Cigarette smoking worsens systemic inflammation in persons with metabolic syndrome

This cross-sectional study was conducted in a population that consisted of 5,503 asymptomatic males and females, free from known diabetes and coronary heart disease, who presented to the Preventive Medicine Center of Albert Einstein Hospital in São Paulo, Brazil, for clinical and laboratory investigations as part of a mandatory occupational health evaluation. Each participant had clinical consultation including a history and physical examination, laboratory examination and abdominal ultrasound scanning as part of their evaluation. Information collected included demographic details, self-reported history of medical conditions such as hypertension and diabetes mellitus, use of medication including antihypertensives, antidiabetics and statins, alcohol use, and a self reported history of current cigarette smoking.

Continuous variables including hs-CRP were examined graphically for normality and are presented as mean ± SD or median (IQR). Categorical variables are expressed as percentages. Student t-tests were used to compare the means of continuous variables between smoking groups (smokers versus non-smokers) while chi-square test of independence was used to compare the frequencies of categorical variables between these two smoking groups. For comparisons of median values of hs-CRP between smokers and non-smokers the wilcoxon rank-sum test was employed.

Median hs-CRP levels as well as their interquartile ranges (IQRs) are presented for each MetS and cigarette smoking category. Similarly, the prevalence of hs-CRP for each of these groups is also graphically presented. We conducted both median linear regression and logistic regression analysis for the effect of smoking on hs-CRP, with hs-CRP expressed as continuous and categorical (hs-CRP >3 mg/L) variables respectively. We chose median linear regression because hs-CRP was non-parametrically distributed. Sub-group analyses were conducted for groups with and without MetS. Interaction terms were created and p-values generated. We conducted additional regression analyses assessing the effect of smoking and MetS individually and together on hs-CRP using the four subject groups described above, with non-smokers free of MetS as the reference group. Finally we conducted similar analysis in sub-groups based on their number of MetS components (elevated waist circumference, triglycerides, blood pressure and glucose, and low HDL-c as earlier mentioned). For each regression analysis univariate and multivariate analysis were conducted adjusting for age, sex, LDL-c, total cholesterol, statin use and anti-hypertensive therapy. Because the definition of MetS included hypertension, dyslipidemia and surrogates for obesity (waist circumference), they were excluded from our models. A p value ≤0.05 was considered statistically significant. All analysis was conducted in STATA version 12 (StataCorp. 2011. Stata Statistical Software: Release 12. College Station, TX: StataCorp LP).

The study population consisted of 5,503 participants. The mean age of the population was 43.1 ± 9.4 years and about 78% of them were male. Approximately 9% (498) were self-reported current smokers while the prevalence of MetS was 20%. About 19% of the population had elevated hs-CRP (>3.0 mg/L). The median (IQR) hs-CRP in the entire population was 1.2 mg/L (0.6-1.4 mg/L) and was significantly higher in smokers than in non-smokers (1.40 mg/L vs. 1.20 mg/L p < 0.001). Among the smokers, 26% had elevated hs-CRP compared to about 19% among the non-smokers (p < 0.001). Other details of the general characteristics are available in Table 1.

The prevalence of MetS was significantly greater among smokers than non-smokers (26.5% vs. 19.8% p < 0.001). In logistic regression analysis before and after controlling for age and sex, antihypertensive and antidiabetic medications and total cholesterol, the odds of MetS was 46% and 36% greater among smokers compared to non-smokers (Unadjusted OR 1.46 95% CI: 1.18, 1.81 p <0.001; Adjusted OR 1.36 95% CI: 1.08, 1.72 p = 0.008).

