Retatrutide: The Triple Agonist That Could Redefine Weight Loss

Introduction: The Triple Agonist Era Begins

The GLP-1 receptor agonist revolution started with semaglutide and expanded with the dual agonist tirzepatide. Now, retatrutide is pushing the boundary further as the first triple agonist—a single molecule that activates GLP-1, GIP, and glucagon receptors simultaneously.

The early clinical data is remarkable. Phase 2 trials showed up to 24.2 percent body weight loss over 48 weeks, surpassing every other obesity medication tested to date. For context, semaglutide achieved approximately 15 percent in the STEP trials, and tirzepatide achieved approximately 21 percent in SURMOUNT-1. Retatrutide represents a meaningful step beyond both.

This article covers the science behind triple agonism, the clinical trial data, how retatrutide compares to existing therapies, and what the approval timeline looks like. For head-to-head comparisons, see our Retatrutide vs Tirzepatide and Retatrutide vs Semaglutide analysis pages.

What Is Retatrutide?

Retatrutide (LY3437943) is developed by Eli Lilly and Company. It is a single peptide molecule engineered to activate three distinct receptors that regulate metabolism, appetite, and energy expenditure. This is a fundamentally different approach from using separate compounds for each receptor—retatrutide does all three with one molecule.

The Three Targets:

1. GLP-1 Receptor (Glucagon-Like Peptide-1). GLP-1 receptor activation reduces appetite, slows gastric emptying, and improves insulin sensitivity. This is the mechanism behind semaglutide (Ozempic, Wegovy) and the GLP-1 component of tirzepatide (Mounjaro, Zepbound). GLP-1 agonism is the backbone of modern obesity pharmacotherapy.

2. GIP Receptor (Glucose-Dependent Insulinotropic Polypeptide). GIP is an incretin hormone that, when combined with GLP-1 agonism, enhances insulin secretion and appears to improve tolerability of GLP-1-related GI side effects. Tirzepatide was the first approved dual GLP-1/GIP agonist, and the GIP component is believed to contribute to tirzepatide's superior efficacy compared to semaglutide alone.

3. Glucagon Receptor. This is the novel addition. Glucagon is traditionally associated with raising blood glucose, but glucagon receptor activation also increases energy expenditure, promotes hepatic fat oxidation, and suppresses appetite through central nervous system pathways. The addition of glucagon receptor agonism is what makes retatrutide a triple agonist and what may explain its superior weight loss results.

Why Adding Glucagon Matters

The inclusion of glucagon receptor agonism is counterintuitive at first glance. Glucagon raises blood sugar—why would you include that in an obesity treatment? The answer lies in glucagon's broader metabolic effects beyond glucose regulation.

Energy Expenditure. Glucagon receptor activation increases thermogenesis and resting energy expenditure. In simple terms, it causes the body to burn more calories at rest. This addresses a fundamental limitation of GLP-1-only approaches: they primarily reduce caloric intake (through appetite suppression) without significantly increasing caloric expenditure. With retatrutide, you get both reduced intake and increased expenditure—attacking the energy balance equation from both sides.

Hepatic Fat Oxidation. Glucagon signaling in the liver promotes fatty acid oxidation—the burning of stored fat for fuel. This is particularly relevant for individuals with non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD), conditions that frequently co-occur with obesity. Phase 2 data showed that retatrutide reduced liver fat by up to 82 percent in participants with MASLD, a striking result.

Appetite Suppression. While GLP-1 is the primary appetite-suppressing component, glucagon receptor activation in the brain also contributes to satiety signaling. This additional appetite suppression pathway may explain why participants in retatrutide trials reported powerful appetite reduction.

The Glycemic Balance. The concern about glucagon raising blood sugar is addressed by the simultaneous GLP-1 and GIP agonism. GLP-1 and GIP both promote insulin secretion and improve glucose regulation. The insulin-promoting effects of GLP-1 and GIP counterbalance the glucose-raising effect of glucagon, resulting in net glycemic improvement rather than deterioration. In clinical trials, retatrutide improved HbA1c in participants with type 2 diabetes despite its glucagon component.

Phase 2 Trial Results: The 24 Percent Breakthrough

The pivotal phase 2 trial for retatrutide in obesity was published in the New England Journal of Medicine in 2023. This randomized, double-blind, placebo-controlled trial enrolled 338 adults with obesity (BMI 30 or higher) or overweight (BMI 27 or higher) with at least one weight-related comorbidity.

