GLP-1 medications have reshaped how doctors treat type 2 diabetes and obesity. Three names dominate the conversation: semaglutide, tirzepatide and retatrutide. They’re related but not the same. This guide explains how each works, what the major trials found, how approved dosing is structured, and what’s still unknown.
Key takeaways
- Semaglutide targets one receptor (GLP-1), tirzepatide two (GLP-1 and GIP), and retatrutide three (GLP-1, GIP and glucagon).
- In their main trials, average weight loss was about 15% for semaglutide 2.4 mg, up to about 21% for tirzepatide 15 mg, and about 24% for retatrutide 12 mg in phase 2.
- Semaglutide and tirzepatide are FDA-approved. Retatrutide was still investigational at the time of writing.
- GI side effects are the most common and are managed mainly by slow dose increases.
What is GLP-1?
Glucagon-like peptide-1 (GLP-1) is a hormone your gut releases after you eat. It:
- Tells the pancreas to release insulin when blood sugar is high
- Lowers glucagon, a hormone that raises blood sugar
- Slows how quickly the stomach empties
- Acts on the brain to increase fullness and reduce appetite
Natural GLP-1 is broken down within minutes. The drugs are engineered analogs that last days, which is why they can be taken once a week. For the underlying biology, see our GLP-1, GIP & Glucagon page.
Side-by-side comparison
| Semaglutide | Tirzepatide | Retatrutide | |
|---|---|---|---|
| Receptors | GLP-1 | GLP-1 + GIP | GLP-1 + GIP + glucagon |
| Maker | Novo Nordisk | Eli Lilly | Eli Lilly |
| Brand names | Ozempic (diabetes), Wegovy (weight), Rybelsus (oral, diabetes) | Mounjaro (diabetes), Zepbound (weight, sleep apnea) | None |
| Half-life | About 1 week | About 5 days | About 6 days (in trials) |
| Key weight-loss trial | STEP 1: ~14.9% at 68 weeks (2.4 mg) vs ~2.4% placebo | SURMOUNT-1: ~15–21% at 72 weeks (5–15 mg) vs ~3% placebo | Phase 2: ~24% at 48 weeks (12 mg) vs ~2% placebo |
| Status | FDA-approved | FDA-approved | Investigational at time of writing |
Trial results are averages among participants in specific studies and don’t predict individual results.
Semaglutide
Semaglutide was the drug that pushed GLP-1s into the mainstream. Beyond weight loss, the SELECT trial found that Wegovy reduced the risk of major cardiovascular events in adults with heart disease and overweight or obesity, which led to an expanded label.
FDA-labeled dosing for Wegovy (weight management)
| Weeks | Weekly dose |
|---|---|
| 1–4 | 0.25 mg |
| 5–8 | 0.5 mg |
| 9–12 | 1 mg |
| 13–16 | 1.7 mg |
| 17 onward | 2.4 mg maintenance |
The prescribing information allows for slower escalation if side effects aren’t tolerated. Always follow the current label and your prescriber.
Tirzepatide
Tirzepatide adds GIP (glucose-dependent insulinotropic polypeptide), a second gut hormone. Why GIP helps is still being studied, but in head-to-head research tirzepatide produced more weight loss than semaglutide on average.
FDA-labeled dosing for Zepbound
Start at 2.5 mg once weekly for 4 weeks. Increase in 2.5 mg steps after at least 4 weeks on the current dose. Maintenance doses are 5 mg, 10 mg or 15 mg weekly, with 15 mg the maximum.
Retatrutide
Retatrutide adds glucagon receptor activity. That sounds backward, since glucagon raises blood sugar, but glucagon also increases energy expenditure and fat burning in the liver. Balanced against GLP-1 and GIP effects, the phase 2 results were the largest average weight loss seen from a single medication at that time.
Retatrutide has no FDA-approved dose. Phase 3 trials were underway at the time of writing. Products sold online as “retatrutide” or “reta” are not approved drugs. Check official Eli Lilly and FDA sources for updates on its status.
Common side effects
- GI effects: nausea, diarrhea, constipation, vomiting and reflux. Most common during dose increases.
- Reduced appetite (which is part of how the drugs work)
- Injection-site reactions
- Loss of lean mass along with fat, which is why protein intake and resistance training are often emphasized
Serious warnings on the labels
- Boxed warning for thyroid C-cell tumors seen in rodents. Not for people with a personal or family history of medullary thyroid carcinoma or MEN 2.
- Pancreatitis, gallbladder problems, kidney injury from dehydration, and low blood sugar when combined with insulin or sulfonylureas
- Delayed stomach emptying can matter before surgery and can affect absorption of oral medications, including some birth control pills with tirzepatide
Brand-name vs compounded vs “research”
Brand-name products are made under FDA drug manufacturing rules. Compounded versions became widespread during shortages, and their legal status shifted as shortages ended. Products labeled “research use only” are a different category entirely. See what RUO really means.
The bottom line
Semaglutide and tirzepatide are well-studied, FDA-approved medications with clear labeled dosing. Retatrutide looks promising but isn’t approved. The right choice depends on your health history, goals, insurance and how you tolerate side effects, which is a conversation for a licensed prescriber.
Frequently asked questions
Which GLP-1 causes the most weight loss?
In published trials, average weight loss was highest with retatrutide (phase 2), followed by tirzepatide, then semaglutide. Only semaglutide and tirzepatide are FDA-approved.
Is tirzepatide a GLP-1?
Tirzepatide activates both GLP-1 and GIP receptors, so it’s a dual agonist. It’s usually grouped with GLP-1 medications.
Is retatrutide FDA-approved?
Not at the time of writing. It was in phase 3 clinical trials. Check official sources for the latest status.
What is the most common side effect of GLP-1 drugs?
Nausea is the most common, followed by other GI effects like diarrhea and constipation. They are usually worst during dose increases.
Medical disclaimer: Pep Guide is for educational purposes only. It is not medical advice, diagnosis or treatment. Research changes over time. Talk to a licensed healthcare provider before starting, stopping or changing any medication or compound.