Tirzepatide vs. Retatrutide: Next-Gen Weight Loss

Two receptors or three? That is the question shaping the next decade of obesity medicine.

Tirzepatide is already here. Sold as Mounjaro for diabetes and Zepbound for weight management, it has delivered weight loss numbers that seemed impossible just five years ago -- up to 25.3% body weight reduction in the longest trial arm. And then Eli Lilly, the same company behind tirzepatide, unveiled something even more ambitious: retatrutide, a triple receptor agonist that adds glucagon signaling to the mix and has posted 28.7% weight loss in its first Phase 3 readout.

Both drugs come from Lilly. Both target the incretin system. But their designs reflect fundamentally different theories about what it takes to move the needle on severe obesity. This article breaks down how they work, what the clinical data actually shows, where the safety profiles diverge, and what all of it means for the future of weight loss treatment.

Quick Comparison Table
How Tirzepatide Works: The Dual Agonist
How Retatrutide Works: The Triple Agonist
Clinical Trial Data: Head-to-Head Numbers
Safety and Side Effects
Beyond Weight Loss: Metabolic Effects
Availability, Cost, and Timeline
Who Might Benefit From Each
The Bottom Line
References

Quick Comparison Table

Feature	Tirzepatide (Mounjaro/Zepbound)	Retatrutide (Investigational)
Drug Class	Dual GIP/GLP-1 receptor agonist	Triple GIP/GLP-1/glucagon receptor agonist
Manufacturer	Eli Lilly	Eli Lilly
Dosing	Once weekly (subcutaneous)	Once weekly (subcutaneous)
Available Doses	2.5, 5, 7.5, 10, 12.5, 15 mg	1, 4, 8, 9, 12 mg (investigational)
Max Weight Loss (Trials)	~25.3% (SURMOUNT-4, 88 weeks)	~28.7% (TRIUMPH-4, 68 weeks)
FDA Status	Approved (T2D: 2022; Obesity: 2023)	Phase 3 trials ongoing
Estimated Market Entry	Available now	Late 2026 to mid-2027 (projected)
Trial Program	SURMOUNT (5 completed Phase 3 trials)	TRIUMPH (1 Phase 3 readout; 7 more expected 2026)
Monthly Cost	$25-$1,086 (varies by coverage)	Not yet priced

How Tirzepatide Works: The Dual Agonist

Tirzepatide is a 39-amino-acid synthetic peptide that activates two receptors simultaneously: GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1). Both are incretin hormones -- natural gut peptides released when you eat.

Here is what each receptor does when activated:

GLP-1 receptor activation slows gastric emptying, meaning food stays in the stomach longer. It signals fullness to the brain through receptors in the hypothalamus and brainstem. It stimulates insulin release in a glucose-dependent way (only when blood sugar is elevated) and suppresses glucagon secretion, which reduces the liver's glucose output.

GIP receptor activation also promotes insulin secretion in response to meals, but it does something GLP-1 does not: it influences lipid metabolism in fat tissue and may improve how efficiently the body stores and burns energy. Tirzepatide has a stronger affinity for the GIP receptor than the GLP-1 receptor, which distinguishes it structurally from GLP-1-only drugs like semaglutide.

The combined effect -- what researchers sometimes call "twincretin" activity -- produces stronger insulin response and greater appetite reduction than either hormone alone. Co-infusion studies showed that GIP and GLP-1 together create a synergistic effect: the whole is meaningfully greater than the sum of its parts.

A C20 fatty di-acid chain attached to the peptide allows it to bind albumin in the blood, extending its half-life to roughly five days and enabling once-weekly dosing. The SURMOUNT trial program confirmed the clinical payoff: at the highest dose (15 mg), participants lost an average of 20.9% of their body weight over 72 weeks.

How Retatrutide Works: The Triple Agonist

Retatrutide keeps everything tirzepatide does -- GIP and GLP-1 receptor activation -- and adds a third target: the glucagon receptor.

