Abstract Body (Do not enter title and authors here): Background: Cardiovascular-kidney-metabolic (CKM) conditions, such as heart failure (HF), chronic kidney disease (CKD), and type 2 diabetes (T2D), commonly coexist. However, whether specific pathways and timing of CKM multimorbidity onset and progression vary in relation to background CKM status has not been rigorously evaluated.

Methods: In this retrospective cohort study using Optum Market Clarity, a longitudinal (2007-2023) US database comprising electronic health records of >80M unique individuals linked to claims, we estimated incidence rates of CKM conditions (clinical cardiovascular disease [cCVD; myocardial infarction, stroke, peripheral artery disease, and atrial fibrillation], HF, CKD, and T2D) and multimorbidity (≥2 CKM conditions). CKM conditions were identified via administrative codes and/or laboratory data. Time-to-onset and progression of CKM multimorbidity was evaluated by baseline CKM status (number/type of CKM conditions), using Cox proportional hazards models.

Results: Overall, 604,732 individuals were included in the analysis (mean [SD] age, 48.4 [17.1] years; 56% female), of which 136,886 (23%) had ≥1 CKM condition at baseline. In patients with 1 CKM condition, HF was associated with the highest rate of progression to CKM multimorbidity (incidence rate, 15.99 per 100 patient-years), followed by CKD, cCVD, and T2D (Figure, A). Among those who experienced progression to CKM multimorbidity, median times to a second CKM condition ranged between 1.2 to 2.0 years. When the full spectrum of baseline CKM status was evaluated, rates of multimorbidity progression and all-cause death generally increased with higher baseline CKM burden (Figure, B). However, progression of CKM multimorbidity varied by background CKM status; cCVD and T2D occurred most frequently among those without CKM conditions, HF and T2D occurred most frequently among those with cCVD, and cCVD occurred most frequently among those with HF, CKD, and T2D.

Conclusions: These findings provide novel insights into pathways and timing of CKM multimorbidity progression in the US, stressing the need for intensive management strategies to prevent or delay the often rapid onset of sequential CKM conditions once one is established.