Retatrutide

What Retatrutide Does

Retatrutide (LY3437943) is Eli Lilly’s investigational triple-hormone-receptor agonist — the first drug to simultaneously activate GLP-1, GIP, and glucagon receptors. Where semaglutide hits one receptor and tirzepatide hits two, retatrutide hits all three. That third receptor — glucagon — is what separates it from everything else on the market.

The mechanisms that matter:

• GLP-1 receptor agonism — suppresses appetite, slows gastric emptying, enhances insulin secretion. The same mechanism behind semaglutide (Ozempic/Wegovy).
• GIP receptor agonism — amplifies insulin response and improves fat metabolism. Shared with tirzepatide (Mounjaro/Zepbound).
• Glucagon receptor agonism — the differentiator. Increases energy expenditure, promotes hepatic fat oxidation, and mobilizes glycogen stores. This is why retatrutide produces more weight loss — it burns more energy in addition to reducing intake.

The triple-agonist approach attacks obesity from both sides: reduce calories in (appetite suppression via GLP-1/GIP) and increase calories out (energy expenditure via glucagon). No other approved or near-approval drug does both at this scale.

Dosing Protocol

Titration Schedule (Based on Phase 2 Trial Design)

Retatrutide is titrated every 4 weeks. Do not skip steps — GI tolerance depends on gradual dose escalation.

Week	Weekly Dose	Notes
1–4	2 mg	Starting dose. Assess GI tolerance.
5–8	4 mg	First escalation. Appetite suppression becomes noticeable.
9–12	8 mg	Significant weight loss begins. Most GI side effects occur here.
13+	12 mg	Maximum studied dose. Maintain if tolerated.

Alternative conservative start (used in some trial arms):

Week	Weekly Dose	Notes
1–4	1 mg	Slower start for sensitive individuals.
5–8	2 mg
9–12	4 mg
13–16	8 mg
17+	12 mg

Key Dosing Parameters

Parameter	Detail
Route	Subcutaneous injection
Frequency	Once weekly, same day each week
Injection sites	Abdomen, thigh, or upper arm. Rotate weekly.
Titration interval	Every 4 weeks
Target maintenance dose	8–12 mg/week
Maximum studied dose	12 mg/week

Dose Adjustment Guidelines

• If GI side effects are severe at any step: Hold at the current dose for an additional 4 weeks before attempting the next increase.
• If side effects persist at the target dose: Step back to the previous tolerated dose. Many users achieve excellent results at 8 mg without needing 12 mg.
• Do not exceed 12 mg/week. This is the maximum studied dose. Higher is not better — it’s just more side effects.

Phase 2 Trial Data

The pivotal Phase 2 data was published in the New England Journal of Medicine (Jastreboff et al., NEJM, 2023 — NCT04881706).

Weight Loss Results (Participants Without Diabetes)

Dose Group	Weight Loss at 24 Weeks	Weight Loss at 48 Weeks
Placebo	-1.6%	-2.1%
1 mg	-7.2%	-8.7%
4 mg	-12.9%	-17.1%
8 mg	-17.3%	-22.8%
12 mg	-17.5%	-24.2%

At the highest dose, participants lost an average of 24.2% of body weight over 48 weeks. The weight loss curve had not plateaued at 48 weeks — suggesting even greater losses with longer treatment.

Glycemic Control (Participants With Type 2 Diabetes)

Metric	Result
A1C reduction (4–12 mg groups)	-1.3% to -2.0%
A1C < 6.5% achieved	Up to 82% of participants
A1C < 5.7% (non-diabetic range) achieved	Up to 31% of participants
Weight loss (12 mg group with T2D)	-16.9% (37.8 lbs average)

For context, a -2.0% A1C reduction is clinically massive. Many participants effectively achieved diabetes remission on lab values.

