Effect of Glucagon-like Peptide-1 (GLP-1) Receptor Agonist Stimulation on Smoking Consumption in Type 2 Diabetes Patients

May 27, 2025 updated by: Shanghai East Hospital

Effect of Glucagon-like Peptide-1 (GLP-1) Receptor Agonist Stimulation on Smoking Consumption in Type 2 Diabetes Patients: Study Protocol of a Randomized, Parallel -Controlled Clinical Trial

Diabetes has become an increasingly serious global health issue. In 2024, approximately 537 million adults were living with diabetes, and this number is projected to rise to 783 million by 2045, representing a 46% increase. Against the backdrop of a growing global diabetes epidemic, smoking among individuals with diabetes poses a significant threat, further exacerbating clinical and public health burdens. Despite over 50 years of tobacco control efforts, smoking remains one of the greatest public health threats in history, causing more than 8 million deaths annually worldwide. Among these, over 7 million deaths result from direct tobacco use, while approximately 1.3 million deaths are attributed to secondhand smoke exposure.

Recent studies have shown that smoking increases the risk of developing prediabetes and diabetes. Moreover, individuals with diabetes who smoke have a higher risk of all-cause mortality, worsened chronic diabetic complications, an increased likelihood of developing cancer and cardiovascular diseases, and greater difficulty in glycemic control. Despite substantial evidence highlighting the detrimental effects of smoking on individuals with diabetes, national surveys from the 1990s indicated similar smoking prevalence rates between individuals with and without diabetes (27.3% and 25.9%, respectively). Although various smoking cessation methods are available, the success rate of quitting remains low, necessitating novel intervention strategies.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes. They exert hypoglycemic effects by stimulating insulin secretion in a glucose-dependent manner, inhibiting glucagon secretion, enhancing glucose uptake in muscle and adipose tissue, suppressing hepatic glucose production, delaying gastric emptying, and reducing appetite. Existing studies suggest that GLP-1 influences the brain's reward system, and GLP-1RAs have been shown to reduce nicotine dependence in animal models. Recent clinical research has demonstrated that GLP-1RAs can be used in combination with nicotine patches to facilitate smoking cessation. However, whether GLP-1RAs alone can directly promote smoking cessation in individuals with diabetes remains unclear. Therefore, this study aims to investigate the potential direct effects of GLP-1RAs on smoking cessation in patients with type 2 diabetes.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

Diabetes has become an increasingly severe global health concern. In 2021, an estimated 537 million adults worldwide were living with diabetes, and this number is projected to rise to 783 million by 2045, reflecting a 46% increase. Against the backdrop of the rising global prevalence of diabetes, smoking has been identified as a major risk factor for its onset, as well as a contributor to poor glycemic control and the progression of chronic diabetes complications. Moreover, smoking is an independent risk factor for elevated HbA1c levels. It has been reported that for every additional 20 pack-years of smoking, HbA1c increases by 0.12%. A meta-analysis of 46 prospective studies revealed that smoking increases the risk of all-cause mortality in patients with diabetes by 48%, the risk of coronary heart disease by 54%, myocardial infarction by 52%, and stroke by 44%. Additionally, smoking has been linked to an increased incidence of proteinuria and diabetic nephropathy.

Despite over 50 years of global tobacco control efforts, smoking remains one of the greatest public health threats in history. Tobacco use is responsible for approximately 8 million deaths annually, with over 7 million attributed to direct smoking and around 1.3 million to second hand smoke exposure. Although numerous smoking cessation interventions are available, the success rate remains suboptimal, highlighting the need for novel strategies. Currently, a combination of pharmacotherapy and counseling is considered the most effective approach for smoking cessation. However, findings from two meta-analyses conducted in 2013 and 2016 suggest that outcomes remain unsatisfactory. The withdrawal symptoms and post-cessation weight gain associated with conventional smoking cessation methods are among the leading causes of relapse.

Patients with T2DM often experience increased hunger. Following smoking cessation, the appetite-suppressing effects of nicotine are diminished, leading to increased food intake. Additionally, smoking cessation may alter gut microbiota, further contributing to weight gain. However, weight gain does not negate the long-term benefits of smoking cessation, which significantly reduces the risk of cardiovascular diseases and all-cause mortality. When exploring novel smoking cessation therapies, it is essential to address both nicotine withdrawal syndrome and the adverse metabolic effects of smoking cessation, such as weight gain, to maximize cessation success rates.

