Zhang YW, Xu MR, Li MH, Li LX. Product of C-reactive protein and fasting C-peptide indicates cardiovascular risk in type 2 diabetes: A real-world study. World J Diabetes 2026; 17(4): 117063 [DOI: 10.4239/wjd.v17.i4.117063]
Corresponding Author of This Article
Lian-Xi Li, MD, PhD, Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai 200233, China. lilx@sjtu.edu.cn
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Endocrinology & Metabolism
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Observational Study
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Apr 15, 2026 (publication date) through Apr 14, 2026
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World Journal of Diabetes
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Zhang YW, Xu MR, Li MH, Li LX. Product of C-reactive protein and fasting C-peptide indicates cardiovascular risk in type 2 diabetes: A real-world study. World J Diabetes 2026; 17(4): 117063 [DOI: 10.4239/wjd.v17.i4.117063]
Ya-Wen Zhang, Man-Rong Xu, Meng-Han Li, Lian-Xi Li, Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China
Author contributions: Li LX supervised the study, conceptualized the research, and acquired funding; Zhang YW was responsible for writing the original draft and visualization; Xu MR conducted the investigation and edited the manuscript; Li MH developed the methodology and performed validation; all authors contributed to the article and approved the submitted version.
Supported by National Natural Science Foundation of China, No. 81770813 and No. 82070866; and the National Key Research and Development Plan, No. 2018YFC1314905.
Institutional review board statement: This study was reviewed and approved by the Ethics Committee of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine [Approval No. 2018-KY-018(K)].
Informed consent statement: All patients had signed written informed consent.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Data sharing statement: All data generated and analyzed in this study are included in the present article. Detailed statistical procedures and the complete dataset are available from the corresponding author upon reasonable request.
Corresponding author: Lian-Xi Li, MD, PhD, Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No. 600 Yishan Road, Shanghai 200233, China. lilx@sjtu.edu.cn
Received: November 28, 2025 Revised: January 8, 2026 Accepted: February 11, 2026 Published online: April 15, 2026 Processing time: 137 Days and 17.7 Hours
Abstract
BACKGROUND
The combined effects of C-reactive protein (CRP) and fasting C-peptide (FCP) on cardiovascular risk remain unclear.
AIM
To introduce a novel variable, the CRP-FCP product and to evaluate whether it better reflects the cardiovascular risk burden than either biomarker alone in patients with type 2 diabetes mellitus (T2DM).
METHODS
Overall, 8486 patients with T2DM were enrolled and stratified into quartiles based on CRP-FCP product to compare their clinical characteristics. The associations of CRP, FCP, and the CRP-FCP product with cardiovascular events (CVEs), cerebrovascular events (CBVEs), and cardio-CBVEs (CCBVEs, defined as the presence of CVEs and/or CBVEs) were analyzed by logistic regression. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the discriminative performance of the CRP-FCP product.
RESULTS
The adjusted prevalences of CVEs, CBVEs, and CCBVEs increased significantly across the CRP-FCP product quartiles (all P < 0.05 for trend). In fully adjusted models, the CRP levels were positively associated with CBVEs (P = 0.016) and CCBVEs (P = 0.005), but not with CVEs (P = 0.070). Conversely, higher FCP levels were associated with an increased risk of CVEs (P = 0.039) and CCBVEs (P = 0.007), but not with CBVEs (P = 0.290). Notably, the CRP-FCP product was independently associated with all three outcomes (all P < 0.05). ROC analyses showed that the area under the curve values of the CRP-FCP product were 0.550 for CVEs, 0.555 for CBVEs, and 0.558 for CCBVEs.
CONCLUSION
The CRP-FCP product was linked to an increased risk of CVEs, CBVEs and CCBVEs. The CRP-FCP product may provide a more comprehensive assessment of the cardiovascular risk burden than CRP or FCP alone in patients with T2DM.
Core Tip: This study introduces the product of C-reactive protein and fasting C-peptide as a novel composite indicator. It better reflects the combined effects of inflammation and insulin resistance and shows more stable associations with cardiovascular and cerebrovascular events than either component alone in patients with type 2 diabetes mellitus, supporting its potential value as a composite marker reflecting the overall cardiovascular risk burden.
