Background Cigarette smoking has been associated with increases in C-reactive protein (CRP) and leukocyte counts (WBC); however, the effects of smoking intensity and smoking cessation on inflammatory markers have not been evaluated prospectively in a large, modern cohort of current smokers. Methods WBC count and high-sensitivity CRP were measured in current smokers enrolled in a randomized, prospective clinical trial of five smoking cessation pharmacotherapies. Smoking intensity parameters included: cigarettes/day, pack-years, Fagerstrom Test of Nicotine Dependence (FTND) score, and carbon monoxide (CO) levels. CRP also was measured after 1 year with assessment of abstinence status. Results The 1,504 current smokers (58% female) were mean (standard deviation): 44.7 (11.1) years old, smoked 21.4 (8.9) cigarettes/day and had a smoking burden of 29.4 (20.4) pack-years. Log (CRP) was not associated with any marker of smoking intensity, except for a weak correlation with pack-years (r=0.05, p=0.047). In contrast, statistically significant correlations were observed between all 4 markers of smoking intensity and WBC count (all p≤0.011). In multivariable models, waist circumference (p<0.001) and triglycerides (p<0.05), but no markers of smoking intensity, were associated with log(CRP). However, pack-years (p=0.002), cigarettes/day (p=0.013), CO (p<0.001), and FTND (p<0.001) were independently associated with WBC count. After 1 year, log(CRP) (p=0.296) and changes in log(CRP) (p=0.455) did not differ between abstainers and continuing smokers. Conclusions Smoking intensity is associated with increased WBC count, but not CRP levels. Smoking cessation does not reduce CRP. The relationship between CRP and smoking intensity may be masked by CRP’s stronger relationship with adiposity.

Background The long-term effects of smoking and smoking cessation on markers of cardiovascular disease (CVD) prognosis obtained during treadmill stress testing (TST) are unknown. The purpose of this study was to evaluate the long-term effects of smoking cessation and continued smoking on TST parameters that predict CVD risk. Methods In a prospective, double-blind, randomized, placebo-controlled trial of 5 smoking cessation pharmacotherapies, symptom-limited TST was performed to determine peak METs, rate-pressure product (RPP), heart rate (HR) increase, HR reserve, and 60-second HR recovery, before and 3 years after the target smoking cessation date. Relationships between TST parameters and treatments among successful abstainers and continuing smokers were evaluated using multivariable analyses. Results At baseline, the 600 current smokers (61% women) had a mean age of 43.4 (SD 11.5) years and smoked 20.7 (8.4) cigarettes per day. Their exercise capacity was 8.7 (2.3) METs, HR reserve was 86.6 (9.6)%, HR increase was 81.1 (20.9) beats/min, and HR recovery was 22.3 (11.3) beats. Cigarettes per day and pack-years were independently and inversely associated with baseline peak METs (P < .001), RPP (P < .01, pack-years only), HR increase (P < .05), and HR reserve (P < .01). After 3 years, 168 (28%) had quit smoking. Abstainers had greater improvements than continuing smokers (all P < .001) in RPP (2,055 mm Hg beats/min), HR increase (5.9 beats/min), and HR reserve (3.7%), even after statistical adjustment (all P < .001). Conclusions Smokers with a higher smoking burden have lower exercise capacity, lower HR reserve, and a blunted exercise HR response. After 3 years, TST improvements suggestive of improved CVD prognosis were observed among successful abstainers.

Weight gain after smoking cessation may increase diabetes mellitus and impaired fasting glucose (IFG) risk. This study evaluated associations between smoking cessation and continued smoking with incident diabetes and IFG three years after a quit attempt. The 1504 smokers (58% female) were mean (standard deviation) 44.7 (11.1) years old and smoked 21.4 (8.9) cigarettes/day. Of 914 participants with year 3 data, the 238 abstainers had greater weight gain, increase in waist circumference, and increase in fasting glucose levels than the 676 continuing smokers (p≤0.008). In univariate analyses, Year 3 abstinence was associated with incident diabetes (OR = 2.60, 95% CI 1.44–4.67, p = .002; 4.3% absolute excess) and IFG (OR = 2.43, 95% CI 1.74–3.41, p<0.0001; 15.6% absolute excess). In multivariate analyses, incident diabetes was associated independently with older age (p = 0.0002), higher baseline body weight (p = 0.021), weight gain (p = 0.023), baseline smoking rate (p = 0.008), baseline IFG (p<0.0001), and baseline hemoglobin A1C (all p<0.0001). Smoking more at baseline predicted incident diabetes among eventual abstainers (p<0.0001); weighing more at baseline predicted incident diabetes among continuing smokers (p = 0.0004). Quitting smoking is associated with increased diabetes and IFG risk. Independent risk factors include older age, baseline body weight, baseline glycemic status, and heavier pre-quit smoking. These findings may help target smokers for interventions to prevent dysglycemia.Trial RegistrationClinicaltrials.gov NCT00332644

Background Reduced triglyceride clearance due to impaired lipoprotein lipase (LPL)-mediated lipolysis contributes to severe hypertriglyceridemia in lipodystrophy. Angiopoietin-like protein 3 (ANGPTL3) and 4 (ANGPTL4) impair clearance of triglycerides by inhibiting LPL. Whether circulating ANGPTL3/4 levels are altered in lipodystrophy and the effects of leptin replacement on these ANGPTLs are unknown. Objective To examine if ANGPTL3/4 levels are elevated in patients with generalized lipodystrophy and assess the effects of leptin replacement on these ANGPTLs. Methods Pre-leptin treatment plasma levels of ANGPTLs in patients with generalized lipodystrophy (n=22) were compared with healthy controls (n=39) using a post-hoc case-control study design. In a prospective, open-label study, we studied the effects of metreleptin therapy (16–32 weeks) on plasma ANGPTL3/4 in patients with generalized lipodystrophy. Results Plasma ANGPTL3 (geometric mean [95% CI]) (223 ng/mL [182,275] vs. 174 [160,189], p=0.02) but not ANGPTL4 levels (55 ng/mL [37,81] vs. 44 [37,52], p=0.26) were higher in patients with lipodystrophy compared with healthy controls. There was a significant decrease in total cholesterol, triglycerides, and glycosylated hemoglobin (A1C) levels following metreleptin therapy. Post-metreleptin, ANGPTL3 concentrations decreased significantly (223 ng/mL [182,275] vs. 175 [144,214], p=0.01) with no change in ANGPTL4 (55 ng/mL [37,81] vs. 48 [32,73], p=0.11). Conclusions These findings suggest that elevated plasma levels of ANGPTL3 in leptin-deficient states is attenuated with leptin therapy.