E-cigs have similar risks to cigs for some diseases and nearly as high for others. Dual use riskier than smoking alone

It is an article of faith among e-cigarette advocates that they are substantially less risky than cigarettes. Rather than being based on the actual associations between e-cigarette use and disease, this belief is based on the fact that e-cigarettes do not burn tobacco, so avoid the toxic combustion products that cigarettes produce.

In recent years, however, evidence on the health risks of e-cigarettes has been rapidly accumulating, including over 100 studies of the associations between e-cigarette use and actual disease in the population.  Nhung Nguyen, Andre Luiz Oliveira da Silva and I just published “Population-Based Disease Odds for E-Cigarettes and Dual Use versus Cigarettes” in NEJM Evidence that uses these epidemiological studies to conclude that for cardiovascular disease, stroke and metabolic disorder e-cigarette risks are similar to cigarettes and for respiratory and oral disease, while lower risk than cigarettes, the risks are still substantial.  Dual use (using e-cigarettes and cigarettes at the same time) is riskier than smoking alone for all outcomes.

To reach these conclusions, we searched the peer reviewed literature through October 1, 2023, yielding 107 papers.  We then pooled the results for disease outcomes where there were at least 5 papers.  There is also limited evidence for other diseases, but there are too few studies to draw conclusions. 

In addition to comparing the risks (quantified with odds ratios) of e-cigarettes with cigarettes – the comparison of most interest when thinking about adult “switching” – we also estimated the risks associated with e-cigarette use and dual use compared to non-use.  All these risks are also elevated.

The finding of comparable or slightly lower risks for e-cigarettes undermines the whole argument that e-cigarettes, as actually used, are an effective tool for harm reduction for smokers, because the harms of e-cigarette use are not substantially below cigarettes. 

As the paper notes, “The odds ratios identified in the epidemiological studies are higher than those predicted by biomarker studies. This direct evidence of disease diverges from conclusions based solely on biomarkers of exposure to tobacco products, which calls into question the FDA’s policy of authorizing tobacco companies to make modified risk claims about products based solely on the fact that some biomarkers of exposure associated with e-cigarettes are lower than those associated with cigarettes. [citations dropped; emphasis added]”

Regarding the dual use findings, the paper notes, “E-cigarettes expose users to a different toxic chemical mix than cigarettes, including compounds formed during heating and aerosolization that are not present in the e-liquid itself. Although there is some overlap, dual use of e-cigarettes and cigarettes together delivers a wider range of toxins than either does alone. These facts, combined with the observation that daily cigarette consumption among exclusive smokers and dual users was not different, may explain the higher odds ratios observed among dual users compared with cigarette smoking alone. It is important to account for dual use when assessing population health impacts of e-cigarette use, because the increased odds ratios associated with dual use compared with just smoking applies among smokers who use e-cigarettes who do not ‘switch completely, raising the overall population impact associated with e-cigarette use. [citations dropped; emphasis added]”

The paper concludes:

The findings of increased odds of several diseases for e-cigarettes compared with nonuse illustrates the substantial risks for people, particularly youth and young adults, who initiate nicotine use with e-cigarettes and former smokers who restart nicotine use with e-cigarettes. Even without considering the millions of youth who initiate nicotine use with e-cigarettes, these results suggest a need for a careful reassessment of the assumption that e-cigarettes are a substantially less harmful alternative to cigarettes, particularly given the fact that, as consumer products, e-cigarettes are not associated with increased smoking cessation and, over the long run, are associated with less cessation and increased odds of becoming a dual user. [citations dropped]

The accompanying editorial by Alexia Perryman and Laura E. Crotty Alexander observed, “Although complete switching by smokers to e-cigarettes may be associated with reduced risk for certain disease outcomes, it is certainly not harmless. Further, incomplete switching that results in dual use of combustible cigarettes and e-cigarettes may increase risk for disease compared with use of combustible cigarettes alone, leading to harm promotion.”

The bottom line: it is time for people – and regulatory agencies like FDA – to stop making decisions on biomarkers and start using real-world data on actual disease risks.

Here is the abstract:

BACKGROUND E-cigarettes are promoted as less harmful than cigarettes. There has not been a direct comparison of health effects of e-cigarettes or dual use (concurrently using e-cigarettes and cigarettes) with those of cigarettes in the general population.

METHODS Studies in PubMed, EMBASE, Web of Science, and PsychINFO published through October 1, 2023, were pooled in a random-effects meta-analysis if five or more studies were identified with a disease outcome. We assessed risk of bias with Risk Of Bias In Non-randomized Studies of Exposure and certainty with Grading of Recommendations, Assessment, Development, and Evaluations. Outcomes with fewer studies were summarized but not pooled.