Citation: Zhang YW, Xu MR, Li MH, Li LX. Product of C-reactive protein and fasting C-peptide indicates cardiovascular risk in type 2 diabetes: A real-world study. World J Diabetes 2026; 17(4): 117063
Cardiovascular diseases (CVDs) are highly prevalent among individuals with diabetes and are frequently associated with substantial disability and mortality. Therefore, early identification of patients with type 2 diabetes mellitus (T2DM) at high risk of CVD using simple and effective biomarkers is imperative to facilitate timely interventions, optimize treatment strategies, and ultimately reduce the negative consequences of cardiovascular complications.
C-reactive protein (CRP), a well-established indicator of low-grade inflammation, is widely recognized as a reliable marker for assessing the risk of CVD. For example, elevated CRP levels were associated with a 53% increased risk of cardiovascular mortality and 43% higher risk of allcause mortality[1]. However, other studies claimed that CRP may not be a reliable marker for evaluating the cardiovascular risk[2,3].
Furthermore, fasting C-peptide (FCP) is considered an indicator of pancreatic β-cell function and a bioactive peptide that potentially influence the development of CVD[4,5]. For example, a study based on the data from the Skaraborg Diabetes Register demonstrated that elevated serum C-peptide levels at baseline were associated with a 2.2-fold and 2.69-fold increased risk of all-cause mortality and cardiovascular mortality, respectively, in patients with newly diagnosed T2DM[6]. In contrast, a meta-analysis reported that low serum C-peptide levels are significantly associated with increased incidence of coronary heart disease and cerebral infarction[7].
Therefore, although CRP and FCP have both been implicated as potential markers of cardiovascular risk, their exact relationships with CVD remain unclear. Furthermore, although numerous studies have examined CRP and FCP individually, their combined effect on cardiovascular risk is not yet explored. Given that CRP is a well-known inflammatory marker and FCP is a well-established insulin resistance indicator, both of which are closely linked to cardiovascular risk, it is plausible that the combined effect of CRP and FCP may provide a more comprehensive assessment of cardiovascular risk than either marker alone. Thus, we created a new variable, the CRP-FCP product, to reflect the combined effect of CRP and FCP.
In this study, we aimed to evaluate the associations of CRP, FCP, and the CRP-FCP product with cardiovascular risk in individuals with T2DM to determine whether the CRP-FCP product can provide a more reliable assessment of cardiovascular risk compared with CRP and FCP alone.
MATERIALS AND METHODS
Subjects and study design
In this cross-sectional, real-world study, a total of 9368 patients with T2DM from Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine were enrolled between January 2003 and December 2012. The study data were derived from our registry-based macrovascular complications in diabetic populations study (Clinical Trial Registration: ChiCTR1800015893)[8]. The exclusion criteria were as follows: (1) Age < 18 years; (2) Incomplete physical examination and clinical parameters; (3) Acute diabetic complications such as diabetic ketoacidosis; (4) Systemic inflammatory disease; (5) Acute infection (serum CRP levels > 10 mg/L)[9]; and (6) Progressive malignancy. Based on these criteria, 882 patients, including 489 men and 393 women were excluded from the analysis. Consequently, a total of 8486 patients with T2DM were included in the present study.
All participants were interviewed to obtain information on the duration of diabetes (DD), history of hypertension (HTN), cardiovascular events (CVEs), and cerebrovascular events (CBVEs), alcohol consumption, smoking habits, and pharmacological treatments including antiplatelet agents, antihypertensive agents (AHAs), and lipid-lowering drugs (LLDs). This study was conducted in accordance with the “Declaration of Helsinki” and approved by the Ethics Committee of Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine [Approval No. 2018-KY-018(K)]. All patients provided written informed consent.
