Appendix 4 shows the characteristics of studies, study design, definition of use and prevalence of use in detail.
Study design (Appendix 4 for details)
The majority of studies reported results of cross-sectional analyses, mostly using self-reported data from large population-based surveys. One study was an experimental animal study (38), three were switch-of-product experimental studies (37, 41, 48). Fifteen papers/12 studies reported results from studies with a prospective design (25, 26, 37-49).
Definitions of use (Appendix 4 for details)
There was great variation both in duration and in frequency of use of products for details. The definitions of ESCC, EC users and DUs were based on self-reports and varied a lot across studies.
Conflict of interest
Sixteen (29%) of the studies had a conflict of interest (COI): two with an EC manufacturer (50, 51), two had received financial support from anonymous contributors (26, 40), and the remaining had a COI with pharmaceutical companies. One study was tobacco-industry-sponsored and found a beneficial effect of replacing ESCC with the ECs they manufactured, also in DUs (41).
Many studies did not find a significant difference between DU and ESCC. After having excluded the study sponsored by the tobacco industry, seven studies found that ESCC had significantly worse outcome than DUs (25, 37, 48, 52-54), two of these were experimental switch-of-product studies with short term outcome (37, 48). Eighteen studies found that DUs had significantly worse outcome than ESCC (11, 17-19, 21, 23, 25, 55-64).
Toxicity and carcinogenicity (Table 1)
Fourteen studies investigated the levels of harmful and potentially harmful substances in urine, blood, hair and saliva of DUs of ECs and CCs and in ESCC. Some studies measured only one or two harmful substances (50, 53, 65) while others tested up to 50 (11). Six studies found that levels of harmful substances were higher in ESCC (37, 41, 48, 52-54). One study found that DUs had higher values for most substances tested, but it did not test for significance (51). Three studies found significantly higher levels of harmful biomarkers in DUs (11, 55, 56), and nine studies found no significant difference. Results of the largest population-based studies, with low risk of selection bias, indicate that real-world DUs’ might be exposed to higher levels of several harmful substances than ESCC.
Three studies had an experimental design with short-term follow-up. In one study, DUs should switch to ESCC for one week. The same or higher levels of carcinogen metabolites were measured in the ESCC period compared with the DU period (37). In the second study, smokers who wanted to stop smoking should switch from ESCC to ECs. After one month, 52% used both ECs and CCs (DUs) but had reduced their tobacco consumption significantly (approx. half of them had smoked less than five CCs in the last week). DUs had significant reductions in carbon monoxide and a major metabolite of acrolein (48), a bladder carcinogen. One study was tobacco-industry-sponsored: ESCC were randomized to DU for five days. DUs’ who had halved the number of CPD had significant reductions in most of the harmful biomarkers assessed (41).
Two studies included long-term users who had used ECs and CCs for at least six months. One study included almost 500 persons (54) and found that DUs and ESCC had similar levels of toxic and carcinogenic substances, but ESCC had significantly higher levels of three tobacco-specific nitrosamines and acrylonitrile than DUs. The other long-term study included almost 200 persons and found that DUs and ESCC had similar levels of toxic and carcinogenic substances, but DUs had a significantly higher level of benzene, a carcinogenic substance (56).
Three studies measured carcinogen and toxin exposure in large samples of the general population, reflecting the levels of real-world use (11, 55, 66). The largest study measured 50 biomarkers of toxicity/carcinogenicity in urine in more than 5,000 adults and found that DUs had significantly higher concentrations of most biomarkers than ESCC (11). The second largest study included almost 3,000 adults, measured over 40 biomarkers of toxicity/carcinogenicity in urine and blood and found that DUs had significantly higher levels of some toxic and carcinogenic biomarkers compared to ESCC (55). A third large population-based study included more than 1,100 persons and found the same levels of metals in DUs and ESCC (66). All three studies had low risk of selection bias, had weighted data and adjusted for relevant confounding (11).
Studies investigating health outcomes (Table 2-4)
One study found that ESCC had significantly worse health outcome than DUs, while 15 studies found the opposite.
Pulmonary outcomes (Table 2)
Fourteen studies investigated pulmonary outcomes. Except for a register-based study (47), all were large population-based surveys including between > 8,000 (67) and almost 900,000 participants (21). Studies presented self-reported symptoms/diagnoses. Two had a longitudinal design (46, 47).
Two studies in adolescents, based on the same survey in 2018, found that odds of asthma were higher in DUs than in ESCC (68, 69), but significance tests were not presented. One of the studies found higher odds of allergic rhinitis (68) in DUs than in ESCC, whereas the other study found comparable odds (69). The same odds of asthma were found in one study, but in analyses of complete data of current users, DUs had a significantly higher risk of asthma than ESCC (67). Three other studies found higher odds of asthma in adolescent (70) and adult DUs (59, 71) than in ESCC, but significance levels were not tested.
One study found the same odds of respiratory symptoms (72), and another study found higher odds in DUs than in ESCC (22) without, however, testing the significance level. Two studies found significantly higher odds of COPD, emphysema and chronic bronchitis (21, 57) and a third of breathing difficulties (58) in DUs rather than in ESCC. Further, one study found higher odds of COPD (71) and one of respiratory disease (46) in a cohort study, but significance levels were not tested.
