Study measuring differences in biomarkers of potential harm after 2+ years of THS use compared with cigarette smoking
What is the relationship between cigarette smoke and biomarkers of potential harm?
Cigarette smoke contains thousands of chemical compounds, including nearly 100 that are recognized as harmful and potentially harmful constituents (HPHCs) by public health institutions and are linked to the development of smoking-related diseases.
However, while it is relatively easy to measure HPHC levels in cigarette smoke or smoke-free product aerosol in the laboratory, these measurements become more difficult once the chemicals are in the body. There are a number of reasons for this, including:
- Chemicals break down or are converted into other products (metabolites) in the body
- The amount of a substance contained in a product, or extracted during use, is not the same as the amount absorbed by the body.
One way to measure the effects of exposure to HPHCs in cigarette smoke and aerosol in the body is to use BoPH. A biomarker is an objective measurement that can indicate an interaction between a biological system and a potential hazard, such as an HPHC. BoPH can indicate changes in morphology, structure, or function symptomatic of the onset of disease. For example, changes in white blood cell count, levels of high-density lipoprotein cholesterol (i.e., “good” cholesterol), or how much air a person can forcefully exhale in one second (FEV1) can all be used as BoPH to provide an indication of a person’s health status or potential risk of disease.
Monitoring changes in BoPH indicative of diseases associated with exposure to cigarette smoke can provide insights into the risk profile of an individual who switches from cigarettes to smoke-free products. Because most smoking-related diseases can take many years to develop, this evidence also provides useful interim information until long-term health outcome data becomes available.
Why was this study conducted?
In this latest study, titled “Differences in biomarkers of potential harm after 2+ years of tobacco heating system use compared to cigarette smoking: a cross-sectional study,” PMI researchers measured levels of nine BoPH associated with smoking-related diseases to determine if these levels are significantly different in those who switched to using THS, compared with smokers, after at least 2 years of real-life use.
Previous findings from exposure-response studies (ERS) demonstrated that participants who predominantly switched to THS for up to 12 months had trajectory changes in all eight* BoPH studied, in the same direction as observed for smoking cessation.
However, these studies on the effects of switching from cigarette smoking to THS involved randomized participants who had not previously used THS, and who continued to smoke cigarettes for up to 30% of daily product consumption (e.g., engaged in dual use). In contrast, this cross-sectional study was designed to verify the earlier ERS results under real-world conditions and demonstrate that the same beneficial effects of switching occur in smokers who independently chose to use THS.
The main objective of the study was to demonstrate favorable differences (in the direction of cessation) in participants who used THS for at least 2 years compared with those who smoked. This was assessed through measurement of BoPH linked to the three main smoking-related diseases (cardiovascular disease [CVD], chronic obstructive pulmonary disease [COPD], and lung cancer) in healthy participants.
The risk markers selected and assessed in the study are all:
- Associated with smoking-related disease
- Negatively impacted by smoking, and
- Known to improve following smoking cessation
The four BoPH assessed for the main objective of the study were:
- White blood cell count (WBC) for inflammation
- 8-Epi-prostaglandin-F2α (8-epi-PGF2α) for oxidative stress
- Carboxyhemoglobin (COHb) for oxygen delivery
- Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) for tobacco-specific genotoxicity
The study also included a secondary set of endpoints to provide additional evidence on the risk reduction potential of switching to THS. Five BoPH were used to measure these endpoints:
- High-density lipoprotein cholesterol (HDL-C) for lipid metabolism
- Soluble intercellular adhesion molecule-1 (sICAM-1) for endothelial function
- 11-Dehydrothromboxane B2 (11-DTX-B2) for blood clotting
- Central vascular augmentation index (AIx) for arterial stiffness
- Forced expiratory volume in 1 second %predicted, post-bronchodilator (FEV1 %pred), for lung function
In addition to exhaled carbon monoxide (CO) and cotinine testing, smoking abstinence was verified by measuring urinary
2-cyanoethylmercapturic acid (2-CyEMA), in order to confirm self-reported status of the participants enrolled in the study.
