Tirzepatide vs Retatrutide vs Semaglutide: Head-to-Head Comparison

The progression from semaglutide to tirzepatide to retatrutide illustrates how additional receptor targets translate into progressively greater metabolic effects.

Semaglutide: GLP-1 Only

Semaglutide provides the foundation shared by all three compounds—GLP-1 receptor activation that suppresses appetite, delays gastric emptying, and enhances glucose-dependent insulin secretion. As a single-agonist, its weight loss mechanism is primarily driven by reduced caloric intake.^[1]

Tirzepatide: GLP-1 + GIP

Tirzepatide adds GIP (glucose-dependent insulinotropic polypeptide) receptor activation to the GLP-1 platform. GIP signaling contributes to appetite regulation through brain pathways complementary to GLP-1 and may improve adipose tissue metabolism and insulin sensitivity. The dual mechanism explains tirzepatide’s ~47% greater weight loss compared to semaglutide in the SURMOUNT-5 head-to-head trial.^[2]

Retatrutide: GLP-1 + GIP + Glucagon

Retatrutide builds on the dual GIP/GLP-1 platform by adding glucagon receptor agonism. Glucagon activation stimulates hepatic lipid oxidation and thermogenesis, introducing an energy expenditure mechanism absent from both semaglutide and tirzepatide. This means retatrutide may reduce weight through both decreased intake and increased caloric burning.^[3]

The Pattern

The data suggest a clear dose-response relationship with receptor count: ~15% weight loss with one receptor (semaglutide), ~22% with two receptors (tirzepatide), and ~24% with three receptors (retatrutide). While each additional receptor adds efficacy, the incremental gain appears to diminish—the jump from single to dual agonism is larger than from dual to triple.

Comparing clinical trial results across different studies requires caution, but the available data provide a clear ranking of efficacy.

Weight Loss Results

Mean body weight reduction at maximum dose in each compound’s primary obesity trial:

• Semaglutide 2.4 mg: 14.9% at 68 weeks (STEP 1, n=1,961, Phase III)^[1]
• Tirzepatide 15 mg: 22.5% at 72 weeks (SURMOUNT-1, n=2,539, Phase III)^[2]
• Retatrutide 12 mg: 24.2% at 48 weeks (Phase II, n=338)^[3]

Direct Head-to-Head Data

The most reliable comparison comes from the SURMOUNT-5 trial, which directly compared tirzepatide 15 mg to semaglutide 2.4 mg: tirzepatide produced 20.2% weight loss versus 13.7% for semaglutide at 72 weeks. No head-to-head trials exist comparing retatrutide to either approved compound.

Response Rates (Percentage Achieving Thresholds)

At maximum dose in respective trials:

• At least 5% loss: Semaglutide 86%, Tirzepatide 96%, Retatrutide 100%
• At least 10% loss: Semaglutide 69%, Tirzepatide 89%, Retatrutide 93%
• At least 15% loss: Semaglutide 51%, Tirzepatide 78%, Retatrutide 83%
• At least 20% loss: Semaglutide ~32%, Tirzepatide 63%, Retatrutide data pending

Important Caveats

Retatrutide’s results come from a smaller Phase II trial (338 participants vs 2,500+ for the others) measured at 48 weeks rather than 68–72 weeks. Phase II trials typically produce larger effect sizes than Phase III confirmatory studies. Additionally, retatrutide’s weight loss curve had not plateaued at 48 weeks, suggesting the final number could be even higher—or it could moderate with longer follow-up and larger populations.

All three compounds share GLP-1-mediated gastrointestinal side effects. The key safety differentiators are the depth of available data and compound-specific risks.

GI Side Effect Rates

• Semaglutide: Nausea ~44%, diarrhea ~30%, vomiting ~24%, constipation ~24%
• Tirzepatide: Nausea 24–33%, diarrhea 17–23%, vomiting 9–13%, constipation 6–11%
• Retatrutide: Nausea 25–45%, diarrhea 15–30%, vomiting 10–20% (Phase II data, dose-dependent)

Tirzepatide generally shows the best GI tolerability, possibly because GIP receptor activation modulates GLP-1’s gastrointestinal effects. Semaglutide and retatrutide have broadly similar GI profiles, though direct comparison is limited by different trial designs.

Cardiovascular Safety

This is where semaglutide has a decisive advantage:

• Semaglutide: The SELECT trial (n=17,604) demonstrated a 20% reduction in major adverse cardiovascular events—heart attacks, strokes, and cardiovascular death. This is the only obesity medication with proven cardiovascular benefit.^[4]
• Tirzepatide: The SURPASS-CVOT cardiovascular outcomes trial is ongoing. Preliminary data suggest cardiovascular safety, but definitive benefit data are not yet available.
• Retatrutide: No cardiovascular outcomes data exist. The glucagon component’s effect on heart rate and blood pressure requires long-term evaluation.

Safety Data Depth

The quality and quantity of safety data varies enormously: semaglutide has data from over 20,000 clinical trial participants plus years of post-marketing use; tirzepatide has extensive Phase III data from thousands of participants; retatrutide has Phase II data from 338 participants. For risk-averse individuals or those with significant medical comorbidities, the depth of semaglutide’s safety profile is a meaningful advantage.

The three compounds occupy very different positions in terms of real-world accessibility.

Available Now

• Semaglutide (Wegovy): FDA-approved since June 2021. Widely prescribed, with established insurance coverage pathways and manufacturer savings programs. Intermittent supply constraints have improved. Also available as Ozempic (diabetes indication) and Rybelsus (oral, diabetes only).
• Tirzepatide (Zepbound): FDA-approved since November 2023. Rapidly gaining market share and insurance coverage. Available as Mounjaro for type 2 diabetes. Pre-filled auto-injector pens.

Not Yet Available

• Retatrutide: Currently in Phase III trials (TRIUMPH program). Accessible only through clinical trial enrollment. Estimated FDA approval: 2026–2027 at the earliest if trials are successful.

Cost Comparison

• Semaglutide (Wegovy): ~$1,300–$1,400/month list price
• Tirzepatide (Zepbound): ~$1,000–$1,100/month list price
• Retatrutide: Not commercially available; pricing unknown

Insurance coverage and manufacturer assistance programs significantly affect actual out-of-pocket costs for both approved medications.

The choice among these three compounds depends on individual priorities, risk tolerance, and timeline.

Choose Semaglutide If:

• Cardiovascular risk reduction is a priority (only option with proven CV benefit)
• You prefer the medication with the longest safety track record
• You want an oral option (Rybelsus for diabetes; high-dose oral in late-stage trials for obesity)
• 14.9% mean weight loss meets your clinical goals

Choose Tirzepatide If:

• Maximum currently available weight loss is the priority (22.5% vs 14.9%)
• GI tolerability is a concern (lower side effect rates than semaglutide)
• You want the strongest approved medication available today
• Cost is a factor (slightly lower list price)

Watch Retatrutide If:

• You have severe obesity requiring maximum possible weight loss
• You have MASH/NASH or fatty liver disease (glucagon receptor benefits)
• You are willing to participate in clinical trials to access the compound
• You have not achieved adequate response on semaglutide or tirzepatide