Abstract
Background
Cardiovascular-kidney-metabolic (CKM) syndrome staging helps identify cardiovascular disease (CVD) risk. Determining how predicted CVD risks vary across CKM stages in the U.S can further improve understanding of disease progression and help guide prevention strategies.
Methods
We analyzed 2011–2020 NHANES data using survey-weighted quantile regression to compare total CVD risks predicted by the PREVENT equations across CKM stages.
Results
Among 12,349 CVD-free adults aged 30–79 (∼122.8 million adults), median (25th – 75th) 10-year and 30-year CVD risks were 0.9% (0.5–2.1%) and 6.0% (3.3–10.1%) in Stage 0, 1.5% (0.7–3.3%) and 8.9% (4.7–14.9%) in Stage 1, 4.6% (2.0–9.2%) and 18.4% (0.4–26.3%) in Stage 2, and 23.5% (21.3–27.1%) and 51.6% (38.3–58.6%) in Stage 3 CKM, respectively. Higher CKM stage generally predicted higher CVD risks. Men had higher risks than women, while race/ethnicity differences were modest.
Conclusion
CVD risks estimated by PREVENT equations increase with higher CKM stage, supporting CKM staging for risk stratification.
Keywords: CKM, CVD risk, prevention, epidemiology, PREVENT
1. Introduction
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States [1], [2]. To better characterize the interrelated burden between CVD, obesity, cardiometabolic disorders, and chronic kidney disease (CKD), the American Heart Association (AHA) recently defined the CKM syndrome, a progressive health disorder that integrates all these risk factors in addition to atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF). The CKM syndrome staging system was developed to identify adults with elevated CVD risk and guide strategies to prevent progression to advanced cardiometabolic disorders and CVD [3], [4].
Aligned with this approach, the AHA also developed the Predicting Risk of Cardiovascular Disease Events (PREVENT) equations to quantify long-term CVD risks using important cardiometabolic factors [5]. Previous prevention guidelines have recommended estimating 10-year ASCVD risks using the Pooled Cohort Equations [6], which were derived from older cohort data, omitted renal function, and did not estimate total CVD risk inclusive of HF [7]. In contrast, the PREVENT equations were derived from a contemporary and demographically diverse cohort of more than 3.2 million U.S. adults and validated in a separate cohort of 3.3 million, incorporating renal function and other metabolic markers to predict the 10- and 30-year risk of both ASCVD and HF, combined as total CVD risk. [8]
Though CKM syndrome is highly prevalent and associated with a greater burden of risk factors [9], the long-term CVD risks of U.S. adults at different CKM stages have not been evaluated. Estimating these risks is critical to understanding the implications of CKM classifications for public health. Using the PREVENT equations to estimate 10- and 30-year CVD risks across CKM stages can quantify the long-term risks associated with CKM progression and guide prevention strategies at the population level. Therefore, we used the PREVENT equations to estimate long-term CVD risks at different CKM stages in a CVD-free contemporary and nationally representative cohort of U.S adults.
2. Methods
In this analysis, we included all non-pregnant adults aged 30–79 years without a self-reported history of CVD using data from the 2011–2020 National Health and Nutrition Examination Survey (NHANES) cycles (Supplemental Fig. 1) [10]. Participants were assigned the highest relevant CKM based on available demographic, anthropometric, laboratory, and medical history data. CKM stages reflect having no risk factors (Stage 0), excess or dysfunctional adiposity or prediabetes (Stage 1), metabolic risk factors or moderate-to-high-risk CKD (Stage 2), or very-high-risk CKD or a predicted 10-year CVD risk ≥20% (Stage 3; specific criteria for staging are detailed in Supplemental Table 1). The 10- and 30-year total CVD risks for participants were calculated using the PREVENT equations across CKM stages [8]. The 10-year risks were calculated for adults aged 30–79, and the 30-year risks were calculated for adults aged 30–59 years. Race/ethnicity were categorized as Non-Hispanic White, Non-Hispanic Black, Hispanic, or Other.
