The last five years have transformed the landscape of obesity and metabolic disease treatment. GLP-1 receptor agonists like semaglutide (Ozempic, Wegovy) proved that pharmacologic therapy could drive double-digit percentage weight loss. Dual agonists like tirzepatide (Mounjaro, Zepbound), which activate both GLP-1 and GIP receptors, raised the bar even higher.
Now, the next wave of incretin drugs is in development: triple agonists. The lead candidate, retatrutide, activates GLP-1, GIP, and glucagon receptors simultaneously.
Phase 2 trial results show unprecedented weight loss - up to 24 percent at 48 weeks in non-diabetic participants - but many questions remain about safety, tolerability, and durability.
This article is a comprehensive guide to triple agonists: what they are, how retatrutide works, what clinical trial results tell us, how it compares to GLP-1s and dual agonists, and the open questions researchers are still asking.
What Are Triple Agonists?
Triple agonists are investigational drugs that activate three hormone receptors involved in appetite, metabolism, and energy expenditure:
GLP-1 receptor: drives satiety, slows gastric emptying, boosts insulin.
GIP receptor: complements GLP-1 effects, may reduce side effects.
Glucagon receptor: increases energy expenditure and fat oxidation.
By engaging all three, triple agonists aim to shift both sides of the energy balance equation: fewer calories in, more calories out.
Incretin Biology: GLP-1, GIP, and Glucagon
GLP-1 (Glucagon-Like Peptide-1)
Secreted by intestinal L-cells after meals.
Enhances insulin secretion, reduces glucagon secretion, slows gastric emptying, and increases satiety.
Pharmacologic GLP-1 agonists (semaglutide, liraglutide) have shown weight loss of 10–15 percent on average.
GIP (Glucose-Dependent Insulinotropic Polypeptide)
Secreted by K-cells in the small intestine.
Potentiates insulin release in a glucose-dependent manner.
Alone, GIP analogs showed modest benefit, but combined with GLP-1 they synergize, as shown in tirzepatide.
Glucagon
Classically known for raising blood glucose by stimulating hepatic glucose production.
Also increases energy expenditure and promotes lipid oxidation.
In obesity, harnessing glucagon’s fat-burning properties may offset the metabolic slowdown that accompanies weight loss.
How Retatrutide Works
Retatrutide is a GLP-1/GIP/glucagon receptor triple agonist.
GLP-1 arm: reduces appetite and improves glucose control.
GIP arm: enhances insulin sensitivity and may improve tolerability of GLP-1 stimulation.
Glucagon arm: increases resting energy expenditure and encourages fat metabolism.
The combined result is decreased caloric intake plus increased caloric burn. This may explain the greater weight loss compared to GLP-1 or dual agonist drugs.
Clinical Trial Results for Retatrutide
Phase 2 Obesity Trial (NEJM, 2023)
Participants: Adults with obesity without diabetes.
Duration: 48 weeks.
Results:
Mean weight loss of 24.2 percent at highest dose.
Over half of participants lost at least 20 percent of baseline body weight.
Improvements in blood pressure, cholesterol, and markers of insulin resistance.
Type 2 Diabetes Cohort
Participants with type 2 diabetes also saw weight loss and glycemic improvements, though less than in non-diabetics (similar to semaglutide and tirzepatide patterns).
Side Effects
GI symptoms (nausea, vomiting, diarrhea) were common but similar to other incretin drugs.
Some participants discontinued due to side effects.
Long-term cardiovascular safety data are not yet available.
Therapy | Receptors Targeted | Avg Weight Loss in Trials | FDA Status | Key Notes | |
|---|---|---|---|---|---|
Semaglutide | GLP-1 | 12–15% (STEP trials) | Approved | Weekly injection, robust data on CV risk reduction | |
GLP-1 + GIP | 20–22% (SURMOUNT trials) | Approved | Dual agonist synergy, superior to semaglutide in head-to-head | ||
Retatrutide | GLP-1 + GIP + Glucagon | Up to 24% (Phase 2) | In trials | Triple mechanism, questions about glucagon safety |
Why Triple Agonists Look Different
Triple agonists may produce stronger results because they increase energy expenditure in addition to reducing intake. Traditional weight loss leads to a metabolic slowdown, but glucagon agonism may counter that adaptation.
Patients may therefore lose more fat mass while preserving more lean mass, although definitive body composition data are still limited.
Open Questions and Safety Concerns
Long-term safety: What happens with chronic glucagon receptor activation? Will cardiovascular effects or muscle catabolism appear with time?
Lean mass preservation: Will retatrutide protect muscle better than GLP-1s, or will loss rates be similar?
Durability: Is the 24 percent loss sustainable for multiple years? What happens when therapy is discontinued?
Tolerability: GI side effects are still common. Will triple agonists prove harder to tolerate than duals?
Indications beyond obesity: Could triple agonists be effective in non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, or sarcopenic obesity?
These questions will be answered in phase 3 studies and longer follow-up.
Where Triple Agonists Might Fit in the Treatment Roadmap
Not first-line yet. GLP-1s are already highly effective and approved.
Step-up therapy. For patients who plateau on GLP-1s or tirzepatide, triple agonists may be next in line.
Severe obesity. Patients needing >20 percent body weight reduction may benefit most.
Research settings. Until more data are available, triple agonists remain investigational.
Lifestyle foundations (nutrition, resistance training, stress, sleep) will always remain essential. Triple agonists may accelerate progress but cannot replace these fundamentals.
Key Takeaways
Triple agonists like retatrutide target GLP-1, GIP, and glucagon receptors simultaneously.
Phase 2 trials show unprecedented weight loss, up to 24 percent at 48 weeks in non-diabetic adults.
They appear to increase energy expenditure as well as reduce intake, setting them apart from GLP-1s.
Safety, tolerability, lean mass preservation, and long-term durability remain open questions.
Triple agonists may become the next generation of obesity and metabolic drugs but are still under investigation.
FAQs
What is retatrutide?
A triple agonist drug in development that activates GLP-1, GIP, and glucagon receptors.
How much weight loss can it produce?
Up to 24 percent of body weight at 48 weeks in phase 2 trials.
How does it compare to semaglutide or tirzepatide?
Retatrutide produced greater average weight loss in early trials. Semaglutide targets only GLP-1. Tirzepatide targets GLP-1 and GIP.
Is retatrutide FDA-approved?
Not yet. It is in clinical development.
What are the risks?
GI side effects are common. Long-term safety of glucagon receptor activation remains unknown.
References
Jastreboff AM, et al. Retatrutide, a Triple GIP, GLP-1, and Glucagon Receptor Agonist, for Obesity. N Engl J Med. 2023.
Drucker DJ. The expanding field of incretin-based therapies. Cell Metab. 2022.
Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021.
Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022.
Nauck MA, et al. Clinical pharmacology of incretin hormones. Lancet Diabetes Endocrinol. 2021.
