Neutrophil-to-lymphocyte ratio enhances mortality prediction beyond c-reactive protein in metabolic syndrome: a multi-cohort study

Background Systemic inflammation is a key driver of cardiovascular risk in metabolic syndrome (MetS). Although C-reactive protein (CRP) is widely used, its prognostic value may be enhanced by cellular immune markers such as the neutrophil-to-lymphocyte ratio (NLR), which integrates innate and adaptive inflammatory pathways. Purposes To evaluate whether NLR provides incremental prognostic value beyond CRP for all-cause and cardiovascular mortality in individuals with MetS. Methods We included participants with MetS from two cohorts: US NHANES (1999–2016) and Chinese Kailuan Study (2006–2019). NLR was calculated as absolute neutrophil count divided by absolute lymphocyte count. CRP was measured in serum samples. Participants were stratified by NLR and CRP quartiles. Multivariable Cox proportional hazards models were used to assess associations of NLR and CRP with all-cause mortality and cardiovascular mortality (based on ICD-10 codes). Joint analyses were conducted to evaluate the additional effects of NLR and CRP on mortality. Predictive performance was assessed using the Framingham Risk Score, with the addition of NLR and CRP, and compared using the c-index. Results A total of 29,472 participants with MetS were included, comprising 14,492 from the NHANES cohort (36.79% women, median age 52.09 years) and 14,980 from the Kailuan cohort (13.49% women, median age 53.21 years). At baseline, participants in the highest NLR group (Q4) were more likely to have a higher waist circumference and a greater prevalence of pre-existing cardiovascular disease compared with those in the Q1 group in both cohorts. Over a median follow-up of 10 years, higher NLR levels were associated with increased risks of all-cause mortality (Q4 vs Q1: NHANES HR=1.84, 95% CI 1.65–2.04; Kailuan HR=1.46, 95% CI 1.30–1.63) and cardiovascular mortality (NHANES HR=1.13, 95% CI 1.04–1.22; Kailuan HR=1.65, 95% CI 1.40–1.95). Importantly, these associations persisted after further adjustment for CRP, indicating independent prognostic value. In joint analysis, participants with concurrent elevations in both NLR and CRP faced the highest mortality risk (p<0.001) (Figure 2). NLR and CRP, in addition to FRS, significantly improved the prediction of all-cause mortality (c-index increase from 0.69 to 0.73). Conclusion Among individuals with MetS, NLR offers prognostic information that is independent of and additional to CRP, suggesting that combining cellular and humoral inflammatory markers could enhance risk stratification.Figure 1Figure 2