What Is Retatrutide—and Is It More Effective Than Semaglutide or Tirzepatide for Weight Loss?
- Joshua Silva, MD
- 3 days ago
- 7 min read
Updated: 3 days ago
Retatrutide is an investigational weight-loss medication that activates three metabolic hormone receptors (GLP-1, GIP, and glucagon). In a Phase 2 clinical trial published in The New England Journal of Medicine, retatrutide produced up to 24.2% average weight loss at 48 weeks, which is numerically greater than results seen with semaglutide or tirzepatide in separate trials. However, because no head-to-head studies exist, retatrutide cannot yet be considered definitively more effective.
What Is Retatrutide and How Is It Different From GLP-1/GIP Medications?
Retatrutide is a once-weekly injectable medication designed to treat obesity by targeting three hormonal pathways involved in appetite and metabolism, whereas current FDA-approved medications target one or two.
How Retatrutide Works — GLP-1, GIP, and Glucagon Receptor Activity
Retatrutide is a triple-receptor agonist, meaning it activates:
GLP-1 receptors → reduce appetite, slow gastric emptying
GIP receptors → enhance insulin response and satiety signaling
Glucagon receptors → increase energy expenditure and fat oxidation
This differentiates it from:
Semaglutide, which activates GLP-1 only
Tirzepatide, which activates GLP-1 and GIP
Why this matters clinically: Adding glucagon receptor activity may increase total energy expenditure, potentially allowing for greater fat loss than appetite suppression alone. This is a mechanistic rationale—not yet definitive proof—behind retatrutide’s strong trial results.
Is Retatrutide a “GLP-3” Medication?
No. “GLP-3” is not a recognized hormone or pharmacologic class. The term is a marketing shorthand sometimes used to describe medications like retatrutide that activate three metabolic hormone receptors, but it does not represent an actual biological pathway.
What People Mean When They Say “GLP-3”
When people refer to “GLP-3,” they are usually describing medications that affect three metabolic targets, such as retatrutide’s activity at:
GLP-1 receptors
GIP receptors
Glucagon receptors
This naming mirrors how:
Semaglutide is often referred to as a “GLP-1” medication
Tirzepatide is sometimes called a “GLP-1/GIP” medication
However, there is no hormone called GLP-3, and no medication activates a “GLP-3 receptor.” From a medical standpoint, retatrutide is more accurately described as a triple-receptor agonist, based on its documented receptor activity.
Is Retatrutide More Effective Than Semaglutide or Tirzepatide for Weight Loss?
In separate clinical trials, retatrutide has produced greater average weight loss at 48 weeks than semaglutide or tirzepatide achieved in their respective studies. However, because these medications have not been directly compared, superiority cannot be conclusively established by scientific research standards.
What the New England Journal of Medicine (NEJM) Trials Show
Retatrutide (Phase 2 trial):
Trial duration: 48 weeks
Mean percent change in body weight ranged from −8.7% to −24.2%, depending on dose
Highest-dose group (12 mg): −24.2% mean change from baseline
Placebo group: −2.1% mean change from baseline
Tirzepatide (SURMOUNT-1):
Trial duration: 72 weeks
Highest approved dose (15 mg): −20.9% mean change from baseline
Placebo group: −3.1% mean change from baseline
Semaglutide (STEP-1):
Trial duration: 68 weeks
Semaglutide 2.4 mg: −14.9% mean change from baseline
Placebo group: −2.4% mean change from baseline
Retatrutide | Tirzepatide | Semaglutide | |
Study Duration | 48 weeks | 72 weeks | 68 weeks |
% Weight Loss | 24.2% | 20.9% | 14.9% |
How to Interpret These Results Correctly
These are cross-trial comparisons, not head-to-head data
Trial duration, dosing schedules, and populations differed
Retatrutide data currently extend to 48 weeks, while comparator trials ran 68–72 weeks
Retatrutide demonstrates exceptionally strong early efficacy, achieving substantial weight loss within a shorter trial duration than comparator studies.
However, because these medications have not been directly compared in randomized trials, retatrutide cannot yet be labeled “more effective” than semaglutide or tirzepatide by accepted clinical research standards.
Does Retatrutide Cause More Side Effects Than Tirzepatide?
In clinical trials, retatrutide’s side effects were similar in type to other GLP-1–based medications, with gastrointestinal symptoms being most common. Side effects were dose-dependent and more frequent at higher doses.
Side Effects Observed in the NEJM Retatrutide Trial
Most common: nausea, vomiting, diarrhea
Typically mild to moderate
Occurred most often during dose escalation
Higher doses were also associated with:
Increased gastrointestinal symptoms
Transient increases in heart rate that peaked mid-trial and declined later
Additional Safety Signals Under Ongoing Evaluation
In later-phase studies, abnormal skin sensations (dysesthesia) have been reported more frequently at higher doses of retatrutide. Similar sensations have been reported rarely with other incretin-based therapies, but the higher reported rates with retatrutide are an area of active evaluation as more peer-reviewed data become available.
Key limitation: Because adverse-event rates have not been directly compared in head-to-head trials, it is not scientifically accurate to conclude that retatrutide causes more side effects than tirzepatide—only that its side-effect profile appears comparable overall, dose-dependent, and still being defined as larger trials are completed.
Is Retatrutide FDA-Approved for Weight Loss?
No. Retatrutide is not FDA-approved for weight loss.
