Retatrutide Clinical Trials: Evaluating Starting Doses and Dose Escalation for Optimal Tolerability

Retatrutide: A Novel Triple Agonist for Obesity and Type 2 Diabetes

Retatrutide is a novel triple agonist targeting the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors. Recent clinical trials have investigated its efficacy and safety for weight loss and glycemic control in individuals with obesity and type 2 diabetes.

Phase 2 Trial Findings

• In a phase 2 randomized controlled trial, retatrutide demonstrated significant dose-dependent reductions in body weight and HbA1c levels compared to placebo and the active comparator dulaglutide (1.5 mg).
• Different retatrutide dose groups were evaluated with varying starting doses and dose escalation regimens over 12 weeks:
  • 4 mg dose group: Starting doses of 2 mg or 4 mg, escalated to 4 mg
  • 8 mg dose group: Starting doses of 2 mg or 4 mg, escalated to 8 mg
  • 12 mg dose group: Starting dose of 2 mg, escalated to 12 mg
• At 24 weeks, least-squares mean changes in HbA1c from baseline were:
  • -1.39% for 4 mg escalation group
  • -1.99% for 8 mg slow escalation group
  • -2.02% for 12 mg escalation group
• At 36 weeks, least-squares mean percentage changes in body weight from baseline were:
  • -7.92% for 4 mg escalation group
  • -16.81% for 8 mg slow escalation group
  • -16.94% for 12 mg escalation group
• Weight reductions with retatrutide doses ≥4 mg were significantly greater than placebo (p≤0.0017) and dulaglutide 1.5 mg (p<0.0001).

Phase 3 Trial Findings

• In a phase 3 trial, retatrutide demonstrated substantial weight reductions at 48 weeks compared to placebo:
  • -8.7% for 1 mg group
  • -17.1% for combined 4 mg group
  • -22.8% for combined 8 mg group
  • -24.2% for 12 mg group
• At 48 weeks, 92-100% of participants on retatrutide doses ≥4 mg achieved ≥5% weight loss, compared to 27% with placebo.

Safety and Tolerability

• The most common adverse events with retatrutide were mild-to-moderate gastrointestinal issues like nausea, vomiting, diarrhea, and constipation.
• Gastrointestinal side effects were dose-related and partially mitigated by using a lower 2 mg starting dose before escalation.
• No severe hypoglycemia or deaths related to retatrutide were reported in the phase 2 trial.

In summary, retatrutide demonstrated promising efficacy for weight loss and glycemic control in individuals with obesity and type 2 diabetes across multiple clinical trials. The gastrointestinal tolerability profile was improved by using lower starting doses and gradual dose escalation.

PubMed

The Lancet

The New England Journal of Medicine

National Library of Medicine