Eli Lilly and Co (NYSE:LLY) said on Thursday that its oral GLP-1 therapy orforglipron demonstrated superior efficacy versus oral semaglutide in a Type 2 diabetes clinical trial.
The head-to-head ACHIEVE-3 trial tested orforglipron against oral semaglutide and found that orforglipron met the primary endpoint and all key secondary endpoints with better outcomes across the board.
Primary and secondary outcomes
For the trial's primary endpoint, participants receiving orforglipron 36 mg experienced an average A1C reduction of 2.2 percentage points, compared with a 1.4 percentage-point reduction among those taking oral semaglutide 14 mg. In a key secondary measure focused on body weight, subjects on orforglipron 36 mg lost an average of 19.7 pounds, equal to a 9.2% reduction from baseline, while those on oral semaglutide 14 mg lost 11.0 pounds, or 5.3%.
The company also reported that orforglipron produced clinically meaningful improvements from baseline in several key cardiovascular risk factors, though the announcement did not provide further numeric detail on those measures.
Safety and tolerability
Treatment discontinuations due to adverse events occurred at a higher rate with orforglipron 36 mg than with oral semaglutide 14 mg. Specifically, 9.7% of patients on orforglipron discontinued because of adverse events compared with 4.9% of those receiving oral semaglutide.
Regulatory status
Lilly said it has submitted regulatory applications for orforglipron in more than 40 countries. The company also indicated there is a potential regulatory action in the United States for an obesity indication expected in the second quarter of 2026.
Clear summary
- In ACHIEVE-3, orforglipron 36 mg lowered A1C by 2.2% versus 1.4% for oral semaglutide 14 mg and produced greater mean weight loss (19.7 pounds, or 9.2%, versus 11.0 pounds, or 5.3%).
- Orforglipron showed clinically meaningful improvements from baseline in key cardiovascular risk factors, according to the company.
- Treatment discontinuation due to adverse events was higher with orforglipron (9.7%) than with oral semaglutide (4.9%).
- Lilly has filed orforglipron with regulators in over 40 countries and expects potential U.S. action for an obesity indication in Q2 2026.
Key points
- Clinical efficacy - Orforglipron achieved superior reductions in both A1C and body weight compared with oral semaglutide in the ACHIEVE-3 trial.
- Safety profile - The trial reported a higher rate of discontinuation due to adverse events for orforglipron versus oral semaglutide.
- Market and regulatory progress - Regulatory submissions have been made in more than 40 countries, with a potential U.S. regulatory action for obesity expected in the second quarter of 2026.
Risks and uncertainties
- Safety discontinuations - A higher discontinuation rate for orforglipron due to adverse events (9.7% versus 4.9%) may affect tolerability perceptions among prescribers and patients; this has implications for the pharmaceutical and broader healthcare sectors.
- Regulatory timing and outcomes - While submissions have been filed in over 40 countries, the timing and outcome of regulatory reviews, including the potential U.S. action in Q2 2026, remain subject to regulatory decisions.
- Limited detail on cardiovascular measures - The company stated orforglipron produced clinically meaningful improvements in key cardiovascular risk factors but did not provide detailed numerical results in the announcement, leaving scope for further scrutiny by clinicians and regulators.
Sectors potentially affected
- Healthcare and pharmaceuticals - Clinical trial results and regulatory progress are directly relevant to drug developers, payers, and providers focused on diabetes and obesity treatments.
- Biotech - Competitive dynamics in GLP-1 therapies and related innovation could influence valuations and strategy within the biotech industry.