High-Sensitivity C-Reactive Protein and Residual Inflammatory Risk in Coronary Artery Disease: The Pathophysiology, Prognosis, and Emerging Therapies

Abstract

Inflammation plays a crucial role in the initiation, progression, and destabilization of atherosclerotic plaques and it contributes to recurrent cardiovascular events in patients with coronary artery disease (CAD). High-sensitivity C-reactive protein (hsCRP) is a well-established biomarker of systemic inflammation and it is a predictor of adverse outcomes, independent of low-density lipoprotein cholesterol (LDL-C) levels. Elevated hsCRP levels are consistently associated with higher event rates in both chronic and acute coronary syndromes, thus reflecting the residual inflammatory risk not addressed by lipid-lowering therapy or revascularization. Imaging studies have revealed that higher hsCRP levels correlate with a greater plaque burden and vulnerability. Recent trials have shown that anti-inflammatory therapies, including low-dose colchicine and interleukin-6 inhibition, can reduce this residual risk, while agents such as glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter 2 inhibitors, and bempedoic acid offer additional anti-inflammatory effects. The integration of anti-inflammatory strategies with intensive lipid management may thus provide additional cardiovascular benefits.

Abbreviations: ACS = acute coronary syndrome, CAD = coronary artery disease, hsCRP = high-sensitivity C-reactive protein, IVUS = intravascular ultrasound, MI = myocardial infarction, OCT = optical coherence tomography, PCI = percutaneous coronary intervention, TCFA = thin-cap fibroatheroma, GLP-1 = glucagon-like peptide-1, SGLT2 = sodium–glucose cotransporter 2

1.Introduction

Coronary artery disease (CAD) remains a leading cause of mortality worldwide despite the widespread use of lipid-lowering therapies and coronary revascularization ¹⁾ . In addition to traditional risk factors, such as hypertension, diabetes mellitus, dyslipidemia, and smoking, inflammation plays a central role in the initiation, progression, and destabilization of atherosclerotic plaques ²⁾ . High-sensitivity C-reactive protein (hsCRP) is a marker of enhanced inflammatory reaction and it is associated with the incidence of CAD ³⁾ . Several studies have demonstrated the impact of high hsCRP levels on the incidence of new and/or recurrent cardiovascular events, irrespective of low-density lipoprotein cholesterol (LDL-C) levels ^{4 - 6)} . Thus, high hsCRP levels have been recognized as a marker of residual inflammatory risk, particularly in patients with established CAD. The higher incidence of recurrent coronary events in patients with CAD and high hsCRP levels is considered to be the result of chronic vascular inflammation and subsequent coronary plaque instability ^{7 , 8)} . The prevalence of thin-cap atheroma prone to plaque rupture and sudden death in patients with high hsCRP levels has been reported ⁹⁾ . Recent randomized clinical trials have investigated whether targeting inflammation can improve the clinical outcomes of patients with CAD. In this review, we summarize the current evidence regarding the prognostic significance of inflammation in patients with chronic and acute coronary syndromes. We also discuss emerging anti-inflammatory therapies and their potential to reduce the residual inflammatory risk and improve clinical outcomes. The overall context of this study is summarized in Fig.1 .

Fig.1. Residual inflammatory risk and potential therapies.

ACS, acute coronary syndrome; CCS, chronic coronary syndrome; CVD, coronary vascular disease; GLP-1RA, glucagon-like peptide-1 receptor agonist; hsCRP, high-sensitivity C-reactive protein.

2.Chronic Coronary Syndrome

Elevated hsCRP levels are consistently linked to an increased cardiovascular risk and plaque vulnerability in chronic coronary syndrome (CCS). Higher hsCRP levels correlate with greater plaque burden, high-risk plaque features, and worse outcomes, even with optimal lipid lowering or post-percutaneous coronary intervention (PCI), indicating residual inflammatory risk. Anti-inflammatory therapies, notably low-dose colchicine and ziltivekimab, have shown substantial reductions in hsCRP and cardiovascular events, with colchicine now receiving Class IIa guideline recommendation ¹⁰⁾ . These findings support hsCRP measurement for risk stratification and highlight the potential benefit of combining lipid-lowering therapy with targeted anti-inflammatory therapy to reduce recurrent events in patients with CCS.

