Orforglipron Demonstrates Sustained Glycemic Control, Weight Loss in Phase 3 ACHIEVE-4 Trial

Orforglipron, an investigational once-daily oral glucagon-like peptide-1 (GLP-1) receptor agonist, demonstrated sustained glycemic control and weight reduction in the phase 3 ACHIEVE-4 trial (NCT05803421)—the longest study of the agent in patients with type 2 diabetes (T2D) to date—according to a news release from Eli Lilly and Company. The top-line results further position oral GLP-1 therapies as a potentially durable and patient-preferred alternative to injectable agents in T2D management.¹

ACHIEVE-4 evaluated the long-term efficacy and safety of orforglipron in adults with T2D, reinforcing prior results from the broader ACHIEVE program, which has enrolled more than 6000 participants globally. The extended duration of ACHIEVE-4 provides important insight into durability of response, a key consideration for chronic disease management and medication adherence.^1,2

Durable Glycemic Control Observed Over Extended Follow-Up

In ACHIEVE-4, orforglipron met the primary end point by demonstrating a noninferior risk of major adverse cardiovascular events, including cardiovascular death, heart attack, stroke, or hospitalization for sudden chest pain, compared with insulin glargine (HR, 0.84; 95% CI, 0.59-1.20; P = .336). Orforglipron also demonstrated clinically meaningful and sustained reductions in hemoglobin A_1c (HbA_1c) over the study period (–1.6% vs –1.0%; estimated treatment difference: –0.66; 95% CI, –0.74 to –0.58; P < .001). These findings build on earlier phase 3 trials in the ACHIEVE program, where HbA_1c reductions of up to approximately 2.2% have been reported, depending on dose and comparator.^1,3

Long-term glycemic durability is critical in T2D, where progressive beta cell dysfunction often necessitates treatment intensification. The sustained HbA_1c reductions observed with orforglipron suggest the therapy may delay the need for escalation to more complex regimens, such as insulin.¹

For pharmacists, these findings highlight the importance of monitoring longitudinal glycemic trends and supporting adherence to therapies that demonstrate durable efficacy. Oral administration may reduce barriers associated with injectable therapies, including needle aversion and complex administration requirements.

Clinically Meaningful Weight Reduction Maintained

Consistent with the GLP-1 receptor agonist class, orforglipron also demonstrated sustained weight loss in ACHIEVE-4 (–8.8%) compared with insulin glargine (estimated treatment difference: –10.42%; 95% CI, –10.92 to –9.93]; P < .001). Prior studies in the program have shown weight reductions exceeding 10% at higher doses, with some trials reporting average losses of approximately 12% over extended follow-up.^1,4

Weight management remains a cornerstone of T2D care, with modest reductions associated with improved glycemic control, cardiovascular risk factors, and overall metabolic health. The durability of weight loss observed in ACHIEVE-4 reinforces the potential role of orforglipron as a dual-purpose therapy targeting hyperglycemia and obesity.¹

Pharmacists are uniquely positioned to counsel patients on lifestyle modifications alongside pharmacotherapy, ensuring that weight loss benefits are maximized and sustained in real-world settings.

Safety Profile Consistent With GLP-1 Class

The safety profile of orforglipron in ACHIEVE-4 was consistent with previous studies and with the established GLP-1 receptor agonist class. Gastrointestinal (GI) adverse events (AEs), including nausea and diarrhea, were the most reported AEs, generally occurring during dose escalation and diminishing over time. Notably, the trial included a thorough analysis of the possibility of drug-induced liver injury, and investigators confirmed there was no hepatic safety signal.¹

Importantly, no new safety signals were identified in the extended-duration study. This is particularly relevant for chronic therapies intended for long-term use, where cumulative safety data are essential for clinical decision-making. Pharmacists play a critical role in mitigating GI AEs through patient education on dose titration, administration timing, and expectations for tolerability. Proactive counseling may improve persistence and reduce discontinuation rates.

Expanding Role of Oral GLP-1 Therapies in Diabetes Care

Orforglipron is a nonpeptide, small-molecule GLP-1 receptor agonist designed for oral administration without food or water restrictions, distinguishing it from earlier oral GLP-1 agents. This added convenience may improve adherence and broaden access to GLP-1–based therapies, particularly among patients who are unwilling or unable to use injectables.^1,5

The growing body of evidence supporting oral GLP-1 therapies aligns with evolving treatment guidelines emphasizing individualized care, weight management, and cardiovascular risk reduction in T2D. As more oral agents like orforglipron are approved by the FDA, the agents may shift treatment paradigms, particularly in earlier lines of therapy.⁶

For pharmacists, the introduction of effective oral GLP-1 options underscores the need for comprehensive medication management, including formulary navigation, adherence support, and patient education. Pharmacists can also play a key role in identifying appropriate candidates for therapy based on clinical characteristics, comorbidities, and patient preferences.

As oral GLP-1 therapies continue to evolve, pharmacists will remain central to optimizing outcomes—bridging clinical evidence with real-world application, improving adherence, and ensuring patients derive maximum benefit from these emerging treatment options.

REFERENCES

1. ACHIEVE-4, the longest phase 3 study of Lilly's Foundayo (orforglipron) to date, reaffirmed its cardiovascular and overall safety profile as well as consistent improvements across key measures of cardiometabolic health. News release. Eli Lilly and Company. April 16, 2026. Accessed April 16, 2026. https://investor.lilly.com/news-releases/news-release-details/achieve-4-longest-phase-3-study-lillys-foundayo-orforglipron

2. Lilly's oral GLP-1, orforglipron, showed compelling efficacy and a safety profile consistent with injectable GLP-1 medicines, in complete phase 3 results published in the New England Journal of Medicine. News release. Eli Lilly and Company. June 21, 2025. Accessed April 16, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-showed-compelling-efficacy-and?utm

3. Halpern L. Orforglipron outperforms oral semaglutide in head-to-head T2D trial. Pharmacy Times. February 26, 2026. Accessed April 16, 2026. https://www.pharmacytimes.com/view/orforglipron-outperforms-oral-semaglutide-in-head-to-head-t2d-trial

4. Lilly's oral GLP-1, orforglipron, demonstrated meaningful weight loss and cardiometabolic improvements in complete ATTAIN-1 results published in the New England Journal of Medicine. News release. Eli Lilly and Company. September 16, 2025. Accessed April 16, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-meaningful-weight?utm

5. Rosenstock J, Hsia S, Ruiz LN, et al. 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

6. McGovern G. FDA approves orforglipron, first GLP-1 pill without time, food, or water restrictions. Pharmacy Times. April 1, 2026. Accessed April 16, 2026. https://www.pharmacytimes.com/view/fda-approves-orforglipron-first-glp-1-pill-without-time-food-or-water-restrictions