The review compares two weight‑loss drugs, semaglutide (a GLP‑1 only agonist) and tirzepatide (both GLP‑1 and GIP agonist). Both cause typical gut side effects, but tirzepatide appears to have fewer overall issues and may actually help bone health and protect the kidneys, making it a potentially safer choice for long‑term use.

Obesity and diabetes are two faces of the same coin, as both disorders are characterized by insulin action defects. The two gut-derived incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and Glucagon-like peptide-1 (GLP-1), play a crucial role in glycemic control. Semaglutide is a GLP-1 receptor agonist, while Tirzepatide acts as a dual agonist for the GLP-1 and GIP receptors. Despite its effectiveness in weight loss, various side effects were reported. This review seeks to explore post-marketing concerns regarding the long-term safety and tolerability of these drugs. Both drugs showed gastrointestinal issues, including nausea, vomiting, pancreatitis, and diarrhea. Moreover, bone remodeling, kidney and thyroid disorders were detected. Tirzepatide was preferred over the commonly used single GLP-1 RAs as it has less reported side effects and enhanced benefits in promoting bone formation and its protective renal effects, especially on decreasing albuminuria and eGFR slopes.