Oral Orforglipron Added to Basal Insulin Cuts HbA1c in Type 2 Diabetes

For adults with type 2 diabetes whose glycemic control remains inadequate despite basal insulin therapy, adding an oral glucagon-like peptide-1 (GLP-1) receptor agonist has long been an attractive but pharmacologically challenging option.¹ Orforglipron (Foundayo; Eli Lilly), a once-daily small-molecule, nonpeptide oral GLP-1 receptor agonist that can be taken without food or water restrictions, may help address that challenge. Results from the phase 3 ACHIEVE-5 (NCT06109311) randomized clinical trial, published in JAMA, showed that adding orforglipron to titrated insulin glargine significantly reduced hemoglobin A_1c (HbA_1c) across all doses while producing clinically meaningful weight loss despite ongoing basal insulin therapy.

The trial enrolled 546 adults with type 2 diabetes and inadequate blood sugar management on insulin glargine, with or without metformin and/or sodium-glucose cotransporter 2 inhibitors, at 72 sites across the US, Brazil, China, Japan, and Romania. Participants had a mean (SD) baseline HbA_1c of 8.5% (0.95%) and a median (IQR) diabetes duration of 14.6 (0.1-40.7) years, representing a population with longstanding, progressive disease. They were randomized 1:1:1:1 to orforglipron 3 mg, 12 mg, or 36 mg once daily, or placebo, on top of their existing background regimen.

HbA_1c Reductions Across All Doses

All 3 orforglipron doses met the primary end point of superiority in HbA_1c reduction from baseline to week 40 compared with placebo (estimated treatment differences: 3 mg once daily, −0.78% [95% CI, −1.02% to −0.55%]; 12 mg once daily, −1.08% [95% CI, −1.33% to −0.83%]; and 36 mg once daily, −1.03% [95% CI, −1.28% to −0.77%]; P < .001 for all). Mean HbA_1c reductions ranged from 1.54% to 2.05% with orforglipron compared with 0.77% with placebo. A significantly greater proportion of participants on orforglipron achieved HbA_1c targets of less than 7% compared with placebo.

“Orforglipron added to titrated insulin glargine resulted in superior reductions in HbA_1c across all doses compared with placebo, with clinically meaningful improvements across key secondary end points including body weight,” wrote the authors.

Body Weight and Metabolic Benefits

One of the most clinically notable findings was the reversal of basal insulin-associated body weight gain. Body weight decreased 2.7% to 6.1% with orforglipron across doses, compared with a 0.6% gain in the placebo group. Fasting serum glucose also declined significantly with orforglipron, and insulin glargine daily doses were reduced across orforglipron groups, suggesting that improved blood sugar management, rather than insulin intensification, drove the HbA_1c benefit.

“The combination of HbA_1c reduction and body weight decrease without additional insulin dose escalation represents a clinically important advantage, particularly for patients with long-standing type 2 diabetes on basal insulin who face the dual challenge of suboptimal blood sugar management and progressive weight burden,” wrote the authors.

Safety and Tolerability

The safety profile was consistent with the GLP-1 receptor agonist class. Gastrointestinal adverse events were more frequent with orforglipron and clustered during the dose-titration period. Hypoglycemia rates for level 2 events were broadly comparable between orforglipron and placebo groups. Three participants on orforglipron experienced severe hypoglycemia vs none on placebo, a finding that warrants continued monitoring. No clinically important new safety signals were identified.

Orforglipron and the Evolving Oral GLP-1 Landscape

ACHIEVE-5 adds to a rapidly expanding evidence base for orforglipron across the ACHIEVE phase 3 program, which has now enrolled more than 6000 adults with type 2 diabetes across 5 global registration trials. In the previously published ACHIEVE-3 trial, orforglipron demonstrated superiority over oral semaglutide in HbA_1c reduction at 52 weeks, with orforglipron 36 mg reducing HbA_1c by 1.91% vs 1.47% with oral semaglutide 14 mg while also producing substantially greater body weight reductions.²

A key differentiator for orforglipron compared with peptide-based oral semaglutide is its pharmacologic structure: As a small molecule, it does not require an absorption enhancer and can be taken without strict fasting requirements, potentially simplifying real-world administration for patients already managing a complex insulin regimen.

Implications for Practice

ACHIEVE-5 provides compelling evidence that orforglipron can meaningfully improve blood sugar management in a population with longstanding, insulin-requiring type 2 diabetes, a group that has historically had limited options for oral intensification without further weight gain.¹

References

1. Giorgino F, D’Souza S, Ludwig L, et al. Orforglipron added to titrated insulin glargine in type 2 diabetes: the ACHIEVE-5 randomized clinical trial. JAMA. Published online June 7, 2026. doi:10.1001/jama.2026.9512
2. Rosenstock J, Yabe D, Cox D, et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. Lancet. 2026;407(10534):1147-1160. doi:10.1016/S0140-6736(26)00202-3