Retatrutide – a triple GIP, GLP-1, and glucagon receptor agonist in obesity

Source: Jastreboff A.M. et al., The New England Journal of Medicine, 2023, 10.1056/NEJMoa2301972


Study Objective

To evaluate the efficacy, safety, and dose-response effect of Retatrutide – a triple GIP, GLP-1, and glucagon receptor agonist – in adults with overweight and obesity. Retatrutide is a peptide agonist with an extended half-life (~6 days), allowing for weekly subcutaneous administration. The study aims to determine the degree of weight reduction and the frequency of adverse events at different doses.


Study Design

  • Type: Phase 2, double-blind, randomized, placebo-controlled study

  • Participants: 338 adults (BMI ≥30 or BMI ≥27 with a coexisting condition)

  • Groups: Retatrutide 1 mg, 4 mg, 8 mg, 12 mg (different initial doses – 2 or 4 mg) and placebo

  • Duration: 48 weeks (plus 4 weeks follow-up)

  • Administration: subcutaneous, 1x weekly

  • Primary endpoint: percentage change in body weight at week 24

  • Secondary endpoints: change in weight at week 48, ≥5%, ≥10%, ≥15% weight reduction; safety and tolerability


Key Results

Weight Reduction

  • Mean percentage change in weight at week 48:

    • 1 mg: −8.7%

    • 4 mg: −17.1%

    • 8 mg: −22.8%

    • 12 mg: −24.2%

    • Placebo: −2.1%

  • 100% of participants on 8 mg and 12 mg achieved ≥5% reduction; 91–93% achieved ≥10%; 75–83% achieved ≥15%

  • 26% of participants on 12 mg achieved ≥30% weight reduction

Cardiometabolic Parameters

  • Improvements in blood pressure, HbA1c, fasting glucose, insulin, LDL-cholesterol

  • 72% of patients with prediabetes achieved normoglycemia

Safety

  • Most common adverse events: gastrointestinal (nausea, diarrhea, constipation), dose-dependent, predominantly mild to moderate

  • Heart rate: slight increase up to week 24, then decrease

  • No severe hypoglycemia, medullary carcinoma, or C-cell hyperplasia


Conclusions

  • Retatrutide induced significant, dose-dependent weight reduction of up to −24.2% over 48 weeks.

  • Improved cardiometabolic profile and glycemic control.

  • Adverse events were similar to those with GLP-1 and GIP-GLP-1 agonists.

  • Suitable for further studies (Phase 3) in patients with obesity.


Limitations

  • Duration – 48 weeks (lack of long-term data)

  • Predominantly white population from the USA – limited generalizability

  • Small proportion of participants with BMI <30


Practical Implications

  • Retatrutide is a potent triple GIP/GLP-1/glucagon receptor agonist with the potential to achieve weight reduction comparable to bariatric surgery.

  • A promising therapy for investigation in obesity without type 2 diabetes.