In a recent press release, Eli Lilly announced the key findings of its phase 3 trial of orforglipron, an oral GLP-1 receptor agonist in type 2 diabetes patients. The other GLP-1 analogues in the market to treat type 2 diabetes and obesity are administered by subcutaneous injection once a week. Comparatively, orforglipron is taken orally daily without any food or water restriction. All of these drugs are taken along with dietary changes and exercise.
In this phase 3 trial, orforglipron was given at three random doses of 3 mg, 12 mg, and 36 mg, starting from 1 mg and then increasing in a stepwise manner (1 mg, 3 mg, 6 mg, 12 mg, 24 mg) at a 4-week interval to reach their final randomized dose. They observed that orforglipron significantly reduced the HbA1C by 1.5% compared to 0.1% in placebo. 65% of the participants taking the highest dose of orforglipron achieved HbA1C less than or equal to 6.5%. Moreover, they observed a reduction in body weight by 7.9% compared to 1.6% in the placebo. The weight reduction did not plateau in 40 weeks, so the possibility of more weight reduction remains. Most of the side effects observed were gastrointestinal related, such as diarrhea, nausea, dyspepsia, constipation, and vomiting. They are also testing orforglipron in obesity; thus, the complete study along with weight management results, will be published later this year. It will be sent to the FDA for approval by the end of this year for obesity and early 2026 for type 2 diabetes. Orforglipron is also being studied for obstructive sleep apnea and hypertension. It was discovered by Chugai Pharmaceutical Co., Ltd. and licensed by Lilly in 2018.
Below is the table comparing orforglipron with other GLP-1 analogues (trizepetatide and semaglutide) in the market for treating type 2 diabetes and obesity.
| Drug name | Orforglipron | Trizepetatide | Semaglutide | ||
| Brand name | Mounjaro | Zepbound | Ozempic | Wegovy | |
| Manufacturing Company | Eli Lilly | Novo Nordisk | |||
| Mechanism of action | GLP-1 receptor agonist | GIP and GLP-1 receptor agonist | GIP and GLP-1 receptor agonist | GLP-1 analog | GLP-1 analog |
| Disease targeting | Type 2 diabetes | Type 2 diabetes | Obesity | Type 2 diabetes | Obesity |
| Route of administration | Oral | Subcutaneous injection | Subcutaneous injection | Subcutaneous injection | Subcutaneous injection |
| Frequency | Daily | Once a week | Once a week | Once a week | Once a week |
| Phase 3 trial | |||||
| Follow-up time | 40 weeks | 40 weeks | 72 weeks | 30 weeks | 68 weeks |
| Sample size | 559 | 478 | 2539 | 388 | 1961 |
| Dose | 3, 12, 36 mg | 5, 10, 15 mg | 5, 10, 15 mg | 0.5 mg, 1 mg | 2.4 mg |
| Efficacy (mean decrease with highest dose compared to placebo) | HbA1C reduced by 1.4% and body weight by 6 kg (6.3%) | HbA1C reduced by 2.11% and body weight by 8.8 kg (10.1%) | Body weight reduced by 17.8% | HbA1C reduced by 1.53% and body weight by 3.56 kg | Body weight reduced by 12.4% |
| Side effects | Mild to moderate gastrointestinal | Mild to moderate gastrointestinal | Mild to moderate gastrointestinal | Mild to moderate gastrointestinal | Mild to moderate gastrointestinal |
| FDA approved in | Not yet | May 13, 2022 | Nov 8, 2023 | Dec 5, 2017 | June 4, 2021 |
Dr. Vinny Negi, Ph.D,
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