This is counterintuitive. Glucagon raises blood sugar. For decades, diabetes treatment was partly about suppressing glucagon. So why would you deliberately activate its receptor in a weight loss drug?

Because glucagon does more than raise blood sugar. When the glucagon receptor is activated, the liver ramps up fatty acid oxidation -- burning stored fat for fuel. Energy expenditure rises. The body shifts from storing calories to spending them. In preclinical models, retatrutide-treated animals showed increased energy expenditure even when their calorie intake was matched to control animals. The drug was not just making them eat less. It was making them burn more.

The receptor potency hierarchy matters here. Retatrutide is most potent at the GIP receptor (EC50: 0.064 nM), moderately potent at GLP-1 (EC50: 0.775 nM), and least potent at the glucagon receptor (EC50: 5.79 nM). This grading appears intentional -- strong enough glucagon activation to boost fat oxidation and energy expenditure, but not so strong that it overwhelms glycemic control.

The result is a three-pronged attack on obesity:

Appetite suppression and slower gastric emptying (GLP-1 and GIP)
Improved insulin secretion and glucose control (GLP-1 and GIP)
Increased energy expenditure and fat burning (glucagon receptor)

Retatrutide has a half-life of approximately six days, allowing once-weekly subcutaneous injection. In the Phase 2 trial, participants on the 12 mg dose lost 24.2% of their body weight at 48 weeks -- and had not yet plateaued, suggesting the full weight loss potential was not captured within the study window.

Clinical Trial Data: Head-to-Head Numbers

No direct head-to-head trial between tirzepatide and retatrutide has been conducted. Comparing results across separate trials always carries limitations -- different patient populations, varying baseline BMIs, different study durations. With that caveat front and center, here is what the data shows.

Tirzepatide: The SURMOUNT Program

The SURMOUNT trials represent one of the most comprehensive Phase 3 obesity programs ever run. Five completed trials, thousands of participants.

SURMOUNT-1 (72 weeks, no diabetes): At the 15 mg dose, participants lost a mean of 20.9% body weight. More than half (57%) of those on 15 mg achieved 20% or greater weight loss. Over 90% achieved at least 5% loss.

SURMOUNT-3 (lifestyle intervention + drug): After a 12-week intensive lifestyle lead-in, tirzepatide added another 18.4% weight reduction over 72 weeks, for a combined treatment effect exceeding 20 percentage points over placebo.

SURMOUNT-4 (weight maintenance): Participants who took tirzepatide for 36 weeks lost 20.9%, then those who continued the drug for another 52 weeks achieved a total loss of 25.3% from study entry. Those switched to placebo regained 14% of body weight -- a stark demonstration of how continued treatment sustains results.

SURMOUNT-5 (head-to-head vs. semaglutide): The first direct comparison between the two biggest names in the field. In this open-label trial of 751 adults with obesity and no diabetes, tirzepatide produced 20.2% weight loss versus 13.7% for semaglutide at 72 weeks -- a statistically significant 6.5-percentage-point gap. Waist circumference followed the same pattern. This trial confirmed what many researchers suspected: dual agonism outperforms GLP-1 alone.

Across all five SURMOUNT trials, a consistent pattern emerged. Weight loss at the 15 mg dose ranged from 20% to 25%, depending on study design and duration. Longer treatment produced more weight loss, and the curves had not fully plateaued even at 72-88 weeks. Body composition analysis from SURMOUNT-1 showed that tirzepatide reduced both fat mass and lean mass, with the ratio of fat-to-lean loss remaining relatively stable across subgroups.

Retatrutide: Phase 2 and TRIUMPH Phase 3

Retatrutide's clinical story is still being written, but the early chapters are striking.