It is currently an investigational medication
Phase 3 clinical trials are ongoing
No FDA-approved indication exists at this time
FDA approval has not yet been granted, and the timing of any regulatory decision is not currently known
Should I Wait for Retatrutide Instead of Starting Semaglutide or Tirzepatide?
For most patients, waiting is not medically advisable.
Why:
Semaglutide and tirzepatide are FDA-approved
They have well-established safety data
Delaying treatment prolongs exposure to obesity-related risks such as diabetes, cardiovascular disease, and fatty liver disease
Retatrutide may become an important future option, but effective, evidence-based treatment is already available.
A Practical, Medical Approach
From a patient-care perspective, it usually makes more sense to start with an FDA-approved weight-loss medication now rather than waiting for a treatment that is still being studied.
If retatrutide becomes FDA-approved in the future and appears to be a good fit, your treatment plan can always be adjusted at that time based on the latest evidence, safety information, and your individual goals.
Bottom Line
Retatrutide may become an important option in the future, but safe, effective, and well-studied treatments are already available today. For most patients, starting treatment sooner—rather than waiting—offers the best chance to improve health and reduce long-term risks.
Do Clinics Offer Retatrutide—and Why Don’t You Prescribe It Yet?
Why Availability Does Not Equal Approval
Patients may already encounter retatrutide in several ways, including:
Clinics advertising it as a weight-loss option
Pharmacies marketing injectable formulations
Online vendors selling “research-grade” peptides
However, availability does not mean a medication is FDA-approved, clinically validated for routine use, or appropriate to prescribe.
The FDA has also stated that retatrutide is not FDA-approved and is not eligible for pharmacy compounding under current federal regulations.
At this time:
Retatrutide does not have an FDA-approved indication
Phase 3 trials are still ongoing
Long-term safety, cardiovascular outcomes, and optimal dosing ranges have not yet been established
How We Decide When a Medication Is Appropriate to Prescribe
As a medical clinic, we base prescribing decisions on more than early efficacy data alone. Before offering a medication to patients, we look for clear evidence of safety, consistency, and regulatory appropriateness, which may include FDA-approved medications or carefully selected compounded therapies when permitted.
Specifically, we consider whether a medication has:
FDA approval for the intended use, or a clear and legally supported role for compounding
Clear and reproducible dosing standards
Well-characterized safety and adverse-event profiles
Appropriate regulatory clarity regarding how it may be prescribed and dispensed
While retatrutide’s early results are promising, it does not yet meet these criteria for routine clinical use.
What to Know If You See Retatrutide Advertised Elsewhere
We understand why patients may be curious when they see retatrutide offered by other providers. It’s important to know that:
There is no FDA-approved retatrutide product for weight loss
Products offered outside clinical trials may vary in formulation, purity, and dosing assumptions
Safety and quality standards may differ
For these reasons, we believe it is safer and more responsible to use FDA-approved medications—or other appropriately regulated therapies with established evidence— until retatrutide completes the approval process.
Our Commitment to Patients
We actively follow the medical literature and clinical trial data on emerging therapies like retatrutide. If and when it becomes FDA-approved and meets appropriate safety and efficacy standards, we will evaluate its role in patient care.
Until then, our focus remains on evidence-based, regulated, and ethically prescribed treatments that prioritize patient safety and long-term outcomes.
Key Takeaway for Patients
Retatrutide represents a promising next generation of obesity treatment, with remarkable early trial results. However, until FDA approval and head-to-head studies are completed, semaglutide and tirzepatide remain the most evidence-based, medically appropriate options for weight loss today.
Disclaimer:
This article is for educational purposes only and is not a substitute for medical advice.
About the Author
Dr. Joshua Silva, MD, is a licensed physician and Medical Director of Potere Health MD. He earned his medical degree from the University of Hawaiʻi John A. Burns School of Medicine and completed residency training in Occupational and Environmental Medicine at the University of Utah, where he also earned a master’s degree in Occupational Health. He later completed a Master of Business Administration with an emphasis in health care administration at Ohio University.
Dr. Silva specializes in evidence-based weight management, including GLP-1 and GIP therapies such as semaglutide and tirzepatide. He provides in-person and virtual care for patients in Salt Lake City, St. George, and Cedar City, Utah.
Sources:
1. Jastreboff AM, Kaplan LM, Frías JP, et al; Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. N Engl J Med. 2023;389(6):514-526. doi:10.1056/NEJMoa2301972.
2. Jastreboff AM, Aronne LJ, Ahmad NN, et al; Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038.
3. Wilding JPH, Batterham RL, Calanna S, et al; Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183.
4. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; Semaglutide and cardiovascular outcomes in obesity without diabetes. N Engl J Med. 2023;389(24):2221-2232. doi:10.1056/NEJMoa2307563.
5. Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metab. 2022. doi:10.1016/j.cmet.2022.07.013.
6. Finan B, Douros JD. GLP-1/GIP/glucagon receptor triagonism gets its try in humans. Cell Metab. 2022;34(1):3-4. doi:10.1016/j.cmet.2021.12.010.
7. ClinicalTrials.gov. A study of retatrutide (LY3437943) once weekly in participants who have obesity or overweight and osteoarthritis of the knee (TRIUMPH-4). Identifier: NCT05931367.
8. US Food and Drug Administration. FDA’s concerns with unapproved GLP-1 drugs used for weight loss. Accessed January 7, 2026.
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