Science FDA (and everyone else) needs to actively engage as they think about whether to authorize Juul and the other ecigs

When I read the FDA’s Technical Project Lead summary of its scientific justification for authorizing the sale of RJ Reynolds’ Vuse Solo e-cigarette, I was struck by the fact that it ignored the broad scientific literature on e-cigarettes and seemed to accept industry-framed arguments.

For example:

  • They ignored the evidence that as consumer products, e-cigarettes do not help smokers quit, that they promote relapse in former smokers.
  • The discussion of health effects was shallow, focusing on the fact that e-cigs deliver lower levels of some toxins and ignoring the huge body of evidence of substantial specific harms.
  • They ignored the evidence that dual use (when smokers add e-cigs rather than “switching completely”) is more dangerous than smoking.
  • They failed to address the evidence that huge numbers of kids are being recruited to nicotine addiction, including making the shocking statement, “Overall, the available evidence to date does not adequately address whether new product use in youth and young adults leads to regular smoking.”

Here are a few papers that FDA needs to address as it considers PMTA applications from Altria’s Juul and the other e-cigarettes. This is also a good introductory reading list on e-cigarettes. All but a one of these papers (the one by Pierce et al on effects of e-cig use on long-term relapse to smoking) were available before the FDA released its Vuse decision and could and should have been integrated into its analysis. I don’t recall any of them being cited in the Vuse decision.

Health advocates should press the FDA to explicitly base its decisions on other e-cigs on all the scientific information, not just what the companies provide.

NOTE: Most of the papers cited below are systematic reviews and meta-analyses that, together, summarize and cite hundreds of other papers. A few of the papers listed are particularly relevant single studies that came out after the systematic reviews and meta-analyses or are in areas not included in the systematic reviews.

Is e-cigarette a tool to help people quit smoking? If so, what is its role in the smoking cessation strategy?

While e-cigarettes as consumer products seemed like a good way to promote smoking cessation the empirical evidence does not support that hope. E-cigarettes as consumer products (what the FDA Center for Tobacco Products [CTP] regulates) do not help smokers quit smoking. 

This result is independent of motivation to quit smoking.  Daily use is associated with significantly more quitting, but nondaily use (the most common pattern) is associated with significantly less quitting.  The overall effect across the entire population is no effect.E-cigarettes as consumer products are associated with increased relapse to cigarette smoking of long-term quitters.  In addition, people who quit smoking with e-cigarettes are at increased risk of relapse compared to people who quit using approved medical therapies or unassisted quitting.

Because consumers incorrectly believe that e-cigarettes are effective self-help devices for smoking cessation, they have displaced demonstrated effective convention therapies, with the effect of prolonging the tobacco epidemic.

(Adding in the effects on youth makes this problem of extending the epidemic even worse.)

In contrast, used as a smoking cessation aid under medical supervision and generally combined with smoking cessation counseling they do have efficacy for quitting.  It therefore might be appropriate to consider them for approval as prescription medicines to be used as part of supervised smoking cessation programs.  The reason I say might is because for medicines to be approved they have to have a favorable benefit/risk ratio.  While once people thought e-cigarettes were substantially less dangerous tan combusted cigarettes (because they don’t produce combustion products), more recent evidence shows substantial pulmonary and cardiovascular toxicity.  There is also limited evidence of carcinogenicity.  Any approval of e-cigarettes as a medicine would have to carefully consider these risks.

Any consideration of e-cigarettes as medicines would be done my the FDA Center for Drug Evaluation and Research (CDER), not CTP. To the best of my knowledge, no tobacco company has submitted an application to CDER to approve its e-cigarette as a smoking cessation medicine.

Meta-analyses of both clinical studies (RCTs) and Consumer product studies (population observational studies)

Wang RJ, Bhadriraju S, Glantz SA. E-Cigarette Use and Adult Cigarette Smoking Cessation: A Meta-Analysis. Am J Public Health. 2021 Feb;111(2):230-246. doi: 10.2105/AJPH.2020.305999. Epub 2020 Dec 22. PMID: 33351653; PMCID: PMC7811087.

Objectives. To determine the association between e-cigarette use and smoking cessation. Methods. We searched PubMed, Web of Science Core Collection, and EMBASE and computed the association of e-cigarette use with quitting cigarettes using random effects meta-analyses. Results. We identified 64 papers (55 observational studies and 9 randomized clinical trials [RCTs]). In observational studies of all adult smokers (odds ratio [OR] = 0.947; 95% confidence interval [CI] = 0.772, 1.160) and smokers motivated to quit smoking (OR = 0.851; 95% CI = 0.684, 1.057), e-cigarette consumer product use was not associated with quitting. Daily e-cigarette use was associated with more quitting (OR = 1.529; 95% CI = 1.158, 2.019) and less-than-daily use was associated with less quitting (OR = 0.514; 95% CI = 0.402, 0.665). The RCTs that compared quitting among smokers who were provided e-cigarettes to smokers with conventional therapy found e-cigarette use was associated with more quitting (relative risk = 1.555; 95% CI = 1.173, 2.061). Conclusions. As consumer products, in observational studies, e-cigarettes were not associated with increased smoking cessation in the adult population. In RCTs, provision of free e-cigarettes as a therapeutic intervention was associated with increased smoking cessation. Public Health Implications. E-cigarettes should not be approved as consumer products but may warrant consideration as a prescription therapy.

Hedman L, Galanti MR, Ryk L, Gilljam H, Adermark L. Electronic cigarette use and smoking cessation in cohort studies and randomized trials: A systematic review and meta-analysis. Tob Prev Cessat. 2021 Oct 13;7:62. doi: 10.18332/tpc/142320. PMID: 34712864; PMCID: PMC8508281.

