What is the recommended dosing regimen for a 10 mg subcutaneous weekly injection of retatrutide in adult patients with obesity (with or without type 2 diabetes)?

Retatrutide 10 mg Dosing Regimen

Retatrutide 10 mg weekly is not an FDA-approved dose; the phase 2 trial evaluated 1 mg, 4 mg, 8 mg, and 12 mg weekly doses, with no 10 mg dose studied. 1 Based on the available evidence, I will outline the dosing framework from the clinical trials and explain how dose selection should proceed.

Current Evidence Base

Studied Doses in Phase 2 Trials

The phase 2 obesity trial (TRIUMPH program precursor) evaluated retatrutide at 1 mg, 4 mg, 8 mg, and 12 mg weekly over 48 weeks. 1 The type 2 diabetes trial similarly tested 0.5 mg, 4 mg, 8 mg, and 12 mg weekly doses. 2 No 10 mg dose was included in either trial, making specific recommendations for this dose impossible based on published evidence.

Weight Loss Efficacy by Dose

At 48 weeks in adults with obesity:

• 1 mg: 8.7% mean weight loss 1
• 4 mg: 17.1% mean weight loss 1
• 8 mg: 22.8% mean weight loss 1
• 12 mg: 24.2% mean weight loss 1

The dose-response curve shows substantial efficacy gains between 4 mg and 8 mg, with more modest additional benefit from 8 mg to 12 mg. 1

Glycemic Control in Type 2 Diabetes

At 24 weeks, HbA1c reductions were:

• 0.5 mg: -0.43% 2
• 4 mg: -1.30% to -1.39% 2
• 8 mg: -1.88% to -1.99% 2
• 12 mg: -2.02% 2

All doses ≥4 mg produced clinically meaningful glucose lowering superior to placebo. 2

Titration Strategy from Clinical Trials

Starting Dose and Escalation

The phase 2 trials used a 2 mg starting dose for all maintenance doses ≥4 mg, with escalation every 4 weeks. 1, 2 For example, participants assigned to 12 mg received:

• Weeks 1-4: 2 mg weekly
• Weeks 5-8: 4 mg weekly
• Weeks 9-12: 8 mg weekly
• Week 13 onward: 12 mg weekly 1

This gradual escalation mitigated gastrointestinal adverse events, which were dose-dependent and mostly mild-to-moderate. 1, 2

Rationale for Slow Titration

Gastrointestinal events (nausea, diarrhea, vomiting) occurred in 35% of retatrutide-treated participants and were partially mitigated by starting at 2 mg rather than 4 mg. 1 The 4-week intervals between dose increases allowed GI symptoms to resolve before further escalation. 1, 2

Safety Profile

Common Adverse Events

The most frequent adverse events were gastrointestinal, including nausea, diarrhea, vomiting, and constipation. 1, 2 These were:

• Dose-related (higher doses → more GI events) 1, 2
• Mostly mild-to-moderate in severity 1, 2
• Partially mitigated by lower starting doses 1

In the type 2 diabetes trial, GI events ranged from 13% (0.5 mg) to 50% (8 mg fast escalation). 2

Cardiovascular Considerations

Retatrutide increased heart rate by up to 6.7 beats/min, peaking at 24 weeks and declining thereafter. 3, 1 This effect is consistent with GLP-1 receptor agonism and may offset some cardiovascular benefits of weight loss. 3 No severe hypoglycemia or deaths occurred during the phase 2 trials. 2

Contraindications

Although not explicitly stated for retatrutide, GLP-1 receptor agonists are contraindicated in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN 2). 4 This contraindication likely applies to retatrutide given its GLP-1 agonist activity.

Metabolic Benefits Beyond Weight Loss

Liver Fat Reduction

In a substudy of participants with metabolic dysfunction-associated steatotic liver disease (MASLD), retatrutide produced dose-dependent liver fat reductions:

• 8 mg: -81.4% mean relative reduction at 24 weeks 5
• 12 mg: -82.4% mean relative reduction at 24 weeks 5
• 79% (8 mg) and 86% (12 mg) achieved normal liver fat (<5%) 5

These reductions were significantly related to improvements in body weight, abdominal fat, insulin sensitivity, and lipid metabolism. 5

Appetite and Eating Behavior

Higher doses (≥8 mg) reduced perceived hunger and disinhibition (tendency to overeat) compared to placebo in adults with type 2 diabetes. 6 Greater weight reduction correlated with decreased hunger (r=0.28), decreased disinhibition (r=0.36), and increased dietary restraint (r=0.31). 6

Clinical Decision Algorithm (Hypothetical 10 mg Dose)

If 10 mg Were to Be Used (Off-Label, Extrapolated)

Since 10 mg is not a studied dose, any use would be off-label and require careful clinical judgment. If a clinician were to consider 10 mg based on interpolation between 8 mg and 12 mg:

1. Start at 2 mg weekly for 4 weeks (consistent with phase 2 protocol) 1, 2
2. Escalate to 4 mg weekly for 4 weeks 1, 2
3. Escalate to 8 mg weekly for 4 weeks 1, 2
4. Escalate to 10 mg weekly (extrapolated; not studied)

Monitoring During Titration

• Assess gastrointestinal tolerance every 4 weeks during dose escalation 1, 2
• Monitor heart rate, as increases peak around 24 weeks 1
• Check weight and metabolic parameters (HbA1c if diabetic, liver enzymes if MASLD) 1, 2, 5
• Evaluate for signs of pancreatitis or gallbladder disease (persistent severe abdominal pain) 4

When to Stop at 8 mg vs. Escalate to 10 mg

If the patient achieves adequate weight loss (≥5% at 12-16 weeks) or glycemic control (HbA1c <7%) on 8 mg, there is no evidence-based reason to escalate further. 4 The incremental benefit from 8 mg to 12 mg in the phase 2 trial was modest (22.8% vs. 24.2% weight loss). 1

If the patient tolerates 8 mg well but requires additional weight loss or glucose lowering, escalation to 10 mg could be considered, recognizing this is extrapolated from the dose-response curve. 1, 2

Critical Caveats

Lack of Direct Evidence

There is no published data on retatrutide 10 mg weekly. All recommendations for this dose are extrapolations from the 8 mg and 12 mg data. 1, 2 The phase 3 TRIUMPH program (launched August 2023) enrolled over 5,800 participants but has not yet reported results. 3

Comparator Studies Needed

No head-to-head trials compare retatrutide to semaglutide or tirzepatide, which are the current standard-of-care GLP-1/GIP agonists. 3 Until such comparisons exist, retatrutide's place in therapy remains uncertain. 3

Cardiovascular Outcomes Unknown

Unlike semaglutide (26% MACE reduction) and tirzepatide (cardiovascular safety demonstrated), retatrutide has no cardiovascular outcome trial data. 4 The heart rate increase observed in phase 2 raises theoretical concerns. 3, 1

Practical Recommendation

If a 10 mg dose is being considered, the most evidence-based approach is to follow the phase 2 titration protocol (2 mg → 4 mg → 8 mg over 12 weeks) and then decide whether to escalate to 10 mg based on individual response. 1, 2 However, given the lack of studied 10 mg data, using either 8 mg (if more conservative) or 12 mg (if maximum efficacy is needed) would be more defensible, as both doses have published safety and efficacy profiles. 1, 2

For patients with established cardiovascular disease, semaglutide 2.4 mg weekly remains the preferred choice due to proven MACE reduction, until retatrutide cardiovascular outcome data become available. 4