Long-term safety of oral orforglipron in Japanese participants with type 2 diabetes (ACHIEVE-J): a multicentre, randomised, open-label, parallel-group phase 3 trial.
Orforglipron showed a high rate of treatment-emergent adverse events in Japanese adults with type 2 diabetes, particularly at higher doses, indicating caution in its use.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
This study evaluated the safety of oral orforglipron in Japanese participants with type 2 diabetes over 52 weeks. Participants received doses of 3 mg, 12 mg, or 36 mg, with 401 individuals randomly assigned to treatment groups. The study found that 85% of participants experienced at least one treatment-emergent adverse event.
Abstract
<h4>Background</h4>Orforglipron, an oral GLP-1 receptor agonist, requires further evaluation in east Asian populations with type 2 diabetes, given this group's distinct pathophysiological characteristics. This study aimed to assess orforglipron as add-on treatment to diet and exercise alone or to oral antihyperglycaemic medications in Japanese participants with type 2 diabetes.<h4>Methods</h4>This multicentre, randomised, open-label phase 3 study was conducted in 40 medical research centres and hospitals in Japan. Adults with type 2 diabetes and elevated glucose levels managing their condition with diet and exercise alone or with one or two oral antihyperglycaemic medications were assigned (1:1:1) via computer-generated random sequence to receive once-daily oral orforglipron (3 mg, 12 mg, or 36 mg). Randomisation was stratified by background therapy, baseline HbA<sub>1c</sub> (≤8·5% or >8·5%), and metformin use (yes vs no; applied only to α-glucosidase inhibitors, thiazolidinedione, and glinides). Investigators, participants, and site staff were not masked to treatment. The primary endpoint was safety for 52 weeks, assessed in all randomly assigned participants who received at least one dose of orforglipron. This study is registered with ClinicalTrials.gov, NCT06010004 (ACHIEVE-J).<h4>Findings</h4>Between Sept 28, 2023, and June 5, 2025, 450 participants were screened and 401 were randomly assigned to three groups (3 mg, n=132; 12 mg, n=135; and 36 mg, n=134). 352 (88%) completed study treatment. 339 participants (85%, 95% CI 80·7-87·8) had at least one treatment-emergent adverse event (TEAE), more frequently in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) than in the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups. Most TEAEs were of mild (267 [67%, 61·8-71·0]) or moderate (63 [16%, 12·5-19·6]) severity. Discontinuations due to an adverse event occurred in 19 of 134 participants (14%, 95% CI 9·3-21·1) in the 36-mg group compared with seven of 132 (5%, 2·6-10·5) in the 3-mg group and 11 of 135 (8%, 4·6-14·0) in the 12-mg group. Across treatment groups, gastrointestinal symptoms were the most common TEAEs leading to study treatment discontinuation (3 mg: 5 [3·8%, 1·6-8·6]; 12 mg: 8 [5·9%, 3·0-11·3]; and 36 mg: 11 [8·2%, 4·7-14·1]). Level 2 (blood glucose <54 mg/dL) hypoglycaemia events occurred in three of 135 participants in the 12-mg group (2%, 0·8-6·3) and in three of 134 in the 36-mg group (2%, 0·8-6·4) groups. No level 3 (severe) hypoglycaemia events occurred. Outcomes were generally similar across background therapies.<h4>Interpretation</h4>Treatment with orforglipron in combination with diet and exercise alone or one or two oral antihyperglycaemic medications for 52 weeks demonstrated an acceptable safety profile in Japanese adults with type 2 diabetes.<h4>Funding</h4>Eli Lilly.<h4>Translation</h4>For the Japanese translation of the abstract see Supplementary Materials section.
Background
This study addresses the safety of orforglipron, an oral GLP-1 receptor agonist, in a specific population of Japanese adults with type 2 diabetes. Prior research indicated the need for further evaluation of this treatment in East Asian populations due to distinct pathophysiological characteristics. Understanding the safety profile in this demographic is crucial for assessing the broader applicability of orforglipron.
Methods
This multicentre, randomised, open-label phase 3 trial involved 401 adults with type 2 diabetes managing their condition with diet and exercise or one to two oral antihyperglycaemic medications. Participants were assigned to receive once-daily doses of orforglipron at 3 mg, 12 mg, or 36 mg for 52 weeks. The primary outcome measure was safety, assessed in all randomly assigned participants who received at least one dose.
Results
The primary endpoint indicated that 339 participants (85%, 95% CI 80·7-87·8) experienced at least one treatment-emergent adverse event. Adverse events were reported more frequently in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) compared to the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups. Gastrointestinal symptoms were the most common reason for treatment discontinuation.
Interpretation
The findings suggest that orforglipron has an acceptable safety profile in this population, although the effect size may not be clinically significant given the high rate of adverse events. The open-label design and potential industry funding raise concerns about bias and the generalizability of results. These factors should be considered when interpreting the implications for clinical practice.
Key findings
- 339 participants (85%, 95% CI 80·7-87·8) had at least one treatment-emergent adverse event (TEAE).
- TEAEs were more frequent in the 36-mg group (118 [88%, 95% CI 81·5-92·5]) than in the 3-mg (107 [81%, 73·5-86·8]) and 12-mg (114 [84%, 77·4-89·6]) groups.
- Discontinuations due to an adverse event occurred in 19 of 134 participants (14%, 95% CI 9·3-21·1) in the 36-mg group.
- Gastrointestinal symptoms were the most common TEAEs leading to study treatment discontinuation (3 mg: 5 [3·8%, 1·6-8·6]; 12 mg: 8 [5·9%, 3·0-11·3]; 36 mg: 11 [8·2%, 4·7-14·1]).
- Level 2 hypoglycaemia events occurred in three of 135 participants in the 12-mg group (2%, 0·8-6·3) and in three of 134 in the 36-mg group (2%, 0·8-6·4).
- No level 3 (severe) hypoglycaemia events occurred.
Limitations
- open-label design may introduce bias
- industry-funded, which could influence outcomes
- short follow-up of 52 weeks may not capture long-term safety
- not masked, affecting participant and investigator perceptions