Impact of hsCRP Levels on Clinical Outcomes

Elevated hsCRP levels have been consistently associated with an increased risk of cardiovascular events in patients with CCS. Sinning et al. assessed the risk of cardiovascular events during a median follow-up of 3.5 years in 1,806 patients with CCS, according to baseline levels of CRP ¹¹⁾ . They showed that each one standard deviation increase in CRP level was associated with a 15% increase in the risk of CAD. Sabatine et al. investigated the incidence of cardiovascular events according to hsCRP levels in 3,771 patients with CCS ¹²⁾ . They reported that compared with patients with an hsCRP ＜1 mg/L, those with an hsCRP of 1–3 mg/L had a 57% increased risk of events, and those with an hsCRP ＞3 mg/L had a 78% increased risk of events. These results are supported by meta-analyses ¹³⁾ . Van Holten et al. showed that higher hsCRP levels consistently indicated an increased risk of CAD in patients with CCS. Therefore, elevated hsCRP levels have been recognized as a marker of high risk for the incidence of cardiovascular disease, in addition to the presence of chronic inflammation in the vascular system ¹⁴⁾ . Moreover, these findings suggest the usefulness of hsCRP measurements for risk stratification of recurrent cardiovascular events among patients with CCS in daily clinical practice. In fact, an evaluation of the hsCRP levels is recommended for patients with CCS, with a Class IIa recommendation in the Guidelines for the Management of Chronic Coronary Syndromes provided by the European Society of Cardiology ¹⁰⁾ .

Impact of hsCRP Levels on Plaque Characteristics

Several studies have investigated coronary plaque characteristics in CCS patients with elevated CRP levels. Pedersen et al. demonstrated that a higher hsCRP level (＞2.0 mg/L) was associated with an increased total plaque burden and degree of luminal stenosis in coronary atherosclerotic lesions assessed by computed tomography (CT) in patients with suspected CAD ¹⁵⁾ . In addition, they reported that CRP ＞2.0 mg/L was associated with a higher prevalence of high-risk plaque, including low-attenuation plaque, positive remodeling, and napkin-ring sign. Similarly, Dai et al. reported that the prevalence of low attenuation plaque and napkin-ring sign was significantly higher in patients with a higher hsCRP (＞3.0 mg/L) than in those with a lower hsCRP (≤ 3.0 mg/L) among patients with CCS in a study using coronary CT ¹⁶⁾ . The association between hsCRP levels and plaque vulnerability in patients with CCS has also been elucidated through intra-coronary imaging modalities, including intravascular ultrasound (IVUS) ^{17 , 18)} and optical coherence tomography (OCT) ^{19 , 20)} . Kubo et al. investigated the morphological characteristics of culprit lesions in patients with stable angina according to CRP levels using virtual histology IVUS ¹⁷⁾ . The authors demonstrated a longer lesion with greater necrotic tissue in patients with elevated hsCRP (≥ 3.0 mg/L). Katamine et al. investigated the morphological characteristics of culprit vessel coronary plaques in patients with stable coronary disease according to CRP levels using OCT ¹⁹⁾ . The authors reported that higher hsCRP (≥ 0.2 mg/dL) were associated with a higher prevalence of vulnerable characteristics, including thin-cap fibroatheroma (TCFA), plaques with macrophages, and layered plaques at any culprit or non-culprit plaques. They further demonstrated that patients with a combination of higher hsCRP levels and the presence of TCFA in the culprit vessel had a higher incidence of myocardial infarction (MI) than those without a median follow-up of 938 days. The presence of TCFA and macrophages is an established marker of future risk of recurrent cardiovascular events ^{21 - 25)} . In addition, the presence of layered plaques is a characteristic of vulnerable plaques ^{26 , 27)} . Taken together, these findings suggest that an elevated hsCRP level is closely associated with plaque instability. This supports the role of inflammation in plaque destabilization and subsequent coronary events.

