Orforglipron, an oral non‐peptide glucagon‐like peptide‐1 receptor agonist, improves markers of β‐cell function and insulin sensitivity in type 2 diabetes

Aug 14, 2025Diabetes, obesity & metabolism

Orforglipron, an oral drug that activates blood sugar control receptors, improves insulin-producing cell function and insulin sensitivity in type 2 diabetes

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Abstract

Orforglipron doses of 12 mg and higher were associated with increases in β-cell function by up to 132% from baseline.

HOMA-B, a measure of β-cell function, significantly improved with orforglipron compared to dulaglutide.
Fasting proinsulin and the proinsulin/insulin ratio improved with orforglipron doses of 12 mg and higher.
HOMA-IR, an indicator of insulin resistance, decreased by up to 23% with orforglipron treatment.
Biomarkers related to insulin sensitivity, such as IGFBP-2 and adiponectin, generally showed improvement with orforglipron.
Improvements in metabolic biomarkers suggest enhanced pancreatic function and insulin sensitivity in participants with type 2 diabetes.

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AIMS: These participant-level exploratory analyses evaluated the effects of orforglipron, a once-daily, orally administered non-peptide glucagon-like peptide-1 receptor agonist, versus dulaglutide and placebo, on β-cell function and insulin sensitivity biomarkers.

MATERIALS AND METHODS: Participants (N = 378) in this 26-week phase 2 study with inadequately controlled type 2 diabetes (T2D) were randomly assigned to orforglipron (3, 12, 24, 36, or 45 mg), dulaglutide (1.5 mg), or placebo. Treatment effects on β-cell function and insulin sensitivity markers were assessed, including homeostatic model assessment indices of β-cell function and insulin resistance (HOMA-B and HOMA-IR, respectively); fasting C-peptide, insulin, serum glucose, and glucagon; adiponectin; insulin-like growth factor binding protein 2; proinsulin; and the proinsulin/insulin ratio.

RESULTS: Orforglipron doses of 12 mg and higher were associated with improved β-cell function and insulin sensitivity. HOMA-B increased up to 123% (C-peptide) and 132% (insulin) with orforglipron doses of 12 mg and higher from baseline to week 4 before stabilising. HOMA-B increases were greater with all orforglipron doses than with dulaglutide. Additional β-cell function biomarkers, such as fasting proinsulin and the proinsulin/insulin ratio, also improved with orforglipron doses of 12 mg and higher compared with baseline and to a greater extent than seen with dulaglutide. HOMA-IR values decreased up to 16% (C-peptide) and 23% (insulin) with orforglipron by week 26. Reductions in HOMA-IR (insulin) were significant versus baseline only for the highest dose. IGFBP-2 and adiponectin, corollary biomarkers of insulin sensitivity, were generally improved with orforglipron.

CONCLUSIONS: Increased HOMA-B and improved metabolic biomarkers suggest that treatment with the orally administered non-peptide GLP-1 receptor agonist orforglipron enhanced pancreatic β-cell function and insulin sensitivity in patients with T2D.

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Orforglipron, an oral non‐peptide glucagon‐like peptide‐1 receptor agonist, improves markers of β‐cell function and insulin sensitivity in type 2 diabetes

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