Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial.
Orforglipron significantly improved HbA1c levels and body weight in adults with type 2 diabetes inadequately controlled by insulin glargine, without increasing hypoglycemia risk.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This study assessed the efficacy and safety of orforglipron added to insulin glargine in adults with type 2 diabetes. Participants received either 3 mg, 12 mg, or 36 mg of orforglipron or placebo for 40 weeks. The addition of orforglipron resulted in a greater reduction in HbA1c compared to placebo.
Abstract
<h4>Importance</h4>The effects of orforglipron, an oral, nonpeptide glucagon-like peptide 1 receptor agonist, added to insulin glargine for treatment of type 2 diabetes have not been described.<h4>Objective</h4>To assess efficacy and safety of orforglipron added to titrated insulin glargine in adults with type 2 diabetes and inadequate glycemic control.<h4>Design, setting, and participants</h4>Randomized, double-blind, phase 3 study conducted at 72 sites across the US, Brazil, China, Japan, and Romania between November 10, 2023, and September 15, 2025, in adults with type 2 diabetes taking insulin glargine with or without metformin and/or sodium-glucose cotransporter 2 inhibitors over 40 weeks.<h4>Interventions</h4>Participants were randomized (1:1:1:1) to receive once-daily 3-mg (n = 137), 12-mg (n = 132), or 36-mg (n = 136) dosages of orforglipron or placebo (n = 141), in addition to titrated insulin glargine.<h4>Main outcomes and measures</h4>The primary outcome was mean hemoglobin A1c (HbA1c) change from baseline to week 40 (for the 12-mg once daily and 36-mg once daily dosages of orforglipron). Key secondary outcomes were mean HbA1c change from baseline (for the 3-mg once daily dosage of orforglipron), proportion of participants achieving HbA1c targets of lower than 7.0% and 6.5% or lower, and mean body weight change and percentage change from baseline to week 40.<h4>Results</h4>Among 546 randomized participants (median age, 61.0 [IQR, 26-95] years; 52.9% male; median duration of type 2 diabetes, 14.6 [IQR, 0.1-40.7] years; mean HbA1c, 8.50% [SD, 0.95%]; mean body mass index, 30.8 [SD, 6.1]), 507 (92.9%) completed the trial. At week 40, the mean changes from baseline in HbA1c were -1.58%, -1.88%, and -1.82% with orforglipron, 3 mg, 12 mg, and 36 mg once daily, respectively, vs -0.79% with placebo. Each dosage of orforglipron was superior to 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%]; 36 mg once daily, -1.03% [95% CI, -1.28% to -0.77%]; P < .001 for all). All key secondary outcomes demonstrated statistically significant differences in favor of orforglipron compared with placebo. Mean percentage body weight change from baseline was -2.6%, -4.8%, and -5.4% with orforglipron, 3 mg once daily, 12 mg once daily, and 36 mg once daily, respectively, vs 0.2% with placebo. The most frequent adverse events with orforglipron were gastrointestinal (mild to moderate). Orforglipron did not increase the risk of clinically significant hypoglycemia vs placebo.<h4>Conclusions and relevance</h4>In participants with type 2 diabetes inadequately controlled by insulin glargine, addition of oral orforglipron significantly improved glycemic control and body weight, without increasing hypoglycemia risk, compared with placebo.<h4>Trial registration</h4>ClinicalTrials.gov Identifier: NCT06109311.
Background
This paper addresses the efficacy of orforglipron, a nonpeptide GLP-1 receptor agonist, when added to insulin glargine in adults with type 2 diabetes. Previous studies have primarily focused on peptide-based GLP-1 agonists, leaving a gap in understanding the effects of nonpeptide alternatives. The significance of this study lies in its potential to expand treatment options for individuals with inadequate glycemic control.
Methods
The study was a randomized, double-blind, phase 3 trial conducted at 72 sites across multiple countries. A total of 546 adults with type 2 diabetes inadequately controlled on insulin glargine were randomized to receive either 3 mg, 12 mg, or 36 mg of orforglipron or placebo for 40 weeks. The primary outcome was the change in HbA1c from baseline to week 40, while key secondary outcomes included body weight change and the proportion of participants achieving specific HbA1c targets.
Results
At week 40, the mean change in HbA1c was -1.58% for 3 mg, -1.88% for 12 mg, and -1.82% for 36 mg of orforglipron, compared to -0.79% with placebo. Each dosage of orforglipron showed statistically significant superiority over placebo (P < 0.001). Additionally, mean percentage body weight change was -2.6% for 3 mg, -4.8% for 12 mg, and -5.4% for 36 mg, compared to 0.2% with placebo.
Interpretation
The findings suggest that orforglipron significantly improves glycemic control compared to placebo, with all doses showing statistically significant reductions in HbA1c. However, the clinical significance of these reductions should be considered, especially since the effect sizes may not be large enough to warrant changes in practice for all patients. Limitations such as the relatively short duration and the specific population studied may affect the generalizability of the results.
Key findings
- -1.58%, -1.88%, and -1.82% HbA1c change with orforglipron 3 mg, 12 mg, and 36 mg respectively at week 40, n=546.
- -0.79% HbA1c change with placebo at week 40, n=546.
- Estimated treatment difference for 3 mg: -0.78% [95% CI, -1.02% to -0.55%]; for 12 mg: -1.08% [95% CI, -1.33% to -0.83%]; for 36 mg: -1.03% [95% CI, -1.28% to -0.77%]; P < 0.001 for all.
- Mean percentage body weight change was -2.6%, -4.8%, and -5.4% with orforglipron 3 mg, 12 mg, and 36 mg respectively vs 0.2% with placebo.
- 92.9% of participants completed the trial.
Limitations
- 40-week follow-up may not capture long-term effects.
- Population may not represent all individuals with type 2 diabetes.
- Study conducted across multiple countries but still limited in scope.
- Randomized trial but potential for unreported confounding factors.