THE COMPOUNDS COMPARED
Semaglutide vs. Tirzepatide vs. Retatrutide — The GLP-1 Compounds Compared
By G1 Peptides · Medically reviewed by the G1 Peptides clinical team · Updated September 24, 2026 · 2 min read
THE SHORT ANSWER
Semaglutide hits one receptor and has the longest track record. Tirzepatide adds GIP and produced more weight loss with similar side effects. Retatrutide adds glucagon on top and posted the largest reductions yet in phase 2 — it is the one G1 currently prescribes. All three are weekly injections escalated over months; the differences are magnitude, side-effect nuance, and what is available to you.
At a glance
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Receptors | GLP-1 | GLP-1 + GIP | GLP-1 + GIP + glucagon |
| Pivotal trial weight loss | ~15% at 68 wk (STEP 1) | ~21% at 72 wk, 15 mg (SURMOUNT-1) | ~24% at 48 wk, 12 mg (phase 2) |
| Weekly dose range | 0.25 → 2.4 mg | 2.5 → 15 mg | 1 → 12 mg (trials) |
| Escalation | ~16 weeks | ~20 weeks | months, individualized |
| FDA status | Approved (Ozempic, Wegovy) | Approved (Mounjaro, Zepbound) | Phase 3 |
| At G1 | Not currently | Not currently | Prescribed |
Semaglutide
The reference compound. In STEP 1, adults without diabetes lost an average of 14.9% of body weight over 68 weeks on 2.4 mg weekly versus 2.4% on placebo (Wilding 2021). It has the longest safety record, cardiovascular outcome data, and the most familiar escalation schedule. Its weaknesses are the ceiling — weight loss plateaus around 15% — and the nausea rate during escalation.
Tirzepatide
Adds GIP (glucose-dependent insulinotropic polypeptide) agonism. In SURMOUNT-1, the 15 mg dose produced 20.9% average weight loss at 72 weeks (Jastreboff 2022); a later head-to-head trial confirmed superiority over semaglutide. Side-effect rates were similar in kind and frequency. The GIP component may partly explain why some people find tirzepatide gentler on the stomach at equivalent effect — though that is individual.
Retatrutide
Adds glucagon receptor agonism to GLP-1 and GIP. Glucagon is counterintuitive in a weight-loss drug — it raises blood sugar — but in combination it increases energy expenditure and strongly reduces liver fat, while the GLP-1 and GIP components keep glucose controlled. In the phase 2 obesity trial, the 12 mg group lost 24.2% of body weight at 48 weeks and had not plateaued (Jastreboff 2023). Side effects were the familiar digestive set, dose-dependent, and mitigated by slower escalation; a small increase in heart rate was noted. Phase 3 trials are ongoing.
How a provider chooses
- Track record vs. magnitude. Semaglutide has the most outcome data; retatrutide has the largest effect. For someone with a lot of weight to lose or significant liver fat, magnitude may win; for someone with cardiovascular history, the outcome data may.
- Tolerance history. Someone who could not tolerate one compound is often tried on another.
- Diabetes and glucose. All three lower HbA1c; tirzepatide is the most potent on glucose among approved drugs.
- Availability and cost. Compounded availability shifts with FDA policy and shortage status; what a pharmacy can make today is part of the decision.
The rest of the pipeline
CagriSema (semaglutide plus the amylin analog cagrilintide) posted ~20–23% in phase 3; survodutide and mazdutide are GLP-1/glucagon dual agonists in phase 3; orforglipron is a once-daily pill with ~12% loss in trials. None is approved yet. Each has a calculator page with the trial dosing for reference.
Next: retatrutide explained.
FREQUENTLY ASKED
Is tirzepatide just a stronger semaglutide?
Not exactly. It targets a second receptor (GIP), and in head-to-head data it produced greater weight loss at its higher doses with a comparable side-effect rate. Some people who did not tolerate semaglutide do well on tirzepatide, and vice versa — receptor profile matters individually.
Why does G1 prescribe retatrutide rather than semaglutide?
Retatrutide's triple-receptor profile produced the largest weight reductions in trials to date, and its glucagon component adds liver-fat and energy-expenditure effects. Which compound is right for a given patient is still an individual decision made at the consultation.
Can I switch between them?
Yes, under provider supervision. Because the maintenance doses are not equivalent, a switch usually restarts at a low dose of the new compound and escalates, rather than jumping straight to a matching step.
SOURCES
- Wilding JPH, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). NEJM (2021)
- Jastreboff AM, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). NEJM (2022)
- Jastreboff AM, et al. Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. NEJM (2023)
This article is educational and is not medical advice. Peptides are prescription medications; whether any of them is appropriate for you is a decision for a licensed provider who knows your history.