Eli Lilly's orforglipron, an oral glucagon-like peptide-1 receptor (GLP-1R) agonist, has shown promising results in reducing cardiovascular and inflammatory biomarkers in a Phase II trial involving obese patients without type 2 diabetes. The data, presented at the European Association for the Study of Diabetes (EASD) 60th Annual Meeting, suggest that orforglipron could offer a convenient and effective approach to managing cardiovascular risk in this population.
The post hoc analysis of the Phase II trial (NCT05048719) revealed that orforglipron significantly reduced high-sensitivity C-reactive protein (hsCRP), a key inflammatory marker, by 41.9% at week 36 with the 12mg dose. This reduction was compared to the 36.2% reduction observed with tirzepatide 15mg at week 26. Interleukin-6 (IL-6), another inflammatory marker, also decreased by 12.6% at the 36mg dose at week 36 of treatment.
Dose-dependent reductions in leptin levels were also observed, with a 39.2% reduction at the highest dose of 45mg, indicating a correlation between leptin reduction and weight loss. Apolipoprotein B (apoB) levels decreased by 11.3 to 13.4%, although this reduction was not dose-dependent, with the lowest dose showing the greatest apoB reduction.
Potential for Hypertension Label
Notably, orforglipron also demonstrated impressive reductions in systolic blood pressure. Eli Lilly acknowledged the potential for a hypertension label but expressed uncertainty about whether similar results would be achieved in a non-obese population. This observation warrants further investigation to determine the broader applicability of orforglipron in managing blood pressure.
Oral Advantage
Orforglipron, a synthetic oral small molecule for daily administration, holds the potential to be the first oral GLP-1R agonist to reach the market. Key opinion leaders (KOLs) interviewed by GlobalData have described oral GLP-1R agonists as a "very interesting evolution," particularly highlighting orforglipron. A European KOL noted the potential advantages of oral administration, stating, "We need to have more data about efficacy and also about side effects... this could be an important step forward also because not having the problem of the injection, of the device, of the pain... Maybe also this will help us to reduce the general cost of the medication."
Prior Trial Data
Previous trials have demonstrated orforglipron's ability to reduce body weight, waist circumference, and body mass index (BMI) in obesity patients, with reductions of up to 14.7%, 13.6cm, and 5.5kg/m², respectively.
