CKM Overlap Common in HF Hospitalizations, Tied to Worse Outcomes

More than 7 in 10 US patients hospitalized for heart failure (HF) had at least 2 additional cardiovascular-kidney-metabolic (CKM) conditions, and a greater CKM burden was associated with stepwise increases in mortality and readmission risk, particularly among patients with HF with reduced ejection fraction (HFrEF), according to a study published in JAMA Cardiology.¹

A 2023 American Heart Association presidential advisory published in Circulation defined CKM syndrome as a systemic disorder arising from connections among heart disease, kidney disease, diabetes, and obesity, and placed patients with clinical cardiovascular disease, including HF, in its most advanced stage (stage 4).² Still, little is known about how often multiple CKM conditions overlap in patients with HF in routine practice, the study authors wrote, because prior estimates come largely from clinical trials, which are more likely to exclude patients with severe multimorbidity or adverse social determinants of health.¹

The investigators analyzed data from the Get With The Guidelines–Heart Failure (GWTG-HF) registry. The in-hospital analysis included 725,205 patients (median [IQR] age, 72.0 [61.0-82.0] years) hospitalized between 2019 and June 2025, and postdischarge outcomes were assessed in 123,271 fee-for-service Medicare beneficiaries (median [IQR] age, 80 [73-87] years) hospitalized between 2019 and 2023. The researchers counted up to 4 CKM conditions beyond HF: atherosclerotic cardiovascular disease, chronic kidney disease (CKD), diabetes, and obesity, defined as a body mass index of 30 or higher.

Fewer Than 1 in 10 Patients Had HF Alone

Only 6.7% of patients had HF with no other CKM condition, while 71.9% had at least 2 and 12.7% had all 4. Overlap was greatest in HF with preserved EF (HFpEF), where 14.6% of patients had all 4 conditions compared with 14.3% of those with mildly reduced EF (HFmrEF) and 10.2% of those with HFrEF. Patients with HFrEF were the most likely to have HF alone (8.6%).

In a sensitivity analysis that added hypertension and hyperlipidemia as fifth and sixth CKM conditions, just 2.0% of patients had isolated HF and 91.8% had at least 2 conditions. The authors noted that CKM overlap in the registry was substantially higher than in landmark HF trial populations and suggested these data could serve as a benchmark for judging whether trials represent the contemporary US HF population.

Mortality Associations Were Strongest in HFrEF

After adjustment, having all 4 CKM conditions vs HF alone was associated with higher odds of in-hospital death across EF phenotypes, but the association was strongest in HFrEF (OR, 5.08; 95% CI, 4.43-5.83), compared with HFmrEF (OR, 2.37; 95% CI, 1.68-3.34) and HFpEF (OR, 2.05; 95% CI, 1.77-2.38; P for interaction < .001). Among patients with HFrEF, unadjusted in-hospital mortality rose from 1.1% with HF alone to 4.5% with all 4 conditions.

A similar pattern held for 1-year postdischarge outcomes in the Medicare cohort. With all 4 conditions, the adjusted HR for all-cause mortality was 2.10 (95% CI, 1.93-2.29) in HFrEF, 1.38 (95% CI, 1.17-1.63) in HFmrEF, and 1.09 (95% CI, 1.03-1.17) in HFpEF. For HF readmission, the corresponding HRs were 2.33 (95% CI, 2.12-2.56), 2.20 (95% CI, 1.82-2.66), and 1.91 (95% CI, 1.77-2.06).

The authors suggested that the lower baseline CKM burden in HFrEF may amplify the relative impact of each added condition, whereas in HFpEF, CKM conditions and HF may share intertwined pathophysiology. In a random forest analysis, CKD was the condition most predictive of poor outcomes for most end points, and for a given number of CKM conditions, profiles that included CKD were generally associated with worse outcomes.

Guideline-Directed Therapy Lagged as CKM Burden Grew

Despite their higher risk, patients with more CKM conditions were less likely to be discharged on renin-angiotensin-aldosterone system inhibitors or mineralocorticoid receptor antagonists (MRAs). For example, 21.9% of patients with all 4 conditions received an MRA at discharge compared with 36.3% of those with HF alone. Sodium-glucose cotransporter 2 inhibitors were prescribed to 20.3% of patients overall, with similar rates regardless of CKM burden, even though these agents have proven benefits in type 2 diabetes and CKD in addition to HF.

The authors said this risk-treatment paradox could stem from the complexity of managing polypharmacy or the perceived risk of adverse effects in fragile, multimorbid patients. They acknowledged that postdischarge findings were limited to fee-for-service Medicare beneficiaries, that participating hospitals may not represent all US hospitals, and that registry data may miss subclinical disease.

“In this contemporary cohort of US patients hospitalized for HF, most patients had multiple additional overlapping CKM conditions,” wrote the researchers of the study. “Increasing CKM multimorbidity was independently associated with stepwise increases in mortality and readmission risk. Although these associations spanned the EF spectrum, the prognostic impact of CKM multimorbidity was greatest in HFrEF and least in HFpEF.”

References

1. Kittipibul V, Ayodele I, Fonarow GC, et al. Cardiovascular-kidney-metabolic overlap in patients hospitalized for heart failure. JAMA Cardiol. Published online September 30, 2026. doi:10.1001/jamacardio.2026.4215
2. Ndumele CE, Rangaswami J, Chow SL, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation. 2023;148(20):1606-1635. doi:10.1161/CIR.0000000000001184