Residual Inflammatory Risk under Lipid-Lowering Therapy or Coronary Intervention

Several studies have demonstrated the impact of higher hsCRP levels on the incidence of new and/or recurrent cardiac events among patients with CCS, irrespective of lipid-lowering therapy ^{6 , 28 - 30)} or a history of PCI ^{5 , 31)} . Nozue et al. investigated the risk of cardiovascular events during a median follow-up of 3.5 years in 169 CCS patients with 8 months of statin therapy classified by hsCRP levels of ＜1.0, 1.0, 3.0, ＞3.0 mg/dL ²⁸⁾ . They reported an incremental frequency of cardiovascular events according to the increase in hsCRP levels. In addition, Pradhan showed that CCS patients with hsCRP ＞3.0 mg/L (median LDL-C 41.7 mg/dL) had a 62% increase in the risk of future cardiovascular events compared to those with hsCRP ＜1.0 mg/L, even when low levels of LDL-C were achieved by lipid-lowering agents with both statin therapy and a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitior ²⁹⁾ . A recent study reported that the hsCRP level was a stronger predictor of future cardiovascular events and mortality than LDL-C level among statin-treated patients ⁶⁾ . Ridker et al. evaluated the relative importance of hsCRP and LDL-C as determinants of the risk for cardiovascular events among 31,245 patients with CCS receiving statins. They demonstrated that the risk of cardiovascular events including cardiovascular death and all-cause death were significantly higher in patients with both residual cholesterol risk and residual inflammatory risk (hsCRP ≥ 2.0 mg/L and LDL-C ≥ 70 mg/dL) than in patients with neither residual inflammatory risk nor residual cholesterol risk (hsCRP ＞2.0 mg/L and LDL-C ＜70 mg/dL). In addition, the authors showed that patients with a higher hsCRP (≥ 2.0 mg/dL) had a two-fold increased risk of cardiovascular death and all-cause death compared to those with a lower hsCRP (＜2.0 mg/dL), irrespective of the LDL-C levels. Park et al. investigated the risk of cardiovascular events during a median follow-up of 3.9 years in 2,691 patients treated with PCI who had baseline CRP measurement ³²⁾ . They showed that the incidence of stent thrombosis, death, and MI was significantly higher in patients with higher hsCRP (≥ 3.0 mg/L) than in those with lower hsCRP (＜3.0 mg/L). The impact of persistently elevated hsCRP levels on the incidence of recurrent cardiovascular events in patients who undergo PCI has also been demonstrated in several studies ^{5 , 30 , 31)} . Kalkman et al. measured the hsCRP levels at least twice in patients undergoing PCI and reported a higher incidence of all-cause mortality and MI at 1 year in patients with persistent elevation of hsCRP (≥ 2.0 mg/L) than in those without persistent elevation. Iwata et al. further demonstrated that Japanese CCS patients with persistently low-grade inflammation (hsCRP ≥ 0.5 mg/L) remained increased cardiovascular risk, regardless of LDL-C levels treated with statin therapy ³⁰⁾ . These findings suggest that elevated hsCRP levels indicate residual inflammatory risk, which is not addressed by lipid-lowering therapy or coronary revascularization.