How It Compares

Retatrutide vs Semaglutide vs Tirzepatide

Metric	Semaglutide (Wegovy)	Tirzepatide (Zepbound)	Retatrutide
Receptor targets	GLP-1	GLP-1 + GIP	GLP-1 + GIP + Glucagon
Max studied weight loss	~14.9% (68 wks)	~22.5% (72 wks)	~24.2% (48 wks)
Time to max loss	68 weeks	72 weeks	48 weeks (not plateaued)
A1C reduction	~1.5%	~2.1%	Up to 2.0%
Dosing frequency	Weekly	Weekly	Weekly
FDA status	Approved	Approved	Phase 3 trials

The key takeaway: retatrutide achieves comparable or greater weight loss in less time than either approved alternative, and the weight loss curve hadn’t flattened — meaning the final numbers could be even higher with longer treatment.

Why the glucagon receptor matters: Semaglutide and tirzepatide primarily reduce caloric intake through appetite suppression. Retatrutide does that and increases energy expenditure via glucagon receptor activation. It’s a fundamentally different pharmacological approach — suppressing intake while simultaneously increasing output.

Side Effects

GI Effects (Primary Concern)

Gastrointestinal side effects are the dominant adverse events, consistent with the GLP-1 class:

Side Effect	Frequency (12 mg group)	Timing
Nausea	Most common	Peaks during dose escalation
Diarrhea	Common	Peaks during dose escalation
Vomiting	Common	Peaks during dose escalation
Constipation	Common	Can occur throughout
Decreased appetite	Expected (it’s the mechanism)	Sustained

Critical pattern: GI side effects occur primarily during dose escalation and are dose-dependent. They are predominantly mild to moderate in severity. The Phase 2 trial showed that using a lower starting dose (2 mg vs. 4 mg) significantly reduced GI adverse events. Slow titration is not optional.

GI Management Strategies

• Eat smaller, more frequent meals — large meals worsen nausea when gastric emptying is slowed
• Avoid high-fat and fried foods during dose escalation weeks
• Stay hydrated — diarrhea and vomiting increase fluid loss
• Time your injection — some users find injecting in the evening or after a light meal reduces next-day nausea
• Ondansetron (Zofran) — anti-nausea medication useful during dose escalation if needed

Other Adverse Events

• Discontinuation rate: 6–16% across retatrutide groups (vs. 0% placebo) in Phase 2
• Increased heart rate: Small increases observed, consistent with GLP-1 class effects
• Injection-site reactions: Mild, transient
• Hypoglycemia risk: Low when used without insulin or sulfonylureas. Higher risk if combined with diabetes medications.

Serious Considerations

• Pancreatitis risk: Theoretical risk shared with all incretin-based drugs. Discontinue immediately if severe abdominal pain occurs.
• Gallbladder events: Rapid weight loss increases gallstone risk regardless of mechanism. Monitor for biliary symptoms.
• Thyroid C-cell tumors: GLP-1 agonists carry a boxed warning based on rodent data. Relevance to humans is debated but cannot be excluded.
• Lean mass preservation: Combine with resistance training and high protein intake. All weight loss drugs reduce some lean mass alongside fat.

Current Status and Access

Retatrutide is not yet FDA-approved. It is in Eli Lilly’s Phase 3 TRIUMPH clinical trial program. Key timeline:

Milestone	Expected Timing
TRIUMPH-4 (Phase 3, first readout)	Completed — met all endpoints
Remaining Phase 3 trials	Data readouts through 2026
Potential NDA submission	Late 2026
Potential FDA approval	Late 2027 (earliest)

Retatrutide is available through some research chemical vendors and compounding pharmacies in certain jurisdictions. The usual caveats about source quality, purity testing, and legal status apply.

What Comes Next

• If you’re currently on semaglutide or tirzepatide and considering switching to retatrutide when available: the transition should be managed by a physician given the overlapping receptor activity
• Pair with resistance training — non-negotiable. Preserving lean mass during aggressive weight loss requires mechanical loading.
• Track body composition, not just scale weight — DEXA scans every 12–16 weeks give a clearer picture than the scale alone
• Monitor labs — fasting glucose, A1C, lipid panel, liver enzymes, and thyroid function at baseline and every 12 weeks during treatment