To our knowledge this is the largest prospective, randomized clinical trial that has evaluated the effects of smoking cessation on lipid and lipoprotein levels. Although smoking is associated with low HDL-C, previous studies suggesting that smoking cessation increases HDL-C levels were from older, observational studies with less contemporary cohorts or from smaller clinical trials. Smokers in our study had higher BMIs than in previous reports, and are more representative of the current United States population.6,8,9,13,29
Despite our subjects being more overweight and gaining weight after smoking cessation, we showed that smoking cessation was related to higher HDL-C and higher total and large HDL particles. Patients with the lowest HDL-related parameters had the largest increases in HDL. After baseline levels of HDL-C and HDL particles, abstinence from cigarette smoking was the next most powerful predictor of changes in these parameters, followed by female sex and weight change. The observation that women had larger increases in HDL-C and HDL particles after smoking cessation is consistent with our previous observation that among current smokers, the association between pack-years of smoking and the presence of carotid plaque was stronger in women,30
and a previous observation that smoking has a stronger association with coronary heart disease incidence in women compared to men.31
The mechanisms by which smoking decreases HDL-C are incompletely understood. Smoking increases catecholamine release, causing a surge in circulating free fatty acids, which may increase VLDL and LDL concentrations and reduce HDL-C concentrations.8
Smoking reduces lecithin-cholesterol acyl-transferase, the enzyme responsible for esterifying free cholesterol and increasing HDL size,32
and may reduce levels of cholesterol ester transfer protein; however, studies of the effects smoking on these enzymes have had mixed results.33–35
In population-based studies, a 1 mg/dL increase in HDL-C has been associated with a 2–3% decrease in CVD events.36,37
This implies that in our subjects, smoking abstinence could reduce CVD events by 4–6% over a decade. Our study also suggests that abstinence from smoking is associated with increases in HDL-C, regardless of baseline smoking intensity. This important finding may encourage clinicians to emphasize abstinence even in light smokers.
Weight gain after smoking cessation can be a significant barrier to quitting.14–16
In our study, those who abstained gained approximately 4 kg more than those who resumed smoking. Increased weight has been associated with lower HDL-C, such that every kilogram of additional weight can reduce HDL-C by 0.5–1%;17,18
however, HDL-C increased by 5.2% among abstainers in our study. Weight gain was independently associated with increased HDL-C as well as total and large HDL particles. This suggests that the impact of weight gain on HDL may be counteracted by the impact of smoking cessation. This important finding has not been reported previously in a cohort of this size. Smoking has been associated with increased triglycerides.6
In our study, abstinence from smoking was associated with only mild triglycerides reductions that were not statistically significant after correcting for multiple comparisons, likely because of the counterbalancing effect of weight gain. Significant changes in LDL-C, LDL particle concentrations, and LDL size were not observed.
Because this was a randomized clinical trial of smoking cessation interventions, there were no non-smoking controls, so we cannot determine the extent to which lipoprotein values normalized after smoking cessation. In smoking cessation studies, it is common for subjects who relapse to drop out or miss follow-up visits.25–27
In our study, 38.6% of subjects did not return for their one year follow-up visit, which is consistent with the 30–43% one year drop-out rates reported in other recent clinical trials of smoking cessation pharmacotherapy.26,27
Subjects who did not attend the follow-up visit had similar age, sex, and race distributions to those that did return, and they smoked a similar number of cigarettes/day at baseline.15
Although significant efforts were made to recruit racially diverse participants, only 16% of the study cohort was non-white. Also, changes in alcohol use and physical activity levels were not included in the analysis because 1-year follow-up data were not yet coded for analysis. Alcohol use and exercise can increase HDL-C levels. Smoking cessation is not associated with increased exercise levels; however, we cannot exclude the possibility that the increases in HDL we observed among abstainers were related to increased alcohol intake. Most smoking cessation trials have not systematically evaluated alcohol use.38
Smoking cessation studies that did evaluate alcohol use have had conflicting results; 39,40
however, our statistical models did not show that baseline exercise levels or alcohol use independently predicted changes in HDL parameters. Although LDL particles and LDL-C did not change significantly with smoking cessation, we did not measure oxidized LDL levels.