Physical examination and laboratory measurements
Serum CRP concentrations were measured using a high-sensitivity immunoturbidimetric assay on a Behring BN II automated analyzer (Dade Behring Inc., Brookfield, CT, United States), with a normal reference range of 0-10 mg/L[10]. FCP levels were determined using an ADVIA Centaur XP immunoassay system (Siemens Healthcare Diagnostics Products GmbH, Germany) with a normal reference range of 0.82-2.50 ng/mL[11]. All measurements were conducted in the central clinical laboratory of our hospital according to the manufacturers’ standardized protocols, with standard laboratory quality control procedures applied and coefficients of variation maintained within clinically acceptable limits. The CRP-FCP product was calculated by multiplying serum CRP and FCP levels, reflecting the potential synergistic interaction between systemic inflammation and insulin resistance, whereby concurrent elevations in both markers may be associated with a higher cardiovascular risk than either marker alone.
Physical examination data, including systolic blood pressure (SBP), diastolic blood pressure (DBP), weight, height, waist circumference (WC), and body mass index (BMI) were measured and calculated according to previously reported methods[12]. Results of laboratory variables, including white blood cell count (WBC), fasting plasma glucose (FPG), 2-hour postprandial plasma glucose (2h PPG), glycosylated hemoglobin (HbA1c), 2-hour postprandial C-peptide (2h C-P), total triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), γ-glutamyl transferase, serum creatinine, serum uric acid (SUA), urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) were collected and calculated according to previously reported procedures[13].
Diagnostic criteria
T2DM was diagnosed based on the 1999 World Health Organization criteria[14]. The definitions of smoking, alcohol consumption, HTN, and obesity (BMI ≥ 25 kg/m2) were consistent with that in previously reported studies[15]. CVEs were defined as a history of angina, myocardial infarction, angioplasty, or coronary artery bypass surgery, while CBVEs were defined as a history of transient ischemic attack, ischemic stroke, or hemorrhagic stroke. CCBVEs were defined as a history of either CVEs, CBVEs, or both[16].
Statistical analysis
All the data were analyzed by SPSS 15.0 software. Normally distributed data were expressed as mean ± SD, while non-normally distributed data were presented as medians with interquartile range. A one-way analysis of variance was carried out to determine the group differences in normally distributed variables, whereas the Kruskal-Wallis test was performed to compare non-normally distributed variables. The χ2 test was used to compare the prevalence data and frequency differences. Binary logistic regression was applied to assess the associations of CRP, FCP, and the CRP-FCP product and its quartiles with CVEs, CBVEs, and CCBVEs. The results were expressed as ORs with 95%CIs.
To minimize the influence of confounding factors, six logistic regression models were constructed: Model 1 was unadjusted; model 2 was adjusted for age, sex, and DD; model 3 included additional adjustments for smoking, alcohol drinking, obesity, and hypertension; model 4 was further adjusted for the use of LLDs, AHAs, and anticoagulants; model 5 incorporated additional adjustments for SBP, DBP, WC, and BMI; model 6 included additional adjustments for TC, HDL, LDL, TG, eGFR, SUA, UAE, FPG, 2h PPG, HbA1C, WBC, and 2h C-P. In addition, general linear regression was conducted to determine the relationship between serum CRP and FCP levels. Finally, receiver operating characteristic (ROC) curve analyses were performed to assess the discriminative performance of the CRP-FCP product for CVEs, CBVEs, and CCBVEs, with the area under the curve (AUC) used as the summary measure. All statistical tests were two-sided, and a P value < 0.05 was considered statistically significant.
RESULTS
Characteristics of the subjects according to the CRP-FCP product quartiles
Based on the CRP-FCP product, all 8486 patients were categorized into quartiles using the cut-off values of < 0.73, 0.73-2.30, 2.31-6.86, and > 6.86 (Table 1). After adjustment for age and sex, significant differences in sex distribution, age, and prevalence of hypertension and obesity were observed across the CRP-FCP product quartiles (all P < 0.05). Moreover, higher CRP-FCP product quartiles were associated with a greater use of AHAs and LLDs, higher SBP and DBP, increased WC and BMI, elevated levels of inflammatory and metabolic markers (including WBC, FPG, 2h PPG, 2h C-P, TG, TC, LDL-C, ALT, SUA, and 24-hour UAE) as well as reduced HDL-C and eGFR levels (all P < 0.05).
Table 1 Characteristics of patients with type 2 diabetes mellitus according to the C-reactive protein-fasting C-peptide product quartiles.
