This article will highlight the available clinical evidence showing the role of biological differences in the effectiveness of smoking cessation pharmacotherapy.
According to the CDC, tobacco use is the single largest preventable cause of death and disease in the United States. Despite continuing declines in cigarette smoking, it kills an estimated 480,000 Americans every year. Additionally, smoking-related illness in the United States costs in excess of $300 billion a year, including nearly $170 billion in direct medical care and $156 billion in lost productivity.1
Within recent years, evidence has started to emerge that biological differences may play a role in the effectiveness of smoking cessation therapy. This article will highlight the available clinical evidence to further explore this topic.
Medication therapy has been shown to help smokers quit, although the likelihood of long-term success remains relatively low. Currently, there are 7 first-line medications used for smoking cessation therapy: 5 variants of nicotine replacement therapy (NRT), varenicline (Chantix), and bupropion sustained release (Zyban). Previous studies have shown these medications to increase the rate of quitting by 50-80% compared to placebo alone.2
Evidence shows pronounced differences in the effects of smoking on men compared with women. Despite the number of male smokers outnumbering females (19% vs 14.7%) and the fact that women are more likely to report a quit attempt than men, studies have shown that women have lower rates of successful quitting. In one pooled analysis of clinical trials, women taking placebo were found to be 50% less likely to quit than men.3
The exact reason for lower quit rates is unclear, however it is known that women take less time to become dependent after initial tobacco use and that hormonal changes during menstruation are believed to deepen withdrawal syndrome and increase cravings.4 Additionally, women may face different stressors and barriers to quitting, including a greater likelihood of depression, greater weight control concerns, greater nonpharmacologic motives for smoking (e.g. socialization), and educational differences.
More importantly, women are at greater risk for smoking-related illnesses including lung cancer and heart disease. Woman may also experience sex-specific consequences of smoking such as altered menstrual function, earlier menopause, infertility, ectopic pregnancy, decreased bone density, and cervical cancer.2
Overview of Evidence
The link between biological factors and smoking cessation therapy effectiveness dates back to the early 2000s. In an article published in Pharmacogenomics, researchers concluded that preliminary evidence “suggests that the efficacy of pharmacotherapy may be influenced by different genetic and biological factors in males and females.” 5
Three years after this article was published, researchers conducted a meta-analysis of 14 studies to assess gender differences in long-term smoking cessation rates with the nicotine patch. Study results found poorer outcomes in women versus men; the increase in percent quit with nicotine versus placebo was about half as great in women.6
More recently, a meta-analysis was conducted looking at gender differences in varenicline efficacy for smoking cessation. The analysis, compiling 16 studies, found that varenicline demonstrated greater efficacy among women smokers for short and immediate-term outcomes and equal efficacy for 1-year outcomes (46% more efficacious at end of treatment; 34% more efficacious at 6-months). The authors concluded that “varenicline may be particularly useful for reducing the sex disparity typically seen in rates of smoking cessation.”7
In a separate analysis of bupropion trials, investigators found no difference in the efficacy by gender at end of treatment, although rates of quitting were lower overall among women.8
In 2016, Smith et al published one of the most robust analyses of gender differences in smoking cessation pharmacotherapy. They designed their study as a network meta-analysis, which allowed for indirect comparisons between treatment groups (varenicline, nicotine patch, bupropion) using placebo as an anchor point. Study results found that for women, varenicline was 41% more effective than nicotine patch and 38% more effective than bupropion. For men, outcomes for those treated with nicotine patch and bupropion were similar to those treated with varenicline. No differences in efficacy were found when comparing bupropion versus nicotine patch.9
The exact biological mechanism behind smoking cessation medication differences between men and women has not been well-defined. Preliminary evidence suggests that nicotine may affect men and women differently, primary because women metabolize, and thereby clear, nicotine at a faster rate than men. This could be an important consideration because faster nicotine metabolism appears to be associated with poorer smoking cessation outcomes with nicotine replacement products. This effect is known to be partially mediated by estrogen.
Smith and colleagues hypothesized that the advantage of varenicline over bupropion and nicotine patch may be the result of gender-specific differences in metabolism of these medications. Nicotine and bupropion both undergo substantial metabolism via CYP2B6, which seem to have greater function in women compared to men. On the other hand, varenicline is not significant metabolized by CYP enzymes, and it has demonstrated similar pharmacokinetic properties for both women and men.7-9
Another proposed mechanism of varenicline involves its effect on mood. Smoking in women has been shown to be more strongly tied to negative affect and stress; varenicline may directly target negative affect and improve mood during nicotine withdrawal. However, it’s important to note bupropion would also be expected to convey this benefit, but the previously mentioned studies did not demonstrate any additional benefit in women versus men.8,9
Despite women being more likely to report attempting to quit smoking than men, studies have shown significantly lower quit rates with women. While the selection of any medication for smoking cessation is patient-specific, varenicline may be particularly advantageous in improving quit rates in women. Conversely, nicotine replacement products have been associated with poorer responses in women.
Notably, in the current US Department of Health and Human Services clinical care guidelines for smoking cessation, it is acknowledged that nicotine replacement therapy may be less effective for women and therefore clinicians should give consideration to other medications, such as varenicline.2