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

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.

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.

Eligibility Criteria:
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.

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