What is the recommended dosing regimen for retatrutide (Glucagon-like peptide-1 (GLP-1) receptor agonist)?

Retatrutide Dosing for Obesity and Type 2 Diabetes

Retatrutide is administered as a once-weekly subcutaneous injection with dose escalation starting at 2 mg, increasing to maintenance doses of 4 mg, 8 mg, or 12 mg based on efficacy and tolerability. 1, 2

Standard Dosing Regimen

Initial Dose and Escalation

• Start at 2 mg subcutaneously once weekly for the initial escalation period 1, 2
• Escalate to target maintenance dose over several weeks to minimize gastrointestinal adverse events 1, 2
• The 2 mg starting dose provides better tolerability compared to initiating at 4 mg, with reduced gastrointestinal side effects 1, 2

Maintenance Doses

• 4 mg once weekly: Produces 17.1% weight loss at 48 weeks and HbA1c reduction of -1.39% at 24 weeks 1, 2
• 8 mg once weekly: Produces 22.8% weight loss at 48 weeks and HbA1c reduction of -1.99% at 24 weeks 1, 2
• 12 mg once weekly: Produces 24.2% weight loss at 48 weeks and HbA1c reduction of -2.02% at 24 weeks 1, 2

Dose Selection Strategy

For Obesity Treatment

• The 8 mg or 12 mg doses provide optimal efficacy, with 100% of participants achieving ≥5% weight loss, 91-93% achieving ≥10% weight loss, and 75-83% achieving ≥15% weight loss at 48 weeks 2
• The 4 mg dose remains effective with 92% achieving ≥5% weight loss and 75% achieving ≥10% weight loss, making it appropriate for patients requiring lower doses due to tolerability 2

For Type 2 Diabetes

• Doses of 8 mg or 12 mg provide superior glycemic control compared to dulaglutide 1.5 mg, with HbA1c reductions exceeding -2% at 24 weeks 1
• The 4 mg dose produces HbA1c reductions comparable to dulaglutide 1.5 mg (-1.39% vs -1.41%) 1

For Metabolic Dysfunction-Associated Steatotic Liver Disease

• The 8 mg and 12 mg doses achieve the greatest liver fat reduction (-81.4% and -82.4% respectively at 24 weeks), with 79-86% of participants achieving normal liver fat (<5%) 3

Administration Details

Injection Technique

• Administer subcutaneously once weekly on the same day each week 1, 2
• Can be given at any time of day, independent of meals 1, 2
• Rotate injection sites (abdomen, thigh, or upper arm) 4

Dose Escalation Timing

• The phase 2 trials used escalation protocols starting at 2 mg with increases every 4 weeks, though specific escalation schedules to reach maintenance doses were not fully detailed in the evidence 1, 2
• Slower escalation (starting at 2 mg rather than 4 mg) significantly reduces gastrointestinal adverse events 1, 2

Safety Monitoring and Adverse Effects

Gastrointestinal Effects

• Nausea, diarrhea, vomiting, and constipation are the most common adverse events, occurring in 35% of participants overall, with dose-dependent increases 1, 2
• These effects are predominantly mild-to-moderate in severity and are partially mitigated by the lower 2 mg starting dose 1, 2
• Gastrointestinal symptoms typically diminish over time 4

Cardiovascular Monitoring

• Monitor heart rate, as dose-dependent increases occur, peaking at 24 weeks (up to 6.7 beats/min increase) and declining thereafter 5, 2
• This heart rate increase may offset some cardiovascular benefits of weight loss and requires clinical attention 5

Hypoglycemia Risk

• No severe hypoglycemia was reported in phase 2 trials 1
• When used with insulin or sulfonylureas, reduce doses of these medications to prevent hypoglycemia, consistent with GLP-1 receptor agonist management 6, 4

Drug Interactions and Contraindications

Avoid Concurrent Use

• Do not combine with other GLP-1 receptor agonists or DPP-4 inhibitors, as retatrutide has GLP-1 agonist activity 6, 4
• Exercise caution when combining with medications that delay gastric emptying 6

Dose Adjustments with Concomitant Medications

• Reduce insulin and sulfonylurea doses when initiating retatrutide to minimize hypoglycemia risk 6, 4
• Monitor glucose levels more frequently during titration in patients with type 2 diabetes 4

Renal Considerations

While specific renal dosing for retatrutide is not established in the evidence provided, other GLP-1 receptor agonists with proteolytic degradation (similar to retatrutide's mechanism) generally do not require dose adjustment in chronic kidney disease 6. However, monitor for gastrointestinal adverse reactions in patients with CKD, as these may affect renal function 6.

Clinical Pearls

• The 12 mg dose provides maximal efficacy but not substantially greater than 8 mg (24.2% vs 22.8% weight loss), so 8 mg may be optimal for balancing efficacy and tolerability 2
• Starting at 2 mg rather than 4 mg is critical for tolerability—the phase 2 trials demonstrated this reduces gastrointestinal adverse events 1, 2
• Weight loss and metabolic improvements are dose-dependent across the entire range from 1 mg to 12 mg 1, 2
• Retatrutide's triple agonist mechanism (GLP-1, GIP, and glucagon receptors) distinguishes it from other agents, though the specific contribution of glucagon receptor agonism remains incompletely defined 5, 7