Lilly’s Orforglipron Beats Oral Semaglutide in Landmark Head-to-Head Phase 3 Trial

Lilly’s Orforglipron Beats Oral Semaglutide in Landmark Head-to-Head Phase 3 Trial

By, Admin 28 February 2026

Eli Lilly and Company has released detailed results from ACHIEVE-3, a pivotal Phase 3 study in type 2 diabetes. The trial directly compared two oral GLP-1 therapies for the first time. The results were published in The Lancet.

Why ACHIEVE-3 Matters?

ACHIEVE-3 is the first head-to-head Phase 3 trial comparing two oral GLP-1 receptor agonists.

Key context:

  • Adults with type 2 diabetes inadequately controlled on metformin
  • 52-week, randomized, open-label Phase 3 study
  • 1,698 participants across six countries

The goal was simple: Can Lilly’s oral GLP-1 outperform oral semaglutide on glycemic control and weight loss?

Trial Design at a Glance

Participants were randomized equally across four treatment arms:

  • Orforglipron 12 mg
  • Orforglipron 36 mg
  • Oral semaglutide 7 mg
  • Oral semaglutide 14 mg

All doses were escalated gradually using step-wise titration over four-week intervals.

Head-to-Head Results: Clear Separation

ACHIEVE-3 met its primary endpoint and went further. Orforglipron outperformed oral semaglutide across:

  • A1C reduction
  • Body-weight loss
  • All key secondary endpoints

Notably:

  • Improvements appeared as early as four weeks
  • Benefits were sustained through 52 weeks

“The differences were clinically meaningful,” said Dr. Julio Rosenstock, lead investigator from University of Texas Southwestern Medical Center.

Cardiometabolic Risk Factors Also Improved

Beyond glucose and weight, orforglipron delivered meaningful improvements from baseline in:

  • Non-HDL cholesterol
  • HDL cholesterol
  • VLDL cholesterol
  • Total cholesterol
  • Triglycerides
  • Systolic blood pressure

These findings strengthen its broader cardiometabolic profile.

Safety and Tolerability Snapshot

The overall safety profile was consistent with prior studies.

Most common adverse events (both drugs):

  • Nausea
  • Diarrhoea
  • Vomiting
  • Dyspepsia
  • Decreased appetite

Discontinuation due to adverse events:

  • Orforglipron: 8.7% (12 mg), 9.7% (36 mg)
  • Oral semaglutide: 4.5% (7 mg), 4.9% (14 mg)

A Key Differentiator: No Food or Water Restrictions

One of orforglipron’s most practical advantages stands out.

  • Once-daily oral dosing
  • Can be taken any time of day
  • No food or water timing restrictions

For long-term diabetes management, convenience can influence adherence.

Regulatory Progress and What’s Next?

Lilly has already submitted orforglipron to regulators in over 40 countries.

  • Potential US FDA action for obesity: Q2 2026
  • Global Phase 3 diabetes program: over 6,000 patients enrolled
  • Remaining registrational trial results expected later this year

About Orforglipron

Orforglipron is a non-peptide, small-molecule oral GLP-1 receptor agonist. Key background:

  • Discovered by Chugai Pharmaceutical Co., Ltd.
  • Licensed by Lilly in 2018
  • Designed for once-daily oral use without intake restrictions

Beyond diabetes, it is also being studied in:

  • Obesity and overweight
  • Obstructive sleep apnea
  • Hypertension in adults with obesity

Bottom Line

ACHIEVE-3 positions orforglipron as a strong next-generation oral GLP-1 candidate. Greater A1C reduction, more weight loss, and simpler dosing may reshape oral GLP-1 therapy. For patients and clinicians, those differences could matter every day.

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