Orforglipron ACHIEVE-3 and ACHIEVE-4: oral GLP-1 agonist succeeds in type 2 diabetes

Eli Lilly has reported positive results from two Phase 3 trials evaluating its oral GLP-1 receptor agonist orforglipron in type 2 diabetes. The company stated that orforglipron demonstrated superior glycemic control in both ACHIEVE-3 and ACHIEVE-4, reconfirming its potential as a foundational treatment in type 2 diabetes management.

Context: a pivotal year for orforglipron

These results add to a remarkable 2025 for orforglipron. In the ACHIEVE-1 Phase 3 trial, published in the New England Journal of Medicine, orforglipron achieved up to 12.4% weight loss in adults with obesity. The FDA subsequently approved orforglipron under the brand name Foundayo for chronic weight management — the first oral GLP-1 agonist to receive such approval.

The ACHIEVE-3 and ACHIEVE-4 trials extend the evidence base into type 2 diabetes, where GLP-1 receptor agonists have long been a cornerstone of pharmacotherapy. If approved for this indication, orforglipron would offer the convenience of an oral tablet — a significant advantage over the injectable GLP-1 agonists currently dominating the market.

Why this matters for peptide researchers

Orforglipron is a synthetic peptide-based GLP-1 receptor agonist administered orally without the need for absorption enhancers — a formulation breakthrough that distinguishes it from earlier oral GLP-1 candidates such as rybelsus (oral semaglutide), which requires fasting and specific dosing conditions. The ACHIEVE programme demonstrates that this oral delivery approach can achieve clinically meaningful glycemic control across diverse patient populations.

For researchers tracking the GLP-1 pipeline, the ACHIEVE-3 and ACHIEVE-4 results reinforce that oral peptide therapeutics are reaching maturity. The shift from injectable to oral formulations could transform patient access and adherence, particularly in type 2 diabetes where long-term treatment persistence is a persistent challenge.

What is known and what remains to be seen

Lilly's press release confirmed that both trials met their primary endpoints, with orforglipron demonstrating superior glycemic control compared to comparators. Detailed results — including specific HbA1c reductions, body weight changes, and safety data — are expected to be presented at an upcoming medical congress and published in a peer-reviewed journal.

Researchers should note that while the topline results are promising, the full datasets will be critical for assessing:

  • Magnitude of HbA1c reduction relative to standard-of-care comparators
  • Safety profile, particularly gastrointestinal adverse events common to the GLP-1 class
  • Cardiovascular outcomes, increasingly expected for new T2D therapies
  • Durability of glycemic control over the full treatment period

UK implications

Orforglipron is not yet licensed in the UK for any indication. The MHRA approved Wegovy (semaglutide) for weight management and, more recently, for metabolic-associated steatohepatitis (MASH). Should orforglipron receive MHRA approval — whether for obesity, type 2 diabetes, or both — it would represent the first oral GLP-1 agonist available to UK patients for these conditions. NICE appraisal would follow to determine NHS access.

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Research use only

This article is for research and educational purposes only. Orforglipron is an investigational and newly approved therapeutic. It is not licensed as a research peptide for non-clinical use. Nothing in this article constitutes medical advice.

This article is AI-researched and editorially reviewed. It is provided for research and educational purposes only and is not medical advice. Research peptides are not licensed for human consumption in the UK.