Study Design. Participants were randomized to one of several retatrutide dose groups (1 mg, 4 mg starting doses escalating to 8 mg or 12 mg, or 4 mg) or placebo, administered as once-weekly subcutaneous injections for 48 weeks. This design tested multiple dose levels to identify the optimal balance of efficacy and tolerability.

Weight Loss Results:

• Placebo group: 2.1 percent weight loss at 48 weeks
• Retatrutide 1 mg: 8.7 percent weight loss
• Retatrutide 4 mg (maintenance dose): 17.1 percent weight loss
• Retatrutide escalated to 8 mg: 22.8 percent weight loss
• Retatrutide escalated to 12 mg: 24.2 percent weight loss

The 24.2 percent weight loss at the highest dose is the largest reported in any phase 2 obesity trial. Moreover, the weight loss curve had not plateaued at 48 weeks, suggesting that even greater reductions might be achievable with longer treatment duration.

Liver Fat Reduction. In a subset of participants evaluated for liver fat, retatrutide reduced hepatic fat content by up to 82 percent at the 12 mg dose. This is one of the most impressive liver fat reduction results ever reported for any pharmacological intervention and suggests retatrutide could be a transformative treatment for MASLD.

Metabolic Improvements. Beyond weight loss, participants showed significant improvements in HbA1c, fasting glucose, lipid profiles, blood pressure, and waist circumference. These cardiometabolic benefits are consistent with, and in some cases exceed, the improvements seen with semaglutide and tirzepatide.

How Retatrutide Compares to Semaglutide and Tirzepatide

Understanding where retatrutide fits requires comparing it to the current leaders in the GLP-1 space. Note that cross-trial comparisons have limitations—different study populations, designs, and durations make direct comparison imperfect. Only head-to-head trials can provide definitive comparisons.

vs. Semaglutide (Wegovy/Ozempic). Semaglutide is a pure GLP-1 receptor agonist. In the STEP 1 trial, injectable semaglutide 2.4 mg weekly achieved approximately 14.9 percent weight loss at 68 weeks. Retatrutide achieved 24.2 percent at 48 weeks—and the curve was still declining. The difference is likely attributable to the additional GIP and glucagon receptor activation that retatrutide provides. For a detailed comparison, see our Retatrutide vs Semaglutide page.

vs. Tirzepatide (Mounjaro/Zepbound). Tirzepatide is a dual GLP-1/GIP agonist. In SURMOUNT-1, tirzepatide 15 mg weekly achieved approximately 20.9 percent weight loss at 72 weeks. Retatrutide's 24.2 percent at 48 weeks compares favorably, and the key differentiator is the glucagon receptor component. The glucagon agonism adds energy expenditure enhancement and hepatic fat oxidation that tirzepatide does not directly provide. Our Retatrutide vs Tirzepatide comparison covers this in detail.

Key Differentiators:

• Weight loss magnitude: Retatrutide shows approximately 3 to 9 percentage points greater weight loss than the current leaders, depending on the comparison
• Energy expenditure: Only retatrutide (via glucagon agonism) increases resting energy expenditure, addressing both sides of the caloric balance equation
• Liver fat: Retatrutide's 82 percent liver fat reduction is the most impressive reported for any single agent
• GI tolerability: GIP agonism may buffer GLP-1-related nausea, similar to tirzepatide's tolerability advantage over semaglutide

For the broader context of weight management peptides, visit our Weight Loss goal page.

Side Effects and Safety Profile

As with all GLP-1 class medications, gastrointestinal side effects are the primary tolerability concern with retatrutide.

GI Side Effects. The most common side effects in the phase 2 trial were nausea, diarrhea, vomiting, and constipation. These were dose-dependent and most common during dose escalation periods. At the highest dose (12 mg), approximately 16 percent of participants experienced moderate-to-severe nausea, though this diminished over time. The GI side effect profile is broadly similar to semaglutide and tirzepatide.

Heart Rate. Small increases in resting heart rate (2 to 4 beats per minute) were observed, consistent with other GLP-1 agonists. This is believed to be related to GLP-1 receptor activation in the cardiovascular system and is not considered clinically significant in most patients, though it warrants monitoring.

Glycemic Effects. Despite the glucagon component, retatrutide improved glycemic control in participants with and without type 2 diabetes. Hypoglycemia was uncommon and occurred primarily in participants concurrently using sulfonylureas or insulin. The GLP-1 and GIP components effectively counterbalanced the glucagon-mediated glucose increase.