Phase 2 trial (48 weeks, published in the New England Journal of Medicine): 338 adults with obesity or overweight (without diabetes) were randomized to retatrutide or placebo. At the 12 mg dose, participants lost 24.2% of body weight -- an average of about 58 pounds over 11 months. At 8 mg, the loss was 22.8%. The threshold data is particularly telling: 100% of participants on the 8 mg and 12 mg doses achieved at least 5% weight loss. At the 12 mg dose, 93% hit 10%, and 83% reached 15% or more. The weight curves had not flattened at 48 weeks, meaning the true ceiling of retatrutide's effect remained unmeasured.

TRIUMPH-4 (68 weeks, Phase 3, obesity + knee osteoarthritis): The 12 mg dose produced 28.7% mean weight loss -- roughly 71.2 pounds on average. The 9 mg dose produced 26.4%. These numbers represent some of the highest weight reductions ever achieved with a pharmaceutical agent. Beyond weight loss, retatrutide reduced knee pain scores (WOMAC) by up to 75.8%, compared with 40.3% for placebo.

Network Meta-Analysis

A 2025 network meta-analysis published in the Journal of the Endocrine Society compared both drugs statistically using pooled data from their respective trials. Retatrutide showed greater absolute weight reduction (mean difference from placebo: -16.34 kg) versus tirzepatide (-11.82 kg). For percentage weight loss, retatrutide achieved -23.77% versus tirzepatide's -16.79%.

These cross-trial comparisons should be treated with appropriate caution. Different study populations and designs make direct comparison imprecise. But the trend is consistent: retatrutide's triple-agonist mechanism appears to produce meaningfully greater weight loss than tirzepatide's dual-agonist approach.

Safety and Side Effects

Both drugs share the gastrointestinal side effects common to all incretin-based therapies. Nausea, diarrhea, vomiting, and constipation are the most frequent complaints, and they are generally dose-related and more common during titration.

Tirzepatide Safety Profile

Tirzepatide benefits from a large and mature safety database. Across the SURMOUNT and SURPASS programs (the latter for diabetes), GI side effects were mostly mild to moderate and declined over time. Serious adverse events were uncommon.

The most common side effects at the 15 mg dose include:

Nausea (~25-30%)
Diarrhea (~18-22%)
Constipation (~10-12%)
Vomiting (~8-12%)

Gradual dose escalation -- starting at 2.5 mg and increasing by 2.5 mg every four weeks -- helps mitigate early GI symptoms. Real-world experience since its 2022 approval has largely confirmed what the trials showed. No major unexpected safety signals have emerged.

Retatrutide Safety Profile

Retatrutide's safety picture is less complete, and the data that does exist shows a somewhat rougher ride.

In TRIUMPH-4, the GI side effect rates at the 12 mg dose were:

Nausea: 43.2% (vs. 10.7% placebo)
Diarrhea: 33.1% (vs. 13.4% placebo)
Constipation: 25.0% (vs. 8.7% placebo)
Vomiting: 20.9% (vs. 0.0% placebo)

These rates run higher than tirzepatide's profile, consistent with what the 2025 network meta-analysis found: retatrutide had a higher relative risk of adverse events (RR 4.10) compared with tirzepatide (RR 2.78) versus their respective placebo arms.

The dysesthesia signal. The most notable new finding from TRIUMPH-4 was dysesthesia -- abnormal touch sensations like tingling, numbness, or unusual skin sensitivity. At the 12 mg dose, 20.9% of patients reported it. At 9 mg, 8.8%. In the placebo arm, just 0.7%. This side effect was not observed in the earlier Phase 2 trial. The events were mostly mild and rarely led to discontinuation, but the dose-response pattern (roughly 1 in 5 patients at the highest dose) has drawn attention from analysts and will be watched closely in upcoming TRIUMPH readouts.

Discontinuation due to adverse events was 18.2% at the 12 mg dose and 12.2% at 9 mg, compared with 4.0% for placebo. Lilly noted these rates were higher in patients with lower baseline BMI and included some discontinuations for "perceived excessive weight loss" -- a problem previous generations of obesity drugs could only dream of having.

