Diabetes therapy : research, treatment and education of diabetes and related disordersFeb 24, 2024

How Eating Food Affects the Absorption, Safety, and Tolerance of Once-Daily Orforglipron, a Non-Peptide GLP-1 Receptor Activator

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Apr 5, 2026

Abstract

and maximum drug concentration were lower by 23.7% and 23.2% in the fed state compared to the fasted state in study A.

In study A, 12 healthy adults received a single 3 mg dose of orforglipron, while study B involved 34 participants who received multiple 16 mg doses.
Both studies showed that pharmacokinetic measures, such as AUC and maximum concentration, decreased when participants were fed compared to when they were fasted.
The reductions in AUC and maximum concentration in study B were 17.6% and 20.9%, respectively, indicating a similar trend to study A.
Half-lives of the drug were comparable between fed and fasted states in both studies.
Gastrointestinal-related conditions were the most common treatment-emergent adverse events, with no serious adverse events or deaths reported.

Simplified

INTRODUCTION: We assessed the effect of the prandial state on the pharmacokinetics, safety, and tolerability of single and multiple doses of orforglipron (LY3502970), an oral, non-peptide glucagon-like peptide 1 receptor agonist (GLP-1 RA), in two studies (A and B).

METHODS: Study A and study B were phase 1, randomized, crossover studies in healthy adults aged 18-65 years and 21-70 years, respectively. Participants received single (3 mg, study A) or multiple (16 mg, study B) oral doses of orforglipron under fasted and fed conditions. Blood samples were collected pre- and postdose to assess area under the concentration-time curve (), maximum observed drug concentration (C), time of C(t), and half-life (t) associated with terminal rate constant. AUC and Cwere analyzed using a linear mixed-effects model. Treatment differences were presented as ratios of geometric least squares means (GLSM). Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse events were assessed. max max max1/2max

RESULTS: Study A included 12 participants (mean age 45.0 years; male 66.7%); study B included 34 participants (mean age 42.8 years; male 88.2%). GLSM AUC and Cwere lower by 23.7% and 23.2% in study A, and 17.6% and 20.9% in study B, in the fed versus fasted states, respectively. In both studies, tand median twere comparable between fed and fasted states. The majority of TEAEs in both studies were gastrointestinal tract-related conditions. No serious adverse events or deaths were reported in either study. max1/2max

CONCLUSION: The observed pharmacokinetic differences due to the prandial state are unlikely to contribute to clinically meaningful differences in the efficacy of orforglipron. The safety profile was consistent with the known profiles of other GLP-1 RAs. Given the absence of prandial restrictions, orforglipron may emerge as a convenient oral treatment option for patients with type 2 diabetes or obesity.

TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03929744 and NCT05110794.

Key numbers

23.7%

Decrease in with food

lower in fed vs. fasted state for 3 mg orforglipron in study A

23.2%

Decrease in with food

lower in fed vs. fasted state for 3 mg orforglipron in study A

17.6%

Decrease in with food

lower in fed vs. fasted state for 16 mg orforglipron in study B

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How Eating Food Affects the Absorption, Safety, and Tolerance of Once-Daily Orforglipron, a Non-Peptide GLP-1 Receptor Activator

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