Daily treatment with oral orforglipron, when added to titrated insulin glargine, has been shown to be beneficial in individuals with inadequately controlled type 2 diabetes (T2D) in the phase 3 ACHIEVE-5 trial.
Over 40 weeks of treatment, mean HbA1c levels decreased by 1.58 percent, 1.88 percent, and 1.82 percent with orforglipron 3 mg, 12 mg, and 36 mg, respectively, as opposed to 0.79 percent with placebo. [JAMA 2026;doi:10.1001/jama.2026.9512]
Orforglipron was also associated with substantial weight loss, with mean body weight percentage reductions of 2.6 percent with the 3-mg dose, 4.8 percent with the 12-mg dose, and 5.4 percent with the 36-mg dose vs an increase of 0.2 percent with placebo.
Each dose of orforglipron was superior to placebo in terms of improving glucose control (p<0.001 for all) and reducing body weight (p<0.001 for all), without increased hypoglycaemia risk, reported first study author Dr Francesco Giorgino from the University of Bari Aldo Moro, Bari, Italy, and colleagues in their paper.
The overall rates of clinically significant hypoglycaemia across the orforglipron groups were below 1 event per patient-year and generally similar or lower relative to that in the placebo group. “This finding is clinically relevant given that 18 percent of participants achieved near normoglycemia with the highest dose of orforglipron (HbA1c <5.7 percent),” Giorgino and colleagues noted.
Severe hypoglycaemia occurred in 1.5 percent of participants who received 12-mg once daily orforglipron and in 0.7 percent of those who received the 36-mg dose.
“For individuals with T2D treated with basal insulin therapy, adding a GLP-1 receptor agonist is an effective strategy to improve glycaemic control, reduce body weight, and minimize hypoglycaemia risk compared with intensification with basal insulin alone,” the authors said. “While basal insulin therapy is a potent treatment option, the fear of hypoglycaemia and weight gain can limit its intensification, preventing patients from achieving their glycaemic goals.”
ACHIEVE-5 provides the first evidence on the efficacy and safety of an oral nonpeptide GLP-1 receptor agonist in combination with a basal insulin regimen in adults with T2D, they said.
ACHIEVE-5
The global phase 3 study was conducted at 72 sites across the US, Brazil, China, Japan, and Romania. It involved adults with T2D who had a baseline HbA1c of between 7 percent and 10.5 percent, BMI of at least 23 kg/m2, and receiving a stable dose of insulin glargine (≥20 IU per day) with or without metformin and/or SGLT-2 inhibitors.
A total of 546 participants (median age 61 years, 52.9 percent male, 25.6 percent Asian, mean HbA1c 8.5 percent, mean BMI 30.8 kg/m2) were randomly assigned to receive orforglipron at 3 mg (n=137), 12 mg (n=132), or 36 mg (n=136) or placebo (n=141) in addition to titrated insulin glargine. Treatment was administered orally, once daily for 40 weeks, followed by a 2-week safety follow-up period.
A total of 507 participants (92.9 percent) completed the trial. Results for other outcomes assessed in the study also favoured orforglipron vs placebo.
At week 40, significantly more participants in the 3-, 12-, and 36-mg orforglipron groups than in the placebo group achieved the HbA1c targets of <7 percent (57 percent, 70 percent, and 65 percent, respectively vs 25 percent; p<0.001 for all) and ≤6.5 percent (43 percent, 60 percent, and 55 percent, respectively, vs 12 percent; p<0.001).
Similarly, a higher percentage of participants treated with orforglipron vs placebo achieved body weight reductions of ≥5 percent (from 30 percent to 48 percent vs 16 percent), ≥10 percent (from 12 percent to 24 percent vs 5 percent), and ≥15 percent (from 4 percent to 12 percent vs 3 percent).
Mean fasting serum glucose decreased by 40, 44.8, and 41.5 mg/dL with orforglipron 3, 12, and 36 mg, respectively, vs 33.5 mg/dL with placebo. Between 48 percent and 60 percent of orforglipron-treated participants achieved the fasting serum glucose goal of <100 mg/dL vs 42 percent of those on placebo.
By week 40, mean daily insulin doses had been titrated to 0.54, 0.58, and 0.58 IU/kg in the orforglipron 3-, 12-, and 36-mg groups, respectively, vs 0.67 IU/kg in the placebo group.
The most common treatment-emergent adverse events (TEAEs) reported in orforglipron-treated participants were gastrointestinal in nature, mostly mild to moderate in severity. TEAEs led to treatment discontinuations in 3.6 percent to 9.6 percent of participants across the orforglipron groups vs 3.6 percent in the placebo group.
Serious adverse events occurred in 5.1 percent in the 3-mg orforglipron group, 6.8 percent in the 12-mg group, 7.4 percent in the 36-mg group, and 4.3 percent in the placebo group. One sudden death not considered related to the study drug was documented in the 36-mg orforglipron group.
The findings from ACHIEVE-5 … “add to the growing literature reporting beneficial effects of incretin-based therapies in reducing adiposity and associated metabolic disorders. These reports are welcome additions, filling in therapeutic knowledge gaps in the management of obesity and T2D in special patient populations,” wrote Drs Kishore Gadde and Jonanne Talebloo from the University of California Irvine School of Medicine, Orange, California, and Dr Steven Heymsfield from Pennington Biomedical Research Center, Baton Rouge, Louisiana, in an accompanying editorial. [JAMA 2026;doi:10.1001/jama.2026.10443]
“There are years of future potential advances to look forward to in the rapidly developing area of pharmacotherapy of metabolic disorders,” they added.
Giorgino presented ACHIEVE-5 at the annual ADA meeting.