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Jump to Key Points Systemic inflammation may surge far earlier than previously thought in patients with adiposity, underscoring the need for early intervention for patients with early-stage cardiovascular-kidney-metabolic (CKM) syndrome.
The largest spike in inflammation occurs between stage 0 and stage 1 of CKM, long before hypertension, diabetes, chronic kidney disease, or plaque buildup appears, according to a new study mapping high-sensitivity C-reactive protein (hsCRP) across the American Heart Association (AHA)’s framework of the five CKM stages.
The study, published in the European Journal of Preventive Cardiology, examined the CKM-inflammation link using a single acute-phase biomarker rather than complicated composite blood-count indices used in some recent research. Those indices include the systemic immune-inflammation index and leukocyte to high-density lipoprotein cholesterol ratio.
Inflammation Across Stages
To map how systemic inflammation tracks across disease progression, researchers analyzed a survey-weighted sample of 4315 US adults from National Health and Nutrition Examination Survey (2015-2018) — a cohort designed to statistically represent 212.8 million American adults.
- hsCRP rose 89% from CKM stage 0 to 1; adiposity drove largest increase.
- Inflammation increased modestly through stages 2-3, then plateaued at stage 4.
- Stage 4 hsCRP likely blunted by widespread statin and anti-inflammatory use.
- Findings support stage-based CKM risk stratification incorporating early inflammation.
- Waist circumference may detect early CKM risk even with normal lipids.
Participants with hsCRP levels > 10 mg/L were excluded to filter out acute infections, ensuring a focus on chronic, low-grade vascular inflammation.
Using physical examination, laboratory, and prescription medication data, investigators categorized participants across the AHA’s five-stage CKM framework:
- Stage 0: No CKM risk factors
- Stage 1: Excess or dysfunctional body fat (adiposity)
- Stage 2: Metabolic risk factors (eg, high blood pressure and diabetes) or chronic kidney disease
- Stage 3: Subclinical cardiovascular disease or very high risk
- Stage 4: Established clinical cardiovascular disease
Regression models adjusted for national survey weighting, demographic factors, blood pressure, lipid panels, glycemic status, smoking, physical activity, and medication use.
The Inflammation Spike
Average hsCRP markers climbed stepwise through the early stages before leveling off in advanced disease: Levels surged from 1.09 mg/L at stage 0 to 2.06 mg/L at stage 1 — an 89% jump driven by excess body fat. From there, levels rose more modestly to 2.75 mg/L at stage 2 and 2.80 mg/L at stage 3, before plateauing at 2.79 mg/L at stage 4, where the widespread use of inflammation-lowering medications such as statins probably stems further increases.
“These findings support incorporating inflammation into early, stage-based CKM risk stratification, consistent with the emphasis on early CKM identification in the 2026 AHA/ACC [American College of Cardiology]/ADA [American Diabetes Association]/ASN [American Society of Nephrology] guideline,” the investigators concluded.
“If that inflammation also predicts who goes on to develop hypertension, diabetes, or kidney disease, stage 1 would be an ideal window to check hsCRP and intervene,” said Douglas Corsi, MD, is an internal medicine resident at Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey, and lead author on the study.
However, he noted, “Our data come from a single point in time, so that link still has to be shown in studies that follow patients forward and in trials testing whether weight loss alone, or therapies that specifically lower inflammation, can slow progression.”
Long-Term Outcomes
In an August 2026 article in Diabetes, Obesity and Metabolism, researchers addressed the same central question across the CKM spectrum. Evaluating 86,829 participants over a multiyear follow-up, investigators tracked all-cause mortality across CKM stages.
Their findings directly connect the early inflammatory surge to concrete survival outcomes: Elevated hsCRP exerted its steepest proportional impact on mortality in early CKM stages (hazard ratio, 1.14 per unit increase at stage 1), whereas its predictive power attenuated completely by stage 4.
Together, both studies demonstrate that early hsCRP screening and targeted preventive care — whether through lifestyle modification, GLP-1 receptor agonists, or metabolic therapies — deliver their highest clinical yield at stage 1. That enables capture of hidden, adipose-driven risk long before standard blood pressure readings or metabolic panels flag overt disease.
Keith C. Ferdinand, MD, a professor of medicine at Tulane University School of Medicine in New Orleans, said the studies augment his belief that waist circumference measurement captured early on, even if “lipids are not abnormal,” can help to assess CKM risk.
“Although the 2026 ACC/AHA Cardiovascular-Kidney-Metabolic (CKM) Syndrome Guideline does not recommend hsCRP for routine screening or standard risk assessment, clinicians may consider inflammatory markers to personalize or refine risk classification,” said Ferdinand, who was not involved in the study.
“Measuring the waist is an economical way to enhance the assessment of increased risk in CKM syndrome and discern the patient who may need more intensive preventive approaches,” he said.
Corsi reported no relevant financial disclosures.
Ferdinand reported consulting with Amgen, Sanofi, Boehringer Ingelheim, Novartis, Janssen, and Eli Lilly.
