Smoking status and cessation duration in relation to the progression of cardio-renal-metabolic multimorbidity: a prospective cohort study from the UK Biobank.

backgroundThis study aimed to investigate the association of smoking status and years since cessation with the onset, progression, and prognosis of cardio-renal-metabolic (CRM) multimorbidity (CRMM).

methodsThis study included participants from the UK Biobank who were free of CRM disease at baseline. Covariates adjusted Cox proportional hazards models were employed to evaluate the associations of smoking status and years since smoking cessation with the risks of individual CRM diseases, including ischemic heart disease (IHD), stroke, type 2 diabetes (T2D), and chronic kidney disease (CKD), as well as with each state in CRMM progression, including first CRM disease (FCRMD), CRMM (defined as the occurrence of two or more CRM diseases), and death. Multi-state models were used to analyze the associations between smoking-related behaviors and CRMM progression. The effects of smoking cessation were further explored within subgroups according to sex, age at smoking initiation, smoking duration, smoking intensity, and genetic risk scores for individual CRM diseases.

resultsIn total, 356,071 participants (median age 57 years; 44.9% male) who were free of CRM disease (healthy) at baseline and had complete information on smoking status were included. During a median follow-up of 13.6 years, 56,786 participants developed a FCRMD, and 11,508 progressed to CRMM, of whom 2,796 subsequently died. Across all transitions from healthy to FCRMD, then to CRMM, and ultimately to death, current smoking had a greater impact on transitions leading to mortality. Compared with never smokers, current smokers had an adjusted hazard ratio of 1.44 (95% CI: 1.40-1.47) for the transition from healthy to FCRMD and 2.49 (95% CI: 2.38-2.60) for the transition from healthy to death. Approximately 25 years of smoking cessation were required for risks across all transitions in CRMM progression among former smokers to became not significantly different from those of never smokers. Compared with current smokers, former smokers experienced significantly lower risks for transitions leading to death shortly after cessation, whereas risk reductions for the transitions from healthy to FCRMD and from FCRMD to CRMM were not observed until more than 5 and 20 years after cessation, respectively. When disease-specific transitions were further considered, longer post-cessation periods were required to achieve significant risk reductions for transitions from healthy to T2D or CKD and from IHD or T2D to death, compared with current smokers. The effects of smoking cessation on CRMM progression varied by sex and previous smoking behavior, but not by genetic susceptibility to specific CRM diseases.

conclusionSmoking has substantial but varied impacts across transitions in CRMM progression and disease-specific pathways. Long-term smoking cessation is an important strategy for reducing the risk of CRMM onset and progression. Individuals with specific prior smoking patterns (e.g., male or heavy smokers) and those at certain transition states warrant particular attention during the short-term period following smoking cessation.