Anti-inflammatory Therapy in Patients with CCS

Anti-inflammatory therapy has recently emerged as an effective strategy for reducing the cardiovascular risk in patients with CCS. Key anti-inflammatory therapies, their potential mechanisms of action, major clinical evidence, and cardiovascular outcomes are summarized in Table 1 . The recommendations of the guidelines are summarized in Table 2 . The LODOCO2 trial demonstrated that low-dose colchicine reduced the risk of cardiovascular death, MI, ischemic stroke, or ischemia-driven coronary revascularization by 31% compared with placebo during a median follow-up of 29 months in patients with stable atherosclerotic CAD ³³⁾ . Although non-cardiovascular mortality was slightly increased, the incidence of pneumonia and gastrointestinal adverse effects was not significantly different from that of the placebo. In addition, a meta-analysis including over 12,000 patients in 11 randomized controlled trials supported the efficacy of colchicine in reducing the risks of MI, stroke, and unstable angina-driven revascularization, with no significant differences in cardiovascular or all-cause mortality when the daily doses did not exceed 0.5 mg ³⁴⁾ . Based on these findings, low-dose colchicine (0.5 mg daily) is recommended for patients with CCS by several clinical guidelines ^{10 , 35)} . In particular, the recent European Society of Cardiology guidelines upgraded the recommendation for the use of colchicine for CCS patients from Class II B to Class II A. Recently, the RESCUE study evaluated the efficacy of Ziltivekimab, a novel human antibody directed against the IL-6 ligand, in reducing inflammation in patients at high cardiovascular risk with elevated hsCRP levels (≥ 2.0 mg/L) ³⁶⁾ . This study demonstrated that the median hsCRP levels decreased by 77% in the 7.5 mg group, 88% in the 15 mg group, and 92% in the 30 mg group, compared with 4% in the placebo group at 12 weeks. The drug was well tolerated without any serious side effects.

Table 1. Potential anti-inflammatory therapies for coronary artery disease.

Drug	Potential mechanism	HsCRP reduction	Clinical outcome	Trial	Study cohort
Ziltivekimab	IL-6 ligand inhibition	↓ 77~92%	Unassessed	RESCUE 36) (2021)	CVD high risk, hsCRP ≥ 2 mg/L
Canakinumab	IL-1β inhibition	↓ 26~41%	↓ MACE 15%	CANTOS 47) (2017)	Post-MI, hsCRP ≥ 2 mg/L
GLP-1RA	NF-κβ inhibition	↓ 37.8%	↓ MACE 20%	SELECT 53) (2023)	CVD, Obesity
Statin	NF-κβ suppression	↓ 37%	↓ MACE 44%	JUPITER 4) (2008)	Primary prevention, hsCRP ≥ 2 mg/L
Bempedoic acid	Unknown	↓ 21.6%	↓ MACE 13%	CLEAR Outcomes 67) (2023)	Statin-intolerant CVD
Colchicine	NLRP3 inflammasome inhibition	↓ 10.1%	↓ MACE 23%	COLCOT 49) (2019)	Post AMI ＜30 days
PCSK9i	Local anti-inflammatory effects	Minimal	↓ MACE 15%	FOURIER 61) (2018)	CVD, High LDL-C
CETP inhibitors	LDL-C and HDL-C modulation	Unassessed	↓ MACE 9%	REVEAL 72) (2017)	CVD
SGLT2i	NLRP3 inflammasome inhibition	Unassessed	↓ MACE 14%	EMPA-REG OUTCOME 51) (2015)	T2D, CVD high risk
Methotrexate	Broad-spectrum cytokine suppression	No effect	No benefit	CIRT 48) (2018)	CAD, metabolic risk

AMI, acute myocardial infarction; CAD, coronary artery disease; CCS, chronic coronary syndrome; CVD, coronary vascular disease; GLP-1RA, glucagon-like peptide-1 receptor agonist; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; KCCQ; Kansas City Cardiomyopathy Questionnaire; IL-6, interleukin-6; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiac events; NF-κ B, Nuclear factor kappa B; NLRP3, NOD-like receptor family pyrin domain containing 3; PCSK9i, proprotein convertase subtilisin-kexin type 9 inhibitor; SGLT2i, Sodium–glucose cotransporter 2 receptor inhibitor; T2D, type 2 diabetes mellitus.

Table 2. Anti-inflammatory therapies recommended in guidelines.

Patient	Guideline	Drug	Class	Level	Description
CCS	ESC guideline 10)	Low-dose colchicine	IIa	A	In CCS patients with atherosclerotic CAD, low-dose colchicine (0.5 mg daily) should be considered to reduce myocardial infarction, stroke, and need for revascularization.
	US guideline 35)	Colchicine	IIb	B-R	In patients with CCD, the addition of colchicine for secondary prevention may be considered to reduce recurrent ASCVD events.
ACS	ESC guideline 73)	Low-dose colchicine	IIb	A	Low-dose colchicine (0.5 mg once daily) may be considered, particularly if other risk factors are insufficiently controlled or if recurrent cardiovascular disease events occur under optimal therapy.
	US guideline 74)	Low-dose colchicine	IIb	B-R	In patients after ACS, low-dose colchicine may be reasonable to reduce risk of MACE.

ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CCD, chronic coronary disease; CCS, chronic coronary syndrome; CVD, coronary vascular disease; ESC, European Society of Cardiology; MACE, major adverse cardiac events; US, United States.

Based on these findings, a combination of intensive lipid-lowering and anti-inflammatory therapies based on LDL-C and hsCRP levels may be a potentially effective strategy to reduce the risk of cardiovascular events in patients with CCS ³⁷⁾ .

3.Acute Coronary Syndrome

High hsCRP levels in patients with acute coronary syndrome (ACS) are strongly linked to increased cardiovascular events, mortality, and vulnerable plaque features. hsCRP serves as a prognostic marker and residual inflammatory risk indicator, prompting recommendations for measurement in ACS ³⁸⁾ . Although statins lower the LDL-C and hsCRP levels, residual inflammation often persists. Other anti-inflammatory therapies, such as canakinumab and low-dose colchicine, reduce both the hsCRP levels and cardiovascular events in selected settings, although the trial results are mixed. These findings support the targeting of both cholesterol and inflammation to optimize the secondary prevention of ACS.

Impact of hsCRP Levels on Clinical Outcomes

The association between higher hsCRP levels and an increased incidence of CAD in patients with ACS has been demonstrated in several studies ^{39 - 44)} . Lindahl et al. investigated the incidence of cardiovascular events according to the baseline hsCRP levels in patients with unstable angina ³⁹⁾ . They showed that the incidence of cardiac death was significantly higher in patients with CRP levels ＞10 mg/L than in those with CRP levels of 2.0 10 mg/L or those with CRP levels ＜2.0 mg/L during a median 37-month follow-up period. Schiele et al. investigated the incidence of 30-day mortality according to the hsCRP level at admission in patients with ACS. They reported that the risk of 30 days mortality was approximately 4-fold greater in the quartile of CRP levels (＞2.2 mg/L) than in the other quartiles ⁴²⁾ . In addition, a meta-analysis of 20 longitudinal studies comprising 2,789 cases from 17,422 patients demonstrated that patients with higher CRP levels (3.1–10.0 and ＞10.0 mg/L after ACS were associated with 1.40-fold and 2.18-fold higher risks of worse adverse outcomes than those with lower CRP levels ≤ 3.0 mg/L ⁴⁴⁾ . These findings suggest the usefulness of hsCRP measurement for the risk stratification of cardiovascular events among patients with ACS. Thus, high hsCRP levels are recognized as a residual inflammatory risk, even in patients with ACS. The Centers for Disease Control and Prevention of America and the American Heart Association recommend that CRP be measured in patients with ACS as an independent marker of prognosis ³⁸⁾ .

Impact of hsCRP Levels on Plaque Characteristics

The association between high hsCRP levels and coronary plaque characteristics in patients with ACS has been demonstrated in several studies. Burke et al. investigated the differences in coronary histopathological findings among 302 autopsies according to the CRP levels ⁹⁾ . The mean staining intensity for CRP of macrophages and lipid cores in plaques was significantly greater in the higher hsCRP group (＞3.0 µg/mL) than in the lower hsCRP group (≤ 3.0 µg/mL). They also reported that the mean number of thin-cap atheromas was significantly greater in the higher hsCRP group than in the lower hsCRP group in coronary deaths. Sano et al. investigated the differences in plaque morphology at the culprit lesions among patients with acute MI according to CRP levels using intravascular ultrasound (IVUS) ⁴⁵⁾ . The authors showed that the prevalence of plaque rupture was higher in the elevated CRP level group (≥ 3.0 mg/L) than in the normal CRP level group. The association between CRP level and plaque vulnerability in non-culprit plaques in patients with ACS has also been demonstrated. Fröbert et al. investigated the prevalence of high-risk plaques in non-culprit coronary lesions in patients with non-ST-segment elevation myocardial infarction classified by hsCRP levels ＜1.0, 1.0, 3.0, ＞3.0 mg/dL using near-infrared spectroscopy and intravascular ultrasound. They reported an incremental frequency of highly lipidic lesions (maximum 4 mm lipid-core burden index [LCBI_4mm] ≥ 324.7) with ≥ 70% burden in non-culprit coronary lesions according to the increase in hsCRP levels. Taken together with these findings, the higher incidence of recurrent cardiovascular events in patients with high hsCRP levels can be attributed to the higher prevalence of vulnerable plaques, including non-culprit ones.

