In recent years, the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has risen in popularity due to their efficacy in managing diabetes, inducing weight loss, and lowering the risk of atherosclerotic cardiovascular disease (ASCVD) events. However, with the exception of oral semaglutide (Rybelsus, Wegovy; Novo Nordisk), all other currently FDA-approved GLP-1 RA and glucose-dependent insulinotropic polypeptide/GLP-1 RA products are injectable formulations. Injections tend to have higher manufacturing costs and may pose challenges related to patient comfort and adherence. Orforglipron, a novel GLP-1 receptor agonist, is under investigation for its potential benefits in the management of type 2 diabetes and obesity, representing a promising advancement within this therapeutic class.
Orforglipron is structurally distinct from other GLP-1 RAs due to its small-molecule, nonpeptide composition.1 In contrast, traditional GLP-1 RAs are large peptide-based molecules. The oral formulation of semaglutide requires the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate to facilitate permeability through lipid membranes and protect the drug from proteolytic degradation by neutralizing gastric pH.2 Despite this alteration to its structure, oral semaglutide exhibits low bioavailability and requires complex dosing instructions: It must be taken on an empty stomach with no more than 4 oz of water, separate from other medications.3 This could be a barrier to patient adherence and can lead to improper administration. In contrast, orforglipron’s smaller, nonpeptide structure allows for more straightforward oral administration without such restrictions, potentially improving convenience and adherence.
The ACHIEVE-1 phase 3 trial (NCT05971940) demonstrates promising results regarding the use of orforglipron for the treatment of type 2 diabetes.4 This 40-week, randomized, placebo-controlled study enrolled 559 participants assigned to orforglipron 3 mg, 12 mg, 36 mg, or placebo. Participants were included if they had a diagnosis of type 2 diabetes inadequately treated with diet and exercise and were not currently on antihyperglycemic therapy, had a hemoglobin A1C (HbA1C) between 7% and 9.5%, and a body mass index (BMI) of 23 or greater. At week 40, the mean HbA1C reductions from baseline were –0.41% (placebo), –1.24% (3 mg), –1.47% (12 mg), and –1.48% (36 mg). All orforglipron doses achieved statistically significant HbA1C reductions compared with placebo.4
Key Takeaways for Pharmacists
1. Orforglipron may expand access to GLP-1 therapy through easier oral administration. Unlike peptide-based GLP-1 RAs and oral semaglutide, orforglipron is a small-molecule, non-peptide agent that does not require complex fasting or water-volume instructions. This simpler dosing could improve adherence and offer patients a more convenient alternative to injections.
2. Clinical trials show strong efficacy for both diabetes and obesity management. In phase 3 studies, orforglipron demonstrated clinically meaningful reductions in HbA1c (up to –1.48%) and significant weight loss in non-diabetic patients (up to –11.2%), positioning it as a promising emerging option for 2 major chronic conditions.
3. GI tolerability and patient counseling will be key considerations. Gastrointestinal adverse effects—especially during dose escalation—were common and led to higher discontinuation rates than placebo. Pharmacists should be prepared to counsel patients on expected side effects, titration strategies, and when to seek follow-up care.
In addition to efficacy in HbA1C reduction in patients with diabetes, orforglipron has also demonstrated weight loss efficacy in nondiabetic patients, as demonstrated by the ATTAIN-1 phase 3 clinical trial (NCT05869903).5 This 72-week, randomized, placebo-controlled study enrolled 3127 participants assigned to receive orforglipron 6 mg, 12 mg, or 36 mg daily, or placebo. Eligible participants had a BMI of 30 or greater, or 27 or greater with at least 1 obesity-related comorbidity, such as hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea. At week 72, the mean percentage change in body weight from baseline was –7.2%, –8.4%, and –11.2% in the orforglipron 6-mg, 12-mg, and 36-mg groups, respectively, compared with –2.1% in the placebo group.5
In both studies, the most frequently reported adverse events with orforglipron were nausea, constipation, diarrhea, vomiting, and dyspepsia.4,5 These adverse effects often occurred during dose escalations. In ATTAIN-1, treatment discontinuation as a result of gastrointestinal (GI) adverse events occurred in 3.5% to 7.0% of participants in the orforglipron groups vs only 0.4% in the placebo group.5 This was similar to ACHIEVE-1, in which 2.2% to 5.7% of participants in the orforglipron groups discontinued due to GI adverse effects, in contrast to no participants in the placebo group.4
About the Author
Jessica Roberts, PharmD, RPh, is a PGY-2 ambulatory care resident at the Mayo Clinic College of Medicine and Science. She is currently completing her community internal medicine rotation and will soon be starting cardiology. Thus far, she has completed rotations in anticoagulation and family medicine.
Although ACHIEVE-1 and ATTAIN-1 demonstrated the efficacy of orforglipron in reducing HbA1C and promoting weight loss, both studies had notable limitations. Neither trial included an active comparator against an approved GLP-1 RA nor other medications currently indicated for diabetes or obesity.4,5 In ACHIEVE-1, participants managed their diabetes solely through diet and exercise at enrollment, limiting the generalizability of the findings to patients already receiving antihyperglycemic therapy. Overall, additional studies are needed to evaluate the long-term effectiveness and safety of orforglipron as well as the potential for ASCVD event risk reduction.
REFERENCES
Sloop KW, Cox AL, Wainscott DB, et al. The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron. Sci Transl Med. 2024;16(778):eadp5765. doi:10.1126/scitranslmed.adp5765
Yu M, Benjamin MM, Srinivasan S, et al. Battle of GLP-1 delivery technologies. Adv Drug Deliv Rev. 2018:130:113-130. doi:10.1016/j.addr.2018.07.009
Rosenstock J, Hsia S, Nevarez Ruiz L, et al; ACHIEVE-1 Trial Investigators. Orforglipron, an oral small-molecule GLP-1 receptor agonist, in early type 2 diabetes. N Engl J Med. 2025;393(11):1065-1076. doi:10.1056/NEJMoa2505669
Wharton S, Aronne LJ, Stefanski A, et al; ATTAIN-1 Trial Investigators. Orforglipron, an oral small-molecule GLP-1 receptor agonist for obesity treatment. N Engl J Med. 2025;393(18):1796-1806. doi:10.1056/NEJMoa2511774
