Purpose of Review <p>This review provides practitioners with an up-to-date overview of the efficacy and safety data of the currently approved weekly Nutrient-Stimulated Hormone (NuSH) therapies, semaglutide and tirzepatide, in managing obesity and weight-related comorbidities.</p> Recent Findings <p>In people with overweight/obesity without diabetes, semaglutide achieved 10.8–14.8% and tirzepatide 17.4–20.8% greater weight loss than placebo. These agents’ pleotropic effects have translated into clinicals trials showing improvement in cardiovascular outcomes, improved quality of life and/or heart failure events in heart failure with preserved ejection fraction, resolution of steatohepatitis and improvement in liver fibrosis, prevention and treatment of type 2 diabetes, and improvement in renal function in chronic kidney disease. Semaglutide has additionally been shown to improve osteoarthritis symptoms and tirzepatide reduces obstructive sleep apnea severity.</p>