BACKGROUND AND PURPOSE:

• Glucagon-like peptide-1 (GLP-1) receptor agonists appear to be effective for the treatment of obesity, but injection as a mode of delivery may prevent patient uptake
• Wharton et al. (NEJM, 2023) evaluated the efficacy and safety of oral orforglipron in adults with obesity or with overweight plus at least one weight-related coexisting condition

METHODS:

• Phase 2, randomized, double-blind trial
• Participants
  • Obesity or overweight and ≥1 weight-related coexisting condition
  • Exclusion: Diabetes
• Intervention
  • 36 weeks of orforglipron at one of four doses: 12 mg | 24 mg | 36 mg | 45 mg
  • Placebo
• Primary outcome
  • Percentage change from baseline in body weight at week 26
• Secondary outcome
  • Percentage change from baseline in body weight at week 36

RESULTS:

• 242 participants
  • Mean body weight at baseline: 108.7 kg | Mean BMI: 37.9
• At week 26, the mean change from baseline in body weight was higher in all orforglipron dose cohorts
• The mean change in body weight increased linearly with increasing dose
  • Orforglipron 12 mg: −8.6 (95% CI, −10.2 to −6.9)
  • Orforglipron 45 mg: −12.6 (95% CI, −14.1 to −11.1)
  • Placebo: −2.0 (95% CI, −3.6 to −0.4)
• The mean change from baseline was higher in all orforglipron dose cohorts at week 36
• A weight reduction of at least 10% by week 36 occurred in more participants in the orforglipron groups
  • Orforglipron 12 mg: 46% (95% CI, 32 to 61)
  • Orforglipron 45 mg: 69% (95% CI, 57 to 81)
  • Placebo: 9% (95% CI, 1 to 17)
• The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures
• Adverse events
  • Most common adverse events: Mild to moderate gastrointestinal events
  • Typically occurred during dose escalation
  • Discontinuation of orforglipron occurred in 10% to 17% of participants across dose cohort
• The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class

CONCLUSION:

• Compared to placebo, the daily use of oral orforglipron was associated with greater weight loss in participants with obesity and overweight with similar outcomes to injectables
• The safety profile of orforglipron is similar to that of other GLP-1 receptor agonists
• The authors state

Daily oral orforglipron was associated with weight reduction and related benefits that appeared to be similar to the efficacy outcomes observed with injectable GLP-1 receptor agonists that have already been approved for weight management

Learn More – Primary Sources:

Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity