Cocktail Treatment with Lifestyle Modification, Incretin-Based Medications, and Endoscopic Sleeve Gastroplasty for Class I, II, III Obesity Patients

Obesity is a progressive disease associated with insulin resistance, dyslipidemia, and elevated risk of Type 2 Diabetes Mellitus (T2D), cardiovascular disease, and mortality [1]. Traditional lifestyle interventions, while foundational, often result in modest and unsustainable weight loss. GLP-1 receptor agonists (GLP-1RA) and GIP/GLP-1 dual agonists (e.g., tirzepatide) demonstrate superior weight and glycemic control. Endoscopic Sleeve Gastroplasty (ESG), a minimally invasive bariatric endoscopy procedure, induces restrictive weight loss and hormonal modulation. A combination strategy [2]: lifestyle changes, incretin-based agents, and ESG may yield synergistic benefits, especially across the obesity spectrum (BMI≥30kg/m²). This cocktail approach is the idea from GLP-1RA combined with bariatric surgery which showed significant improvements in weight control [3-5].

Lifestyle modification remains first-line therapy and includes caloric restriction, physical activity, and behavioral interventions. Moderate calorie deficit (500-1000kcal/day) and ≥150 minutes/week of moderate exercise can yield 5-10% weight loss and modest improvements in GLP-1 and GIP profiles. However, these interventions alone often fall short and are noted with high recidivism rates. Exercise improves incretin sensitivity and postprandial GLP-1 secretion [6]. Studies in obese adults and adolescents show enhanced GLP-1 response after acute and chronic aerobic training, independent of weight loss, supporting its additive metabolic role.6

GLP-1RAs (e.g., semaglutide, liraglutide) and GIP/GLP- 1 dual agonists (e.g., tirzepatide) are cornerstones of obesity pharmacotherapy. These agents enhance insulin secretion, delay gastric emptying, suppress appetite, and promote significant weight loss (up to 15-25% in clinical trials). Real-world and trial data suggest greater efficacy when combined with behavioral and dietary interventions. Incretin-based therapy also improves lipid profile, hepatic steatosis, and cardiovascular outcomes. Adverse effects (e.g., nausea, vomiting) are generally temporary and associated with dosage. In Class III obesity, pharmacologic therapy can serve as bridge to or augmentation of procedural options. Long-term adherence to pharmacotherapy is low, with 7% to 18% of patients stopping medication within 12 months in clinical trials [7,8]. While in applying GLP-1RAs, Sirtuin 1 inhibitors should be avoided since Sirtuin 1 is important to GLP-1 function with exercise [9,10].

ESG mimics the restrictive mechanism of surgical sleeve gastrectomy by endoscopically reducing stomach volume with transmural suturing. Also, ESG slows gastric emptying, which increases the feeling of satiety. This procedure was Food and Drug Administration (FDA)-approved in 2022 for Body Mass Index (BMI) 30 to 50, based on the outcome of the MERIT study [11]. Weight loss of 15-20% at 12 months is typical, with improvement in T2D, non-alcoholic fatty liver disease, and hypertension. ESG does not involve resection or malabsorption, allowing for preservation of nutrient absorption and reversibility. Importantly, ESG influences gut hormones, increasing postprandial GLP-1 and peptide YY, potentially enhancing the effect of concurrent GLP-1RA therapy. Patients undergoing ESG may require structured nutritional guidance and psychological support to maintain weight loss and prevent regain. In combination with lifestyle modifications and GLP-1Ras, Badurdeen et al. [12] showed liraglutide use starting 5 months after ESG could significantly improvement in weight reduction [12]. Because of more data focusing on pharmacological combination with ESG, in this review, we focused on the cocktail strategy with using ESG.

Combining lifestyle modification, incretin-based pharmacotherapy, and ESG offers mechanistic complementarity: lifestyle targeting behavior and insulin sensitivity, incretin therapy addressing appetite regulation and glycemic control, and ESG inducing anatomical restriction and hormonal changes. The decision to combine pharmacologic and endoscopic therapy for weight loss should be made on the basis of communication with the patient and patient’s goals. It is important to understand patient goals and medical comorbidities when deciding on the ideal approach. Gala K et al. [13] they published a study showing that in the control of lifestyle modifications, patients receiving GLP-1RAs after ESG lost more weight than those who did not. ESG combined with lifestyle changes results in a 15.4% weight reduction [13]. Therefore, lifestyle modification is the cornerstone of obesity treatment; medications can enhance weight loss, but weight regain often occurs after stopping them. ESG could offer durable effects in weight control and have synergic benefits with the lifestyle modifications and pharmacological therapy. Physicians should discuss with the patients and make the strategy in choosing the perfect cocktail mixture.

Cocktail treatment using lifestyle modification, incretin-based medications, and ESG represents a rational, evidence-supported, and patient-centred strategy for treating class 1 to 3 obesity. Its adaptability, tolerability, and synergistic mechanism contribute to its use in clinical practice. Future studies should explore optimal sequencing, cost-effectiveness, and long-term outcomes.