Introduction
Traditional combustible cigarettes (CCs) contain over 9,500 chemicals, including nicotine, aldehydes, and tobacco-specific nitrosamines. The U.S. Food and Drug Administration’s 2012 list of hazardous substances in tobacco products and smoke includes 93 compounds, 79 of which are carcinogenic [1]. Because of these toxicities, smoking is a major cause of respiratory diseases, cardiovascular diseases, chronic obstructive pulmonary disease, and stroke, while secondhand smoke increases the risk of respiratory disease and lung cancer.
Heated tobacco products (HTPs) are devices designed to reduce the harmful effects of traditional cigarettes by heating tobacco rather than burning it. These products generate an inhalable nicotine aerosol and have gained popularity as a potentially safer alternative to CCs, as they contain relatively lower levels of toxic chemicals, such as nicotine, tobacco-specific nitrosamines, and carbonyls [2].
Efforts to regulate smoking in Korea began with the Tobacco Business Act of 1986, which mandated cigarette warning labels and advertising restrictions. In 1995, the National Health Insurance Act was enacted, which designated non-smoking areas and regulated cigarette vending machine installations, further strengthening smoking control measures [3,4]. However, since 2008, the decline in smoking prevalence has slowed, whereas HTP sales have steadily increased. In 2020, 3.59 billion cigarettes were sold in Korea, of which 10.6% were HTPs, making Korea the second-largest HTP market after Japan [5].
A review of the chronic health effects of HTP use concluded that the certainty of evidence remains very low, primarily because of the predominance of cross-sectional designs and lack of high quality interventions and prospective studies to establish causality [6]. This study aimed to investigate the health effects of HTP and CC use, as well as cessation, by tracking health outcomes using a prospective cohort design.
Methods
Sample
This prospective cohort study was approved by the Research Ethics Review Committee of Keimyung University Dongsan Hospital (2022-06-047). The requirement for informed consent was waived by the IRB. A total of 750 males were enrolled, including 250 HTP users, 250 age-matched (± 2 years) CC users, and 250 quitters. The HTP user group was selected from individuals who underwent health examinations between 2021 and 2022. The CC user group was randomly selected from individuals in the same age range who also underwent health examinations during the same period. All participants received information on the health risks of smoking and were advised on how to quit CC or HTP use. A follow-up test was conducted 2 years (18 ± 8 months) later.
Outcome measures
Health behaviors, including smoking history, disease history, sleep patterns, alcohol consumption, and exercise habits, were collected through structured telephone interviews.
Respiratory function was assessed via spirometry to determine forced vital capacity (FVC), FVC%, forced expiratory volume (FEV), FEV%, peak expiratory flow (PEF), and PEF%.
Body mass index; vital signs; inflammatory markers (erythrocyte sedimentation rate and high-sensitivity C-reactive protein); metabolic markers (fasting blood sugar, glycosylated hemoglobin, and homeostasis model assessment index); lipid profile; tumor markers (alpha-fetoprotein [AFP], carbohydrate antigen 19-9 [CA 19-9], carcinoembryonic antigen [CEA], and prostate-specific antigen [PSA]); liver function (aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, lactate dehydrogenase, total protein, albumin, and albumin/globulin ratio); serum amylase; kidney function (blood urea nitrogen, creatinine, and glomerular filtration rate); uric acid; thyroid function (triiodothyronine and free thyroxine); complete blood count (white blood cells, red blood cells, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, platelet count, red cell distribution width, and platelet distribution width); and electrolytes (sodium, potassium, calcium, and phosphorus) were compared among the HTP, CC, and quitter groups.
Of the 750 participants, 417 (56%) completed the follow-up assessment. An additional 145 follow-up tests were collected from a subset of 333 participants, resulting in 562/750 (75%) follow-up data collected by March 2025.
Results
Baseline characteristics
The mean age was 48.8 ± 9.49 years and was similar across groups (aged 26–72 years). The number of cigarettes smoked in the CC group (n = 250) was 16.1 ± 6.4, and the smoking period was 12.9 ± 6.5 years. The number of cigarettes smoked in the HTP group (n = 250) was 24.6 ± 8.4, and the smoking period was 3.2 ± 2.0 years. The average cessation period in the quitter group (n = 250) was 4.9 ± 2.8 years. Body mass index (kg/m²) was slightly higher in quitters (25.7 ± 3.4) than in CC (25.0 ± 3.3) and HTP users (25.5 ± 3.2). Systolic blood pressure was highest in quitters (127.3 ± 13.0 mmHg), while diastolic blood pressure was highest in HTP users (79.7 ± 10.5 mmHg). All HTP users had the longest smoking duration (median, 25 years), whereas CC users reported a median duration of 16 years. Quitters had a median quit duration of 3 years. The frequency of comorbidities was high in the following order: hypertension (19%), diabetes (10%), hyperlipidemia (17%), heart disease (2%), gout, and intervertebral disc disease. Snoring prevalence was 31.3% and 27.0% in the HTP and CC groups, which was higher than 18.5% in the quitter group, respectively.
