Pharmacotherapy for smoking cessation: effects by subgroup defined by genetically informed biomarkers
Abstract
Background
Smoking cessation therapies are not effective for all smokers, and researchers are interested in identifying those subgroups of individuals (e.g. based on genotype) who respond best to specific treatments.
Objectives
To assess whether quit rates vary by genetically informed biomarkers within pharmacotherapy treatment arms and as compared with placebo. To assess the effects of pharmacotherapies for smoking cessation in subgroups of smokers defined by genotype for identified genome‐wide significant polymorphisms.
Search methods
We searched the Cochrane Tobacco Addiction Group specialised register, clinical trial registries, and genetics databases for trials of pharmacotherapies for smoking cessation from inception until 16 August 2016.
Selection criteria
We included randomised controlled trials (RCTs) that recruited adult smokers and reported pharmacogenomic analyses from trials of smoking cessation pharmacotherapies versus controls. Eligible trials included those with data on a priori genome‐wide significant (P < 5 × 10‐8) single‐nucleotide polymorphisms (SNPs), replicated non‐SNPs, and/or the nicotine metabolite ratio (NMR), hereafter collectively described as biomarkers.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. The primary outcome was smoking abstinence at six months after treatment. The secondary outcome was abstinence at end of treatment (EOT). We conducted two types of meta‐analyses‐ one in which we assessed smoking cessation of active treatment versus placebo within genotype groups, and another in which we compared smoking cessation across genotype groups within treatment arms. We carried out analyses separately in non‐Hispanic whites (NHWs) and non‐Hispanic blacks (NHBs). We assessed heterogeneity between genotype groups using T², I², and Cochrane Q statistics.
Main results
Analyses included 18 trials including 9017 participants, of whom 6924 were NHW and 2093 NHB participants. Data were available for the following biomarkers: nine SNPs (rs1051730 (CHRNA3); rs16969968, rs588765, and rs2036527 (CHRNA5); rs3733829 and rs7937 (in EGLN2, near CYP2A6); rs1329650 and rs1028936 (LOC100188947); and rs215605 (PDE1C)), two variable number tandem repeats (VNTRs; DRD4 and SLC6A4), and the NMR. Included data produced a total of 40 active versus placebo comparisons, 16 active versus active comparisons, and 64 between‐genotype comparisons within treatment arms.
For those meta‐analyses showing statistically significant heterogeneity between genotype groups, we found the quality of evidence (GRADE) to be generally moderate. We downgraded quality most often because of imprecision or risk of bias due to potential selection bias in genotyping trial participants.
Comparisons of relative treatment effects by genotype
For six‐month abstinence, we found statistically significant heterogeneity between genotypes (rs16969968) for nicotine replacement therapy (NRT) versus placebo at six months for NHB participants (P = 0.03; n = 2 trials), but not for other biomarkers or treatment comparisons. Six‐month abstinence was increased in the active NRT group as compared to placebo among participants with a GG genotype (risk ratio (RR) 1.47, 95% confidence interval (CI) 1.07 to 2.03), but not in the combined group of participants with a GA or AA genotype (RR 0.43, 95% CI 0.15 to 1.26; ratio of risk ratios (RRR) GG vs GA or AA of 3.51, 95% CI 1.19 to 10.3).
Comparisons of treatment effects between genotype groups within pharmacotherapy randomisation arms
For those receiving active NRT, treatment was more effective in achieving six‐month abstinence among individuals with a slow NMR than among those with a normal NMR among NHW and NHB combined participants (normal NMR vs slow NMR: RR 0.54, 95% CI 0.37 to 0.78; n = 2 trials). We found no such differences in treatment effects between genotypes at six months for any of the other biomarkers among individuals who received pharmacotherapy or placebo.
Authors' conclusions
We did not identify widespread differential treatment effects of pharmacotherapy based on genotype. Some genotype groups within certain ethnic groups may benefit more from NRT or may benefit less from the combination of bupropion with NRT. The reader should interpret these results with caution because none of the statistically significant meta‐analyses included more than two trials per genotype comparison, many confidence intervals were wide, and the quality of this evidence (GRADE) was generally moderate. Although we found evidence of superior NRT efficacy for NMR slow versus normal metabolisers, because of the lack of heterogeneity between NMR groups, we cannot conclude that NRT is more effective for slow metabolisers. Access to additional data from multiple trials is needed, particularly for comparisons of different pharmacotherapies.
PICOs
Plain language summary
Do people's genes affect how effective medicines can be in helping people to quit smoking?
Background
Quitting smoking dramatically reduces risk of premature death, but rates of smoking cessation remain low, even with the help of smoking cessation treatments. Recent research has suggested that differences in parts of our genes, called 'genotypes', may help us to tell which smokers could be helped most by different treatments. However, more research is needed to confirm whether or not our genes affect how effective different treatments are at helping people to quit.
Study characteristics
We searched for studies of smokers treated with medicine to help them quit. We looked at people's genes and at how well their bodies could process nicotine, as this might help us to identify people more likely to quit successfully. We found 33 studies relevant to our review, and we were able to get enough information for 18 clinical trials, including over 9000 smokers, that looked at different medicines used to help people to stop smoking.
Key results
The results suggest that smokers with specific genotypes may be more likely to be successful quitting smoking with the use of nicotine replacement therapies compared with smokers who do not have those specific genotypes. Smokers whose bodies process nicotine more slowly may also benefit more from nicotine replacement therapy. We did not see effects of genes on the effectiveness of medicines other than nicotine replacement therapy.
Quality of evidence
These results should be interpreted with caution because the included studies did not assign treatments to smokers on the basis of genotype or the rate at which they process nicotine, and because a small number of clinical trials were included in some comparisons.
