The first direct comparison of two oral GLP-1 routes
On 26 February 2026, The Lancet published ACHIEVE-3, the first Phase 3 trial to compare an oral non-peptide GLP-1 receptor agonist with an oral peptide GLP-1 receptor agonist head-to-head in type 2 diabetes. The trial randomised 1,698 adults whose diabetes was inadequately controlled on metformin to one of four once-daily arms: orforglipron 12 mg or 36 mg, or oral semaglutide 7 mg or 14 mg.
The two molecules reach the same receptor by different routes. Orforglipron is a small molecule that needs no absorption enhancer and carries no fasting or water-intake restrictions. Oral semaglutide is a peptide formulated with the enhancer SNAC and taken on an empty stomach. ACHIEVE-3 is the first randomised test of what those two delivery strategies produce in the clinic.
What the trial measured
The primary endpoint was change in HbA1c from baseline at 52 weeks, assessed as a non-inferiority comparison between the lower- and higher-dose arms. On the efficacy estimand, orforglipron 36 mg lowered HbA1c by 2.2 percentage points against 1.4 points for oral semaglutide 14 mg; orforglipron 12 mg lowered it by 1.9 points and oral semaglutide 7 mg by 1.1 points.
On weight, the efficacy estimand gave orforglipron 36 mg a 9.2% reduction from a baseline of 97.0 kg, against 5.3% for oral semaglutide 14 mg. The 12 mg and 7 mg arms reduced weight by 6.7% and 3.7% respectively. On the treatment-regimen estimand the pattern held with smaller margins.
Tolerability
Gastrointestinal adverse events, chiefly nausea and diarrhoea, were more frequent at the higher orforglipron doses, consistent with the GLP-1 class. Overall discontinuation rates sat within the range expected for incretin-based therapies, and the investigators reported no unexpected safety signals. These are trial observations reported as data, not guidance for use.
The UK position
The MHRA authorised orforglipron (Foundayo) on 10 August 2026 for weight management and type 2 diabetes. It is a prescription-only medicine and the first oral non-peptide GLP-1 licensed in Europe. A NICE appraisal for obesity is expected on 18 November 2026; a marketing authorisation is not an NHS commissioning decision, and the tablet is not currently available on the NHS. Oral semaglutide (Wegovy tablet) was authorised on 11 June 2026.
What the result does and does not show
ACHIEVE-3 shows that a non-peptide small molecule can match or exceed a peptide oral GLP-1 on glycaemic and weight endpoints at 52 weeks. It does not show long-term cardiovascular or renal outcomes, it does not compare either oral agent with the injectable GLP-1 and dual GIP/GLP-1 medicines, and it ran across sites in the United States, Argentina, China, Japan, Mexico and Puerto Rico rather than in a UK population.
The evidence grade for the specific 52-week HbA1c and weight comparisons is Strong: a large, randomised, actively controlled Phase 3 trial with published primary endpoints. That grade does not extend to outcomes the trial did not measure.
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