Prevalence of CVEs, CBVEs, and CCBVEs stratified by sex, age, and DD
Figure 1 presents comparisons of the prevalence of CVEs, CBVEs, and CCBVEs across different groups. Men had a significantly higher prevalence of CVEs, but a lower prevalence of CCBVEs compared with women (5.3% vs 3.6%, P < 0.001 for CVEs; 14.4% vs 15.7%, P = 0.006 for CCBVEs; Figure 1A). Furthermore, the prevalence of CVEs, CBVEs, and CCBVEs showed significant increasing trends with both advancing age and longer DD (all P < 0.001 for trend; Figure 1B and C).
Figure 1 Prevalence of cardiovascular, cerebrovascular, and cardio-cerebrovascular events stratified by sex, age, and duration of diabetes.
A-C: Prevalence of cardiovascular events, cerebrovascular events (CBVEs), and cardio-CBVEs stratified by sex (A), age (B), and duration of diabetes (C). CVEs: Cardiovascular events; CBVEs: Cerebrovascular events; CCBVEs: Cardio-cerebrovascular events; DD: Duration of diabetes.
Levels of CRP, FCP, and CRP-FCP product stratified by sex, age, and DD
Figure 2 shows comparisons of serum CRP and FCP levels and the CRP-FCP product, stratified by sex, age, and DD among patients with T2DM. Women had significantly higher levels of CRP, FCP, and the CRP-FCP product than men (all P < 0.001; Figure 2A, D, and G). Regarding age, the oldest age group (≥ 70 years) exhibited markedly higher levels of CRP, FCP, and the CRP-FCP product compared with other groups (all P < 0.001 for trend; Figure 2B, E, and H). In terms of the DD, both the serum CRP levels and CRP-FCP product showed a pronounced decreasing trend with longer DD, while FCP levels demonstrated an initial increase followed by a decrease (all P < 0.001 for trend; Figure 2C, F, and I).
Figure 2 Levels of C-reactive protein, fasting C-peptide, and the C-reactive protein-fasting C-peptide product stratified by sex, age, and duration of diabetes.
A-C: Serum C-reactive protein (CRP) levels stratified by sex (A), age (B), and duration of diabetes (DD; C); D-F: Serum fasting C-peptide (FCP) levels stratified by sex (D), age (E), and DD (F); G-I: CRP-FCP product levels stratified by sex (G), age (H), and DD (I). CRP: C-reactive protein; FCP: Fasting C-peptide; DD: Duration of diabetes.
Comparison of CRP, FCP, and CRP-FCP product levels according to the status of CVEs, CBVEs, and CCBVEs, and their trends across product quartiles
Figure 3 demonstrates comparisons of CRP, FCP, and CRP-FCP product as well as the prevalence of CVEs, CBVEs, and CCBVEs across different groups. Patients with CVEs, CBVEs, or CCBVEs had significantly higher serum CRP levels and CRP-FCP product values than those without (all P < 0.05; Figure 3A and C). Serum FCP levels were significantly higher in patients with CVEs or CCBVEs (both P < 0.001), but not in those with CBVEs (P = 0.217; Figure 3B).
Figure 3 Comparison of C-reactive protein, fasting C-peptide, and C-reactive protein-fasting C-peptide product levels according to the cardiovascular, cerebrovascular, and cardio-cerebrovascular event status, and their trends across product quartiles.
A-C: Serum C-reactive protein (CRP; A), fasting C-peptide (FCP; B) and CRP-FCP (C) levels in patients with and without cardiovascular events (CVEs), cerebrovascular events (CBVEs), and cardio-CBVEs (CCBVEs); D: Prevalence of CVEs, CBVEs, and CCBVEs stratified by CRP-FCP product quartiles; E and F: Serum CRP (E) and FCP (F) levels stratified by CRP-FCP product quartiles; G: Correlation between serum CRP and FCP levels. CRP: C-reactive protein; FCP: Fasting C-peptide; CVEs: Cardiovascular events; CBVEs: Cerebrovascular events; CCBVEs: Cardio-cerebrovascular events.