Introduction: The aim of this systematic review and meta-analysis was to assess the association between e-cigarette use and subsequent smoking cessation in cohort studies and randomized controlled trials (RCT). Methods: A systematic literature search was finalized 11 November 2019 using EMBASE, Cochrane Library, Scopus, PubMed Health, NICE evidence search, PROSPERO, CRD, PsycInfo, and PubMed including Medline. Inclusion criteria were: reporting empirical results; longitudinal observational design with a minimum of 3 months of follow-up; including general population samples; and allowing for comparison between users and non-users of e-cigarettes. Studies rated as having high risk of bias were excluded. The procedures described by PRISMA were followed, and the quality of evidence was rated using GRADE. Results: Twenty-eight longitudinal, peer-reviewed publications from 26 cohort studies, and eight publications from seven RCTs assessing the association between e-cigarette use and smoking cessation were included in this review. A random-effects meta-analysis based on 39147 participants in cohort studies showed a pooled unadjusted odds ratio (OR) for smoking cessation among baseline e-cigarette users compared with baseline non-users of 0.97 (95% CI: 0.67-1.40), while the adjusted OR was 0.90 (95% CI: 0.63-1.27). The pooled odds ratio for smoking cessation in RCTs was 1.78 (95% CI: 1.41-2.25). The evidence for cohort studies was graded as very low and for RCTs as low. Conclusions: We did not find quality evidence for an association between e-cigarette use and smoking cessation. Although RCTs tended to support a more positive association between e-cigarette use and smoking cessation than the cohort studies, the grading of evidence was consistently low.

E-cigarettes and relapse among former smokers:

Barufaldi LA, Guerra RL, de Albuquerque RCR, Nascimento A, Chança RD, de Souza MC, de Almeida LM. Risk of smoking relapse with the use of electronic cigarettes: A systematic review with meta-analysis of longitudinal studies. Tob Prev Cessat. 2021 Apr 27;29:29. doi: 10.18332/tpc/132964. PMID: 33928198; PMCID: PMC8078138.

Introduction: The use of e-cigarettes has been the subject of a public health debate on their possibility of undermining efforts for tobacco control. The aim of this study was to synthesize the risk of smoking relapse with the use of e-cigarettes by former smokers. Methods: MEDLINE, EMBASE, PsycInfo and LILACS were searched without restriction to language or date of publication. Longitudinal observational studies evaluating the association between e-cigarette use and smoking relapse were selected by two independent reviewers, and disagreements solved by discussion with a third researcher. Data extraction and risk of bias assessment were also carried out by two independent reviewers. The meta-analysis was performed using the random effect Mantel-Haenszel model. Results: From 632 retrieved records, six studies were eligible and described, while three were included in the quantitative synthesis. The studies were conducted in the USA, UK and France, with final sample size varying from 374 to 4094 former smokers. Risk of relapse was 2.03 (95% CI: 1.39-2.96) among former smoker users than non-users of e-cigarettes, and 1.38 (95% CI: 1.11-1.65) when pooling the adjusted association measures. Long-term former smokers were the main contributors for the higher relapse risk, while the impact of frequency of exposure to e-cigarettes (past, non-daily, daily) was uncertain. Conclusions: Considering the growing popularity of e-cigarettes among former smokers, our results point to the great potential for an increase in the frequency of relapse to conventional smoking and vaping for those who move to regular use of e-cigarettes.

Pierce JP, Chen R, Kealey S, Leas EC, White MM, Stone MD, McMenamin SB, Trinidad DR, Strong DR, Benmarhnia T, Messer K. Incidence of Cigarette Smoking Relapse Among Individuals Who Switched to e-Cigarettes or Other Tobacco Products. JAMA Netw Open. 2021 Oct 1;4(10):e2128810. doi: 10.1001/jamanetworkopen.2021.28810. PMID: 34665239.

Importance: Although e-cigarettes are not approved as a cessation device, many who smoke believe that e-cigarettes will help them quit cigarette smoking successfully. Objective: To assess whether people who recently quit smoking and who had switched to e-cigarettes or another tobacco product were less likely to relapse to cigarette smoking compared with those who remained tobacco free. Design, setting, and participants: This cohort study analyzed a nationally representative sample of US households that participated in 4 waves of the Population Assessment of Tobacco and Health Study (conducted 2013 through 2017), combining 2 independent cohorts each with 3 annual surveys. Eligible participants were individuals who smoked at baseline, had recently quit at the first follow-up, and completed the second follow-up survey. Exposures: Use of e-cigarettes or alternate tobacco products at follow-up 1 after recently quitting smoking. Main outcomes and measures: Weighted percentage of participants with over 12 months abstinence by follow-up 2. Results: Of a total of 13 604 participants who smoked cigarettes at baseline, 9.4% (95% CI, 8.7%-10.0%) recently had quit smoking (mean age, 41.9; 95% CI, 39.7-46.6 years; 641 [43.2%] women) Of these, 22.8% (95% CI, 19.7%-26.0%) had switched to e-cigarettes, with 17.6% (95% CI, 14.8%-20.5%) using them daily. A total of 37.1% (95% CI, 33.7%-40.4%) used a noncigarette tobacco product and 62.9% (95% CI, 59.6%-66.3%) were tobacco free. Rates of switching to e-cigarettes were highest for those who were in the top tertile of tobacco dependence (31.3%; 95% CI, 25.0%-37.7%), were non-Hispanic White (26.4%; 95% CI, 22.3%-30.4%), and had higher incomes (annual income ≥$35 000, 27.5%; 95% CI, 22.5%-32.4% vs <$35 000, 19.3%; 95% CI, 16.3%-22.3%). At follow-up 2, unadjusted relapse rates were similar among those who switched to different tobacco products (for any tobacco product: successfully quit, 41.5%; 95% CI, 36.2%-46.9%; relapsed with significant requit, 17.0%; 95% CI, 12.4%-21.6%; currently smoking, 36.2%; 95% CI, 30.9%-41.4%). Controlled for potential confounders, switching to any tobacco product was associated with higher relapse rate than being tobacco free (adjusted risk difference, 8.5%; 95% CI, 0.3%-16.6%). Estimates for those who switched to e-cigarettes, whether daily or not, were not significant. While individuals who switched from cigarettes to e-cigarettes were more likely to relapse, they appeared more likely to requit and be abstinent for 3 months at follow-up 2 (17.0%; 95% CI, 12.4%-21.6% vs 10.4%; 95% CI, 8.0%-12.9%). Conclusions and relevance: This large US nationally representative study does not support the hypothesis that switching to e-cigarettes will prevent relapse to cigarette smoking.

Can e-cigarette be considered as a tool for tobacco harm reduction?

                No.

                For e-cigarettes to contribute to harm reduction, two facts need to be true: (1) e-cigarettes as Consumer products need to increase smoking cessation and (2) E-cigarettes need to not be appealing to youth.  The answer to both these questions is “no.”

The question of the relative toxicity of e-cigarettes compared to cigarettes only becomes relevant if the answer to both the questions above would have been  “yes.”

Having said that, there is strong and growing evidence that e-cigarettes adversely affect the pulmonary and cardiovascular systems.  Here are recent reviews of these effects. 

Keith R, Bhatnagar A. Cardiorespiratory and Immunologic Effects of Electronic Cigarettes. Curr Addict Rep. 2021 Mar 5:1-11. doi: 10.1007/s40429-021-00359-7. Epub ahead of print. PMID: 33717828; PMCID: PMC7935224.

Purpose of review: Although e-cigarettes have become popular, especially among youth, the health effects associated with e-cigarette use remain unclear. This review discusses current evidence relating to the cardiovascular, pulmonary, and immunological effects of e-cigarettes. Recent findings: The use of e-cigarettes by healthy adults has been shown to increase blood pressure, heart rate, and arterial stiffness, as well as resistance to air flow in lungs. Inhalation of e-cigarette aerosol has been shown to elicit immune responses and increase the production of immunomodulatory cytokines in young tobacco-naïve individuals. In animal models, long-term exposure to e-cigarettes leads to marked changes in lung architecture, dysregulation of immune genes, and low-grade inflammation. Exposure to e-cigarette aerosols in mice has been shown to induce DNA damage, inhibit DNA repair, and promote carcinogenesis. Chronic exposure to e-cigarettes has also been reported to result in the accumulation of lipid-laden macrophages in the lung and dysregulation of lipid metabolism and transport in mice. Although, the genotoxic and inflammatory effects of e-cigarettes are milder than those of combustible cigarettes, some of the cardiorespiratory effects of the two insults are comparable. The toxicity of e-cigarettes has been variably linked to nicotine, as well as other e-cigarette constituents, operating conditions, and use patterns. Summary: The use of e-cigarettes in humans is associated with significant adverse cardiorespiratory and immunological changes. Data from animal models and in vitro studies support the notion that long-term use of e-cigarettes may pose significant health risks.

Tarran R, Barr RG, Benowitz NL, Bhatnagar A, Chu HW, Dalton P, Doerschuk CM, Drummond MB, Gold DR, Goniewicz ML, Gross ER, Hansel NN, Hopke PK, Kloner RA, Mikheev VB, Neczypor EW, Pinkerton KE, Postow L, Rahman I, Samet JM, Salathe M, Stoney CM, Tsao PS, Widome R, Xia T, Xiao D, Wold LE. E-Cigarettes and Cardiopulmonary Health. Function (Oxf). 2021 Feb 8;2(2):zqab004. doi: 10.1093/function/zqab004. PMID: 33748758; PMCID: PMC7948134.

E-cigarettes have surged in popularity over the last few years, particularly among youth and young adults. These battery-powered devices aerosolize e-liquids, comprised of propylene glycol and vegetable glycerin, typically with nicotine, flavors, and stabilizers/humectants. Although the use of combustible cigarettes is associated with several adverse health effects including multiple pulmonary and cardiovascular diseases, the effects of e-cigarettes on both short- and long-term health have only begun to be investigated. Given the recent increase in the popularity of e-cigarettes, there is an urgent need for studies to address their potential adverse health effects, particularly as many researchers have suggested that e-cigarettes may pose less of a health risk than traditional combustible cigarettes and should be used as nicotine replacements. This report is prepared for clinicians, researchers, and other health care providers to provide the current state of knowledge on how e-cigarette use might affect cardiopulmonary health, along with research gaps to be addressed in future studies.

Gotts JE, Jordt SE, McConnell R, Tarran R. What are the respiratory effects of e-cigarettes? BMJ. 2019 Sep 30;366:l5275. doi: 10.1136/bmj.l5275. Erratum in: BMJ. 2019 Oct 15;367:l5980. PMID: 31570493; PMCID: PMC7850161.