In a cohort of military personnel incident cases of acute respiratory infections (in- and outpatient diagnoses) in the last 9 months were investigated, and the study found that DUs had higher incident rate of acute respiratory infections than ESCC but significance level was not tested (47). Finally, different pulmonary responses were found in mice exposed to both aerosol from EC and smoke from CC than in mice exposed to smoke from CC only. Dual exposure increased airway resistance compared with mice exposed to smoke from CC only but significance level was not stated (38).
Cardiovascular and metabolic outcomes (Table 3)
Eleven studies investigated the cardiovascular and metabolic outcomes in DUs and in ESCC. All, except two studies (48, 73), were large population-based surveys with self-reported symptoms/diagnoses, including from almost 3,500 (74) to almost 450,000 (23) adults.
The largest study from the general population found significantly higher odds of self-reported CVD (stroke, myocardial infarction or coronary heart disease) (23) and significantly higher odds of self-reported premature CVD in DUs than in ESCC. The second largest nationally representative study found significantly higher odds of self-reported stroke (61) in DUs compared with ESCC, and another large survey found a significantly greater proportion of DUs reporting past/current arrhythmia than ESCC (58). Further, a large survey found that DUs had higher odds of myocardial infarction and stroke than CCU, but significance levels were not tested (75).
Three surveys investigated cardiovascular risk factors. One found that DUs had a significantly higher prevalence odds ratio of cardiovascular risk factors and diagnosis of metabolic syndrome than ESCC (17). One found that DUs had significantly higher odds of elevated human c-reactive protein, a biomarker of inflammation and predictor of cardiovascular disease, than ESCC (60). The last found that DUs had significantly higher odds of abdominal obesity than ESCC, but otherwise found no significant differences, even though there was a tendency to higher odds in DUs than in ESCC, except for blood pressure, for which ESCC had higher odds (18). This contrasts with a survey finding that DUs had higher odds of hypertension than ESCC, but a significant difference was not reached (24).
Three population-based surveys investigated diabetes-related measures. One study found that DUs had similar fasting glucose as ESCC (17), and another found that DUs had higher glycosylated hemoglobin levels than ESCC, but the significance level was not tested (76). A third study found the same levels of insulin resistance (74). In a clinical study, non-invasive vascular function testing was performed in almost 500 young persons, and the study found that DUs had similar arterial stiffness as ESCC (73).
Other health effects (Table 4)
Twenty studies investigated other health effects. Eight of the studies were based on cohorts (42) (25, 26, 39, 40, 43-45), four of these were follow-ups to the same study (25, 26, 40, 45).
In the prospective study with the longest follow-up, almost 1,400 persons were included at baseline (26). Adherence was high for six years. After one year, DUs had the same self-reported health as ESCC (45). Two years after baseline, DUs still had the same self-reported health as ESCC and a significantly higher probability of serious adverse events (25). However, six out of ten DUs stopped using ECs and continued to smoke, those who still were DUs at the 24-month follow-up had significant improvement in self-rated health. After four years, there was still no significant difference in self-reported health score and possible smoking-related disease between the DU group and CC users, but the study found generally worse outcomes in DUs (40). After six years, a possibly smoking-related disease was recorded in 10% of the participants, with no significant differences from the baseline group. Moreover, self-reported health showed a very small change over time in all groups. DUs had an adjusted odds ratio (OR) 1.48 (0.81–2.70 95% CI) of a possibly smoking-related disease and an adjusted coefficient 0.16 (-0.08, 0.39 95% CI) of self-rated health compared with ESCC. The results did not differ substantially when the sample was restricted to those who did not switch smoking/vaping group or to those who were visited or had their outcomes confirmed through a linkage with hospital discharge abstracts (26). Advanced analyses and adjustment for many confounders was performed.
Four studies included pregnant women. Two found higher odds of giving birth to a small-for-gestational-age child among DUs than ESCC, but significance level was not tested (42, 43) whereas one found that DUs and ESCC had the same risk of small-for-gestational-age (49). This study also found that DUs had lower odds of preterm birth than ESCC, but significance level was not tested (49). The last study found that offspring of DUs had same birthweight, Apgar score and mean gestation at delivery as ESCC and that offspring of DUs had a higher rate of admission to neonatal intensive care unit and higher incidence of birthweight <10th centile than ESCC, but significance level was not tested (39). Further, a prospective study found lower fecundability ratio in DUs than in ESCC, but not significantly different (44).
Two large surveys looked at sleep in adolescents. One study found that high-school students with DU were significantly more likely to report insufficient sleep compared with ESCC (64). The other study also found that DUs had a higher risk of sleep-related complaints than ESCC, but it was not significant (77). The third study including adolescents found higher odds of dental problems than ESCC, but the significance level was not tested (78).
Two large population-based surveys investigated SARS-CoV-2(COVID-19)-related issues. Both found that DUs had higher odds of symptoms and higher odds of confirmed/suspected COVID-19 diagnosis than ESCC, but significance levels were not tested (20, 79).
Further, population-based surveys found significantly worse median general health scores (58) and significantly higher levels of uric acid and prevalence of hyperuricemia (19) in DUs than in ESCC and the same prevalence of poor physical health (72). An interview survey in more than 4,000 homeless adults found that DUs had significantly higher rates of cancer compared to ESCC (63). A large survey in male soldiers found that DUs had significantly worse fitness than ESCC (62). Finally, a clinical study found that DUs had higher levels of most biomarkers of systemic inflammation than ESCC, but the difference was not significant (80).