The prevalence of CVEs, CBVEs, and CCBVEs showed a remarkable upward trend across CRP-FCP product quartiles (P for trend = 0.001, 0.002, and < 0.001, respectively; Figure 3D). Additionally, both serum CRP and FCP levels increased progressively across the CRP-FCP product quartiles (both P < 0.001 for trend; Figure 3E and F), and a positive correlation was observed between serum CRP and FCP levels (r = 0.102, P < 0.001; Figure 3G).
Prevalence of CVEs, CBVEs, and CCBVEs stratified by CRP and FCP levels
Figure 4 shows the prevalence of CVEs, CBVEs, and CCBVEs stratified by the serum CRP and FCP levels. After controlling for age, sex, and DD, patients with a CRP level of > 3 mg/L had a significantly higher CVEs prevalence compared with those with lower CRP levels (both P < 0.01), while no significant difference was observed between the CRP < 1 mg/L and 1-3 mg/L groups (P = 0.995, Figure 4A). Moreover, the prevalence of CBVEs and CCBVEs increased significantly across CRP categories (all P < 0.05; Figure 4B and C). Additionally, patients with a CRP level < 1 mg/L had significantly lower FCP levels compared with that in the other two groups (P for trend = 0.001; Figure 4D).
Figure 4 Prevalence of cardiovascular, cerebrovascular, and cardio-cerebrovascular events stratified by C-reactive protein and fasting C-peptide levels.
A-C: Prevalence of cardiovascular events (CVEs; A), cerebrovascular events (CBVEs; B), and cardio-CBVEs (CCBVEs; C) stratified by serum C-reactive protein (CRP) levels; D: Serum fasting C-peptide (FCP) levels stratified by serum CRP levels; E-G: Prevalence of CVEs (E), CBVEs (F), and CCBVEs (G) stratified by serum FCP levels; H: Serum CRP levels stratified by serum FCP levels. CRP: C-reactive protein; FCP: Fasting C-peptide; CVEs: Cardiovascular events; CBVEs: Cerebrovascular events; CCBVEs: Cardio-cerebrovascular events.
Regarding FCP, patients with levels above the normal range had a higher prevalence of CVEs and CCBVEs compared with those with normal or low levels (P < 0.01; Figure 4E and G), while no significant difference was observed for CBVEs (Figure 4F). Furthermore, serum CRP levels demonstrated a significant upward trend across FCP categories (P = 0.003 for trend; Figure 4H).
Associations of CRP, FCP, and CRP-FCP product with CVEs, CBVEs, and CCBVEs
Table 2 shows the associations of CRP, FCP, and CRP-FCP product with CVEs, CBVEs, and CCBVEs in T2DM. After full adjustment (model 6), serum CRP levels were positively associated with CBVEs (OR = 1.149; 95%CI: 1.026-1.287; P = 0.016) and CCBVEs (OR = 1.155; 95%CI: 1.045-1.277; P = 0.005), but not with CVEs (P = 0.070). Higher serum FCP levels were associated with an increased risk of CVEs (OR = 1.190; 95%CI: 1.009-1.403; P = 0.039) and CCBVEs (OR = 1.212; 95%CI: 1.054-1.394; P = 0.007), but not with CBVEs (P = 0.290). In contrast, the CRP-FCP product was independently associated with all three outcomes: CVEs (OR = 1.014; 95%CI: 1.001-1.027; P = 0.041), CBVEs (OR = 1.014; 95%CI: 1.004-1.024; P = 0.006), and CCBVEs (OR = 1.017; 95%CI: 1.009-1.026; P < 0.001).
Table 2 Associations of C-reactive protein, fasting C-peptide, and C-reactive protein-fasting C-peptide product with cardiovascular, cerebrovascular, and cardio-cerebrovascular events, OR (95%CI).
ROC curve analyses for CRP-FCP product in predicting CVEs, CBVEs, and CCBVEs
Supplementary Figure 1 presents the ROC curves of the CRP-FCP product for CVEs, CBVEs, and CCBVEs. The corresponding AUC values were 0.550 for CVEs, 0.555 for CBVEs, and 0.558 for CCBVEs.
DISCUSSION
In this real-world study, we proposed a novel composite biomarker that integrates CRP and FCP into a single index, termed the CRP-FCP product, and evaluated its associations with cardiovascular risk among 8486 patients with T2DM. Our findings indicated that the CRP-FCP product demonstrated more consistent associations with cardio-cerebrovascular outcomes than either CRP or FCP alone.