Discontinuation Rate. The discontinuation rate due to adverse events was relatively low across dose groups, comparable to rates seen in semaglutide and tirzepatide trials. This suggests that the tolerability of retatrutide is in line with the existing GLP-1 class despite the additional receptor targets.

Long-Term Safety. As a phase 2 compound, long-term safety data beyond 48 weeks is limited. Phase 3 trials (the TRIUMPH program) will provide the longer-duration safety data needed for regulatory approval. The class-level safety signals for GLP-1 medications (thyroid C-cell tumor risk in rodents, pancreatitis risk, gallbladder disease) are being monitored in the retatrutide program as well. For an overview of peptide safety considerations, see our Are Peptides Safe? guide.

Phase 3 Trials and Approval Timeline

Eli Lilly launched the phase 3 TRIUMPH clinical trial program for retatrutide, which includes multiple trials across different indications.

TRIUMPH-1: Evaluating retatrutide for chronic weight management in adults with obesity. This is the pivotal trial for an FDA obesity indication.

TRIUMPH-2: Evaluating retatrutide for weight management in adults with obesity and type 2 diabetes.

TRIUMPH-3: Evaluating retatrutide for MASLD (metabolic dysfunction-associated steatotic liver disease), capitalizing on the remarkable liver fat reduction data from phase 2.

Approval Timeline. Based on typical phase 3 timelines and Eli Lilly's stated plans, the earliest potential FDA approval for retatrutide is expected in late 2026 to 2027. The MASLD indication could follow on a similar or slightly later timeline. These timelines are estimates and depend on enrollment speed, trial outcomes, and regulatory review timelines.

Market Context. By the time retatrutide reaches the market, it will compete with an established GLP-1 landscape that includes injectable and oral semaglutide, tirzepatide, and potentially other dual and triple agonists from competing pharmaceutical companies. The question will not be whether retatrutide works—the phase 2 data is compelling—but whether its incremental efficacy over tirzepatide justifies its cost and whether patients and providers see value in switching from established therapies.

Beyond Weight Loss: Other Potential Applications

The metabolic effects of triple agonism extend beyond weight loss, and several additional indications are being explored:

MASLD/NASH. The 82 percent liver fat reduction in phase 2 is one of the most exciting findings. Non-alcoholic fatty liver disease affects approximately 25 percent of the global population, and there are limited pharmacological treatments. Retatrutide's ability to dramatically reduce liver fat through combined GLP-1 (insulin sensitization), GIP (metabolic regulation), and glucagon (hepatic fat oxidation) pathways positions it as a potential first-line treatment for this condition.

Cardiovascular Disease. GLP-1 agonists have demonstrated cardiovascular benefits in multiple outcome trials (SUSTAIN-6, SELECT). Whether the addition of GIP and glucagon agonism enhances or modifies these cardiovascular benefits is an important question that phase 3 and post-marketing studies will need to address.

Sleep Apnea. Significant weight loss consistently improves obstructive sleep apnea. Tirzepatide recently demonstrated efficacy in treating sleep apnea independent of weight loss. Retatrutide, with even greater weight loss potential, may similarly benefit this common obesity comorbidity.

Kidney Disease. GLP-1 agonists have shown renoprotective effects (the FLOW trial for semaglutide). Whether triple agonism provides additional kidney benefits is an area of active research interest.

The Bottom Line

Retatrutide represents the next frontier in metabolic pharmacotherapy. By combining GLP-1, GIP, and glucagon receptor agonism in a single molecule, it attacks obesity and metabolic disease from three complementary angles: appetite suppression, incretin-mediated glycemic improvement, and glucagon-driven energy expenditure enhancement.

The phase 2 data—24.2 percent weight loss at 48 weeks with the weight curve still declining—is the most impressive obesity pharmacotherapy result published to date. The liver fat reduction data (82 percent) opens a potential new therapeutic frontier in MASLD treatment. And the safety profile, while requiring longer-term confirmation in phase 3, appears consistent with the established GLP-1 class.

What remains to be determined is whether phase 3 results confirm the phase 2 promise, what the long-term safety profile looks like beyond 48 weeks, and how retatrutide will be positioned relative to tirzepatide and semaglutide in clinical practice. The TRIUMPH program will provide those answers over the next 1 to 2 years.

For the full compound profile, visit our Retatrutide compound guide. For comparisons with existing therapies, see Retatrutide vs Tirzepatide and Retatrutide vs Semaglutide. And for the broader weight management landscape, explore our Weight Loss goal page.