What is the known dosing regimen for retatrutide?

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 depending on treatment goals and tolerability.

Standard Dosing Regimen

Initial Dose and Escalation Schedule

• Start with 2 mg subcutaneously once weekly as the initial dose for most patients, which serves as the escalation starting point for higher maintenance doses 1, 2.
• Escalate to 4 mg once weekly after 4 weeks if targeting moderate weight loss (approximately 17% at 48 weeks) 2.
• Escalate to 8 mg once weekly for more robust weight reduction (approximately 23% at 48 weeks), typically after 4 weeks at 4 mg 2.
• Escalate to 12 mg once weekly for maximal weight loss (approximately 24% at 48 weeks), following gradual dose increases 2.

Alternative Starting Doses

• A 4 mg starting dose (without initial 2 mg escalation) can be used but is associated with higher rates of gastrointestinal adverse events compared to the 2 mg starting approach 1, 2.
• A 1 mg once-weekly dose produced modest weight loss (-8.7% at 48 weeks) and may be appropriate for patients requiring minimal intervention or with high sensitivity to gastrointestinal side effects 2.

Type 2 Diabetes-Specific Dosing

Glycemic Control Targets

• For HbA1c reduction, doses of 4 mg or higher are required to achieve clinically meaningful glucose lowering, with the 8 mg and 12 mg doses producing HbA1c reductions of approximately 2% at 24 weeks 1.
• The 0.5 mg dose is insufficient for meaningful glycemic control (HbA1c reduction of only -0.43% at 24 weeks) and should not be used for diabetes management 1.
• Doses of 8 mg and 12 mg demonstrated superior HbA1c reduction compared to dulaglutide 1.5 mg (p=0.0019 and p=0.0002, respectively) 1.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

• For liver fat reduction, 8 mg or 12 mg doses are optimal, achieving 81-82% relative reduction in liver fat at 24 weeks and normalization of liver fat (<5%) in 79-86% of participants 3.
• The 4 mg dose produces moderate liver fat reduction (57% relative reduction) with 52% achieving normal liver fat levels 3.

Administration Details

Injection Technique

• Administer subcutaneously once weekly at any time of day, with or without meals, in the abdomen, thigh, or upper arm 1, 2.
• No dose adjustments are required for renal or hepatic impairment based on available data 1.

Safety Monitoring and Adverse Events

Gastrointestinal Side Effects

• Nausea, diarrhea, vomiting, and constipation are dose-dependent, occurring in 13-50% of participants depending on dose and escalation strategy 1.
• Starting at 2 mg rather than 4 mg partially mitigates gastrointestinal adverse events while maintaining efficacy 2.
• Most gastrointestinal events are mild to moderate and do not require treatment discontinuation 1, 2.

Cardiovascular Considerations

• Heart rate increases are dose-dependent, peaking at 24 weeks with increases up to 6.7 beats per minute, then declining thereafter 4, 2.
• Monitor heart rate regularly, particularly in patients with pre-existing cardiovascular conditions, as this effect may offset some cardiovascular benefits of weight loss 4.

Body Composition Changes

• The proportion of lean mass loss to total weight loss is similar to other obesity treatments (approximately 25-30% of weight loss from lean mass), providing reassurance that excessive lean mass is not lost despite greater overall weight reduction 5.
• Total fat mass reduction is dose-dependent: 15.2% with 4 mg, 26.1% with 8 mg, and 23.2% with 12 mg at 36 weeks 5.

Common Pitfalls to Avoid

• Do not skip the 2 mg starting dose when targeting 8 mg or 12 mg maintenance doses, as this significantly increases gastrointestinal intolerance 2.
• Do not use the 0.5 mg or 1 mg doses for type 2 diabetes management when meaningful HbA1c reduction is the goal, as these doses are insufficient 1.
• Do not escalate doses faster than every 4 weeks, as rapid titration increases adverse event rates without improving efficacy 1, 2.
• Monitor for hypoglycemia when combining with insulin or sulfonylureas, though retatrutide monotherapy does not cause severe hypoglycemia 1.