Anti-inflammatory Therapy in Patients with ACS

Statins are the foundation of the secondary prevention in patients with ACS, primarily because of their low-density lipoprotein cholesterol (LDL-C)-lowering effects. In addition, statins exert anti-inflammatory effects, including reduction in hsCRP levels. The PROVE-IT TIMI 22 trial demonstrated that intensive statin therapy with atorvastatin not only achieved greater LDL-C reduction compared to moderate-intensity pravastatin but also significantly lowered hsCRP levels ⁴⁶⁾ . Additionally, patients who achieved both LDL-C ＜70 mg/dL and hsCRP ＜2.0 mg/L had the lowest rates of recurrent cardiovascular events. These findings highlight the prognostic importance of targeting both cholesterol and inflammation in ACS patients. Similarly, the JUPITER trial showed that rosuvastatin significantly reduced cardiovascular events in apparently healthy individuals with normal LDL-C levels but elevated hsCRP (≥ 2.0 mg/L), further supporting the dual role of statins in modulating lipid and inflammatory pathways ⁴⁾ . Despite the widespread use of statins, a considerable proportion of patients continue to exhibit a residual inflammatory risk, as reflected by persistently elevated hsCRP levels. To address this issue, several clinical trials have investigated the efficacy of anti-inflammatory therapies in ACS patients. The CANTOS study investigated the effects of the IL-1β inhibitor canakinumab in 10,061 patients with a history of MI and persistently elevated hsCRP level (≥ 2.0 mg/L). Patients were randomized to receive 50 mg, 150 mg, or 300 mg of canakinumab or placebo ⁴⁷⁾ . There was a significant reduction in hsCRP levels in the three canakinumab groups compared to the baseline and placebo groups. In addition, the primary endpoint (a 2-year composite of non-fatal MI, non-fatal stroke, and cardiovascular death) was reduced by 15% in the 150 mg canakinumab group compared with the placebo group. However, there was an increase in fatal infections in the canakinumab group compared to the placebo group. The CIRT trial investigated the effects of low-dose methotrexate (15-20 mg once weekly) in 4,786 patients with previous MI or multivessel coronary disease and additional type 2 diabetes or metabolic syndrome. Low-dose methotrexate did not reduce the hsCRP levels and it also did not result in fewer cardiovascular events than placebo ⁴⁸⁾ . The COLCOT trial evaluated the efficacy of low-dose colchicine (0.5 mg daily) in 4,745 patients with a recent MI within 30 days ⁴⁹⁾ . Although no significant difference in the change in hsCRP was observed between the colchicine group and placebo, the colchicine-treated group experienced a 23% lower incidence of cardiovascular events compared to the placebo group over a median of 23 months. The incidence of pneumonia (0.9 vs. 0.4%, P = 0.03) was significantly higher in the colchicine-treated group than in the placebo group. Based on these findings, in 2023, the U.S. Food and Drug Administration approved the use of low-dose colchicine to reduce the risk of cardiovascular events in adult patients with established atherosclerotic disease or multiple risk factors for cardiovascular disease. Recently, the CLEAR trial examined the effects of colchicine in 7,000 patients with MI treated with PCI ⁵⁰⁾ . The least-squares mean CRP level at 3 months, adjusted according to the baseline values, was 30% lower in the colchicine group than in the placebo group. However, no significant difference in the incidence of major adverse cardiovascular events was observed during the median 3-year follow-up period. The incidence of diarrhea (10.2 vs. 6.6%, p＜0.001) was significantly higher in the colchicine group than that in the placebo group, although the incidence of serious infections (2.5 vs. 2.9%, p = 0.85) was comparable. These findings raise questions about the consistency of colchicine’s cardiovascular benefits and suggest that patient selection or treatment timing may influence its efficacy.