Glucagon-like peptide-1 (GLP-1), a gut hormone, has garnered significant research interest. It is an incretin hormone secreted by intestinal L-cells in response to nutrient intake. GLP-1 acts on the hypothalamus to enhance satiety and reduce food intake while also delaying gastric emptying. GLP-1 receptor agonists (GLP-1RA) are widely used for the treatment of T2DM. They exert glucose-lowering effects by stimulating insulin secretion in a glucose-dependent manner, inhibiting glucagon secretion , increasing glucose uptake in muscle and adipose tissues, suppressing hepatic glucose production, delaying gastric emptying, and reducing appetite.

Furthermore, GLP-1 is implicated in the shared neurobiological mechanisms of addiction via the mesolimbic reward system. Endogenous GLP-1 is produced in the nucleus tractus solitarius (NTS) of the brainstem and acts as a neurotransmitter released in multiple brain regions involved in reward processing. This suggests that GLP-1 may modulate addiction-related behaviours by attenuating neural responses in reward-related brain regions. However, no studies have yet investigated the effects of GLP-1RA on smoking cessation in patients with T2DM. In particular, it remains unclear whether GLP-1RA, at standard therapeutic doses for T2DM, can simultaneously reduce nicotine dependence.

Neuroimaging studies have shown that chronic nicotine use induces cognitive, structural, and functional alterations in the brain. Functional imaging research has identified the insula as a critical region involved in smoking behaviour. A negative correlation has been observed between cortical thickness in insular subregions and nicotine dependence. Additionally, functional imaging studies have demonstrated a positive correlation between nicotine dependence and activation of the anterior and posterior insula in response to smoking-related cues. Recent research has further revealed a negative correlation between nicotine dependence and connectivity between the left and right dorsal and left ventral anterior insula and the superior parietal lobule (SPL), including the left precuneus. The insula has thus been identified as a potential target for nicotine dependence treatment. Moreover, the left praecuneus has been proposed as a neuroimaging biomarker for nicotine addiction, with regional homogeneity (ReHo) values in the right superior frontal gyrus and left praecuneus distinguishing nicotine-dependent individuals.

To date, no studies have investigated nicotine dependence in patients with T2DM. Based on these findings, we hypothesize that GLP-1RA may modulate neural responses in reward-processing regions of the brain, thereby reducing nicotine dependence and cigarette consumption in patients with T2DM.

Study Type

Interventional

Enrollment (Estimated)

46

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Shanghai
      • Shanghai, Shanghai, China, 200120
        • Department of Endocrinology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Male patients aged 18-75 years.
  2. Diagnosis of type 2 diabetes mellitus (T2DM) based on the World Health Organization (WHO) criteria.
  3. A history of smoking for at least one year.
  4. Fagerström Test for Nicotine Dependence (FTND) score ≥4.
  5. Eligible for treatment with glucagon-like peptide-1 receptor agonists (GLP1-RAs) or dipeptidyl peptidase-IV (DPP-IV) inhibitors but have not previously used these medications.
  6. Patients who fully understand the study, voluntarily participate, and sign the informed consent form.

Exclusion Criteria:

  1. Diagnosis of type 1 diabetes or other specific types of diabetes.
  2. Presence of diabetic ketoacidosis or severe diabetic complications.
  3. Patients with severe cardiovascular, hepatic, renal, neurological, immune, or hematological diseases.
  4. Presence of severe infections, malignancies, recent surgeries, or major trauma.
  5. A history of severe recurrent hypoglycemia.
  6. Severe gastrointestinal disorders, such as gastroparesis.
  7. Poor adherence or inability to attend scheduled follow-up visits.
  8. A history of pancreatitis or a high risk of developing pancreatitis.
  9. Presence of severe psychiatric disorders, including schizophrenia, paranoid psychosis, bipolar disorder, or intellectual disability.