Safety Comparison Summary

Safety Factor	Tirzepatide	Retatrutide
GI side effects	Common, mostly mild-moderate	More frequent, dose-dependent
Nausea rate (highest dose)	~25-30%	~43%
Dysesthesia	Not reported	8.8-20.9% (dose-dependent)
Discontinuation (AEs)	Low (~5-7%)	Higher (~12-18%)
Long-term data	3+ years of real-world use	Phase 3 (68 weeks max)
Post-marketing experience	Extensive	None (not yet approved)

Beyond Weight Loss: Metabolic Effects

Weight loss alone does not capture the full story. Both drugs produce broad metabolic improvements, but retatrutide's glucagon receptor activity gives it a potential edge in one area in particular: the liver.

Liver Fat

This is where retatrutide separates itself most dramatically from every other drug in the obesity pipeline. In a Phase 2a substudy of participants with metabolic dysfunction-associated steatotic liver disease (MASLD), retatrutide at 12 mg reduced liver fat by 86% at 48 weeks. At 8 mg, the reduction was 81.7%. Among those on the highest doses, 89-93% achieved normal liver fat levels (below 5%).

These numbers are extraordinary. Tirzepatide also reduces liver fat, but not to this degree. The difference likely stems from glucagon receptor activation, which stimulates hepatic fatty acid oxidation -- the liver literally burns its stored fat. Levels of beta-hydroxybutyrate, a biomarker of fat oxidation, increased two- to threefold in retatrutide-treated patients, with the largest increases occurring by week 24, right when most of the liver fat reduction happened.

For the estimated 100 million Americans with fatty liver disease, this is not an academic detail. It could represent a genuine therapeutic advance.

Cardiovascular and Metabolic Markers

Both drugs improve the usual panel of metabolic markers: blood pressure, triglycerides, LDL cholesterol, HbA1c, fasting glucose, and fasting insulin. Tirzepatide has more granular data here, simply because it has been studied longer and in more populations.

Retatrutide's Phase 2 data showed significant improvements in insulin sensitivity (HOMA2-IR reduced by up to 69.3%) and increases in adiponectin (up to 99.3%) -- both meaningful metabolic signals. Whether these translate into hard cardiovascular outcomes like reduced heart attacks and strokes is a question the ongoing TRIUMPH cardiovascular outcomes trial is designed to answer.

Availability, Cost, and Timeline

Tirzepatide: Available Now

Tirzepatide has been on the market since 2022 (Mounjaro for type 2 diabetes) and 2023 (Zepbound for weight management). It is the established option.

Pricing: Zepbound carries a list price of $1,086 per month. What patients actually pay varies widely. With commercial insurance and a savings card, copays can be as low as $25 per month. Lilly's direct-to-patient program (LillyDirect) offers single-dose vials at $299 per month for self-pay patients. Insurance coverage is expanding but remains uneven -- roughly 16-43% of employers covered GLP-1 drugs for weight loss as of 2025, with the number trending upward in 2026. Medicare Part D coverage for weight loss indications is expected to expand this year.

For a comprehensive look at how Zepbound compares to other branded GLP-1 drugs on the market, see our full market comparison.

Retatrutide: Not Yet Available

Retatrutide remains investigational. It cannot be prescribed, purchased, or legally obtained outside of clinical trials. Any online source claiming to sell retatrutide is operating outside regulatory oversight.

Timeline: The TRIUMPH-4 Phase 3 results dropped in December 2025. Seven more Phase 3 readouts are expected throughout 2026. Lilly has not announced an official NDA submission date, but analyst projections place it in late 2025 to early 2026, with FDA approval possible in late 2026 to mid-2027. GlobalData projects approval in 2027, with peak sales forecasts of $15.6 billion by 2031.

