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Aim: The aim was to investigate the effects of lotiglipron, a once‐daily, oral small‐molecule glucagon‐like peptide‐1 (GLP‐1) receptor agonist, in participants with type 2 diabetes (T2D) or obesity. Materials and Methods: A phase 2, randomized, double‐blind, placebo‐controlled, dose‐ranging study investigated the efficacy and safety of lotiglipron. The study was terminated early for safety reasons after routine data and monitoring review. The planned analyses for the end points were modified prior to unblinding the study. Results: In total, 901 participants were treated with at least one dose of the study drug (T2D cohort: n = 512, obesity cohort: n = 389). Although the majority of participants who were randomly assigned to higher doses did not reach their target maintenance dose, statistically significant changes in HbA1c and body weight were observed. In the T2D cohort, reductions in HbA1c were observed across all lotiglipron doses at week 16 (p < 0.0001), with least squares mean decreases up to −1.44% (90% confidence interval [CI]: −1.63, −1.26) (lotiglipron 80 mg), versus placebo, −0.07% (90% CI: −0.25, 0.11). In the obesity cohort, decreases in body weight were observed across all lotiglipron doses at week 20 (p < 0.01), up to −7.47% (90% CI: −8.50, −6.43) (lotiglipron 200 mg, five‐step titration), versus placebo, −1.84% (90% CI: −2.85, −0.83). Across cohorts, the most frequently reported treatment‐emergent adverse events were gastrointestinal related (most mild to moderate severity), with nausea being the most common (ranging from 4% [placebo] to 28.8% [80 mg] in the T2D cohort and 12.5% [placebo] to 60.6% [200 mg, four‐step titration] in the obesity cohort). Transaminase elevations were observed in a subset of participants (6.6% and 6.0% of participants on lotiglipron in the T2D and obesity cohorts, respectively, compared with 1.6% on placebo in the obesity cohort). Conclusions: The efficacy (HbA1c and/or body weight) of a range of lotiglipron doses was demonstrated in T2D and obesity cohorts. The safety profile was largely consistent with what has been previously known about the mechanism of action. Our results are unique in reporting elevations in liver transaminases in a subset of participants treated with lotiglipron, with attempts to identify the at‐risk population unsuccessful and therefore clinical development of lotiglipron terminated. ClinicalTrials.gov: NCT05579977. [ABSTRACT FROM AUTHOR]