To evaluate the effect of GLP-RAs on nicotine dependence in patients with type 2 diabetes mellitus, as assessed by changes in the Fagerström Test for Nicotine Dependence (FTND) score.

To assess the effects of GLP-1RAs on smoking exposure, measured by exhaled CO levels, and on smoking cessation rate, as well as on metabolic parameters.

To explore changes in brain functional activity and connectivity in addiction-related regions using fMRI, and to investigate potential associations between neural measures, nicotine dependence, and metabolic changes.

This two-arm randomized controlled trial is designed to evaluate the efficacy and safety of GLP-1RAs in cigarette smoking cessation compared with control treatment. Eligible participants who provide written informed consent will be randomly assigned in a 1:1 ratio to receive either a GLP-1RA or a DPP-4 inhibitor (DPP-4i). The study is being conducted at the Department of Endocrinology, Shanghai East Hospital, starting in June 2025. Participants are not required to have an intention to quit smoking at the time of enrollment.

The research team will not provide any structured smoking cessation counseling or smoking cessation pharmacotherapy during the study period. Participants will undergo a structured intervention period, with follow-up assessments conducted at predefined time points to evaluate cigarette smoking cessation outcomes, nicotine dependence levels, and other relevant clinical parameters. All participants will be required to adhere to the follow-up plan as outlined in the study protocol. The study pathway is illustrated in Figure 1. The trial is registered at ClinicalTrials.gov (NCT06924697).

Patients may withdraw from the study at any time for the following reasons:

After confirming eligibility and obtaining informed consent, patients will undergo a comprehensive baseline assessment. This includes recording demographic and anthropometric data (age, sex, and body mass index [BMI]) and a detailed medical history focused on diabetes and cigarette smoking status. Laboratory evaluations will include a complete blood count and routine blood chemistry (liver and kidney function tests, electrolytes, and coagulation profile), lipid panel, thyroid function tests, and measurements of HbA1c, insulin, and C-peptide levels. Urine samples will be collected for analysis of urine albumin-to-creatinine ratio (UACR). Exhaled CO levels will be measured, and the FTND questionnaire will be administered to assess baseline nicotine dependence. Additionally, each patient will undergo a baseline resting-state fMRI scan to assess functional connectivity in addiction-related brain regions.

Participants in the experimental group will receive GLP-1RA treatment, while those in the control group will receive a DPP-4 inhibitor. The dosage for both groups will be determined according to standard therapeutic regimens for their diabetes treatment. In the GLP-1RA group, GLP-1RA therapy was prescribed in accordance with routine clinical practice and standard titration protocols. The GLP-1RA agents used in this study primarily included semaglutide and liraglutide. Semaglutide is initiated at 0.25 mg once weekly and titrated to a target maintenance dose of 0.5–1.0 mg once weekly, as tolerated. Liraglutide is initiated at 0.6 mg once daily and titrated to a target dose of 1.2–1.8 mg once daily. Dose adjustments are performed according to tolerability and routine clinical guidelines. The specific GLP-1RA agent and achieved maintenance dose will be recorded for each participant. To enhance participant retention, research staff will contact patients by phone prior to scheduled follow-up visits. The follow-up schedule for this trial is outlined in Table 1.

At baseline (week 0), informed consent will be obtained from all participants. After medical history collection and eligibility assessment, patients will be randomized to either the GLP-1RA group or the DPP-4i group. BMI will be recorded at weeks 0, 1, 4, 8, 12, and 24. Any adverse events occurring during the study period will be documented at each visit.

Blood samples will be collected at baseline, week 12, and week 24 for laboratory analysis. These tests will include complete blood count, liver and kidney function tests, electrolytes, coagulation profile, HbA1c, lipid panel, thyroid function, insulin, and C-peptide levels. Urine samples will be collected at baseline, week 12, and week 24 for UACR test.

To evaluate cigarette smoking behavior and nicotine dependence, the FTND will be administered at baseline (week 0) and at weeks 1, 4, 8, 12, and 24. FTND scores will be recorded at each time point. Table 2 presents the FTND questionnaire.

Exhaled CO levels will be measured at baseline (week 0), week 12, and week 24.

At baseline and 24 weeks, participants will undergo resting-state functional MRI scans to investigate treatment effects. MRI data will be acquired at Shanghai East Hospital using a 3.0 Tesla MRI scanner with a standard head coil. Resting-state functional images will be obtained using a gradient-echo echo-planar imaging (EPI) sequence with the following parameters: repetition time (TR) ≈ 2000 ms, echo time (TE) ≈ 30 ms, flip angle ≈ 90°, field of view ≈ 220 × 220 mm², matrix size ≈ 64 × 64, slice thickness ≈ 3.5 mm, and no inter-slice gap. High-resolution T1-weighted structural images will be acquired for anatomical reference. Resting-state functional connectivity (rsFC) analysis will be conducted to assess correlations in blood-oxygen-level-dependent (BOLD) signal fluctuations between different brain regions in the absence of explicit tasks (11–13). Changes in functional connectivity and brain structure will be analyzed in addiction-related regions, including the praecuneus, lingual gyrus, and paracentral lobule.