Survey weights were applied to account for the complex survey design, with variance estimation using Taylor series linearization, in accordance with the NHANES analytic guidelines [10]. Prevalence estimates were age-standardized to the 2010 U.S Census. Given the skewed distribution of calculated risks, 10- and 30-year CVD risks were reported as medians and interquartile ranges. To assess differences in the distribution of PREVENT-predicted CVD risk across CKM stages and subgroups, we compared median risks using survey-weighted quantile regression at the median (τ = 0.5), adjusting for age, sex, and race/ethnicity. All analyses were conducted using Stata BE version 19 (StataCorp; 2025) and R version 4.3.2. NHANES data are publicly available and deidentified; this study was therefore exempt from review by the Yale University Institutional Review Board.
3. Results
The final study cohort included 12,349 participants, representing 122.8 million U.S. adults without CVD. The mean age was 50.6 (SD 10.7) years, 49.9% were women, 66.9% Non-Hispanic White, 14.9% Hispanic, 9.4% Non-Hispanic Black, 5.8% Non-Hispanic Asian, and 3.0% Other race/ethnicity. After survey weighting, 9.2% (95% CI: 8.4–10.1%) of U.S. adults were in Stage 0, and 28.4% (95% CI: 27.2–29.7%) in Stage 1. The majority, 57.3% (95% CI: 55.9–58.7%), were classified as Stage 2, while only 5.0% (95% CI: 4.6–5.5%) were in Stage 3 (Fig. 1). Clinical risk factors across CKM stages are shown in Supplemental Table 2.
Fig. 1.
Prevalence of CKM Stages and Median 10-Year and 30-Year Total Cardiovascular Disease Risk.
Bars represent the prevalence of each CKM stage in the U.S. primary prevention adult population aged 30–79 years (left axis). Lines represent median PREVENT 10-year (orange) and 30-year (red) total cardiovascular disease (CVD) risk with 25th–75th percentiles (right axis). Ten-year and 30-year risks increased across CKM stages (P for trend <0.001).
The median (25th–75th percentile) 10-year CVD risk increased progressively across CKM stages, from 0.9% (0.5–2.1%) in Stage 0 to 23.5% (21.3–27.1%) in Stage 3. Overall, 87.8% (95% CI, 85.5–89.8%) of adults with Stage 0 and 85.5% (95% CI, 84.3–86.6%) with Stage 1 had 10-year risks below 7.5%, compared with 70.3% (95% CI, 69.3–71.3%) of those with Stage 2. Similarly, 30-year CVD risks rose from 6.0% (3.3–10.1%) in Stage 0 to 51.6% (38.3–58.6%) in Stage 3. Furthermore, 93.4% (95% CI, 89.4–95.9%) of adults in Stage 0 and 86.6% (95% CI, 84.8–88.2%) in Stage 1 had a 30-year CVD risk below 20%, compared with only 61.5% (95% CI, 59.9–62.9%) of those with Stage 2 (Table 1 & Fig. 1). Higher CKM stages had significantly higher CVD risks in all pairwise comparisons except for 10-year risks with Stage 1 vs. 0 (Supplemental Table 3).
Table 1.
PREVENT 10- and 30-year total cardiovascular disease risks based on cardiovascular-kidney-metabolic syndrome stage.