Electronic cigarettes (e-cigarettes) are alternative, non-combustible tobacco products that generate an inhalable aerosol containing nicotine, flavors, propylene glycol, and vegetable glycerin. Vaping is now a multibillion dollar industry that appeals to current smokers, former smokers, and young people who have never smoked. E-cigarettes reached the market without either extensive preclinical toxicology testing or long term safety trials that would be required of conventional therapeutics or medical devices. Their effectiveness as a smoking cessation intervention, their impact at a population level, and whether they are less harmful than combustible tobacco products are highly controversial. Here, we review the evidence on the effects of e-cigarettes on respiratory health. Studies show measurable adverse biologic effects on organ and cellular health in humans, in animals, and in vitro. The effects of e-cigarettes have similarities to and important differences from those of cigarettes. Decades of chronic smoking are needed for development of lung diseases such as lung cancer or chronic obstructive pulmonary disease, so the population effects of e-cigarette use may not be apparent until the middle of this century. We conclude that current knowledge of these effects is insufficient to determine whether the respiratory health effects of e-cigarette are less than those of combustible tobacco products.

There are also meta-analyses showing that e-cigarette use increases the risk of respiratory disease.

Wills TA, Soneji SS, Choi K, Jaspers I, Tam EK. E-cigarette use and respiratory disorders: an integrative review of converging evidence from epidemiological and laboratory studies. Eur Respir J. 2021 Jan 21;57(1):1901815. doi: 10.1183/13993003.01815-2019. PMID: 33154031; PMCID: PMC7817920.

Background: Use of electronic cigarettes (e-cigarettes) is prevalent among adolescents and young adults, but there has been limited knowledge about health consequences in human populations. We conduct a systematic review and meta-analysis of results on respiratory disorders from studies of general-population samples and consider the mapping of these results to findings about biological processes linked to e-cigarettes in controlled laboratory studies. Method: We conducted a literature search and meta-analysis of epidemiological studies on the association of e-cigarette use with asthma and with COPD. We discuss findings from laboratory studies about effects of e-cigarettes on four biological processes: cytotoxicity, oxidative stress/inflammation, susceptibility to infection and genetic expression. Results: Epidemiological studies, both cross-sectional and longitudinal, show a significant association of e-cigarette use with asthma and COPD, controlling for cigarette smoking and other covariates. For asthma (n=15 studies), the pooled adjusted odds ratio (aOR) was 1.39 (95% CI 1.28-1.51); for COPD (n=9 studies) the aOR was 1.49 (95% CI 1.36-1.65). Laboratory studies consistently show an effect of e-cigarettes on biological processes related to respiratory harm and susceptibility to illness, with e-cigarette conditions differing significantly from clean-air controls, although sometimes less than for cigarettes. Conclusions: The evidence from epidemiological studies meets established criteria for consistency, strength of effect, temporality, and in some cases a dose-response gradient. Biological plausibility is indicated by evidence from multiple laboratory studies. We conclude that e-cigarette use has consequences for asthma and COPD, which is of concern for respirology and public health.

Xian S, Chen Y. E-cigarette users are associated with asthma disease: A meta-analysis. Clin Respir J. 2021 May;15(5):457-466. doi: 10.1111/crj.13346. Epub 2021 Mar 15. PMID: 33683790.

Background: At present, there are more than 300 million asthma patients in the world. Electronic cigarettes (e-cigarettes) are considered as a new way of smoking and are loved by young people. The relationship between e-cigarettes and asthma risk is still controversial. Therefore, we conducted a meta-analysis to explore the relationship between e-cigarettes and asthma. Methods: We searched PubMed, Embase, and Web of Science for research results published before august 2020. All data analysis was through R version 3.6.3. Publication bias was assessed using funnel plots, Begg’s rank correlation test, and Egger regression asymmetry tests. Most of the included studies were adjusted for potential confounding factors. Results: This meta found the association of e-cigarette use with asthma, and the combined OR value was 1.27 (95% CI = 1.17-1.37). We found the significant association of current e-cigarette usage with asthma (OR = 1.30, 95% CI = 1.17-1.45), and the former use of e-cigarettes also had an association with asthma (OR = 1.22, 95% CI = 1.08-1.39). Then, when e-cigarettes were used in combination with traditional cigarettes, the association odds with asthma was 1.47 (95% CI = 1.13-1.91), which was higher than that of users who used traditional cigarettes (OR = 1.33, 95% CI = 1.19-1.49). In subgroup analysis, adult and female e-cigarette users were more closely associated with asthma. Conclusion: In short, in this meta-analysis, we found that current or former use of e-cigarettes are associated with the prevalence of asthma. However, the specific relationship required more rigorous design for further verification.

There have not been enough epidemiological studies of e-cigarette use and heart disease to conduct a meta-analysis, but here are two showing effects of e-cigarettes.  Note that, like lung disease, dual use is more dangerous than just smoking or just using e-cigarettes.

Alzahrani T, Pena I, Temesgen N, Glantz SA. Association Between Electronic Cigarette Use and Myocardial Infarction. Am J Prev Med. 2018 Oct;55(4):455-461. doi: 10.1016/j.amepre.2018.05.004. Epub 2018 Aug 22. Erratum in: Am J Prev Med. 2019 Oct;57(4):579-584. PMID: 30166079; PMCID: PMC6208321.

