Electronic nicotine delivery systems versus combustible cigarettes: A systematic review and meta-analysis of biomarkers of harm from randomized controlled trials.

Abstract

e22520 Background: Electronic nicotine delivery systems (ENDS) advertised harm reduction, yet their long-term oncologic and toxic safety remains uncertain. While eliminating combustion reduces many toxicants, ENDS aerosols still deliver nicotine and residual carcinogens capable of DNA damage and inflammation. Randomized evidence on how switching from cigarettes to ENDS affects validated biomarkers of harm is limited; therefore, we conducted a systematic review and meta-analysis of RCTs assessing changes in established tobacco related biomarkers of harm among adults switching to ENDS versus continued smoking controls. Methods: RCTs published through October 2025 were identified in PubMed, Scopus, Web of Science, Cochrane Library, and ClinicalTrials.gov. Eligible trials reported pre- and post-intervention changes in blood, urine, or exhaled breath biomarkers among ENDS users and continued smoking. Two reviewers independently performed study selection, data extraction, and risk of bias assessment RoB 2. Within-arm effects were calculated as standardized mean change with raw score standardization (SMCR): (X̄-post − X̄-pre)/SD-pre. Between-arm SMCR differences, SMCRDs (ENDS SMCR - continued smoking SMCR), were pooled using random effects inverse variance meta-analysis. Heterogeneity, meta regression, and subgroup analyses were performed. Results: ENDS substitution was associated with insignificant reductions in urinary NNAL (7 trials; SMCRD = −0.43, 95% CI: −1.05 to 0.19; I² = 99.8%), urinary 3-hydroxypropyl mercapturic acid or 3-HPMA (6 trials; SMCRD = −2.84, 95% CI: −6.79 to 1.10; I² = 99.8%), urinary S-phenyl mercapturic acid or SPMA (6 trials; SMCRD = −1.09, 95% CI: −3.15 to 0.96; I² = 99.8%), and exhaled CO or COHb (8 trials; SMCRD = −3.83, 95% CI: −9.89 to 2.23; I²=99.7%). ENDS substitution insignificantly increased blood Cotinine (5 trials; SMCRD = 0.49, 95% CI: −0.10 to 1.09; I²=94.8%). All tests for subgroup differences in SMCRs between ENDS and continued smoking were insignificant (p > 0.05). Meta-regression identified follow-up duration as a significant moderator of the SPMA SMCRD (p < 0.001). A significant reduction in SPMA was observed only at short follow-up, including trials with follow-up <1 month (5 trials; SMCRD = −1.59, 95% CI: −1.89 to −1.28) and a 5-day subgroup (4 trials) showing a pooled SMCRD of −2.14 (95% CI: −3.54 to −0.74; I² = 41.2%). Conclusions: Switching ENDS did not consistently reduce biomarkers of toxicant exposure; although SPMA showed short-term decreases that were dependent on follow-up duration. Our conclusions are limited by high heterogeneity, limited trials, follow-up, and variability in ENDS products, biomarkers, and adherence. Longer term randomized and outcome based studies are needed to determine whether these exposure patterns translate into meaningful reduced risk.