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 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.