| 10-Year CVD Risk (Median % [25th, 75th percentile]) in Adults Aged 30–79 Years |
||||
|---|---|---|---|---|
| Stage 0 (n = 883) 9.2% (8.4–10.1%) |
Stage 1 (n = 3243) 28.4% (27.2–29.7%) |
Stage 2 (n = 7397) 57.3% (55.9–58.7%) |
Stage 3 (n = 826) 5.0% (4.6–5.5%) |
|
| Overall (n = 12,349) | 0.9 (0.5–2.1) | 1.5 (0.7–3.3) | 4.6 (2.0–9.2) | 23.5 (21.3–27.1) |
| Age Category: | ||||
| 30–39 | 0.4 (0.3–0.6) | 0.6 (0.4–0.9) | 0.9 (0.7–1.6) | – |
| 40–49 | 1.0 (0.7–1.5) | 1.4 (0.9–1.9) | 2.5 (1.7–3.8) | – |
| 50–59 | 2.5 (1.9–3.5) | 2.9 (2.2–4.0) | 5.2 (3.6–7.6) | 21.9 (20.6–24.4) |
| 60–69 | 5.8 (4.1–6.6) | 5.9 (4.6–7.8) | 9.9 (7.6–11.7) | 22.8 (21.0–24.8) |
| 70–79 | 13.8 (8.9–17.3) | 12.1 (9.6–14.7) | 15.3 (13.1–17.4) | 23.9 (21.6–27.8) |
| Sex | ||||
| Men | 1.4 (0.7–3.4) | 1.9 (0.9–4.1) | 4.7 (2.1–9.5) | 23.4 (21.3–27.1) |
| Women | 0.7 (0.3–1.5) | 1.2 (0.5–2.8) | 4.5 (1.9–8.9) | 23.6 (21.3–27.5) |
| Race/Ethnicity | ||||
| White | 1.0 (0.5–2.4) | 1.9 (0.8–3.9) | 4.9 (2.3–9.6) | 23.1 (21.2–26.7) |
| Hispanic | 0.8 (0.4–1.5) | 1.1 (0.6–2.1) | 3.7 (1.5–8.2) | 23.6 (21.3–27.2) |
| Black | 0.8 (0.4–1.4) | 1.1 (0.6–2.3) | 4.7 (1.9–8.9) | 24.6 (22.1–28.9) |
| Asian | 0.7 (0.4–1.5) | 1.0 (0.5–2.2) | 3.9 (1.7–8.7) | 24.0 (21.4–27.4) |
| Other | 0.5 (0.4–1.4) | 1.0 (0.6–2.6) | 4.0 (1.7–9.5) | 22.5 (20.6–30.4) |
| 30-Year CVD Risk (%, Median [25th, 75th percentile]) in Adults Aged 30–59 Years |
||||
|---|---|---|---|---|
| Stage 0 (n = 791) 11.1% (10.1–12.2%) |
Stage 1 (n = 2708) 32.5% (31.1–33.9%) |
Stage 2 (n = 4898) 55.9% (54.3–57.5%) |
Stage 3 (n = 51) 0.4% (0.2–0.6%) |
|
| Overall (n = 8448) | 6.0 (3.3–10.1) | 8.9 (4.7–14.9) | 18.4 (10.4–26.3) | 51.6 (38.3–58.6) |
| Age Category: | ||||
| 30–39 | 3.1 (2.1–4.6) | 4.3 (2.9–6.4) | 7.1 (4.9–11.1) | – |
| 40–49 | 7.7 (5.7–10.4) | 10.3 (7.4–13.7) | 16.3 (11.9–22.2) | 39.7 (15.9–63.3) |
| 50–59 | 15.2 (12.2–18.8) | 17.9 (14.5–22.0) | 25.9 (20.8–32.3) | 54.9 (48.7–57.0) |
| Sex | ||||
| Men | 8.4 (4.6–13.6) | 11.0 (6.4–17.5) | 19.9 (11.9–27.7) | 54.6 (39.7–63.3) |
| Women | 4.8 (2.5–8.4) | 6.8 (3.4–12.1) | 16.6 (8.5–23.8) | 48.7 (28.1–55.5) |
| Race/Ethnicity | ||||
| White | 6.4 (3.4–10.6) | 9.9 (5.2–15.9) | 18.7 (11.1–25.9) | 51.5 (38.3–58.6) |
| Hispanic | 5.5 (3.1–9.9) | 7.5 (4.4–12.4) | 17.2 (8.8–26.2) | 54.9 (27.8–63.3) |
| Black | 5.8 (2.9–9.8) | 7.8 (4.4–13.2) | 19.4 (11.1–29.5) | 52.8 (41.9–57.0) |
| Asian | 5.3 (2.8–9.2) | 7.1 (3.6–12.6) | 16.6 (9.5–25.3) | 57.8 (53.4–58.8) |
| Other | 3.7 (2.6–8.8) | 7.1 (3.9–14.9) | 18.1 (9.0–27.9) | 39.7 (39.7–45.3) |
Values shown are median 10-year and 30-year total CVD risks (%) with interquartile ranges (25th, 75th percentile) based on the PREVENT equations. All estimates are survey-weighted and age-standardized to the 2010 U.S Census population and account for the NHANES complex survey design. Cells without numbers included <10 participants and were therefore not reported.
