Physicians' Academy for Cardiovascular Education

Choice of optimal treatment for smoking cessation guided by nicotine metabolite biomarker

Lerman C et al., Lancet Respir Med 2015

Lerman C, Schnoll RA, Hawk LW, et al.
Lancet Respir Med 2015; Published Online January 12, 2015;


Pharmacotherapies for tobacco dependence show a substantial variability both in therapeutic response and adverse effects. The identification of biomarkers may improve the treatment choice as well as outcomes [1]. The nicotine-metabolite ratio (NMR;  3ʹ-hydroxycotinine/cotinine) is a genetically informed biomarker of nicotine clearance derived from nicotine during smoking, which reflects the activity of the liver enzyme CYP2A6.
This study investigated whether NMR status (normal versus slow metabolisers) predicts the response to nicotine patch compared to varenicline, a widely used non-nicotine replacement therapy medication [2,3] for smoking cessation. To this end, 1246 participants seeking treatment for smoking cessation were enrolled in this multicentre, randomised, placebo-controlled trial. Participants were randomly assigned to either 11 weeks of placebo, nicotine patch or varenicline and every treatment included behavioural counselling. Subjects were followed up to 12 months after the target quit date. The primary endpoint was 7 day point prevalence abstinence (biochemically verified) at the end of treatment.

Main results

  • In normal metabolisers, varenicline was more efficacious than nicotine patch (odds ratio (OR): 2.17, 95%CI: 1.38–3.42; P=0.001), which was not the case in slow metabolisers (OR: 1.13,  95%CI: 0.74–1.71; P=0.56).
  • A significant NMR-by-treatment interaction (ratio of odds ratios (ORR): 1.96; 95%CI 1.11–3.46; P=0.02) showed that slow (versus normal) metabolisers reported greater severity of overall side-effect with varenicline versus placebo (β=–1.06; 95%CI: –2.08 to –0.03; P=0.044).


Treating normal metabolisers with varenicline and slow metabolisers with nicotine patch could optimise quit rates while minimising side-effects. Normal metabolisers, compared to slow metabolisers, smoke more cigarettes per day [4], have enhanced responses in the brain’s dopamine reward circuitry when viewing smoking cues [5], show greater daily fluctuation in blood (and presumably brain) nicotine concentrations than slow metabolisers which could contribute to a greater reward from smoking [6]. For normal metabolisers, varenicline may increase dopamine concentrations in brain reward pathways, which may explain the higher efficacy than nicotine patch. These results support the potential clinical validity of the nicotine metabolite ratio as a biomarker to guide the choice of therapy for individual smokers.
Find this article on



1.Bough KJ, Lerman C, Rose JE, et al. Biomarkers for smoking cessation. Clin Pharmacol Ther 2013; 93: 526-38.
2.Cahill K, Stevens S, Perera R, et al.. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst Rev 2013; 5: CD009329.
3.Gonzales D, Rennard SI, Nides M, et al. Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 2006; 296: 47-55.
4.Rao Y, Hoff mann E, Zia M, et al. Duplications and defects in the CYP2A6 gene: identifi cation, genotyping, and in vivo eff ects on smoking. Mol Pharmacol 2000; 58: 747-55.
5.Tang DW, Hello B, Mroziewicz M, et al. Genetic variation in CYP2A6 predicts neural reactivity to smoking cues as measured using fMRI. Neuroimage 2012; 60: 2136-43.
6. 33 Sofuoglu M, Herman AI, Nadim H, et al. Rapid nicotine clearance is associated with greater reward and heart rate increases from intravenous nicotine. Neuropsychopharmacology 2012; 37: 1509-16.