RESULTS We identified 124 odds ratios (94 cross-sectional and 30 longitudinal) from 107 studies. Pooled odds ratios for current e-cigarette versus cigarette use were not different for cardiovascular disease (odds ratio, 0.81; 95% confidence interval, 0.58 to 1.14), stroke (0.73; 0.47 to 1.13), or metabolic dysfunction (0.99; 0.91 to 1.09) but were lower for asthma (0.84; 0.74 to 0.95), chronic obstructive pulmonary disease (0.53; 0.38 to 0.74), and oral disease (0.87; 0.76 to 1.00). Pooled odds ratios for dual use versus cigarettes were increased for all outcomes (range, 1.20 to 1.41). Pooled odds ratios for e-cigarettes and dual use compared with nonuse of either product were increased (e-cigarette range, 1.24 to 1.47; dual use, 1.49 to 3.29). All studies had low risk of bias. Results were generally not sensitive to study characteristics. Limited studies of other outcomes suggest that e-cigarette use is associated with additional diseases.

CONCLUSIONS There is a need to reassess the assumption that e-cigarette use provides substantial harm reduction across all cigarette-caused diseases, particularly accounting for dual use.

Q&A about the study

• How did we compare e-cigarette (and dual use) risks with cigarette risks?

We used the odds ratio as an estimate of risk.  (A few studies used other measures of risk; we treated all as approximations of the odds ratios.)  In some studies the odds ratios were estimated by including both e-cigarette and cigarette use in the same multivariate (statistical) analysis, yielding estimates for each product controlling for the use of the other.  Other studies stratified (separated) people based on their e-cigarette and cigarette use (or both) and estimated the odds ratios separately.  A few studies reported both analyses, which generally yielded similar risk estimates.  When pooling the odds ratios we used the smaller estimates for studies that estimated risk both ways.

To be included in our analysis, each study had to control for cigarette smoking or be of never smokers.

• How do we know if the disease in e-cigarettes users isn’t just remaining damage from their smoking days, especially given that we don’t always know the sequencing between disease and e-cigarette adoption?

Our analysis is based on current use, usually the past 30 days.  Some of the studies also controlled for former smoking in their analysis.  Whether the study controlled for former use did not affect the odds ratio estimates.  In addition, several studies limited themselves to never-smokers and still found risks associated with e-cigarette use.

In addition, for many diseases, effects of smoking start to reverse quickly when someone stops. 

• Given the time lag for at least some tobacco-caused disease, would we expect at this point to see large differences in disease risk between e-cig users and cigarette smokers.  Do we have any sense of how long the e-cigarette users have been using them?

Few of the papers reported how long or how intensively people had been using e-cigarettes.  The fact is that however long they have been using them was long enough and intensively to pick up a disease signal.  The biology shows that the cardiovascular, stroke, metabolic, asthma and oral effects begin quickly.  COPD takes longer, but the risks start being manifest in a few years.  The slower development of COPD may explain the lower odds ratios for COPD compared to other diseases.

• Most of the studies were cross-sectional (a snapshot in time) rather than longitudinal (where people are followed forward in time).  Doesn’t that limit your ability to draw conclusions?

It is well-established that cross-sectional studies only permit identifying associations rather than causality and we take care to avoid making causal statements in the paper.  The reality is that most epidemiology is based on cross-sectional studies because they are much simpler and less expensive to complete than longitudinal studies, which require following people forward in time for many years.  The results for the cross-sectional and longitudinal studies were similar except for dual use vs. cigarettes, which increases the confidence we have in our conclusions about the association between e-cigarette use and disease.

• What about cancer?

There was only one paper reporting cancer results, which is not enough to produce a quantitative risk estimate.  Biological evidence, however, suggests that e-cigarettes pose substantial cancer risks. E-cigarette users and smokers experience similar levels of DNA damage—more than twice the amount found in people who do not use either product. At least 543 cancer-related genes are adversely affected in people who use e-cigarettes, 44% of what cigarettes do. Breathing e-cigarette aerosol causes lung cancer and bladder hyperplasia in mice.  Cancer accounts for about one-third of smoking-caused deaths.

The full citation for the paper is: Glantz SA, Nguyen N, Oliveira da Silva AL. Population-Based Disease Odds for E-Cigarettes and Dual Use versus Cigarettes. NEJM Evidence 2024; 3(3): DOI: 10.1056/EVIDoa2300229. It is available here. The accompanying editorial is here.

New York Times story citing the paper.

E-cigarette advocate’s criticism of the paper and our reply.