  10. Contraindications to magnetic resonance imaging (MRI), such as metallic implants, pacemakers, or claustrophobia.

    -

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: GLP-1 group
Drug: Application of GLP-1RAs drugs
The pharmacological intervention will be given as an add-on to the standardised psychosocial T2DM treatment paradigm. Patients self-inject Semaglutide once a week or use other GLP-1RAs
Active Comparator: DPP-4i group
Drug: DPP-4i group
The pharmacological intervention will be given as an add-on to the standardised psychosocial T2DM treatment paradigm. Patients took the DPP-4i according to their actual needs.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Fagerstrom Test of Nicotine Dependence (FTND) scores
Time Frame: From enrollment to the end of treatment at 24 weeks.At weeks 0 and 24
To evaluate smoking behavior and nicotine dependence before and after treatment, the Fagerström Test for Nicotine Dependence (FTND) will be administered at weeks 0, 1, 4, 12, and 24. Patient scores will be recorded.
From enrollment to the end of treatment at 24 weeks.At weeks 0 and 24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Functional MRI changes
Time Frame: From enrollment to the end of treatment at 24 weeks.At weeks 0 and 24
fMRI will be conducted at weeks 0 and 24 to investigate potential treatment effects. Resting-state functional connectivity (rsFC) analysis will be performed to assess time-dependent consistency of blood oxygen level-dependent (BOLD) or perfusion fMRI signal fluctuations between different brain regions in the absence of explicit tasks, providing insights into brain activity. Changes in resting-state functional connectivity, structural connectivity, and brain morphology will be analysed in addiction-related brain regions, including the praecuneus, lingual gyrus, and paracentral lobule. All participants will undergo fMRI scans at baseline and after 24 weeks of treatment.
From enrollment to the end of treatment at 24 weeks.At weeks 0 and 24
Laboratory testing
Time Frame: From enrollment to the end of treatment at 24 weeks.At weeks 0, 12, and 24
Blood samples will be collected at baseline (week 0), week 12, and week 24 for the assessment of complete blood count, liver and kidney function, electrolytes, coagulation profile, HbA1c, lipid profile, thyroid function, proinsulin, insulin, and C-peptide levels. Urine samples will be collected at baseline (week 0), week 12, and the final visit (week 24) for urinalysis, with a particular focus on urinary albumin levels and the albumin-to-creatinine ratio for intergroup comparisons.
From enrollment to the end of treatment at 24 weeks.At weeks 0, 12, and 24
Exhaled Carbon Monoxide (CO) Test
Time Frame: From enrollment to the end of treatment at 24 weeks.At weeks 0, 12, and 24
Exhaled CO levels will be assessed at weeks 0, 12, and 24 to monitor smoking status.
From enrollment to the end of treatment at 24 weeks.At weeks 0, 12, and 24
Adverse reactions
Time Frame: From enrollment to the end of treatment at 24 weeks.At weeks 0, 4, 12, and 24
At baseline (week 0), informed consent will be obtained from all participants. Following medical history collection and eligibility assessment based on inclusion and exclusion criteria, patients will be randomly assigned to either the GLP-1RA group or the DPP-4i group. Any adverse events occurring during the study period will also be documented.
From enrollment to the end of treatment at 24 weeks.At weeks 0, 4, 12, and 24
BMI
Time Frame: From enrollment to the end of treatment at 24 weeks.At weeks 0, 4, 12, and 24
From enrollment to the end of treatment at 24 weeks.At weeks 0, 4, 12, and 24

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Shanghai East Hospital

Investigators

  • Study Director: jun Song, doctoral degree, East Hospital, Tongji University School of Medicine, Shanghai

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

June 21, 2025

Primary Completion (Estimated)

January 11, 2026

Study Completion (Estimated)

July 1, 2026

Study Registration Dates

First Submitted

March 16, 2025

First Submitted That Met QC Criteria

April 6, 2025

First Posted (Actual)

April 11, 2025

Study Record Updates

Last Update Posted (Actual)

May 31, 2025

Last Update Submitted That Met QC Criteria

May 27, 2025

Last Verified

March 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EC.D(BG).025.04.0

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified patient raw data, statistical analysis programs, and the study protocol.

IPD Sharing Time Frame

After the study concludes, IPD will be available.Data will be available for a period of five years following the completion of the study.

IPD Sharing Access Criteria

Eligible researchers must submit a detailed research plan, which will be reviewed by the principal investigator before data access is granted. To ensure data security and formal communication, all data-sharing matters must be arranged via the institutional telephone number +86-21-38804518. After approval, the institution will provide the information to the relevant applicants. Personal email addresses will not be accepted as official contact methods.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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