For the exercise tolerance test, a 6-minute walking test was performed in 300 participants. The 6-minute walking distance was not significantly different among the HTP, CC, and quitter groups (Table 1).
Respiratory function changes
Respiratory function measures—including FVC, FVC%, FEV, and FEV%—were not significantly different among the HTP, CC, and quitter groups. PEF and PEF% were significantly lower in CC users than in HTP users or quitters (Table 2).
Inflammatory marker changes
Regarding inflammatory markers, erythrocyte sedimentation rate was significantly lower in quitters than in the HTP and CC user groups. White blood cell count and high-sensitivity C-reactive protein were not significantly different among the HTP, CC, and quitter groups (Table 3).
Metabolic marker changes
Among metabolic markers, fasting blood sugar, HbA1c, and homeostasis model assessment index were not significantly different among the HTP, CC, and quitter groups. Total cholesterol was significantly lower in quitters than in the HTP and CC user groups. High-density lipoprotein cholesterol was significantly higher in HTP users than in CC users and quitters (Table 4).
Cancer marker changes
Among tumor markers, AFP was significantly lower in quitters compared with that in the HTP and CC user groups. CA 19-9 was significantly higher in quitters compared with those in the HTP and CC user groups. CEA and PSA levels were not significantly different among HTP, CC, and quitter groups (Table 5).
Other laboratory changes
Regarding liver function, changes in aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, lactate dehydrogenase, total protein, albumin, albumin/globulin ratio, and serum amylase were not significantly different among the HTP, CC, and quitter groups. Kidney function markers—including blood urea nitrogen, creatinine, glomerular filtration rate, and uric acid—were not significantly different among the three groups. Thyroid function markers, including triiodothyronine, free thyroxine, and thyroid-stimulating hormone, were also not significantly different among groups.
For complete blood count, white blood cell count, red blood cell count, hemoglobin, hematocrit, and mean corpuscular volume were measured. Changes in mean corpuscular hemoglobin, platelet count, red cell distribution width, platelet distribution width, and erythrocyte sedimentation rate were not significantly different among the HTP, CC, and quitter groups. Changes in electrolyte levels—including sodium, potassium, calcium, and phosphorus—were not significantly different among the three groups.
Intraocular pressure changes were also not significantly different among the HTP, CC, and quitter groups.
Discussion
This cohort study tracked changes in health outcomes over time among HTP users, CC users, and quitters. The preliminary results suggest that HTP use may be harmful compared to quitting but potentially less harmful than continued use of CCs.
PEF and PEF% were significantly lower in CC users than in HTP users or quitters. Because PEF is a valuable measure for tracking large airway obstruction over time, further longitudinal monitoring is warranted.
The erythrocyte sedimentation rate and total cholesterol were significantly lower in quitters than in the HTP and CC user groups. High-density lipoprotein cholesterol was significantly higher in HTP users than in CC users and quitters. Both HTP and CC use may increase systemic inflammation and depression [7].
The tumor marker AFP was significantly lower in quitters compared with that in the HTP and CC user groups, whereas CA 19-9 was significantly higher in quitters than in the HTP and CC user groups.
The baseline cohort results have been published. Health behaviors among CC users, HTP users, and quitters were compared using baseline data. Nondrinkers were more common in the CC user group, and regular drinkers were more common in the HTP user group. The amount and frequency of high- and moderate-intensity exercise did not differ between the CC and HTP groups. However, the HTP group performed more anaerobic exercise than the CC group [8].
The risk of smoking continuation among electronic cigarette users was 1.8 times higher than among conventional cigarette users. After adjusting for confounding variables, the risk of smoking continuation in HTP users was 2.1 times higher than in CC users, while another study reported it to be 1.5 times higher [9].
Respiratory function among HTP users and quitters showed statistically significant differences in FEV and FVC, with lower values observed in current HTP users than in quitters [10]. Lung nodules were frequently observed among smokers in low-dose chest computed tomography scans performed for cancer screening [11].
Tumor markers—AFP, CA 19-9, CEA, and PSA—were evaluated. AFP levels were highest in the HTP user group, CA 19-9 levels peaked in the quitter group, CEA levels were highest in the CC user group, and PSA levels were highest in the HTP user group [12].
This study’s strength lies in its use of a prospective cohort design to assess general health outcomes. Ongoing longitudinal follow-up will help clarify the long-term health impacts of HTP use, CC use, and smoking cessation.
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