The primary hypothesis is that at the 6-month follow-up, the GLP-1RA group will have a mean FTND score reduction of approximately 2 points compared with the control group. Based on previous randomized studies evaluating the effects of GLP-1 receptor agonists on smoking-related outcomes and nicotine dependence, the standard deviation of FTND scores was estimated to be approximately 2 points, and a 2-point reduction was considered clinically meaningful (14, 15). To detect this difference with 80% power at a 0.05 significance level, and accounting for an anticipated 10% dropout rate, 23 participants per group (46 total) are required. The anticipated dropout rate was set at 10%, considering that participants are receiving standard diabetes treatments within routine clinical care and that regular follow-up contacts are implemented to enhance retention. Even with a modestly higher dropout rate, the study would retain adequate power to detect clinically meaningful differences in FTND scores.

After obtaining informed consent and completing baseline assessments, participants will be randomly assigned in a 1:1 ratio to the GLP-1RA group or the control group. The randomization sequence will be generated by an independent statistician and sealed in sequentially numbered, opaque envelopes managed by an independent administrator. A study nurse or investigator not involved in outcome assessments will open the envelope to reveal each participant’s group allocation. Outcome assessors and data analysts will remain blinded until the database is locked for final analysis.

All personnel involved in data collection, entry, the data manager, statistician, and outcome assessor, will receive training on data management procedures. Upon completion of the treatment phase, all participant information will be fully documented in the original case report forms (CRFs). Data will be collected and managed using an electronic data capture (EDC) system designed for clinical research. The system will support role-based access control, data validation rules, audit trails, and version control to ensure data quality and integrity. Source data verification and regular data monitoring will be conducted according to predefined procedures. Any data modifications will be tracked with timestamps and user identification.

All research-related paper documents will be securely preserved, while electronic files will be stored on a password-protected computer to ensure data security. Both paper and electronic records will be retained for at least five years after the study’s publication. If reviewers or readers have inquiries regarding the published data, they may contact the corresponding author to request access to the original dataset. Confidential patient information, such as names and phone numbers, will be strictly protected.

All participants and researchers should first receive training and complete the study, including follow-up steps. All the data will be strictly stored in the electronic database.

Throughout the research process, we will try our best to prevent the loss of participants. To ensure the punctuality and effectiveness of follow-up visits, we will communicate with patients by Social Networking Service or telephone during the study to improve patient compliance. Researchers will check the authenticity, accuracy, and completeness of the data obtained. After the validation is complete, the data will be locked for final data analysis. This series of data should be kept for no less than five years.

An independent statistician will perform data analysis using SPSS v.27 on an intention-to-treat basis, with a two-sided significance level of 0.05. Baseline characteristics will be compared using t-tests or Mann-Whitney U tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables. Primary endpoints (FTND scores, exhaled CO, and cigarette smoking cessation rates) will be analyzed using generalized estimating equations (GEE) or repeated measures ANOVA, adjusting for baseline values. Secondary endpoints (e.g. HbA1c, BMI, cigarette smoking urge scores, and fMRI-derived measures) will be analyzed using t-tests, Mann-Whitney U tests, or Spearman correlation analysis. Subgroup analyses will evaluate the effects of adjunctive cigarette smoking cessation medications while controlling for potential confounders (age, BMI, diabetes duration, etc.). Exploratory analyses will further examine the associations between changes in metabolic parameters and smoking-related outcomes to assess potential mediation effects. Missing data will be handled primarily using the GEE model, with sensitivity analyses via multiple imputation if needed. Adverse events will be summarized descriptively and compared using chi-square tests; reasons for withdrawal will be assessed qualitatively. fMRI data will be explored using Regional Homogeneity (ReHo) and rsFC analyses to assess local and whole-brain changes. ReHo will be computed using Kendall’s coefficient of concordance (KCC) for each voxel and compared using voxel-wise tests with multiple comparisons corrected. For rsFC, time series will be extracted from predefined seed regions, correlated with other voxels, transformed to z-scores, and compared between groups using a general linear model (GLM) with cluster-level correction (p<0.05). Regression analyses will control for potential confounders (e.g. cigarette smoking level, age, socioeconomic status).

Safety assessments will encompass the reporting of adverse events and serious adverse events, alongside clinical laboratory evaluations, physical examinations, and follow-up assessments.

Any modifications to the study protocol that may influence study conduct, patient benefit, or safety—such as changes in study objectives, design, participant population, sample size, procedures, or major administrative aspects—will require a formal amendment. Such amendments will be reviewed and approved by the ethics committee before implementation and will be reported to the relevant health authorities in accordance with local regulations.

·This is a single-center, randomized, parallel-group controlled trial evaluating the effects of GLP-1RAs on nicotine dependence and smoking-related outcomes in patients with T2DM.

·The 24-week follow-up is longer than that of most prior pharmacological studies assessing smoking-related outcomes, allowing evaluation of sustained changes in nicotine dependence and smoking exposure.

·The protocol integrates objective measures of smoking exposure and exploratory neuroimaging endpoints to investigate potential neurobiological mechanisms.

The absence of a placebo group may limit causal inference regarding the effects of GLP-1RAs on nicotine dependence and smoking-related outcomes.

·Smoking status and nicotine dependence are partially assessed using self-reported questionnaires, which may introduce reporting bias and affect measurement accuracy.

·More than one GLP-1RA agent is permitted within the intervention arm; therefore, the study is designed to evaluate class effects rather than molecule-specific differences.

·Only male participants are enrolled to reduce sex-related biological heterogeneity, which may limit the generalizability of the findings to female populations.