ArticlesUse of the nicotine metabolite ratio as a genetically informed biomarker of response to nicotine patch or varenicline for smoking cessation: a randomised, double-blind placebo-controlled trial
Introduction
Despite substantial reductions in tobacco use since the 1960s, rates of tobacco use have remained stable in the USA for the past decade1 and have increased in low-income countries.2 Worldwide, about 6 million annual deaths are attributable to tobacco use,2 and US$200 billion is spent on tobacco-related health-care costs.3 Smoking cessation treatments approved by the US Food and Drug Administration include nicotine replacement therapies, bupropion, and varenicline. Although transdermal nicotine patch is the safest and most widely used form of pharmacotherapy in the USA and Europe,4 end-of-treatment quit rates in clinical trials rarely exceed 30%.5 The efficacy of nicotine patch is comparable with bupropion,6 but could be lower than varenicline.7, 8 However, varenicline's efficacy might be offset by the greater likelihood of side-effects.9 The substantial individual variability in therapeutic response and side-effects provides a strong rationale to validate novel biomarkers to optimise pharmacotherapy choice.10
We identified a genetically informed biomarker of nicotine clearance, specifically the ratio of two metabolites derived from nicotine during smoking, 3′-hydroxycotinine and cotinine, referred to as the nicotine-metabolite ratio (NMR). The NMR reflects the activity of the liver enzyme CYP2A6, the major nicotine-metabolising and cotinine-metabolising enzyme. A substantial advantage of the NMR over CYP2A6 genotyping is that it incorporates both genetic and environmental (eg, oestrogen) effects on CYP2A6 activity and nicotine clearance.11 Retrospective analyses of previous randomised trials have shown that slow metabolisers (lower NMR values and rates of nicotine clearance) respond well to nicotine patch, with no incremental benefit from the non-nicotine replacement therapy medication bupropion; normal metabolisers do more poorly than slow metabolisers on nicotine patch, but benefit from bupropion.12, 13, 14, 15 To date, no study has examined whether the NMR predicts the efficacy of varenicline, a widely used non-nicotine replacement therapy medication that is more efficacious than bupropion.16, 17
To translate these findings to practice, we did the first NMR-stratified placebo-controlled randomised trial of nicotine patch versus varenicline among 1246 smokers. Although CYP2A6 does not contribute to varenicline metabolism, previous bupropion trial data14 suggested that a non-nicotine replacement therapy medication would aid quitting among normal metabolisers. Among normal metabolisers, we expected varenicline to be more efficacious than nicotine patch, whereas among slow metabolisers, we expected nicotine patch and varenicline to be equally efficacious.
Section snippets
Study design and participants
We randomly assigned participants by NMR group to one of three treatment groups: placebo (placebo pill plus placebo patch); nicotine patch (placebo pill plus active patch); or varenicline (active pill plus placebo patch) (figure 1). Our primary aim was to compare the efficacy of nicotine patch versus varenicline by NMR group (normal metabolisers vs slow metabolisers). A placebo condition was included to examine side-effects of treatment by NMR group.
We undertook the clinical trial at four
Results
Retention rates at end of treatment exceeded 70% and retention did not vary across treatment groups or NMR group (figure 1). The treatment groups did not differ on demographic and smoking history variables (table 1). Slow metabolisers were younger (p=0·02), less likely to be white (p<0·0001), more likely to be male (p=0·001), and smoked fewer cigarettes per day (p<0·001), versus normal metabolisers, as reported previously.27 Sex differences in the NMR groups are expected because of oestrogen
Discussion
In this biomarker-stratified randomised clinical trial, varenicline was better than nicotine patch for normal metabolisers, but had equivalent efficacy for slow metabolisers. Slow metabolisers, but not normal metabolisers, reported more overall side-effects on varenicline (vs placebo). Although slow metabolisers were oversampled to be about 50% of the intention-to-treat sample, 40% of smokers attending the study intake were classified as slow metabolisers by the 0·31 cutpoint (appendix). Thus,
References (36)
- et al.
Nicotine metabolic rate predicts successful smoking cessation with transdermal nicotine: a validation study
Pharmacol Biochem Behav
(2009) - et al.
Genetic variation in CYP2A6 predicts neural reactivity to smoking cues as measured using fMRI
Neuroimage
(2012) - et al.
Unemployment, measured and perceived decline of economic resources: Contrasting three measures of recessionary hardships and their implications for adopting negative health behaviors
Soc Sci Med
(2014) - et al.
Prospective cohort study of the effectiveness of smoking cessation treatments used in the “real world”
Mayo Clin Proc
(2014) Quitting smoking among adults—United States, 2001–2010
MMWR Morb Mortal Wkly Rep
(2011)World Health Organization tobacco fact sheet (no. 339)
(2013)- Eriksen M, Mackay J, Ross H. The tobacco atlas, 4th edn. Atlanta, GA: American Cancer Society; New York, NY: World Lung...
- et al.
Impact of UK policy initiatives on use of medicines to aid smoking cessation
Tob Control
(2005) - et al.
Treating tobacco use and dependence: 2008 update. Clinical practice guideline
(2008) - et al.
Antidepressants for smoking cessation
Cochrane Database Syst Rev
(2007)
Varenicline versus transdermal nicotine patch for smoking cessation: results from a randomised open-label trial
Thorax
Fifty-two-week continuous abstinence rates of smokers being treated with varenicline versus nicotine replacement therapy
Addiction
Effectiveness and safety of varenicline as an aid to smoking cessation: results of an inter-Asian observational study in real-world clinical practice
Int J Clin Pract
Biomarkers for smoking cessation
Clin Pharmacol Ther
Nicotine metabolite ratio as an index of cytochrome P450 2A6 metabolic activity
Clin Pharmacol Ther
Association of nicotine metabolite ratio and CYP2A6 genotype with smoking cessation treatment in African-American light smokers
Clin Pharmacol Ther
Nicotine metabolite ratio predicts efficacy of transdermal nicotine for smoking cessation
Clin Pharmacol Ther
Toward personalized therapy for smoking cessation: a randomized placebo-controlled trial of bupropion
Clin Pharmacol Ther
Cited by (224)
Genomic medicine to reduce tobacco and related disorders: Translation to precision prevention and treatment
2023, Addiction NeuroscienceInfluence of Genes in the Individualization of Smoking Cessation Pharmacological Treatment
2023, Archivos de BronconeumologiaThe use of biomarkers to guide precision treatment for tobacco use
2023, Addiction Neuroscience