If history is any guide, expect another 12-18 months of insurance access battles after approval before retatrutide becomes widely available -- a pattern familiar to anyone who tracked tirzepatide's rollout.

Who Might Benefit From Each

These are general considerations, not medical recommendations. Any decision about weight loss medication should involve a physician who knows your full medical history.

Tirzepatide may be the right fit if:

You want a proven, FDA-approved treatment available today
You prefer a drug with years of real-world safety data
You have type 2 diabetes alongside obesity (tirzepatide has robust glycemic data)
You are looking for a treatment your insurance may already cover
You have had success with GLP-1 drugs and want a step up in efficacy

Retatrutide may be worth watching if:

You need more aggressive weight loss than current options provide
You have significant fatty liver disease (MASLD/MASH)
You are interested in enrolling in a clinical trial
You have not responded adequately to existing incretin therapies
You are willing to wait for approval and accept the unknowns of a newer drug

For broader context on how these drugs fit into the evolving peptide-based approach to obesity, including other emerging agents like survodutide, see our clinical evidence guides.

The Bottom Line

Tirzepatide changed what was possible in obesity medicine. Retatrutide may change it again.

The data, even viewed conservatively, tells a consistent story. Tirzepatide's dual-agonist mechanism delivers 20-25% body weight reduction with a well-characterized safety profile and years of clinical experience. Retatrutide's triple-agonist approach -- adding glucagon receptor activation to drive fat burning and energy expenditure -- pushes the ceiling higher, with 26-29% weight loss in Phase 3 and liver fat reductions that no other drug in the class has matched.

But more is not always better. Retatrutide's higher side effect rates, the emerging dysesthesia signal, and the complete absence of long-term safety data mean it carries more uncertainty. Tirzepatide is a known quantity backed by five completed Phase 3 trials, millions of prescriptions filled, and an expanding evidence base from real-world use.

There is also a practical dimension. Tirzepatide is available right now. Retatrutide is probably 12-24 months from FDA approval, assuming the remaining TRIUMPH trials go well. For someone struggling with severe obesity today, "wait for the next drug" is rarely good advice.

The most likely future is not either/or but both/and. Different patients will benefit from different approaches. Some may start on tirzepatide now and switch to retatrutide later. Some may need the liver-fat-lowering effects that triple agonism uniquely provides. Some may do perfectly well on a dual agonist and never need the third receptor.

What matters is that the options are expanding. Five years ago, losing 20% of body weight with a weekly injection was science fiction. Now it is an FDA-approved treatment -- and a triple agonist that pushes past 25% is closing in on approval. The gap between what obesity medicine can offer and what patients actually need is narrowing. Fast.

References

Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387:205-216. doi:10.1056/NEJMoa2206038
Jastreboff AM, et al. Triple-hormone-receptor agonist retatrutide for obesity -- a Phase 2 trial. New England Journal of Medicine. 2023;389:514-526. doi:10.1056/NEJMoa2301972
Aronne LJ, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38-48.
Wadden TA, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 Phase 3 trial. Nature Medicine. 2023;29:2909-2918.
Lilly press release. Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. December 11, 2025.
Sanyal AJ, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized Phase 2a trial. Nature Medicine. 2024;30:2037-2048.
Network meta-analysis: Comparative efficacy and safety of tirzepatide vs retatrutide in weight loss. Journal of the Endocrine Society. 2025.
Rodriguez PJ, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. New England Journal of Medicine. 2025. doi:10.1056/NEJMoa2416394
Lilly. Retatrutide TRIUMPH registrational clinical trial program. ClinicalTrials.gov: NCT05931367.
Eli Lilly and Company. Zepbound prescribing information. Updated 2025.

This article is for educational purposes only and does not constitute medical advice. PeptideJournal.org does not sell peptides or recommend specific treatments. Consult a qualified healthcare provider before making any decisions about medications discussed in this article.

Last reviewed: February 2026

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