ACHIEVE-5 reports orforglipron improves A1C and weight on top of basal insulin

Results from the Phase 3 ACHIEVE-5 trial, published in JAMA, show that adding once-daily oral orforglipron to titrated insulin glargine improved blood sugar control and reduced body weight in adults with type 2 diabetes that was not well controlled on basal insulin alone ^[1]. The trial reported no increase in clinically significant low blood sugar compared with placebo ^[1].

Orforglipron is an oral, nonpeptide GLP-1 receptor agonist being studied for type 2 diabetes ^[1]. Unlike semaglutide and tirzepatide, which are peptides given by injection (semaglutide is also sold as the oral tablet Rybelsus), orforglipron is a small molecule taken as a daily pill. Until now, evidence for orforglipron in people already on basal insulin has been limited, even though that is a common point in diabetes care where doctors consider adding a GLP-1 drug ^[1].

What the trial tested

ACHIEVE-5 was a randomized, double-blind, placebo-controlled trial run at 72 centers in the United States, Brazil, China, Japan and Romania between November 2023 and September 2025 ^[1]. It enrolled 546 adults with inadequately controlled type 2 diabetes who were taking insulin glargine, with or without metformin and/or SGLT-2 inhibitors ^[1]. Participants were assigned to once-daily oral orforglipron at 3 mg, 12 mg or 36 mg, or to placebo, on top of titrated insulin glargine, for 40 weeks ^[1].

The group was not newly diagnosed. Median age was 61 years, median diabetes duration was 14.6 years, mean HbA1c was 8.5% and mean body mass index was 30.8 kg/m² ^[1]. Nearly all participants — 92.9% — finished the trial ^[1]. The study was led by Francesco Giorgino of the University of Bari Aldo Moro in Italy, with an international research team ^[1].

The numbers

At 40 weeks, HbA1c fell by 1.58%, 1.88% and 1.82% with the 3 mg, 12 mg and 36 mg doses, compared with 0.79% with placebo ^[1]. All three doses produced significantly greater A1C reductions than placebo, and people on orforglipron were significantly more likely to reach recommended A1C targets ^[1].

Body weight dropped by an average of 2.6%, 4.8% and 5.4% across the three doses, while the placebo group gained 0.2% ^[1]. That contrast matters because insulin itself often adds weight.

Gastrointestinal side effects — mostly mild to moderate — were the most commonly reported problems, a pattern familiar from other GLP-1 drugs ^[1]. Orforglipron did not increase the risk of clinically significant hypoglycemia compared with placebo ^[1].

The investigators listed several limitations. The standardized insulin titration protocol may not match routine practice or other insulin regimens; the 40-week duration was relatively short; adjustments to background insulin may have influenced the results; and continuous glucose monitoring was not used ^[1].

Why it matters for patients

Many people with long-standing type 2 diabetes end up on basal insulin and still miss their A1C goals. Today, the usual next step often involves an injectable GLP-1 medicine. ACHIEVE-5 tested whether a daily pill can do that job in the same setting, and the trial reported both better glucose control and weight loss without a rise in serious low blood sugar ^[1].

For people who are reluctant to add a second injection, or who have trouble storing and handling injectable products, an oral option in this specific situation could change the conversation with a clinician. The trade-offs seen here were stomach-related side effects, which were mostly mild to moderate ^[1].

It is also worth noting what the trial did not address. Results beyond 40 weeks, effects on heart or kidney outcomes, and how orforglipron compares head-to-head with injectable GLP-1 drugs in insulin users were not part of this report ^[1].

What happens next

ACHIEVE-5 adds to the evidence base for orforglipron in type 2 diabetes. US approval status, launch timing, pricing and insurance coverage for the medicine have not been reported here, and no dosing guidance for patients follows from these findings — those decisions rest with regulators and prescribing clinicians.