Orforglipron plus basal insulin cut A1C and weight in ACHIEVE-5 Phase 3 trial
Orforglipron, an experimental once-daily pill, improved blood sugar and weight when added to basal insulin in a Phase 3 trial, though it is not described as approved for type 2 diabetes.
Adults with type 2 diabetes that was not well controlled on insulin glargine had larger drops in A1C and lost more weight when they added once-daily oral orforglipron than when they added a placebo, according to Phase 3 results published in JAMA [1].
The trial, called ACHIEVE-5, enrolled 546 adults at 72 centers in the United States, Brazil, China, Japan and Romania between November 2023 and September 2025. It was randomized, double-blind and placebo-controlled. Participants took orforglipron at 3 mg, 12 mg or 36 mg once a day, or a placebo, on top of titrated insulin glargine, for 40 weeks. They could also be taking metformin, an SGLT-2 inhibitor, or both [1].
At the start, the median age was 61, the median duration of diabetes was 14.6 years, the average A1C was 8.5% and the average body mass index was 30.8. About 93% of participants completed the trial [1].
What the trial found
At 40 weeks, A1C fell by 1.58%, 1.88% and 1.82% at the 3 mg, 12 mg and 36 mg doses, compared with 0.79% in the placebo group. All three doses produced significantly greater reductions than placebo, and people taking orforglipron were significantly more likely to reach recommended A1C targets than those taking placebo [1].
Body weight fell by 2.6%, 4.8% and 5.4% at the three doses, while the placebo group gained 0.2%. The report gives weight change as percentages and does not state the changes in pounds or kilograms [1].
Gastrointestinal side effects were the most commonly reported and were mostly mild to moderate. Clinically significant hypoglycemia was no more common with orforglipron than with placebo [1].
The investigators listed several limits. The standardized insulin titration protocol used in the trial may not reflect routine clinical practice or other insulin regimens. Forty weeks is relatively short. Adjustments to background insulin may have influenced the results, and the trial did not use continuous glucose monitoring [1]. The study was led by Francesco Giorgino of the University of Bari Aldo Moro in Italy [1].
Orforglipron is an oral, nonpeptide GLP-1 receptor agonist being investigated for type 2 diabetes. The report describes injectable GLP-1 receptor agonists as well established, but says evidence for an oral GLP-1 in people already taking basal insulin had been limited [1].
Why it matters for patients
Most GLP-1 medicines used for diabetes and weight are given by injection. This trial tested a once-daily pill in people who were already using basal insulin, a group that often has had type 2 diabetes for many years [1].
The study added orforglipron on top of insulin rather than replacing it. Whether the drug could reduce how much insulin someone needs has not been reported from this trial [1].
The blood sugar effect was largest at the two higher doses, which were similar to each other, and smallest at 3 mg. The difference from placebo was roughly 0.8 to 1.1 percentage points at 40 weeks [1].
For people using insulin, the hypoglycemia finding is notable: the trial found no increase in clinically significant low blood sugar compared with placebo. That finding comes from a trial that used a set insulin titration schedule, which the investigators said may not match routine practice [1].
Gastrointestinal side effects were the most common problem reported, which is consistent with how this drug class is described in the report [1].
Several practical questions are not answered in the report. It does not say whether orforglipron has been approved for type 2 diabetes, what it would cost, or whether insurers would cover it. It also does not report how the drug compares head-to-head with injectable GLP-1 medicines, or what happens beyond 40 weeks [1].
What happens next
The report does not include a filing date or an expected FDA decision date for a type 2 diabetes indication, and no such timeline has been reported [1]. The concrete dates in the record are the trial's enrollment window, November 2023 to September 2025, and publication of the results in JAMA, where the study appears as JAMA 2026;336(5):389-399 [1].
Longer-term safety and whether the weight and blood sugar changes persist after 40 weeks have not been reported [1].
Sources
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