4.Anti-inflammatory Effects of Other Agents

A variety of other pharmacological agents have been evaluated for their potential to reduce residual inflammatory risk in CAD, targeting diverse inflammatory pathways ( Table 1 ) .

Glucagon-like Peptide-1 Receptor Agonist

Agonists of the glucagon-like peptide-1 (GLP-1) receptor are used in the management of type 2 diabetes and overweight or obesity and have been shown to reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes or obesity at high cardiovascular risk ^{51 - 54)} . The SELECT trial investigated the efficacy of weekly subcutaneous semaglutide 2.4 mg among 17,604 patients with a BMI of 27 or greater and preexisting cardiovascular disease but without diabetes ⁵³⁾ . The incidence of cardiovascular events was 20% lower in the semaglutide group than in the placebo group over a median follow-up of 39.8 months. Additionally, this trial showed that semaglutide significantly lowered hsCRP levels by 37.8%. Recently, the SOUL trial demonstrated that once-daily oral semaglutide (maximal dose, 14 mg) reduced the risk of MACE by 14% compared with placebo during a median follow-up of 49.5 months in patients with type 2 diabetes and established atherosclerotic cardiovascular disease, chronic kidney disease, or both ⁵⁴⁾ . This trial also showed that oral semaglutide maintained lower hsCRP levels over 104 weeks compared with placebo (geometric mean level at week 104 1.56 vs. 2.01 mg/L). These findings suggest that GLP-1 receptor agonists have anti-inflammatory effects in addition to metabolic benefits.

Sodium-glucose Cotransporter 2 inhibitor

Sodium–glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering agents that have demonstrated significant cardiovascular and renal benefits in patients with type 2 diabetes and heart failure. Large randomized trials, such as EMPA-REG OUTCOME ⁵⁵⁾ and DAPA-HF ⁵⁶⁾ have shown reductions in major adverse cardiovascular events and hospitalization for heart failure, irrespective of glycemic control. However, these trials did not specifically assess the hsCRP level reduction as the primary endpoint. Several studies have suggested that SGLT2 inhibitors exert anti-inflammatory effects. Hattori et al. showed that empagliflozin (10 mg daily) treatment for 12 months significantly reduced hsCRP levels by 54% compared to baseline in Japanese patients with type 2 diabetes and insulin resistance ⁵⁷⁾ . A systematic review of 23 clinical studies with 1,654 patients demonstrated that SGLT2 inhibitors significantly reduced the hsCRP levels independent of HbA1c reduction or other confounder ⁵⁸⁾ . These findings suggested that SGLT2 inhibitors may exert anti-inflammatory effects.

Proprotein Convertase Subtilisin-Kexin Type 9 Inhibitor

PCSK9 inhibitors are monoclonal antibodies that significantly lower LDL-C levels and reduce cardiovascular events ⁵⁹⁾ . However, its impact on systemic inflammation remains unclear. In the FOURIER trial, treatment with evolocumab reduced LDL-C levels by 59% at 48 weeks compared to a placebo, although there was no significant effect on hsCRP levels ⁶⁰⁾ . Furthermore, a meta-analysis of over 4,100 patients in 10 randomized controlled trials demonstrated that PCSK9 monoclonal antibodies, including evolocumab and alirocumab, did not significantly reduce hsCRP levels, irrespective of treatment duration, agent type, or patient characteristics ⁶¹⁾ . These findings suggest that although PCSK9 inhibitors effectively reduce residual cholesterol risk, they do not directly address residual inflammatory risk in patients with CAD. Nonetheless, several studies have indicated potential localized anti-inflammatory effects of PCSK9 inhibitors within the vascular wall. Marfella et al. demonstrated that PCSK9 inhibitor therapy was associated with significant reductions in atherosclerotic plaque expression of the NLRP3 inflammasome, caspase-1, IL-1β, TNF-α, and NF-κB compared to other lipid-lowering therapies in patients undergoing carotid endarterectomy, although hsCRP levels remained comparable between the two groups ⁶²⁾ . Preclinical studies have also shown that PCSK9 may contribute to vascular inflammation and endothelial dysfunction, independent of LDL receptor degradation ⁶³⁾ . Taken together, these findings suggest that PCSK9 inhibitors may provide vascular benefits independent of lipid-lowering, although further research is required to clarify their role in modifying residual inflammatory risk and improving the clinical outcomes.

