American Journal of Pharmacy and Health Research

Background: Type 2 diabetes mellitus and obesity frequently coexist and contribute to cardiovascular and renal complications. Semaglutide, a long-acting glucagon-like peptide-1 receptor agonist, has expanded incretin pharmacology beyond glucose lowering toward broader cardiometabolic therapy. Methods: This narrative review integrated pharmacological and clinical evidence on semaglutide. Priority was given to pivotal randomized controlled trials, cardiovascular and renal outcome trials, pharmacokinetic studies and clinically relevant follow-up studies from the SUSTAIN, PIONEER, STEP, SELECT and FLOW programmes. Results: Semaglutide enhances glucose-dependent insulin secretion, suppresses glucagon, reduces appetite and energy intake, and delays gastric emptying. Once-weekly subcutaneous and once-daily oral formulations produced clinically important reductions in glycated hemoglobin and body weight. Semaglutide reduced major adverse cardiovascular events in high-risk patients with type 2 diabetes, lowered cardiovascular events in patients with established cardiovascular disease and obesity without diabetes, and slowed chronic kidney disease progression in patients with diabetes and chronic kidney disease. Gastrointestinal adverse effects were the main tolerability limitation, and substantial weight regain occurred after treatment withdrawal. Conclusion: Semaglutide is an important cardiometabolic therapy; optimal use requires patient selection, gradual dose escalation, monitoring and long-term treatment planning.

Background: Obesity and type 2 diabetes mellitus are chronic metabolic disorders with substantial cardiovascular, renal and metabolic consequences. Many established glucagon-like peptide-1 receptor agonists are peptide medicines administered by injection, creating practical barriers for patients. Orforglipron is an orally active, nonpeptide small-molecule glucagon-like peptide-1 receptor agonist developed to provide incretin-based metabolic efficacy without injections. Methods: An integrated review was prepared from two supplied 2026 sources: a Drug of the Month article emphasizing medicinal chemistry, receptor binding and regulatory milestones, and a comprehensive review synthesizing pharmacology, pharmacokinetics, clinical efficacy, safety and future directions. Findings were organized descriptively across structure, mechanism, pharmacokinetics, efficacy and tolerability. Results: Orforglipron activates the glucagon-like peptide-1 receptor through a predominantly Gs-biased, transmembrane allosteric binding mode, increasing cyclic adenosine monophosphate signalling, enhancing glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying and promoting satiety. Phase 2–3 evidence showed clinically meaningful reductions in glycated haemoglobin and dose-dependent weight loss of approximately 12–15% at higher doses in obesity. The principal tolerability limitation was gastrointestinal adverse effects, concentrated during dose escalation. Conclusion: Orforglipron represents a significant advancement in oral incretin pharmacotherapy. Long-term comparative effectiveness, cardiovascular and renal outcomes, real-world persistence and evidence in underrepresented populations remain important research gaps.