Results are in from ACHIEVE-3, the first head-to-head Phase 3 study evaluating the safety and efficacy of orforglipron, an oral small molecule GLP-1 receptor agonist with no food or water restrictions, compared to oral semaglutide.
The study looked at adults with type 2 diabetes not adequately controlled with metformin. According to what the publication in the magazine reports Lancetorforglipron demonstrated superiority over oral semaglutide on the primary endpoint and all key secondary endpoints, with significantly greater improvements in glycated hemoglobin by weight.
What the research says
The 52-week study enrolled 1,698 participants in four treatment groups: orforglipron 12 and 36 milligrams and oral semaglutide 7 and 14 milligrams. Orforglipron also demonstrated clinically relevant improvements from baseline on key cardiovascular risk factors, including non-HDL cholesterol, HDL cholesterol, VLDL cholesterol, total cholesterol, systolic blood pressure, and triglycerides.
“In direct comparison with oral semaglutide, the ACHIEVE 3 study demonstrated treatment superiority on specific key endpoints, including glycated hemoglobin control and body weight reduction. These results confirm the potential of orforglipron as a new oral therapeutic option for the treatment of adults with type 2 diabetes”
reports Stefano Del Prato, Affiliate Professor, Center for Interdisciplinary Health Science Research, Sant’Anna University School of Pisa.
The overall safety and tolerability profile of orforglipron in ACHIEVE-3 was consistent with what was observed in previous studies. For orforglipron and oral semaglutide, the most common adverse events were nausea, diarrhea, vomiting, dyspepsia, and decreased appetite. Treatment discontinuation rates due to adverse events were 8.7% (12 mg) and 9.7% (36 mg) for orforglipron, compared to 4.5% (7 mg) and 4.9% (14 mg) for oral semaglutide.
Lilly has submitted orforglipron to regulatory authorities in more than 40 countries; In the United States, submission for the type 2 diabetes indication is expected later this year.
How orforglipron works
Orforglipron is an investigational oral, once-daily, small molecule (non-peptide) glucagon-like peptide-1 (GLP-1) receptor agonist that can be taken at any time of the day without restrictions on food or water intake.
Why it is important to act on GLP-1
The acronym GLP-1 indicates a target for drugs already in clinical use. We are talking about a particular hormone which, based on the combined action that highlights the link between the intestine and the brain, is produced naturally after meals. When this phenomenon occurs the hormone basically functions as a natural control system (obviously not the only one) of blood sugar. That is, it stimulates insulin secretion and inhibits glucagon secretion by the pancreas. In this sense, Glucagon-like peptide 1, the English term that expresses this hormonal component, becomes part of the so-called incretins.
But be careful: GLP-1 does not limit its activity to the production of insulin by the pancreas, resulting in better use of sugars introduced with food. In fact, it also promotes the slowing down of gastric emptying. For this reason you feel more “full” and the sense of satiety increases, reducing your appetite.
Not only that. Together with another “ingredient” of metabolism, GIP, it also acts on the brain. In practice, at the level of the central nervous system it modifies the nervous activity of neurons whose task is to control hunger and satiety. And this also helps to induce a sense of fullness, with a substantial reduction in the quantity of food introduced.
The drug orforglipron was discovered by Chugai Pharmaceutical Co., Ltd. and licensed to Lilly in 2018.
