategies and novel therapeutics. However, most current RCTs still emphasize lipid profile modulation (particularly LDL-C reduction) or isolated targeting of individual risk factors, which limits the overall preventive impact. Therefore, future studies should adopt integrative approaches to quantify the specific contributions of all residual risk components.

Recognition of residual cardiovascular risk signifies that secondary prevention of CVD has entered an era of integrated risk management. This conceptual shift moves beyond the traditional “LDL-C lowering” paradigm toward a multi-target and comprehensive management strategy. Residual risk should now be understood as an interconnected network involving lipid disorders, inflammation, thrombosis, and metabolic dysregulation. In this context, clinicians should not be content with LDL-C goal attainment alone but rather adopt a “residual risk perspective”. They are encouraged to proactively screen and manage TG, Lp(a), glucose, and inflammatory markers to uncover and address hidden risk pathways.

Building upon this new paradigm, precision subtyping based on biomarkers and genetic information will become a cornerstone of future prevention. Such stratification will enable individualized treatment strategies tailored to patients with distinct residual risk profiles. Moreover, emerging agents that specifically target refractory risk factors such as Lp(a) are expected to fundamentally reshape the prevention and treatment landscape in the coming years.

Within this evolving framework, traditional Chinese medicine offers unique advantages through its multi-target regulatory potential, encompassing lipid modulation, endothelial protection, and anti-inflammatory or antioxidant effects. A multicentre prospective cohort study further showed that adding Tongxinluo Capsules to standard therapy significantly improved blood lipid profiles and hemodynamic parameters in patients with chronic coronary syndrome. Over 3-12 months, the Tongxinluo group exhibited more pronounced reductions in TC and LDL-C, as well as more stable improvements in mean platelet volume and hematocrit, compared with the control group (all P < 0.05). However, the study did not evaluate 1-year MACE outcomes[89]. Similarly, adjunctive therapy with Guanxin Danshen Dripping Pills and ticagrelor enhanced angina symptom relief (94.34% vs 81.13%) and decreased inflammatory and thrombotic biomarkers compared with monotherapy[90]. To bridge traditional wisdom and evidence-based medicine, future RCTs should further elucidate TCM’s mechanistic effects on residual risk pathways such as cholesterol transport, plaque stabilization, and inflammation control.

However, despite these promising findings, current TCM studies remain limited by small sample sizes, short follow-up periods, and insufficient standardization in formulations and syndrome differentiation. High-quality, large-scale RCTs are still needed to verify independent efficacy, ensure long-term safety, and clarify mechanisms within an evidence-based framework for residual risk reduction.

Building on these findings, the integration of TCM and Western medicine represents a promising direction for addressing residual cardiovascular risk. TCM provides multi-target regulatory effects that complement the precision, standardization, and mechanistic clarity of Western therapeutics. When combined, these complementary approaches can establish a synergistic and patient-centered framework for prevention and treatment. To realize this potential, further efforts are needed to standardize formulations, unify evaluation criteria, and conduct rigorous randomized controlled trials to provide robust clinical evidence. Ultimately, the integration of TCM and Western medicine is expected to create a comprehensive and evidence-based strategy for residual risk reduction, contributing to more precise and holistic cardiovascular protection in the future.