We used a panel of 8 patho-mechanistically relevant BoPHs to estimate the long-term risk reduction of switching to THS on the development of the main smoking-related diseases (CVD, COPD, and lung cancer) compared to continued smoking over a period of 12 months.
If predominant switching to THS use has the potential to reduce the occurrence of adverse health outcomes and disease risk relative to continued smoking, it should impact the selected BoPHs in the same direction as reported in the literature following smoking cessation.
The primary analysis was performed in subjects classified as predTHS users as the potential benefit from switching to THS is assumed only if cigarette consumption is reduced to an absolute minimum. However, it was expected that some smokers randomized to use THS would not be completely adherent as product satisfaction is a critical component of adherence.
In the THS randomized arm, 55.6% of subjects were classified as predTHS users and 44.4% as dual users (THS and cigarettes). The reduction in exposure to HPHCs in the predTHS group compared to the cig group was lower compared to previous publications including an independent review [28, 54]. This is likely related to the allowance of up to 30% concomitant use of cigarettes. Despite the substantial reduction from baseline in the daily cigarette consumption of the predTHS group, subjects reported an average consumption of 1.6 cigarettes per day. In the dual use group (an average of 9.2 cigarettes per day), if the exposure was decreased relative to the cig group, it was lower than in the predTHS group. (Self-reported product use is provided in Supplementary Table 8.).
Our results in predTHS users substantiate the beneficial impact of THS use versus cigarette smoking, with most of the changes in the BoPHs (increases or decreases) in line with those reported upon 1 year of smoking cessation.
Lipid metabolism was improved, as reflected by higher levels of HDL-C and Apo A1 across the study. The absence of a clear or consistent decrease in LDL-C or Apo B levels was expected [55–57].
In coherence with the lipid metabolism evidence, BoPHs for endothelial dysfunction and platelet activation (s-ICAM-1 and 11-DTX-B2), inflammation and oxidative stress (WBC and 8-epi-PGF2α), and oxygen transport impairment (COHb) were all consistently reduced in predTHS users in a similar manner as observed following smoking cessation.
No intergroup differences were noted in platelet count, albumin, or fibrinogen levels. This is consistent with the findings in the literature, as changes in fibrinogen levels may take over 2–5 years to develop [58, 59], and findings on changes in platelet count are controversial [60–62]. In the present study, a consistent reduction in hs-CRP level was observed within 12 months of switching to THS, although this change is usually reported following 2–5 years of cessation .
Homocysteine levels are reported to decrease upon smoking cessation , but the predTHS group in the present study showed a slight increase in these levels. This was possibly due to their concomitant use of cigarettes . It may also be related to diet, which could be another confounding factor. For example, a diet relatively low in fruits, vegetables, and dairy products may raise homocysteine levels .
The results from the predTHS group overall, are characteristic of a lower atherogenic profile that could indicate a reduction in cardiovascular risk, particularly when considering that HDL-C levels [66, 67], WBC count, and 8-epi-PGF2α and s-ICAM-1 levels are reported to be predictive of decreased future adverse cardiovascular outcomes .
Predominant use of THS had a beneficial and consistent impact on respiratory function, with a lesser decline in FEV1%pred, FVC %pred, FEV1/FVC ratio, and FEF25 − 75%pred in the predTHS group over 12 months, as well as a decrease in regular coughing versus smokers. Together with the decrease in inflammation and oxidative stress, this could indicate a reduction in risk for respiratory diseases such as COPD. This inference is supported by the findings of other studies: (i) improvement in mucociliary clearance in smokers ; (ii) in a 1-year cohort, IQOS users showed improvement from baseline in total COPD assessment (40%), ability to walk longer, and spirometry outcomes ; (iii) a substantial decrease in annual exacerbations in COPD patients who used IQOS for 3 years versus those who continued smoking .
Similarly, the reduction in exposure to total NNAL in predTHS users, a carcinogenic suggested as a risk marker for lung cancer , is another propitious indicator for smokers to switch to THS.
Dual users showed modifications in BoPHs but to a much lower extent. This result is coherent with the lower reduction of exposure versus predominant THS use. The impact of cigarette smoking was verified in predTHS users when we evaluated the magnitude of changes in the 8 key BoPHs by using 2CyEMA exposure to quantify cigarette smoking intensity. We observed that lower exposure to 2CyEMA was associated with a higher beneficial impact on the BoPHs, except in the case of HDL-C, which presented a different profile. At this stage, no plausible explanation can be found for the difference in the HDL-C profile.
Overall, the data clearly indicates an inverse dose response between the number of cigarettes smoked per day and the magnitude of the beneficial effects when switching to THS. Using THS exclusively in place of cigarette is critical to further reduce disease risk and achieve harm reduction. In the real-world—where smokers choose to try the product and continue if they have a satisfactory experience—the adherence is likely to be higher, and the beneficial impact on BoPHs could be more pronounced.
The improvement in the levels of BoPH observed in smokers who switch to THS are consistent with the findings from a review of heat-not-burn products  and 2 studies on THS [73, 74]. One observational, cross-sectional, study reported an increase of 13.9% in HDL-C levels and a decrease of 12.4% in sICAM-1, 17.4% in WBC, 32.6% in 11-DTX-B2, and 28.9% in 8-epi-PGF2α levels in exclusive Ploom TECH users versus continued smokers over an average of 1.2 years . The differences between Ploom TECH users and never smokers in this study were not significant. Similarly, the authors observed a difference of 8.5% in FEV1%pred between Ploom TECH users and smokers in favor of the heat-not-burn users. The beneficial effects of using this alternative to cigarettes were of a lower magnitude than observed in never smokers. In a previous 1-year study, where smokers were randomized to continue smoking or switched to exclusive use of the Glo heated tobacco product, similar beneficial changes were reported . It is likely that up to 30% concomitant use of cigarettes by the predTHS users (as self-reported) in our study explains the lower magnitude of effects on BoPHs than those reported in these previous publications.
One of the strengths of our study was the large sample size, along with the measurement of multiple BoPHs over 12 months of THS use. These BoPH indicated the impact of THS on various patho-mechanisms on the causal pathway to smoking-related diseases. When compared with the effect of smoking cessation over the same timeframe, this approach is valuable to provide early insights into the long-term risk reduction associated with alternatives to cigarettes, such as THS, in the absence of epidemiological data.
This study has some limitations. Self-reported product use has limited accuracy. Despite the balance in demographic characteristics across the 4 groups of product use at baseline, our “per-exposure” analysis instead of per randomization arm could have introduced an imbalance at the end of the study. We also observed high variability in some BoPHs. Moreover, the study does not provide insights on clinical outcomes. A study to detect a difference in clinical outcomes would have necessitated a much longer-term follow-up, particularly in smokers without a disease diagnosis.
In smokers who switched from cigarettes to predominant THS use, our study shows reduction of exposure to HPHCs and favorable changes on multiple BoPH, indicative of lipid metabolism, endothelial dysfunction, platelet activation, lung function, oxygen transport, carcinogenicity, inflammation, and oxidative stress. This data brings additional scientific evidence of the potential of THS to further reduce the risk of the main smoking-related diseases, in smokers who would otherwise continue to smoke cigarettes.