Introduction: Electronic cigarettes (e-cigarettes) are promoted as a less risky alternative to conventional cigarettes and have grown in popularity. Experimental and clinical evidence suggests that they could increase the risk of myocardial infarction. Methods: The National Health Interview Surveys of 2014 (n=36,697) and 2016 (n=33,028) were used to examine the cross-sectional association between e-cigarette use (never, former, some days, daily) and cigarette smoking (same categories) and myocardial infarction in a single logistic regression model that also included demographics (age, gender, BMI) and health characteristics (hypertension, diabetes, and hypercholesterolemia) using logistic regression. Data were collected in 2014 and 2016 and analyzed in 2017 and 2018. Results: Daily e-cigarette use was independently associated with increased odds of having had a myocardial infarction (OR=1.79, 95% CI=1.20, 2.66, p=0.004) as was daily conventional cigarette smoking (OR=2.72, 95% CI=2.29, 3.24, p<0.001). Former and some day e-cigarette use were not significantly associated with having had a myocardial infarction (p=0.608 and p=0.392) whereas former (OR=1.70, p<0.001) and some day cigarette smoking (OR=2.36, p<0.001) were. Odds of a myocardial infarction were also increased with history of hypertension (OR=2.32, p<0.001); high cholesterol (OR=2.36, p<0.001); and diabetes (OR=1.77, p<0.001); and age (OR=1.65 per 10 years, p<0.001). Women (OR=0.47, p<0.001) had lower odds of myocardial infarction. Conclusions: Daily e-cigarette use, adjusted for smoking conventional cigarettes as well as other risk factors, is associated with increased risk of myocardial infarction.

Osei AD, Mirbolouk M, Orimoloye OA, Dzaye O, Uddin SMI, Benjamin EJ, Hall ME, DeFilippis AP, Stokes A, Bhatnagar A, Nasir K, Blaha MJ. Association Between E-Cigarette Use and Cardiovascular Disease Among Never and Current Combustible-Cigarette Smokers. Am J Med. 2019 Aug;132(8):949-954.e2. doi: 10.1016/j.amjmed.2019.02.016. Epub 2019 Mar 8. PMID: 30853474.

Background: The prevalence of e-cigarette use in the United States has increased rapidly. However, the association between e-cigarette use and cardiovascular disease remains virtually unknown. Therefore, we aimed to examine the association between e-cigarette use and cardiovascular disease among never and current combustible-cigarette smokers. Methods: We pooled 2016 and 2017 data from the Behavioral Risk Factor Surveillance System (BRFSS), a large, nationally representative, cross-sectional telephone survey. We included 449,092 participants with complete self-reported information on all key variables. The main exposure, e-cigarette use, was further divided into daily or occasional use, and stratified by combustible-cigarette use (never and current). Cardiovascular disease, the main outcome, was defined as a composite of self-reported coronary heart disease, myocardial infarction, or stroke. Results: Of 449,092 participants, there were 15,863 (3.5%) current e-cigarette users, 12,908 (2.9%) dual users of e-cigarettes + combustible cigarettes, and 44,852 (10.0%) with cardiovascular disease. We found no significant association between e-cigarette use and cardiovascular disease among never combustible-cigarette smokers. Compared with current combustible-cigarette smokers who never used e-cigarettes, dual use of e-cigarettes + combustible cigarettes was associated with 36% higher odds of cardiovascular disease (odds ratio 1.36; 95% confidence interval, 1.18-1.56); with consistent results in subgroup analyses of premature cardiovascular disease in women <65 years and men <55 years old. Conclusion: Our results suggest significantly higher odds of cardiovascular disease among dual users of e-cigarettes + combustible cigarettes compared with smoking alone. These data, although preliminary, support the critical need to conduct longitudinal studies exploring cardiovascular disease risk associated with e-cigarette use, particularly among dual users.

There is also an association between e-cigarette use and stroke.

Bricknell RAT, Ducaud C, Figueroa A, Schwarzman LS, Rodriguez P, Castro G, Zevallos JC, Barengo NC. An association between electronic nicotine delivery systems use and a history of stroke using the 2016 behavioral risk factor surveillance system. Medicine (Baltimore). 2021 Sep 10;100(36):e27180. doi: 10.1097/MD.0000000000027180. PMID: 34516517; PMCID: PMC8428735.

Electronic nicotine delivery systems (ENDS) are growing in use and many of the health implications with these devices remain unknown. This study aims to assess, using a survey representative of the USA general population, if an association exists between a history of ENDS use and a history of stroke.This cross-sectional study was a secondary data analysis using the 2016 behavioral risk factor surveillance system survey. The main exposure variable of the study was a self-reported history of ENDS use. The main outcome was a self-reported history of stroke. Covariates included sex, race, traditional cigarette use, smokeless tobacco use, chronic kidney disease, diabetes, myocardial infarction, and coronary artery disease. Unadjusted and adjusted logistic regression analyses were done. Adjusted odds ratios (AOR) and their corresponding 95% confidence intervals (CI) were calculated.Of the 486,303 total behavioral risk factor surveillance system survey participants, 465,594 met the inclusion criteria for this study of ENDS use and stroke. This study shows that current ENDS use was positively associated with a history of stroke. AOR of some daily ENDS use with stroke was 1.28 (95% CI: 1.02-1.61) and AOR of current daily ENDS use with stroke was 1.62 (95% CI: 1.18-2.31). The majority (55.9%) of current daily ENDS users reported former traditional cigarette smoking. Female sex, non-white ethnicity, elderly age, chronic kidney disease, coronary artery disease, diabetes, and traditional cigarette use characteristics were all also associated with increased odds of reporting a stroke.This study found a statistically significant and positive association between ENDS use and a history of stroke. Further research is warranted to investigate the reproducibility and temporality of this association. Nevertheless, this study contributes to the growing body of knowledge about the potential cardiovascular concerns related to ENDS use and the need for large cohort studies.

These results are not surprising given that e-cigarettes deliver thousands of chemicals to users.

