Semaglutide vs. Tirzepatide vs. Liraglutide and What Retatrutide Changes

At some point this month, a patient is going to ask you about retatrutide. They may call it "reta." They may already be taking it.

Retatrutide is not FDA approved. It is the strongest drug in its class so far, with 28.3% weight loss at 80 weeks in its first large obesity trial.

Liraglutide, the drug that started all this, delivered about 8% weight loss in a year. 

So the drugs got roughly three times stronger in about a decade, and some patients are getting the newest one from websites that sell it "for research use only." Which drug works is now the easy question. The harder one is what each drug costs your patient metabolically, and whether you had a baseline before it started.

Your patient may start with or without you. If they are thinking about weight loss its better to have a baseline. Explore our specialty lab tests for weight loss and management.

Key Takeaways 

• Each new drug adds a receptor target. Liraglutide and semaglutide act on GLP-1, tirzepatide adds GIP, and retatrutide adds glucagon on top of both.
• Retatrutide is investigational and not FDA approved. The FDA says it cannot be used in compounding under federal law,  and the FDA has warned about products sold online.
• Weight loss is not all fat. In the STEP 1 body-scan substudy, semaglutide reduced fat mass by 19.3% and lean mass by 9.7%, while lean mass as a share of body weight rose by 3.0 percentage points. In SURMOUNT-1, tirzepatide reduced fat mass by 33.9% and lean mass by 10.9%.
• Lipids can move a lot during weight loss. Retatrutide cut triglycerides by up to 41.0% in one trial, so repeat testing during treatment may be worth considering
• Routine bloodwork does not detect these drugs. It shows their downstream effects, so a patient's own report of use may be the only way to know. 
  
   

The GLP-1 Family Tree Is Getting Complicated

The GLP-1 family tree used to be one branch. Now it has three. Each generation adds a hormone receptor, and each receptor changes both what the drug does and what you may want to watch. 

 Headline weight loss from each drug’s main obesity trial:

• Liraglutide 3.0 mg: 8.0% vs. 2.6% with placebo at 56 weeks (SCALE)
• Semaglutide 2.4 mg: 14.9% vs. 2.4% with placebo at 68 weeks (STEP 1)
• Tirzepatide 15 mg: 20.9% vs. 3.1% with placebo at 72 weeks (SURMOUNT-1)
• Retatrutide 12 mg: 28.3% vs. 2.2% with placebo at 80 weeks (TRIUMPH-1, topline)

These numbers come from different trials with different patients and durations, so compare them loosely. Only semaglutide and tirzepatide have been tested against each other directly.

Before Ozempic, There Was Liraglutide

Liraglutide was the proof of concept. It showed that a GLP-1 receptor agonist can produce meaningful weight loss.  

A daily schedule gives patients 365 chances a year to miss a dose. Weekly dosing cuts that to 52. 

Liraglutide still shows up in practice for a few reasons: 

• Cost. The FDA approved the first generic of Victoza in December 2024, and the first generic of Saxenda launched in August 2025.
• Track record. Liraglutide was first approved in the U.S. in 2010.

For this comparison, liraglutide is the baseline. It shows what one receptor, dosed daily, produces.  

Semaglutide Changed the Conversation

Semaglutide acts on the same single receptor as liraglutide. The difference is a half-life of approximately 1 week, which allows weekly dosing, and a larger effect. In STEP 1, it produced 14.9% weight loss at 68 weeks.  

Tirzepatide Didn’t Just Add Another Letter

Tirzepatide is the first approved drug that activates two incretin receptors, GIP and GLP-1, in a single molecule. 

Lab research in human fat cells suggests tirzepatide also acts on GIP receptors in adipose tissue, where it may influence how fat is stored and released. Researchers are still working out how much each receptor contributes.  

Retatrutide Adds a Third Target and a Lot More Questions

Retatrutide is an investigational once-weekly injection from Eli Lilly. It activates three receptors: GIP, GLP-1, and glucagon.

So is retatrutide a GLP-1? Partly. It is a GLP-1 receptor agonist, but it is not only one. Calling it “a GLP-1” leaves out the part that makes it different.

What Glucagon Adds to the Equation  

Adding glucagon looks backward at first, because glucagon raises blood glucose. So why put it in a metabolic drug? 

One proposed reason is energy expenditure. Dr. Lovelle explained the problem it is meant to solve: 

“When you calorie restrict, you are also decreasing energy expenditure.”

Dr. Susan Lovelle, Access Live (21:32)

A drug that reduces intake while supporting energy expenditure may, in theory, soften the weight regain many patients see after stopping. That idea has not been proven in trials. 

Retatrutide has also been studied in the liver, in a Phase 2 substudy of people with metabolic dysfunction-associated steatotic liver disease (MASLD), the 12 mg dose reduced liver fat by 82.4% at 24 weeks, and 86% of participants on that dose reached normal liver fat. The authors reported that liver fat reductions were related to changes in body weight, abdominal fat, and metabolic measures. 

Is Retatrutide FDA Approved? Not Yet. 

As of October 2026, retatrutide is not approved for any use. Lilly has said it plans to submit retatrutide to the FDA in the first quarter of 2027.

In August 2026, Lilly also opened a limited early access pathway for a narrow group of patients with refractory obesity and serious complications who cannot enroll in a trial.

The Retatrutide Gray Market Is Already Here 

Retatrutide is sold online as a research peptide, and the FDA has warned against products labeled “for research purposes” or “not for human consumption” that are sold for human use. The agency has sent warnings to telehealth companies, ingredient suppliers, and repackagers that distribute retatrutide.

Dr. Rusilko described the wider peptide market this way:

“If you’re getting peptides offline from some telemedicine clinic where they ask you three questions and don’t check in-depth lab testing, that’s dangerous.”

Dr. Ivan Rusilko, The Lifestyle Medicine Podcast (2:20)

 The FDA notes that unapproved versions do not undergo its review for safety, effectiveness, or quality.

 ▶ Watch: How to Compliantly Add High-Margin Peptide Protocols to Your Practice with Andy Triggs