Jul 09, 2025
At ADA 2025, Eli Lilly showcased promising Phase III data for orforglipron, a novel, oral, non-peptide GLP-1 receptor agonist, reinforcing its potential to transform the treatment paradigm for type 2 diabetes. With five ongoing studies in Type II diabetes (T2D) and two in obesity, the company aims to file for obesity approval by Q4 2025 and T2D in H1 2026.
ADA 2025 Coverage Abstract: Orforglipron Phase III Trial in Type 2 Diabetes
In the 40-week, double-blind, placebo-controlled Phase III ACHIEVE-1 trial, 559 adults with early-stage T2D (treated only with diet and exercise) were randomized to receive orforglipron at doses of 3 mg, 12 mg, or 36 mg, or placebo. The trial population had a mean baseline HbA1c of 8.0% and a mean duration of diabetes of 4.4 years, with 94.1% completing the trial. The primary endpoint—change in HbA1c from baseline to Week 40—was met across all doses. HbA1c reductions were –1.24% (3 mg), –1.47% (12 mg), and –1.48% (36 mg), compared to –0.41% with placebo. All differences were statistically significant (p<0.001), with final HbA1c levels ranging from 6.5% to 6.7%, suggesting strong glycemic control. Secondary endpoints showed dose-dependent reductions in body weight: –4.5% (3 mg), –5.8% (12 mg), and –7.6% (36 mg), versus –1.7% with placebo. Improvements were also observed in fasting serum glucose, triglycerides, and non-HDL cholesterol. Importantly, early glycemic improvements were evident as early as Week 4, supporting its suitability for early-stage intervention.
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Safety
Orforglipron exhibited a favorable safety profile consistent with the GLP-1 class. The most commonly reported adverse events were mild-to-moderate gastrointestinal symptoms, primarily during dose escalation. No severe hypoglycemia events were reported. Discontinuations due to adverse events ranged from 4.4% to 7.8% across orforglipron groups, compared to 1.4% in the placebo arm, suggesting overall good tolerability.
KOL Views
The rapid onset of glycemic control and the alignment of efficacy with leading injectable GLP-1 agents acts as key differentiators. The ability to deliver meaningful HbA1c and weight reductions in an oral formulation is seen as a significant step forward, particularly for patients hesitant or unable to use injectable therapies. – Expert Opinion
These are important results. Having new oral agents that lower glucose but also meaningfully lower weight well beyond levels seen with most existing diabetes therapies is critical to future T2D care. This is because recent research has shown excess weight not only leads to T2D in the first place in many but that is also a major contributor to many of its associated complications. – Expert Opinion
Conclusion
The Phase III results presented at ADA 2025 underscore orforglipron’s potential to become a disruptive force in the incretin-based therapy landscape. By delivering efficacy comparable to leading injectable GLP-1 receptor agonists—demonstrated by significant HbA1c and weight reductions—with the added convenience of oral administration, orforglipron directly addresses one of the major barriers to broader GLP-1 adoption: Patient reluctance toward injections. The early onset of action, dose-dependent metabolic benefits, and manageable safety profile reinforce its suitability for early intervention in T2D and possibly for prediabetic populations in the future.
From a market access and public health perspective, orforglipron offers the potential to democratize GLP-1 therapy, expanding its reach into primary care and geographies where cold-chain or injection training is impractical. With regulatory filings expected in obesity (Q4 2025) and T2D (H1 2026), orforglipron is poised to carve out a significant share in a rapidly expanding metabolic market, particularly as the demand for oral, scalable, and adherence-friendly therapies continues to accelerate. Its strong clinical profile not only solidifies Eli Lilly’s leadership in the incretin space but also broadens the competitive gap with peers lacking robust oral alternatives.
Article in PDF
Jul 09, 2025
At ADA 2025, Eli Lilly showcased promising Phase III data for orforglipron, a novel, oral, non-peptide GLP-1 receptor agonist, reinforcing its potential to transform the treatment paradigm for type 2 diabetes. With five ongoing studies in Type II diabetes (T2D) and two in obesity, the company aims to file for obesity approval by Q4 2025 and T2D in H1 2026.
ADA 2025 Coverage Abstract: Orforglipron Phase III Trial in Type 2 Diabetes
In the 40-week, double-blind, placebo-controlled Phase III ACHIEVE-1 trial, 559 adults with early-stage T2D (treated only with diet and exercise) were randomized to receive orforglipron at doses of 3 mg, 12 mg, or 36 mg, or placebo. The trial population had a mean baseline HbA1c of 8.0% and a mean duration of diabetes of 4.4 years, with 94.1% completing the trial. The primary endpoint—change in HbA1c from baseline to Week 40—was met across all doses. HbA1c reductions were –1.24% (3 mg), –1.47% (12 mg), and –1.48% (36 mg), compared to –0.41% with placebo. All differences were statistically significant (p<0.001), with final HbA1c levels ranging from 6.5% to 6.7%, suggesting strong glycemic control. Secondary endpoints showed dose-dependent reductions in body weight: –4.5% (3 mg), –5.8% (12 mg), and –7.6% (36 mg), versus –1.7% with placebo. Improvements were also observed in fasting serum glucose, triglycerides, and non-HDL cholesterol. Importantly, early glycemic improvements were evident as early as Week 4, supporting its suitability for early-stage intervention.
Safety
Orforglipron exhibited a favorable safety profile consistent with the GLP-1 class. The most commonly reported adverse events were mild-to-moderate gastrointestinal symptoms, primarily during dose escalation. No severe hypoglycemia events were reported. Discontinuations due to adverse events ranged from 4.4% to 7.8% across orforglipron groups, compared to 1.4% in the placebo arm, suggesting overall good tolerability.
KOL Views
The rapid onset of glycemic control and the alignment of efficacy with leading injectable GLP-1 agents acts as key differentiators. The ability to deliver meaningful HbA1c and weight reductions in an oral formulation is seen as a significant step forward, particularly for patients hesitant or unable to use injectable therapies. – Expert Opinion
These are important results. Having new oral agents that lower glucose but also meaningfully lower weight well beyond levels seen with most existing diabetes therapies is critical to future T2D care. This is because recent research has shown excess weight not only leads to T2D in the first place in many but that is also a major contributor to many of its associated complications. – Expert Opinion
Conclusion
The Phase III results presented at ADA 2025 underscore orforglipron’s potential to become a disruptive force in the incretin-based therapy landscape. By delivering efficacy comparable to leading injectable GLP-1 receptor agonists—demonstrated by significant HbA1c and weight reductions—with the added convenience of oral administration, orforglipron directly addresses one of the major barriers to broader GLP-1 adoption: Patient reluctance toward injections. The early onset of action, dose-dependent metabolic benefits, and manageable safety profile reinforce its suitability for early intervention in T2D and possibly for prediabetic populations in the future.
From a market access and public health perspective, orforglipron offers the potential to democratize GLP-1 therapy, expanding its reach into primary care and geographies where cold-chain or injection training is impractical. With regulatory filings expected in obesity (Q4 2025) and T2D (H1 2026), orforglipron is poised to carve out a significant share in a rapidly expanding metabolic market, particularly as the demand for oral, scalable, and adherence-friendly therapies continues to accelerate. Its strong clinical profile not only solidifies Eli Lilly’s leadership in the incretin space but also broadens the competitive gap with peers lacking robust oral alternatives.