Men had higher 10-year and 30-year CVD risks than women at all CKM stages except for Stage 3 (Supplemental Table 4). Compared to White adults, Hispanic and Black adults had higher median 10-year CVD risks within most CKM stages, although differences were typically small (<1% for Stages 0–2). White adults generally had the lowest median 30-year risks within CKM Stages 0–2, though several comparisons were not statistically significant; there were no differences in 30-year risks by race/ethnicity for CKM 3 (Supplemental Table 5).
4. Discussion
In this nationwide analysis of U.S. adults, we found that predicted 10- and 30-year CVD risks estimated by the PREVENT equations consistently increased with progressing CKM stage. These findings support CKM staging as a practical framework for long-term risk stratification. Notably, the majority of U.S adults without CVD were classified as Stage 2 and had a higher CVD risk compared with those in Stages 0 or 1, highlighting the population-level risk burden and the need for earlier identification before the clinical development of CVD [3], [5].
One of the primary findings of our study was that most adults classified as Stage 0 or 1 had significantly lower 10-year risks than those in Stage 2, underscoring the importance of preventing progression to Stage 2, which comprised more than half of the U.S. primary prevention population (71 of 123 million represented adults). Higher Stage 2 risks were seen consistently regardless of age. For example, among adults aged 30–39 years, the median 30-year risk in stage 2 was already elevated at 7.1%. Adults aged 50–59 years in Stage 2 had a median 30-year risk of 26%, compared to <20% for adults in the age group with Stage 0–1. This pattern suggests Stage 2 is a critical inflection point where 30-year risks may be elevated despite relatively low 10-year risks. The absence of a significant difference in 10-year predicted risk between Stages 0 and 1 likely reflects the relative contributions of individual variables in the PREVENT equations. Stage 1 is distinguished mainly by excess adiposity, which is accounted for with BMI in the PREVENT equations and likely contributes modestly to short-term predicted risk. The metabolic and renal abnormalities defining Stage 2 and 3 are stronger determinants of estimated risk and frequently also occur with excess adiposity, resulting in more substantial risk differences.
Our results provide additional information on adults with Stage 3 CKM. By definition, Stage 3 includes individuals with severe renal dysfunction and/or a predicted 10-year CVD risk of ≥20%, resulting in markedly higher risk estimates as expected. This group comprised only 5.0% of the population, but these adults have the highest absolute risk and therefore warrant aggressive risk factor management. Since adults with Stage 2 CKM could later be classified as Stage 3 with poor risk factor control and predicted risks exceeding 20%, individuals close to this threshold also need aggressive prevention of new risk factors and optimal management of existing ones to reduce their future CVD incidence.