Tehrani MW, Newmeyer MN, Rule AM, Prasse C. Characterizing the Chemical Landscape in Commercial E-Cigarette Liquids and Aerosols by Liquid Chromatography-High-Resolution Mass Spectrometry. Chem Res Toxicol. 2021 Oct 18;34(10):2216-2226. doi: 10.1021/acs.chemrestox.1c00253. Epub 2021 Oct 5. PMID: 34610237.

The surge in electronic cigarette (e-cig) use in recent years has raised questions on chemical exposures that may result from vaping. Previous studies have focused on measuring known toxicants, particularly those present in traditional cigarettes, while fewer have investigated unknown compounds and transformation products formed during the vaping process in these diverse and constantly evolving products. The primary aim of this work was to apply liquid chromatography-high-resolution mass spectrometry (LC-HRMS) and chemical fingerprinting techniques for the characterization of e-liquids and aerosols from a selection of popular e-cig products. We conducted nontarget and quantitative analyses of tobacco-flavored e-liquids and aerosols generated using four popular e-cig products: one disposable, two pod, and one tank/mod. Aerosols were collected using a condensation device and analyzed in solution alongside e-liquids by LC-HRMS. The number of compounds detected increased from e-liquids to aerosols in three of four commercial products, as did the proportion of condensed-hydrocarbon-like compounds, associated with combustion. Kendrick mass defect analysis suggested that some of the additional compounds detected in aerosols belonged to homologous series resulting from decomposition of high-molecular-weight compounds during vaping. Lipids in inhalable aerosols have been associated with severe respiratory effects, and lipid-like compounds were observed in aerosols as well as e-liquids analyzed. Six potentially hazardous additives and contaminants, including the industrial chemical tributylphosphine oxide and the stimulant caffeine, were identified and quantified in the e-cig liquids and aerosols analyzed. The obtained findings demonstrate the potential of nontarget LC-HRMS to identify previously unknown compounds and compound classes in e-cig liquids and aerosols, which is critical for the assessment of chemical exposures resulting from vaping.

Can e-cigarette encourage young people to start smoking?

 Yes.

Here are two reviews and meta-analyses of effects on youth initiation and two important papers published after the review was published:

Khouja JN, Suddell SF, Peters SE, Taylor AE, Munafò MR. Is e-cigarette use in non-smoking young adults associated with later smoking? A systematic review and meta-analysis. Tob Control. 2020 Mar 10;30(1):8–15. doi: 10.1136/tobaccocontrol-2019-055433. Epub ahead of print. PMID: 32156694; PMCID: PMC7803902.

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.

Yoong SL, Hall A, Turon H, Stockings E, Leonard A, Grady A, Tzelepis F, Wiggers J, Gouda H, Fayokun R, Commar A, Prasad VM, Wolfenden L. Association between electronic nicotine delivery systems and electronic non-nicotine delivery systems with initiation of tobacco use in individuals aged < 20 years. A systematic review and meta-analysis. PLoS One. 2021 Sep 8;16(9):e0256044. doi: 10.1371/journal.pone.0256044. PMID: 34495974; PMCID: PMC8425526.

Background: This systematic review described the association between electronic nicotine delivery systems and electronic non-nicotine delivery systems (ENDS/ENNDS) use among non-smoking children and adolescents aged <20 years with subsequent tobacco use. Methods: We searched five electronic databases and the grey literature up to end of September 2020. Prospective longitudinal studies that described the association between ENDS/ENNDS use, and subsequent tobacco use in those aged < 20 years who were non-smokers at baseline were included. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess risk of bias. Data were extracted by two reviewers and pooled using a random-effects meta-analysis. We generated unadjusted and adjusted risk ratios (ARRs) describing associations between ENDS/ENNDS and tobacco use. Findings: A total of 36 publications met the eligibility criteria, of which 25 were included in the systematic review (23 in the meta-analysis) after exclusion of overlapping studies. Sixteen studies had high to moderate risk of bias. Ever users of ENDS/ENNDS had over three times the risk of ever cigarette use (ARR 3·01 (95% CI: 2·37, 3·82; p<0·001, I2: 82·3%), and current cigarette use had over two times the risk (ARR 2·56 (95% CI: 1·61, 4·07; p<0·001, I2: 77·3%) at follow up. Among current ENDS/ENNDS users, there was a significant association with ever (ARR 2·63 (95% CI: 1·94, 3·57; p<0·001, I2: 21·2%)), but not current cigarette use (ARR 1·88 (95% CI: 0·34, 10·30; p = 0·47, I2: 0%)) at follow up. For other tobacco use, ARR ranged between 1·55 (95% CI 1·07, 2·23) and 8·32 (95% CI: 1·20, 57·04) for waterpipe and pipes, respectively. Additionally, two studies examined the use of ENNDS (non-nicotine devices) and found a pooled adjusted RR of 2·56 (95% CI: 0·47, 13·94, p = 0.035). Conclusion: There is an urgent need for policies that regulate the availability, accessibility, and marketing of ENDS/ENNDS to children and adolescents. Governments should also consider adopting policies to prevent ENDS/ENNDS uptake and use in children and adolescents, up to and including a ban for this group.

Staff J, Kelly BC, Maggs JL, Vuolo M. Adolescent electronic cigarette use and tobacco smoking in the Millennium Cohort Study. Addiction. 2021 Jul 19. doi: 10.1111/add.15645. Epub ahead of print. PMID: 34286880.