Our results revealed that serum CRP levels were positively associated with CBVEs and CCBVEs, but not with CVEs, providing additional insight into an area of ongoing debate. Prior studies examining the relationship between CRP and cardiovascular risk in T2DM have yielded inconsistent results, with some reporting positive associations[17-19], and others observing no significant association[20-22]. For example, a 30-month follow-up study of 5380 patients with T2DM revealed a graded relationship between serum CRP levels and major adverse CVEs, with cumulative incidences of 11.5%, 14.6%, and 18.4% for CRP levels of < 1 mg/L, 1-3 mg/L, and > 3 mg/L, respectively[23]. Similarly, in a high-risk T2DM cohort with established vascular complications, both the baseline and follow-up CRP levels > 3.0 mg/L significantly predicted total and major CVEs[24]. In contrast, the collaborative atorvastatin diabetes study found no predictive value of baseline CRP for cardiovascular outcomes during 3.8 years of follow-up[22]. These discrepancies may be attributed to variations in the study populations, especially baseline cardiovascular risk, outcome definitions, follow-up durations, and selected cardiovascular endpoints.
For FCP, higher serum levels were positively associated with an increased risk of CVEs and CCBVEs, but not with CBVEs. These findings are partially supported by prior studies. A cross-sectional study involving 4793 diabetic participants demonstrated a similar trend to our findings with a CVD prevalence of 33%, 34%, 37%, and 44% across ascending C-peptide quartiles, though their values were higher than those observed in our cohort[25]. However, a large-scale study of 55636 individuals (11.1% with pre-existing T2DM) reported no association between C-peptide levels and CVD risk in individuals with diabetes, but revealed a U-shaped relationship between C-peptide levels and CVD risk in individuals without diabetes[26]. Similarly, a recent meta-analysis also stated that the close association between serum C-peptide and CVD risk was only observed in cross-sectional studies, but not in cohort studies[27]. Furthermore, another meta-analysis suggested that low but not high C-peptide levels were associated with an increased risk of coronary heart disease (OR = 4.89; 95%CI: 1.13-21.24; P < 0.05) and cerebral infarction (OR = 3.24; 95%CI: 0.59-17.66; P < 0.05) in patients with T2DM[7]. Given these conflicting findings, the role of C-peptide in evaluating CVD risk remains uncertain and warrants further investigation through well-designed prospective cohort studies.
Based on these considerations, we propose the CRP-FCP product as a novel composite indicator that integrates the biological effects of both CRP and FCP. Chronic low-grade inflammation, as reflected by circulating CRP, and insulin resistance, as indicated by serum FCP, are well-established contributors to the CVD risk[28-30]. The CRP-FCP product integrates these two interrelated pathways and captures their reciprocal interaction, whereby inflammation exacerbates insulin resistance, which in turn amplifies the inflammatory responses[31]. This self-perpetuating cycle may accelerate cardiovascular and cerebrovascular pathogenesis. Mechanistically, CRP has been implicated in endothelial dysfunction and atherogenesis through the amplification of inflammatory signaling, particularly in the setting of dyslipidemia[32,33]. In parallel, elevated FCP, as a surrogate marker of insulin resistance, is associated with metabolic disturbances, including increased circulating free fatty acids, ectopic lipid accumulation, and vascular smooth muscle cell proliferation, which may further contribute to atherosclerotic progression[34]. Therefore, by capturing the synergistic interplay between systemic inflammation and metabolic dysregulation, the CRP-FCP product may provide a more comprehensive and stable biomarker for cardiovascular risk stratification than either measure alone.
