ACHIEVE-5 is a phase 3, randomised, double-blind trial across 72 sites in the US, Brazil, China, Japan and Romania. It enrolled 546 adults with type 2 diabetes taking insulin glargine, with or without metformin and/or an SGLT2 inhibitor, whose control remained inadequate. Participants were randomised 1:1:1:1 to once-daily orforglipron 3 mg, 12 mg, 36 mg, or placebo, with glargine titrated throughout in every arm.
The population is recognisably a real clinic population rather than an idealised one: median age 61, median diabetes duration 14.6 years, mean HbA1c 8.50%, mean BMI 30.8. Retention was high, with 507 of 546 (92.9%) completing 40 weeks.
At week 40, mean HbA1c fell by 1.58%, 1.88% and 1.82% in the 3 mg, 12 mg and 36 mg arms against 0.79% with placebo, and every dose was superior to placebo. The reported estimated treatment difference for the lowest dose was -0.78% (95% CI -1.02% to -0.55%). Note that the benefit at 12 mg was not obviously greater than at 36 mg, which is worth watching as longer-term data arrive.
What makes this notable is not the magnitude, which is broadly what an added GLP-1 receptor agonist achieves, but the route. Intensifying beyond basal insulin has meant either prandial insulin, with its hypoglycaemia and weight penalties, or an injectable GLP-1. An oral option in that slot changes the conversation for patients who have already reached their tolerance for injections.
- 546 adults with type 2 diabetes on titrated glargine, 40 weeks, four arms
- HbA1c -1.58%/-1.88%/-1.82% (3/12/36 mg) vs -0.79% placebo, from 8.50% baseline
- All doses superior to placebo; 3 mg ETD -0.78% (95% CI -1.02 to -0.55)
- Glargine was titrated in all arms, so this is add-on, not insulin substitution
- First reported data for an oral GLP-1 receptor agonist added to basal insulin
The statistics, in plain English
Placebo patients improved by 0.79% because their insulin was being titrated too. So the fair comparison is the gap between groups, not the fall within them: roughly one extra percentage point of HbA1c attributable to the drug. The 95% CI of -1.02 to -0.55 for the lowest dose means the true added benefit is very unlikely to be smaller than about half a percentage point.
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