Aims: To evaluate the catalyst, diversion and common liability hypotheses by examining associations between e-cigarette use and tobacco cigarette smoking at modal ages 14 and 17 years, controlling for adolescent and infancy risk factors. Design: Intergenerational, prospective cohort data from the Millennium Cohort Study (MCS). Nationally representative sample of infants born September 2000 to January, 2002. Setting: United Kingdom. Participants: Parent and child data from 10 625 youth assessed in infancy and modal ages 11, 14 and 17 years. Measurements: Age 14 and 17 e-cigarette and combustible cigarette use (recency, frequency). Potential confounders were age 11 risk factors (e.g. alcohol use, externalizing behaviors, parental tobacco use, permissiveness), infancy risk factors (e.g. maternal smoking during pregnancy, smoke exposure in infancy) and demographic characteristics. Findings: Among youth who had not smoked tobacco by age 14 (n = 9046), logistic regressions estimated that teenagers who used e-cigarettes by age 14 compared with non-e-cigarette users, had more than five times higher odds of initiating tobacco smoking by age 17 [odds ratio (OR) = 5.25, 95% confidence interval (CI) = 3.28-8.38] and nearly triple the odds of being a frequent tobacco smoker at age 17 (OR = 2.91, 95% CI = 1.56-5.41), net of risk factors and demographics. Among youth who had not used e-cigarettes by age 14 (n = 9078), teenagers who had smoked tobacco cigarettes by age 14 had three times higher odds of initiating e-cigarettes by age 17 (OR = 2.98, 95% CI = 1.74-5.09) compared with non-tobacco smokers and nearly three times higher odds of frequently using e-cigarettes at age 17 (OR = 2.90, 95% CI = 1.21-6.95), net of confounders. Similar links between e-cigarette and tobacco cigarette use were observed in regressions following coarsened exact matching. Conclusions: E-cigarette use by age 14 is associated with increased odds of tobacco cigarette initiation and frequent smoking at age 17 among British youth. Similarly, tobacco smoking at age 14 is associated with increased odds of both e-cigarette initiation and frequent use at age 17.

Martinelli T, Candel MJJM, de Vries H, Talhout R, Knapen V, van Schayck CP, Nagelhout GE. Exploring the gateway hypothesis of e-cigarettes and tobacco: a prospective replication study among adolescents in the Netherlands and Flanders. Tob Control. 2021 Jul 5:tobaccocontrol-2021-056528. doi: 10.1136/tobaccocontrol-2021-056528. Epub ahead of print. PMID: 34226262.

Background: Studies demonstrated that adolescent e-cigarette use is associated with subsequent tobacco smoking, commonly referred to as the gateway effect. However, most studies only investigated gateways from e-cigarettes to tobacco smoking. This study replicates a cornerstone study revealing a positive association between both adolescent e-cigarette use and subsequent tobacco use; and tobacco and subsequent e-cigarette use in the Netherlands and Flanders. Design: The longitudinal design included baseline (n=2839) and 6-month (n=1276) and 12-month (n=1025) follow-up surveys among a school-based cohort (mean age: 13.62). Ten high schools were recruited as a convenience sample. The analyses involved (1) associations of baseline e-cigarette use and subsequent tobacco smoking among never smokers; (2) associations of e-cigarette use frequency at baseline and tobacco smoking frequency at follow-up; and (3) the association of baseline tobacco smoking and subsequent e-cigarette use among non-users of e-cigarettes. Findings: Consistent with prior findings, baseline e-cigarette use was associated with higher odds of tobacco smoking at 6-month (OR=1.89; 95% CI 1.05 to 3.37) and 12-month (OR=5.63; 95% CI 3.04 to 10.42) follow-ups. More frequent use of e-cigarettes at baseline was associated with more frequent smoking at follow-ups. Baseline tobacco smoking was associated with subsequent e-cigarette use (OR=3.10; 95% CI 1.58 to 6.06 at both follow-ups). Conclusion: Our study replicated the positive relation between e-cigarette use and tobacco smoking in both directions for adolescents. This may mean that the gateway works in two directions, that e-cigarette and tobacco use share common risk factors, or that both mechanisms apply.

Pierce JP, Chen R, Leas EC, White MM, Kealey S, Stone MD, Benmarhnia T, Trinidad DR, Strong DR, Messer K. Use of E-cigarettes and Other Tobacco Products and Progression to Daily Cigarette Smoking. Pediatrics. 2021 Feb;147(2):e2020025122. doi: 10.1542/peds.2020-025122. Epub 2021 Jan 11. PMID: 33431589; PMCID: PMC7849197.

Objectives: To identify predictors of becoming a daily cigarette smoker over the course of 4 years. Methods: We identified 12- to 24-year-olds at wave 1 of the US Population Assessment of Tobacco and Health Study and determined ever use, age at first use, and daily use through wave 4 for 12 tobacco products. Results: Sixty-two percent of 12- to 24-year-olds (95% confidence interval [CI]: 60.1% to 63.2%) tried tobacco, and 30.2% (95% CI: 28.7% to 31.6%) tried ≥5 tobacco products by wave 4. At wave 4, 12% were daily tobacco users, of whom 70% were daily cigarette smokers (95% CI: 67.4% to 73.0%); daily cigarette smoking was 20.8% in 25- to 28-year-olds (95% CI: 18.9% to 22.9%), whereas daily electronic cigarette (e-cigarette) vaping was 3.3% (95% CI: 2.4% to 4.4%). Compared with single product triers, the risk of progressing to daily cigarette smoking was 15 percentage points higher (adjusted risk difference [aRD] 15%; 95% CI: 12% to 18%) among those who tried ≥5 products. In particular, e-cigarette use increased the risk of later daily cigarette smoking by threefold (3% vs 10%; aRD 7%; 95% CI: 6% to 9%). Daily smoking was 6 percentage points lower (aRD -6%; 95% CI: -8% to -4%) for those who experimented after age 18 years. Conclusions: Trying e-cigarettes and multiple other tobacco products before age 18 years is strongly associated with later daily cigarette smoking. The recent large increase in e-cigarette use will likely reverse the decline in cigarette smoking among US young adults.