Our current findings support the CRP-FCP product as a simple and practical clinical marker for reflecting the combined inflammatory and metabolic burden associated with the cardiovascular risk in patients with T2DM. While CRP was closely associated with CBVEs only and FCP with CVEs only, the CRP-FCP product demonstrated a robust and independent association with both CVEs and CBVEs after adjusting for multiple confounding factors. This finding is consistent with the evidence from previous studies. For instance, a previous study reported that in patients with hypertension with cerebral infarction, both serum CRP levels and the homeostasis model assessment of insulin resistance index were positively correlated with the diameter of cerebral infarction and neurological prognosis (all P < 0.05)[35]. Similarly, a Danish cohort study with a 4.8-year follow-up reported that patients with T2DM with elevated levels of both CRP and C-peptide faced significantly higher risks of CVEs (HR = 1.61; 95%CI: 1.10-2.34) and all-cause mortality (HR = 2.36; 95%CI: 1.73-3.21) compared with those with low levels of both biomarkers[36]. Consistent with this finding, the CRP-FCP product integrates both biomarkers into a continuous composite index to reflect their joint association with the cardiovascular risk. These findings highlight the added predictive value of combining inflammatory and metabolic markers as reflected by CRP and FCP, underscoring the importance of addressing both inflammation and insulin resistance in cardiovascular risk stratification and assessment in patients with T2DM.
From a public health perspective, ROC analyses indicated that the CRP-FCP product exhibited a modest discriminative accuracy for CVEs, with an AUC value of approximately 0.55, suggesting limited utility as a standalone, threshold-based diagnostic marker. Nevertheless, the CRP-FCP product captures both the inflammatory burden and insulin resistance, domains not fully reflected in conventional risk scores such as the Framingham Risk Score or Systematic Coronary Risk Evaluation system, which primarily incorporate age, sex, blood pressure, lipid profiles, and smoking status[37,38]. When considered alongside these established tools, the CRP-FCP product may provide complementary information for cardiovascular risk stratification. Specifically, with prospective validation, the CRP-FCP product could enhance early identification of high-risk individuals and facilitate the reclassification of patients at intermediate risk, thereby supporting more personalized decisions regarding monitoring intensity and preventive interventions. Future prospective studies are needed to validate its complementary value to established risk scores in cardiovascular risk stratification rather than as a standalone diagnostic marker.
Our study has several limitations that should be acknowledged. First, the cross-sectional design cannot establish causal relationships between the CRP-FCP product and CVEs. Prospective, longitudinal studies are needed to further assess its utility as a reliable biomarker in T2DM. Second, as our study included only East Asian participants, the generalizability of the CRP-FCP product to other populations may be limited. Specifically, compared with Caucasian populations, Asian populations tend to develop insulin resistance and T2DM at a lower BMI, often accompanied by earlier β-cell dysfunction and greater visceral adiposity, both of which are closely linked to systemic inflammation and cardiometabolic risk[39,40]. Moreover, the baseline circulating CRP concentrations are generally lower in Asian populations than in Western cohorts, which may influence the calibration and performance of the CRP-FCP product[41]. Therefore, validation of the CRP-FCP product in multi-ethnic populations with diverse metabolic and inflammatory backgrounds is warranted to assess its generalizability and clinical relevance. Additionally, the reliance on single measurements of CRP and FCP may introduce intra-individual variability. Future studies should assess the feasibility and clinical utility of repeated or longitudinal measurements to enhance the stability and reliability of cardiovascular risk stratification. Collectively, although the CRP-FCP product represents a novel composite biomarker, it has not yet been validated as a definitive clinical indicator. Further validation in larger, independent cohorts and prospective studies is needed to confirm its reliability, robustness, and generalizability in diverse populations before routine clinical application can be considered.
CONCLUSION
The CRP-FCP product, integrating markers of systemic inflammation and insulin resistance, was independently associated with CCBVEs in patients with T2DM. Compared with CRP or FCP alone, this composite index demonstrated more consistent associations across multiple cardiovascular outcomes. These findings suggest that the CRP-FCP product may provide complementary information for cardiovascular risk assessment in T2DM. Further validation in prospective studies and diverse, multi-ethnic populations is warranted to elucidate its clinical relevance and generalizability.
ACKNOWLEDGEMENTS
We sincerely thank all the research participants of the present study for their invaluable contributions.
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Creativity or innovation: Grade C, Grade C, Grade C, Grade C
Scientific significance: Grade B, Grade C, Grade C, Grade C
P-Reviewer: Horowitz M, MD, PhD, Professor, Australia; Musa DII, PhD, Professor, Nigeria; Wang X, Associate Professor, China S-Editor: Lin C L-Editor: A P-Editor: Xu ZH
