Beyond Prognosis: A Systematic Review of the Neutrophil-to-Lymphocyte Ratio as a Modifiable Cardiovascular Biomarker

The neutrophil-to-lymphocyte ratio (NLR) is an accessible marker of systemic inflammatory activity associated with adverse cardiovascular outcomes, but whether it is modifiable through intervention and whether its reduction corresponds to cardiovascular benefit remain uncertain.This systematic review evaluated randomized evidence concerning the effects of pharmacological, nutritional, lifestyle, and procedural interventions on NLR among adults with established cardiovascular disease or elevated cardiovascular risk.MEDLINE via PubMed, Scopus, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched for studies published from January 1, 2021, through July 31, 2026.Eligible studies included randomized controlled trials, randomized crossover trials, and secondary analyses of randomized trials reporting treatment-related changes in NLR.The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidance.Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool, its crossover adaptation, and the Quality In Prognosis Studies (QUIPS) tool, where appropriate.Twelve studies involving 1,741 participants were included and synthesized narratively.Direct interleukin-6 (IL-6) inhibition produced the clearest dosedependent reduction in NLR, while glutathione, cardiac rehabilitation, time-restricted eating, curcumin, normobaric hyperoxia, and selected nutritional strategies also demonstrated potentially favorable effects.Findings for sodium-glucose cotransporter 2 inhibitors were inconsistent, with early empagliflozin initiation modulating inflammatory activity in one trial but producing no treatment-specific reduction in NLR during post-infarction recovery in another.Several studies associated lower inflammatory activity with improved ventricular function, global longitudinal strain (GLS), coronary plaque behavior, infarct volume, or neurological severity; however, few formally examined whether NLR independently predicted or mediated these effects.Clinical cardiovascular outcomes were infrequently reported and generally underpowered.Methodological limitations included small sample sizes, heterogeneous measurement schedules, post hoc analyses, multiple biomarker comparisons, and incomplete reporting of NLR outcomes.NLR appears to be a modifiable, context-dependent inflammatory marker, but current randomized evidence does not establish it as a therapeutic target or validated surrogate for cardiovascular benefit.Future trials should prespecify serial NLR assessments and determine whether phenotype-specific changes provide incremental prognostic or treatment monitoring value.