All studies have shown that youth who initiate with e-cigarettes are at substantially increased risk of going on to Smoke cigarettes.  The more recent studies are finding higher risks.

While some of the youth who initiate nicotine use with e-cigarettes are similar to youth who initiate with e-cigarettes, a substantial fraction of youth who initiate with e-cigarettes have a risk profile that makes it unlikely that they would initiate with cigarettes.  As a result, e-cigarette use is expanding the tobacco epidemic by bringing in low risk youth.

Here is a recent paper on this question.  They include citations to several other studies that found similar results using other datasets.

Creamer MR, Dutra LM, Sharapova SR, Gentzke AS, Delucchi KL, Smith RA, Glantz SA. Effects of e-cigarette use on cigarette smoking among U.S. youth, 2004-2018. Prev Med. 2021 Jan;142:106316. doi: 10.1016/j.ypmed.2020.106316. Epub 2020 Nov 30. PMID: 33272598; PMCID: PMC7796895.

Objective: To determine if the declining trend in U.S. youth cigarette smoking changed after e-cigarettes were introduced, and if youth e-cigarette users would have been likely to smoke cigarettes based on psychosocial and demographic predictors of smoking. Methods: An interrupted time series analysis was used for cross-sectional data from the 2004 to 2018 National Youth Tobacco Surveys (NYTS) to assess changes in cigarette and e-cigarette use over time. A multivariable logistic regression model used 2004-2009 NYTS data on psychosocial risk factors to predict individual-level cigarette smoking risk from 2011 to 2018. Model-predicted and actual cigarette smoking behavior were compared. Results: The decline in current cigarette smoking slowed in 2014 (-0.75 [95% CI: -0.81, -0.68] to -0.26 [95% CI: -0.40, -0.12] percentage points per year). The decline in ever cigarette smoking accelerated after 2012 (-1.45 [95% CI: -1.59, -1.31] to -1.71 [95% CI: -1.75, -1.66]). Ever and current combined cigarette and/or e-cigarette use declined during 2011-2013 and increased during 2013-2014 with no significant change during 2014-2018 for either variable. The psychosocial model estimated that 69.0% of current cigarette smokers and 9.3% of current e-cigarette users (who did not smoke cigarettes) would smoke cigarettes in 2018. Conclusions: The introduction of e-cigarettes was followed by a slowing decline in current cigarette smoking, a stall in combined cigarette and e-cigarette use, and an accelerated decline in ever cigarette smoking. Traditional psychosocial risk factors for cigarette smoking suggest that e-cigarette users do not fit the traditional risk profile of cigarette smokers.

There is evidence that prohibiting e-cigarette sales entirely prevents growth in youth use.  See the following paper about the Thai experience and results from other countries cited in it.

Patanavanich R, Aekplakorn W, Glantz SA, Kalayasiri R. Use of E-Cigarettes and Associated Factors among Youth in Thailand. Asian Pac J Cancer Prev. 2021 Jul 1;22(7):2199-2207. doi: 10.31557/APJCP.2021.22.7.2199. PMID: 34319044.

Objective: The study explored e-cigarette use among youth and associated factors in Thailand. Methods: This was a cross sectional study of 6,045 seventh grade students selected using a multistage design. Self-administered questionnaires relating to the socio-demographic characteristics, history of cigarette and e-cigarette uses, friends’ and family’s use of e-cigarettes, knowledge and perception of e-cigarette use, history of alcohol uses, and life assets were gathered. Multivariate logistic regression models were used to examine the variables and their association with e-cigarette use. Results: Prevalence of ever e-cigarette use was 7.2% and current e-cigarette use was 3.7%. We found that current cigarette smoking (AOR 4.28, 95% CI: 2.05-8.94), parental e-cigarette use (AOR 6.08, 95% CI: 2.81-13.17), peer e-cigarette use (AOR 3.82, 95% CI: 2.19-6.65), peer approval of smoking (AOR 1.95, 95% CI: 1.11-3.41), and unaware of e-cigarettes’ risk (AOR 5.25, 95% CI: 2.67-10.34). were significantly associated with current use of e-cigarettes. Male sex, poor academic achievement, and poor life assets (power of wisdom) were only significantly associated with ever e-cigarette use. Conclusion: Prevalence of current e-cigarette use among Thai middle school students did not change significantly since the government banned importation and sales of e-cigarettes in 2015, suggesting that the Thai ban has been a success. Factors associated with e-cigarette use among Thai youth were consistent with other countries. Ever e-cigarette use, increased, but less than in countries without a ban. To strengthen efforts to prevent youth from e-cigarette use and addiction, the government should improve law enforcement, especially against online marketing and strengthen school-based anti-smoking programs to include e-cigarette lessons, educating parents and the public about the harm of e-cigarettes, including secondhand effects on non-users.

What about menthol, flavors and issues around marketing and advertising?

The presentation above does not include these areas. There is also important research in these areas that the FDA did not address in its Vuse decision.

Published by Stanton Glantz

Stanton Glantz is a retired Professor of Medicine who served on the University of California San Francisco faculty for 45 years. He conducts research on tobacco and cannabis control and cardiovascular disease/

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