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Convincing analysis that e-cigs are a gateway to cigarette smoking from studies around the world

Last March Jasmine Khouja and colleagues published “Is e-cigarette use in non-smoking young adults associated with later smoking? A systematic review and meta-analysis” in Tobacco Control.  This is the most comprehensive meta-analysis to data and convincingly shows that youth and young adults (up to age 30) who initiate nicotine use with e-cigarettes are, much more likely to be smoking cigarettes later.

The paper includes 17 studies from the US, UK, Mexico, Germany, and the Netherlands. Every single one of these studies showed that e-cigarette use was associated with significantly increased odds of subsequent cigarette smoking initiation.

The paper includes impressive sensitivity analysis that presents analyses of unadjusted and adjusted odds (for a wide range of potential confounders) of subsequent smoking, how e-cigarette use and smoking were assessed, where the studies were done (US, UK, other countries), and whether or not studies included only youth (<18 years old) or young adults (18+ years old).  While these different analyses led to slightly different overall estimates of risk, the results were always statistically significant and positive.

The fact that the results are so consistent despite how the data are subdivided is strong evidence that the association is real.

The subanalysis of the UK studies (Figure S10, aOR 3.85, 95% CI 2.18-6.81) is especially impressive and shows similar risks as for the US studies (Figure S9, aOR 2.95, 95% CI 2.14-4.06).  This should put to bed the claim made by some UK advocates that the evidence for a gateway effect for e-cigarettes is some kind of unique US phenomenon.

From the point of view of assessing the population effects of e-cigarettes, the analysis in this paper is about as good as it gets.

The authors discuss the “common liability hypothesis” which posits that kids who use e-cigarettes and cigarettes share common factors that could somehow explain the strong and consistent association they find.  This is surprising, given the fact that several studies, including one we published that cites several others, that show that around three-quarters of youth who initiate tobacco product use with e-cigarettes have risk profiles that would lead you to not expect that they would start with cigarettes.

Given the strength of this analysis, I was surprised that the authors minimized the impact of their own findings, including holding out the promise that e-cigs were a good cessation tool from adults (a question not addressed in the paper):

In conclusion, there is a strong consistent association in observational studies between e-cigarette use among non-smokers and later smoking. However, findings from published studies do not provide clear evidence that this is explained by a gateway effect rather than shared common causes of both e-cigarette use and smoking. This emphasises the need for a scientific forum to discuss the evidence to date and directions for future research. Future research should consider including relevant potential confounders, such as better measures of impulsivity and other measures of propensity to risk taking, and objective measures of smoking status in order to better explore the potential role of e-cigarettes as a gateway to smoking. Studies that explore the genetic underpinnings of these behaviours and use negative control outcomes may also help improve our understanding of the association between e-cigarette use and later smoking. A scoping review, including qualitative evidence, could provide a clearer understanding of the why e-cigarette use is associated with later smoking. Importantly, any recommendations regarding e-cigarette regulations to limit the burden of future smoking must consider the potential beneficial impact of e-cigarette use on smoking cessation.

Maybe it’s because the authors are from England.

Here is the abstract:

Objective The aim of this review was to investigate whether e-cigarette use compared with non-use in young non-smokers is associated with subsequent cigarette smoking.

Data sources PubMed, Embase, Web of Science, Wiley Cochrane Library databases, and the 2018 Society for Research on Nicotine and Tobacco and Society for Behavioural Medicine conference abstracts.

Study selection All studies of young people (up to age 30 years) with a measure of e-cigarette use prior to smoking and an outcome measure of smoking where an OR could be calculated were included (excluding reviews and animal studies).

Data extraction Independent extraction was completed by multiple authors using a preprepared extraction form.

Data synthesis Of 9199 results, 17 studies were included in the meta-analysis. There was strong evidence for an association between e-cigarette use among non-smokers and later smoking (OR: 4.59, 95% CI: 3.60 to 5.85) when the results were meta-analysed in a random-effects model. However, there was high heterogeneity (I2=88%).

Conclusions Although the association between e-cigarette use among non-smokers and subsequent smoking appears strong, the available evidence is limited by the reliance on self-report measures of smoking history without biochemical verification. None of the studies included negative controls which would provide stronger evidence for whether the association may be causal. Much of the evidence also failed to consider the nicotine content of e-liquids used by non-smokers meaning it is difficult to make conclusions about whether nicotine is the mechanism driving this association.

The full citation is Khouja JN, Suddell SF, Peters SE, et al.  Is e-cigarette use in non-smoking young adults associated with later smoking? A systematic review and meta-analysis.  Tobacco Control Published Online First: 10 March 2020. doi: 10.1136/tobaccocontrol-2019-055433.  It is available here.

Stan Glantz/UCSF