Since CKM is a relatively new framework, increased awareness of the risk factors that lead to CKM progression is needed. Development of hypertension, hypertriglyceridemia, metabolic syndrome, diabetes, or CKD classifies an otherwise healthy asymptomatic individual as Stage 2, resulting in significantly higher long-term CVD risks compared with Stages 0–1. For those in Stage 0–1 CKM, these conditions can often be prevented by prioritizing a healthy lifestyle, including weight management, physical activity, and a high-quality diet [3], [11]. For patients in Stage 2, additional evidence-based treatments, including antihypertensives, lipid-lowering therapies, SGLT2 inhibitors, and GLP-1 agonists, are important to maintain health and reduce long-term risks [4], [6]. Effective therapeutic strategies for Stage 2 patients could potentially result in CKM reversal to earlier stages, further lowering risk [12]. Further work is needed on incorporating CKM staging and risk prediction using the PREVENT equations into routine clinical care, including electronic health records. Future investigation will also be needed to assess how the CKM framework influences clinical practice patterns, prevention strategies, and patient outcomes.
The study is limited by the cross-sectional design and did not evaluate disease progression or clinical outcomes. Adults with risk factor values outside of the recommended ranges for risk estimation were excluded, and our findings are therefore limited to the population for whom PREVENT risks can be calculated. The number of adults less than 60 years of age with Stage 3 CKM was very small (n = 51), and therefore 30-year predicted risks for this group in our study should be interpreted with caution for prevalence estimates and in guiding clinical practice.
In conclusion, our findings underscore the utility of CKM staging in stratifying long-term CVD risk based on the PREVENT equations and further highlight the importance of identifying high-risk individuals who may benefit from intensified prevention efforts. The substantial proportion of U.S. adults classified as Stage 2, coupled with their elevated long-term CVD risk, highlights the need for early identification and targeted prevention strategies, such as aggressive lifestyle modification, risk factor control, use of novel therapies, and increasing public awareness.
CRediT authorship contribution statement
Mohammed Essa: Writing – review & editing, Writing – original draft, Visualization, Validation, Software, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. Devesh Malik: Resources, Data curation. Yuan Lu: Writing – review & editing. Huanhuan Yang: Writing – review & editing, Project administration, Data curation. Erica S. Spatz: Writing – review & editing. Harlan M. Krumholz: Writing – review & editing. Kamil F. Faridi: Writing – review & editing, Writing – original draft, Visualization, Supervision, Methodology, Investigation, Conceptualization.
Disclosures
M Essa: Dr. Essa reports no relevant disclosures.
D Malik: Mr. Malik reports no relevant disclosures.
Y Lu: Dr. Lu receives support from the Sentara Research Foundation, the National Heart, Lung, and Blood Institute of the National Institutes of Health (under awards R01HL69954 and R01HL169171), and the Patient-Centered Outcomes Research Institute (under award HM-2022C2-28354) outside of the submitted work.
H Yang: Dr. Yang reports no relevant disclosures.
ES Spatz: Dr. Spatz receives funding from the National Heart, Lung, and Blood Institute (R01HL151240), and the Patient Centered Outcomes Research Institute (HM-2022C2-28354).
HM Krumholz: Dr. Krumholz has received options for Element Science and Identifeye and payments from F-Prime for advisory roles. He is a co-founder of and holds equity in Hugo Health, Refactor Health, and ENSIGHT-AI. He is associated with research contracts through Yale University from Janssen, Kenvue, Novartis, and Pfizer.
KF Faridi: Dr. Faridi receives research funding from the NIH/NHLBI (K23HL161424).
Ethical statement
This study involved analysis of publicly available, de-identified data from the National Health and Nutrition Examination Survey (NHANES). Because NHANES data are anonymized and released for public use, this analysis was considered as non–human subject research and did not require consent, and it was considered exempt by the Institutional Review Board at Yale University. The original NHANES protocols were approved by the National Center for Health Statistics Research Ethics Review Board, and all participants provided written informed consent at the time of data collection. This research was conducted in accordance with principles of research integrity, transparency, and responsible reporting.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.ahjo.2026.100839.
Appendix A. Supplementary data
Supplementary material
References
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