Among those without MetS, there was no significant difference in the median hs-CRP between smokers and non-smokers (p = 0.11) however, among those with MetS, the median hs-CRP was significantly higher in smokers (2.4 mg/L, IQR 1.2-4.8 mg/L) than in non-smokers (1.8 mg/L, IQR 1.0-3.1 mg/L) (p = 0.002; Figure 1). In the unadjusted linear regression analysis comparing smokers to non-smokers, smoking was associated with a 0.20 mg/L (95% CI: 0.07, 0.33) increase in median hs-CRP in the entire population and 0.60 mg/L (95% CI: 0.10, 1.01) increase in hs-CRP among those with MetS (Table 2). However, among those without MetS, smoking had no effect on hs-CRP (regression coefficient 0.10, 95% CI: -0.04, 0.24). Similar associations were found in the fully adjusted model. In addition, there was significant interaction between MetS and smoking in univariate (p = 0.002) and both multivariate analyses (p = 0.001) (Table 2).

In the group without MetS, there was no significant difference in the prevalence of elevated hs-CRP among smokers versus non-smokers (20% vs. 17% p = 0.08) however among those with MetS the hs-CRP prevalence was 42.4% among smokers compared to 26.8% among non-smokers (p < 0.001).These results are depicted in Figure 2. In a fully adjusted logistic regression model, cigarette smoking was associated with a 55% increase in the odds of elevated hs-CRP in the entire population (OR 1.55, 95% CI: 1.25, 1.92) and more than double the odds of elevated hs-CRP among those with MetS (OR 2.05, 95% CI: 1.40, 3.01). However, there was no significant effect of smoking on hs-CRP in the population without MetS (OR 1.29, 95% CI: 0.98, 1.69). Again, there was significant interaction between MetS and smoking on hs-CRP in unadjusted (p = 0.049) and the age and sex adjusted models (p interaction = 0.05) but not in the fully adjusted model (p interaction = 0.076). Details of the results of the logistic regression analysis are shown in Table 2.

There was a stepwise increase in the median hs-CRP and the prevalence of elevated hs-CRP in the following order: non-smokers without MetS, smokers without MetS, non-smokers with MetS and smokers with MetS (Figures 1 and 2). In adjusted regression analysis hs-CRP was 1.3 mg/L (95% CI: 1.0, 1.6) and 0.7 mg/L (95% CI: 0.6, 0.8) higher among smokers with MetS and non-smokers with MetS compared to non-smokers without MetS. However, there was no significant increase in hs-CRP associated with smokers without MetS compared with non-smokers without MetS (β = 0.11 95% CI: -0.1, 0.3). Again, compared with non-smokers without MetS, smokers with MetS and non-smokers with Mets were 4 times and 2 times more likely to have elevated hs-CRP while the risk was not significantly elevated for those who smoke but do not have MetS (OR 1.30 95% CI: 1.0, 1.7). Details can be found in Table 3.

Both smoking and MetS are among the leading causes of preventable CVD related deaths in the US and globally. Although the prevalence of smoking and other traditional CVD risk factors (dyslipidemia and hypertension) in the US has decreased from 1960 to 2000, the same period has seen a dramatic rise in the prevalence of obesity and MetS [1, 28]. Despite the decline in smoking rates, 19% of the US population are smokers and cigarette smoking still accounts for over 400,000 deaths yearly in the US, 32% of which are CVD related [1, 29]. Globally, tobacco use accounts for about 10% of all CVD related mortality, with the highest occurrences being in low to mid-income countries [2]. Yet awareness about the cardiovascular implications of cigarette smoking are still unacceptably low considering that smoking is a completely preventable cause of CVD [2].

From the results of this study, the absence of smoking, even in the presence of MetS is associated with a 50% reduction in risk of systemic inflammation. Other studies have demonstrated that smoking cessation substantially reduces CVD risk [30]. This study also emphasizes the importance of assessing smokers for metabolic abnormalities and establishing smoking status in those who present with features of the MetS. Smoking cessation attempts need to be more rigorous in those with MetS. There is strong argument that smoking cessation may benefit smokers with MetS [17] since smoking cessation improves insulin sensitivity [31] and could break the interaction between the two.

Our study, as well as others, underscores the need for active pursuant of smoking cessation in the general population by modifying smoking related public health policies and intensive interventions in clinical practice especially among those who have metabolic abnormalities or MetS. Moreover, further studies are needed to understand the processes responsible for the additive effect of smoking and MetS on inflammation.