Semaglutide vs tirzepatide vs retatrutide: the 2026 GLP-1 ladder

Three drugs dominate the GLP-1 conversation in 2026. One has been around since 2017 and is the most-prescribed globally. One displaced it in head-to-head trials in 2022. One is phase 3, Lilly-owned, and changing what "maximum weight loss" means. If you are trying to pick, here is the honest ladder.

The short version

Semaglutide (Ozempic, Wegovy, Rybelsus): GLP-1 only. Weekly injection (or daily pill). Average ~15% weight loss over 68 weeks at max dose. Widely available. Most insurance coverage.

Tirzepatide (Mounjaro, Zepbound): GLP-1 + GIP dual agonist. Weekly injection. Average ~21% weight loss over 72 weeks at 15 mg. Better tolerated at high doses than semaglutide in head-to-head trials.

Retatrutide (no brand name yet, phase 3): GLP-1 + GIP + glucagon triple agonist. Weekly injection. Phase 2 data (Rosenstock et al., NEJM 2023) showed 24% weight loss at 48 weeks at the highest dose. Phase 3 results expected late 2026. Not approved yet anywhere.

Mechanism, in one paragraph

All three drugs are long-acting peptides that activate gut hormone receptors involved in appetite and glucose control.

GLP-1 (glucagon-like peptide-1) is released after eating and does three things: tells the pancreas to release insulin, slows gastric emptying, and signals fullness to the brain. Semaglutide is a GLP-1 agonist.

GIP (glucose-dependent insulinotropic polypeptide) also stimulates insulin release and appears to help with fat metabolism in ways still being characterized. Tirzepatide adds GIP to semaglutide's GLP-1. The GIP component seems to reduce nausea at higher doses, which is why tirzepatide is tolerated at effective doses that would have kicked patients off semaglutide.

Glucagon (the third receptor retatrutide hits) sounds counterintuitive because glucagon raises blood sugar. But in the context of a triple-agonist at balanced affinity, the glucagon activity appears to increase energy expenditure (your metabolism burns more) while the GLP-1 and GIP activity keep appetite suppressed. The result in phase 2 was the highest weight loss seen in any GLP-1-class trial.

Head-to-head data

SURMOUNT-1 (tirzepatide): 20.9% mean weight loss at 15 mg over 72 weeks.

STEP-1 (semaglutide 2.4 mg): 14.9% mean weight loss over 68 weeks.

SURPASS-2 (tirzepatide vs semaglutide in T2D): tirzepatide 15 mg produced 11.2% weight loss vs semaglutide 1.0 mg at 5.7% over 40 weeks. Roughly 2x better, but at a higher tirzepatide dose than STEP-1 semaglutide.

Retatrutide phase 2 (Rosenstock et al., NEJM 2023): 24.2% weight loss at 12 mg over 48 weeks. Phase 3 results pending.

Important caveat: these trials enrolled different populations. SURMOUNT-1 selected for obesity without diabetes. SURPASS-2 selected for T2D patients. Comparing across trials is directionally useful but not a clean head-to-head.

Side effect profiles

All three cause GI side effects as primary class-dependent. Nausea, diarrhea, constipation, occasional vomiting. Intensity scales with dose and stability at dose.

Semaglutide: nausea peaks around dose increases (every 4 weeks during titration). Discontinuation from GI side effects is roughly 7% in STEP trials.

Tirzepatide: similar GI pattern, slightly lower discontinuation rate at roughly 4-7% in SURMOUNT. The GIP component likely explains the better tolerability at high doses.

Retatrutide: GI side effects are reported at similar rates in phase 2. One interesting signal: the triple agonist showed slightly higher rates of palpitations and mild heart rate elevation. This is consistent with the glucagon-mediated increase in energy expenditure. Not clinically serious in phase 2, but worth watching in phase 3.

All three share the same class-wide cautions: personal or family history of medullary thyroid carcinoma (MTC) or MEN2 is a contraindication. Pancreatitis history is a flag. Severe gastroparesis pre-existing is a flag.

Cost as of April 2026

Semaglutide:

• Brand Ozempic (diabetes): ~$900-1,050/mo US list
• Brand Wegovy (obesity): ~$1,350/mo US list
• Compounded semaglutide (telehealth): $197-$350/mo
• Generic versions: not yet approved in US. Some markets have them.

Tirzepatide:

• Brand Mounjaro (diabetes): ~$1,000/mo US list
• Brand Zepbound (obesity): ~$1,060/mo US list
• Compounded tirzepatide: $250-$500/mo US telehealth
• Thailand clinic (brand): $180-$450/mo

Retatrutide: not on the market yet. Once launched, expect US pricing to match or slightly exceed Zepbound given the efficacy profile.

Compounded retatrutide exists in research-chem form through some grey-market vendors. We do not recommend it. Phase 3 is ongoing; the exact stable formulation Lilly will ship is not yet public; current research-chem versions are unknown-process API that may differ from what eventually gets approved.

Which should you take?

Honest decision framework:

Semaglutide if: insurance covers Wegovy, you have had pancreatitis before (the data is slightly better), or you are already stable on it and it is working.

Tirzepatide if: you want the best-published efficacy among currently-approved drugs, you can access compounded or Bangkok-clinic pricing, or you did not tolerate semaglutide at effective dose.

Retatrutide when available: if phase 3 confirms the 24%+ weight loss at the tolerable dose and you are in the camp that wants maximum efficacy over established track record. Expect 2027 US approval at earliest.

Do not stack. Combining GLP-1 class drugs is a legitimately dangerous idea that shows up in biohacker forums. The receptor saturation is the mechanism; doubling up does not double the effect, it just increases side-effect intensity and unknown interaction risk.

The Panya take

For Phase 1, our quiz routes everyone to tirzepatide by default. The reason is simple: it has the best published efficacy among drugs you can actually buy today, and the Thai clinic pricing makes it the most cost-effective option globally. When retatrutide approves, we will add a retatrutide routing path.

If you want the semaglutide match instead (because insurance covers it, because you prefer the track record, or because the GI tolerability concerns you), take the quiz and note the preference in the email response. We maintain vendor coverage for semaglutide too, though we do not lead with it.

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Citations: Wilding JPH et al. "Once-Weekly Semaglutide in Adults with Overweight or Obesity." NEJM 2021 (STEP-1); Jastreboff AM et al. NEJM 2022 (SURMOUNT-1); Frías JP et al. NEJM 2021 (SURPASS-2); Rosenstock J et al. "Retatrutide Phase 2." NEJM 2023; Eli Lilly and Novo Nordisk 2024-2025 investor disclosures.