Abstract Body (Do not enter title and authors here): Background: Water fasting, defined as the complete abstinence from caloric intake, has been shown to be safe for up to 21 days with benefits including weight loss, improved blood pressure, and reductions in inflammation and insulin resistance. However, evidence remains limited regarding its use beyond 21 days, particularly in patients with extreme obesity and in combination with GLP-1 receptor agonists. We present a novel case of a patient with premortem obesity (BMI 94, 740 lbs) who underwent a 26-day medically supervised inpatient fasting protocol, including 21 days of water-only fasting with Tirzepatide co-administration, ultimately achieving surgical eligibility for bariatric intervention.

Case Description: SL was a 44-year-old male with morbid obesity and heart failure with preserved ejection fraction. Despite treatment with Tirzepatide, he had continued to gain weight and was not a candidate for bariatric surgery due to his size and comorbidities. He elected to undergo a prolonged water fast in combination with continued Tirzepatide use. During 26 days of fasting including 21 days of water-only fasting, he experienced a 125-lb weight loss. He also experienced resolution of his chronic anemia, hypoxia, and leg wounds along with improved blood pressure, mobility, and decreased depressive symptoms. Left ventricular mass also decreased significantly. After a controlled refeeding phase, he underwent successful robotic-assisted sleeve gastrectomy without major complications.

Discussion: This case represents the first documented prolonged water fast for treatment of morbid obesity since 1973 and is the first to incorporate a GLP-1 agonist. The intervention was well-tolerated, with only minor adverse effects such as transient transaminitis. SL's outcomes suggest that prolonged fasting, especially when combined with GLP-1 therapy, may safely reverse various metabolic and cardiovascular diseases. These improvements, coupled with significant quality-of-life gains, underscore fasting’s potential as a pre-surgical optimization strategy. The case also raises questions about genetic predispositions to obesity and suggests a future role for fasting in targeted therapeutic strategies.

Conclusion: Prolonged water fasting combined with GLP-1 receptor agonist therapy was a safe and effective intervention in a patient with refractory morbid obesity, leading to substantial metabolic, functional, and psychological improvements and enabling life-saving bariatric surgery.