Faculty of Medicine and Health, Sydney Medical School
Abstract
Background The majority of obese patients remain untreated, creating the need for an effective, well-tolerated, safe and appealing therapeutic approach. Endoluminal therapies have the potential to fulfil this unmet clinical need, though traditionally, these approaches mimic the restrictive elements of bariatric surgery but ignore the complex physiologic and neurohormonal mechanisms responsible for bariatric surgeries’ weight-independent reduction in metabolic comorbidities. Hypothesis The overarching hypothesis of this thesis was that although endoluminal gastric space occupying and restrictive interventions result in weight loss, weight-independent improvements in obesity related comorbidities require eradication of the gastric mucosa. Aims The aims of this thesis were to assess the efficacy and safety of the intragastric balloon (IGB) and endoscopic sleeve gastroplasty (ESG), and to evaluate whether gastric mucosal devitalization (GMD) is a potential therapeutic approach to treat patients with obesity. Methods Gastric space occupation and gastric volume reduction were modelled using IGB and ESG, respectively. To evaluate the effects of GMD (without alteration in gastric volume), high fat diet rats were compared to GMD, laparoscopic sleeve gastrectomy (LSG), and sham rats. To determine the translatability of GMD, the feasibility, efficacy and safety of GMD was compared to LSG and sham in a porcine model. Results The clinical research demonstrated that IGBs and ESG result in clinically meaningful weight loss with an acceptable safety profile. However, neither produced improvements in metabolic parameters that were disproportionate to the weight loss observed. GMD resulted in a reduction in body weight and visceral adiposity, improved serum lipid and glucose profiles, and reduced liver lipid content. GMD also resulted in a significant reduction in blood pressure, plasma renin activity and cardiac as well as aortic lipid droplet deposition. In a porcine model, GMD reduced visceral adiposity, with outcomes greater than what would be expected from weight loss alone. Conclusions Weight-independent metabolic improvements can be achieved by selecting the gastric mucosa as a therapeutic target; therefore, endoscopic GMD is a new potential approach for the management of obesity
