Cardiovascular-Kidney-Metabolic Versus Non-Cardiovascular-Kidney-Metabolic First Long-Term Conditions and Multimorbidity Development Risk: A Large Comparative Cohort Study in Japan, the UK, and Denmark
Background: Preventing multimorbidity requires understanding how long-term conditions begin to accumulate. Clinical management of a first long-term condition may provide an opportunity for secondary prevention of multimorbidity. Cardiovascular-kidney-metabolic (CKM) conditions share interconnected risk factors and established monitoring and risk-reduction pathways, but whether progression differs after a first CKM versus non-CKM condition remains unclear.Methods: We conducted a retrospective cohort study of adults aged 18 years and older in Japan, the UK, and Denmark, with no or one of 22 harmonised conditions most relevant in primary care. We used a continuous-time multistate framework to examine progression from a first condition to two conditions (MM2), then three or more conditions (MM3+), and death after MM2. We estimated three-year absolute risks and HRs, using time-split Cox models (0–1, 1–3, and ≥3 years), stratified by sex and adjusted for age and calendar year.Findings: We included 3 258 240 participants in Japan, 1 570 985 in the UK, and 3 391 192 in Denmark. Three-year absolute multimorbidity risk was higher after CKM first conditions than non-CKM first conditions: Japan: 44·7% versus 38·8%, UK: 32·9% versus 22·2%, Denmark: 40·2% versus 32·8%. CKM-first trajectories had higher hazards of progression to multimorbidity than non-CKM-first trajectories across all countries and time bands. Corresponding HRs for non-CKM versus CKM first conditions ranged from 0·84 to 0·97 in Japan, 0·69 to 0·86 in the UK, and 0·70 to 0·90 in Denmark. After MM2, associations with MM3+ varied by pattern, age, country, and time; the non-CKM-to-non-CKM pattern had the highest mortality hazard across countries.Interpretation: A first CKM condition was associated with faster progression to MM2, but absolute risk after a first non-CKM condition remained substantial. After MM2, further accumulation and mortality varied by disease composition and recorded sequence. Secondary prevention for multimorbidity should address both CKM-first and non-CKM-first trajectories.