Bempedoic Acid

Bempedoic acid is an oral ATP citrate lyase inhibitor that lowers the low-density lipoprotein cholesterol (LDL-C) levels by targeting cholesterol synthesis upstream of HMG-CoA reductase ⁶⁴⁾ . Its activation occurs predominantly in the liver but not in the skeletal muscle, which may reduce the potential for adverse effects on muscles ⁶⁵⁾ . The CLEAR Outcomes trial investigated the efficacy of bempedoic acid (180 mg daily) in 13,970 statin-intolerant patients with or at a high risk for cardiovascular disease ⁶⁶⁾ . The incidence of cardiovascular events was 13% lower in the bempedoic acid group than in the placebo group over a median follow-up of 40.6 months. The trial also demonstrated a significant reduction in hsCRP levels in the bempedoic acid group compared to the placebo group, thus supporting its potential anti-inflammatory effects. Both LDL-C and hsCRP lowering effects were confirmed in Japanese patients with hypercholesterolemia in the CLEAR-J trial ⁶⁷⁾ . These findings suggest that bempedoic acid may contribute not only to lipid reduction but also to the attenuation of residual inflammatory risk in patients with CAD.

Cholesteryl Ester Transfer Protein Inhibitors

Cholesteryl ester transfer protein (CETP) inhibitors have been developed to modify the lipid profiles by increasing the high-density lipoprotein cholesterol (HDL-C) levels and reducing the LDL-C levels ^{68 , 69)} . Obicetrapib is a highly selective cholesteryl ester transfer protein inhibitor with hydrophilicity that accommodates more avid and selective binding to the CETP tunnel ⁷⁰⁾ . The REVEAL trial showed a 9% relative risk reduction in major coronary events with anacetrapib compared to a placebo over a median follow-up of 4.1 years in more than 30,000 patients with established atherosclerotic vascular disease ⁷¹⁾ . Recently, Nicholls et al. conducted a phase 3 clinical trial in patients with familial hypercholesterolemia or a history of atherosclerotic cardiovascular disease, whose LDL-C levels remained above the target levels despite high-intensity statin therapy ⁷²⁾ . They reported that the addition of obicetrapib resulted in an approximately 30% reduction in the LDL-C levels after 84 days of treatment. Although obicetrapib has demonstrated substantial LDL-C reduction, no data on its effects on hsCRP have been reported. Future large-scale clinical trials may clarify whether CETP inhibition also addresses residual inflammatory risk.

Conclusions

Inflammation plays a central role in the progression and destabilization of atherosclerotic plaques, contributing to recurrent cardiovascular events in patients with coronary artery disease. A higher hsCRP level is recognized as a marker of residual inflammatory risk, irrespective of lipid control or revascularization. Recent advances in anti-inflammatory therapies, including colchicine, ziltivekimab, SGLT2 inhibitors, GLP-1 receptor agonists, and bempedoic acid, have provided promising strategies to reduce both cholesterol-related and inflammatory residual risks. Further research is required to establish the optimal patient selection and combination therapies that target both pathways.

Conflict of Interest

Dr. Minami received remuneration from Amgen K.K., Novartis Pharma K.K., and Otsuka Pharmaceutical Co., Ltd. Dr. Ako received remuneration from Amgen K.K., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd, DAIICHI SANKYO Co., Ltd, ONO Pharmaceutical Co., Ltd, Bayer Yakuhin, Ltd., and Kowa Pharmaceutical Co. Ltd. Mochida Pharmaceutical Co., Ltd.

Funding Source:

None.

Acknowledgements

During the preparation of this manuscript, the authors used ChatGPT-4o [OpenAI] to enhance the quality of the English language.