Lilly’s Oral GLP-1, Orforglipron, Achieves Superior Glycemic Control and Weight Loss in Head-to-Head Phase 3 Trials

Eli Lilly and Company announced positive topline results from two pivotal Phase 3 trials, ACHIEVE-2 and ACHIEVE-5, for its investigational oral medication, orforglipron. The drug is a once-daily, non-peptide oral glucagon-like peptide-1 (GLP-1) receptor agonist.

In both studies, all tested doses of orforglipron (3 mg, 12 mg, and 36 mg) successfully met the primary and all key secondary endpoints at 40 weeks, demonstrating significant A1C reduction, meaningful weight loss, and improvements in multiple cardiovascular risk factors.

This adds to previous findings from the ACHIEVE-3 trial, where orforglipron showed greater efficacy than oral semaglutide.

“Orforglipron has now demonstrated superiority over two active comparators in clinical trials for type 2 diabetes,” said Jeff Emmick, M.D., Ph.D., senior vice president of product development, Lilly Cardiometabolic Health.

Key Trial Results

The two trials confirmed orforglipron’s potential to become a foundational treatment for Type 2 Diabetes (T2D) across various treatment settings:

1. ACHIEVE-2 (Orforglipron vs. Dapagliflozin)

Trial Design: A head-to-head comparison against dapagliflozin ($10 \text{ mg}$), a widely used SGLT-2 inhibitor, in T2D adults inadequately controlled on metformin.
Outcome: Orforglipron demonstrated superiority to dapagliflozin in A1C reduction.
- Highest dose (36 mg) reduced A1C by up to $-1.7\%$ (efficacy estimand), compared to $-0.8\%$ with dapagliflozin.
- This superior performance over an SGLT-2 inhibitor reinforces its potential as a compelling alternative treatment.

2. ACHIEVE-5 (Orforglipron with Basal Insulin)

Trial Design: Assessed orforglipron versus placebo in adults with T2D and inadequate glycemic control while on titrated insulin glargine (basal insulin), with or without other background therapies.
Outcome: Orforglipron showed superior efficacy when used as an add-on therapy.
- Highest dose (12 mg) reduced A1C by an additional $-2.1\%$ (efficacy estimand), compared to $-0.8\%$ with placebo (both groups receiving titrated insulin).
- This finding confirms significant A1C reduction and weight loss when combined with titrated basal insulin.

Statistical Significance: All doses of orforglipron achieved statistical significance versus the comparator/placebo (p<0.001) for both A1C reduction and weight loss.

Safety Profile and Regulatory Timeline

Safety & Tolerability: The overall safety profile was consistent with previous studies. The most common adverse events were gastrointestinal-related (e.g., nausea, vomiting, diarrhea) and generally mild-to-moderate in severity. No hepatic safety signal was observed.
Convenience: Orforglipron is notable for its convenience as an oral, non-peptide GLP-1 RA that can be taken any time of the day without restrictions on food and water intake, unlike some other oral GLP-1 drugs.
Next Steps:
- The final global registration trial, ACHIEVE-4, expects results in the first quarter of 2026.
- Lilly plans to submit orforglipron for the obesity indication to global regulatory agencies by the end of 2025.
- Regulatory submission for the T2D treatment is planned for 2026.