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Background: Life-style interventions, including smoking cessation and weight control are of importance for managing future escalating prevalence of obesity. Smoking habits and obesity have jointly great impact on mortality, however mechanisms behind the effect and variables involved in the obesity paradox is still unknown.

Objectives: This study examines risk factors for all-cause, cardiovascular, and cancer mortality in males and females with high cardiovascular risk, mediated by smoking habits, body mass index (BMI, kg/m2), and serum phosphate (S-P) levels.

Methods: Patients were admitted to the Vindeln Patient Education Center in groups of 30 for a four-week residential comprehensive program (114 hours) focusing on smoking cessation, stress reduction, food preferences and selections, and physical exercise. The follow-up, in years from 1984 to 2014 corresponds to 30 years. This study included 2,504 patients (1,408 females and 1,096 males). Cox regression analysis was used to assess mortality risk associated with smoking habits, low and high BMI, and low and high S-P levels.

Results: High BMI (>34,2 kg/m2), current smoking, type 2 diabetes mellitus (T2DM), high serum calcium (S-Ca), mmol/L and high systolic blood pressure (SBP, mmHg) were associated with all-cause mortality irrespective of sex. Former and current smoking females had a high all-cause mortality (adjusted hazard ratio [HR] 1.581; 95% CI 1.108–2.256, adjusted hazard ratio [HR] 1.935; 95% CI 1.461–2.562, respectively) while current smoking and high BMI increased risk for cardiovascular mortality (adjusted hazard ratio [HR] 3.505; 95% CI 2.140–5.740 and [HR] 1.536; 95% CI 1.058–2.231, respectively). Neither low nor high levels of S-P predicted all-cause, cardiovascular disease (CVD) and cancer mortality in males or females while low levels of S-P predicted all-cause mortality in smokers (adjusted hazard ratio [HR] 1.713; 95% CI 1.211–2.424). In non-smokers, low BMI (<27.6 kg/m2) was protecting and high BMI a risk for all-cause mortality. In males, ischemic heart disease (IHD), and low serum albumin (S-Alb) were associated with all-cause mortality. In females, an interaction between high BMI and smoking (HbmiSM) decreased the cardiovascular mortality (adjusted hazard ratio [HR] 0.410; 95% CI 0.179–0.937, respectively).

Conclusions: High BMI and current smoking were associated with all-cause mortality in both males and females in the present high cardiovascular-risk cohort. In current smokers and non-smokers, T2DM and high S-Ca were associated with an increase in all-cause mortality, while low S-P was associated with all-cause mortality in smokers. Interaction between high BMI and smoking contribute to the obesity paradox by being protective for cardiovascular mortality in females.