*Total NNAL, COHb, WBC, FEV1 %pred, HDL-C, sICAM-1, 11-DTX-B2, and 8-epi-PGF2α
How was the study conducted?
The study was conducted in 37 healthcare institutions across six countries in Asia and Europe. A total of 974 participants were assigned to one of three study groups based on their tobacco consumption patterns as follows:
- Current smoker: At least 10 years of self-reported cigarette smoking (≥10 cigarettes/day on average, without daily use of other tobacco or nicotine product use over the 2 years prior to the study).
- THS user: At least 2 years of self-reported THS use (≥10 tobacco sticks/day on average, without daily use of other tobacco or nicotine product use over the 2 years prior to the study), after at least 8 years of self-reported cigarette smoking (≥10 cigarettes/day on average).
- Former smoker: Complete cessation of all tobacco or nicotine-containing products (TNPs) for at least 2 years prior to the study (verified based on urinary cotinine of <100 ng/mL and CO breath test of <10 ppm) after at least 8 years of self-reported cigarette smoking (≥10 cigarettes/day).
Data from 888 participants was analyzed (n=296 in each group). The study took place over 2 days: a single assessment visit and an additional follow-up day to capture any adverse events that may have emerged as part of the study. In addition to sample collections (blood, serum, plasma, urine), study tests (spirometry, AIx, pulse wave velocity, electrocardiogram), and physical examinations, participants completed a set of self-reported questionnaires on tobacco product use history, lifestyle and diet, quality of life, perceived risk, and dependence.
The diagram below shows the study flow.
What do the results show?
The study showed that the nine BoPH analyzed were significantly different in THS users compared with current smokers—indicating that switching to THS was associated with favorable differences in biological pathways that are negatively impacted by smoking.
THS users had BoPH levels indicating reduced cigarette smoke exposure, lower levels of inflammation, and less oxidative stress than current smokers. Favorable differences were also observed in BoPH related to lipid metabolism, endothelial dysfunction, platelet activation, lung function, and arterial stiffness compared with current smokers.
Importantly, the BoPH related to endothelial function, platelet activation, and oxidative stress, which were not significantly improved in the earlier ERS studies, were significant in the present real-world study.
Because this study enrolled healthy participants, all values were expected to be in normal ranges, but differences could still be observed based on self-selected lifestyle choices. Healthy smokers who switched to THS for at least 2 years had BoPH levels significantly different from those of current smokers and similar to those of former smokers.
Overall, the study results demonstrated that:
- Switching was associated with favorable differences in BoPH related to biological pathways impacted by cigarette smoke (inflammation, oxidative stress, oxygen transport, genotoxicity, lipid metabolism, endothelial function, and blood clotting potential), as well as better cardiovascular and respiratory function compared with current smokers.
- Former smokers had slightly more favorable differences compared with current smokers than current THS users, reinforcing the fact that quitting tobacco and nicotine use altogether is the best option for health.
- Exposure to nicotine, measured as part of the additional objectives, was similar between THS users and current smokers, suggesting successful adaptation to THS.
This study represents a single snapshot in time, so it is not possible to prove causal relationships between switching to THS and the observed BoPH differences between groups. It is also important to note that factors besides cigarette smoking can affect these BoPH. However, the differences in all nine BoPH measured were significantly different from current smokers, and seven were at similar levels to those measured in former smokers, making it unlikely that the results were due to chance or other environmental factors.
Why is this study important?
The results from this study add to the existing body of evidence indicating that adults who replace cigarette smoking with THS use, especially those who fully switch, have a lower risk of smoking-related harm than those who continue to smoke. At the same time, the results also demonstrated that nicotine levels were very similar between current smokers and THS users, while former smokers had a 96-98% lower level of nicotine exposure. This is significant because nicotine is important for smokers to accept smoke-free products as an alternative to cigarettes.
The closer the effects of switching to THS are to the effects of cessation, the greater the confidence that the results are clinically relevant and will lead to reductions in smoking-related diseases in the long term. This is why data from studies such as this, comparing switching with smoking as well as with cessation, is crucial for helping policy and regulatory decision makers to make informed, scientifically sound decisions regarding tobacco harm reduction.
