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Peptides for Obesity: Clinical Evidence Review

Obesity treatment has been transformed by peptide therapeutics. Between 2021 and 2025, GLP-1 receptor agonists went from niche diabetes drugs to front-page news, producing weight loss results that had previously required surgery.

Obesity treatment has been transformed by peptide therapeutics. Between 2021 and 2025, GLP-1 receptor agonists went from niche diabetes drugs to front-page news, producing weight loss results that had previously required surgery. In December 2025, the World Health Organization issued its first-ever guideline on GLP-1 therapies for obesity -- a signal of just how strong the evidence has become.

But "peptides for obesity" is a broad category. It includes FDA-approved medications backed by trials involving tens of thousands of patients. It also includes compounds that failed their clinical trials years ago but are still sold through peptide clinics. This review walks through the clinical evidence for every major peptide studied for obesity, separating what the data actually shows from what marketing materials suggest.

Table of Contents

Why Peptides Work for Obesity

Obesity is not a willpower problem. It is a disease driven by hormonal signaling, neurological reward circuits, and metabolic set points that resist weight loss. Peptides work for obesity because they intervene at these biological levels rather than simply restricting food intake.

The dominant mechanism is incretin mimicry. Your gut naturally releases GLP-1 (glucagon-like peptide-1) after meals, signaling satiety to the brain and slowing stomach emptying. In people with obesity, these signals are often blunted. GLP-1 receptor agonists like semaglutide and tirzepatide amplify this signaling far beyond what the body produces naturally, reducing appetite at the level of the hypothalamus and altering food reward pathways [1, 2].

A second mechanism involves direct metabolic effects. Glucagon receptor activation (targeted by newer agents like retatrutide) increases hepatic fat oxidation and energy expenditure. GIP receptor agonism, the other half of tirzepatide's dual action, appears to improve fat metabolism through pathways researchers are still working to fully map [3].

A third, more modest mechanism involves growth hormone-mediated lipolysis. Peptides like AOD-9604 and tesamorelin aim to break down stored fat directly, without suppressing appetite. This approach sounds appealing in theory. In practice, the weight loss it produces is a fraction of what GLP-1 drugs achieve.

The reason for that gap is straightforward: energy balance is primarily driven by caloric intake. A drug that reduces food intake by 20-30% will produce far greater weight loss than one that modestly increases the rate at which fat is burned. This is exactly what clinical trial data shows, as the sections below make clear.

FDA-Approved GLP-1 Peptides

Three peptide-based medications are currently FDA-approved for chronic weight management. Each has been tested in large, randomized, placebo-controlled trials -- the gold standard for evaluating a drug's efficacy.

Semaglutide (Wegovy)

Semaglutide is a once-weekly GLP-1 receptor agonist that became the benchmark for modern obesity pharmacotherapy. Its clinical trial program, known as STEP (Semaglutide Treatment Effect in People with obesity), is one of the largest ever conducted for a weight loss medication.

Key trial results:

  • STEP 1 (1,961 adults without diabetes): Mean weight loss of 14.9% over 68 weeks, versus 2.4% with placebo. More than half (51%) of semaglutide-treated participants lost at least 15% of body weight [1].
  • STEP 3 (with intensive behavioral therapy): Mean weight loss of 16.0% at 68 weeks, showing that combining semaglutide with structured lifestyle intervention produces somewhat better results [4].
  • STEP 5 (2-year data): Weight loss was sustained at 104 weeks, with 77.1% of participants maintaining at least 5% weight loss at the two-year mark. This addressed early concerns about durability [5].
  • STEP 8 (head-to-head vs. liraglutide): Semaglutide produced 15.8% weight loss versus 6.4% for liraglutide, settling the comparison between the two GLP-1 drugs [6].
  • STEP UP (higher 7.2 mg dose): The newer dose achieved 20.7% weight loss at 72 weeks, with 33% of participants losing 25% or more of body weight. Over 93% lost at least 5% [7].

The side effect profile is consistent across trials: gastrointestinal symptoms (nausea, diarrhea, constipation, vomiting) are the most common adverse events, reported in roughly 80% of semaglutide-treated participants versus 54% with placebo. Most are mild to moderate, occur during dose escalation, and diminish over time [1].

Semaglutide is approved for adults with a BMI of 30 or higher, or 27 or higher with at least one weight-related condition.

Tirzepatide (Zepbound)

Tirzepatide targets two incretin receptors -- GLP-1 and GIP -- making it a "dual agonist." Its SURMOUNT trial program has produced the highest weight loss numbers of any approved obesity medication.

Key trial results:

  • SURMOUNT-1 (2,539 adults without diabetes): Mean weight loss of 16.0% (5 mg), 21.4% (10 mg), and 22.5% (15 mg) over 72 weeks [2]. A meta-analysis of pooled data found that 56% of participants on the highest dose lost 20% or more of body weight [8].
  • SURMOUNT-4 (continuation study): Participants who continued tirzepatide for a total of 88 weeks lost 25.3% of body weight from baseline. Those randomized to placebo after 36 weeks regained an average of 14%, demonstrating that continued treatment is needed for sustained results [9].
  • SURMOUNT-5 (head-to-head vs. semaglutide): Tirzepatide at maximum tolerated dose produced 20.2% weight loss versus 13.7% for semaglutide at its maximum tolerated dose over 72 weeks (P<0.001) [10]. This was the first direct comparison between the two drugs.
  • Body composition data: DXA substudy from SURMOUNT-1 showed tirzepatide significantly reduced fat mass. It also reduced lean mass, though the proportion lost as lean mass was consistent with what is expected during significant weight loss [11].

Tirzepatide's safety profile is similar to other incretin therapies. Gastrointestinal events are the most common side effects. The drug also reduced waist circumference by an average of 14 cm over placebo across trials, and improved blood pressure, triglycerides, and markers of glucose metabolism [8].

Approved for adults with a BMI of 30 or higher, or 27 or higher with at least one weight-related condition.

Liraglutide (Saxenda)

Liraglutide was the first GLP-1 receptor agonist approved for weight management (2014). It requires daily subcutaneous injection and produces more moderate weight loss than semaglutide or tirzepatide. However, it has the longest post-market safety track record.

Key trial results:

  • SCALE Obesity and Prediabetes (3,731 patients): Mean weight loss of 8.0% over 56 weeks, versus 2.6% with placebo. About 63% achieved at least 5% weight loss, and 33% lost more than 10% [12].
  • SCALE Diabetes (846 patients with type 2 diabetes): Weight loss of 6.0% at the 3.0 mg dose, versus 2.0% with placebo over 56 weeks [13].
  • SCALE Maintenance: Liraglutide helped sustain weight loss achieved through initial diet-based interventions.
  • SCALE Teens (251 adolescents): Significantly reduced BMI standard deviation score compared to placebo, establishing efficacy in younger populations [14].

Liraglutide's place in treatment has shifted since semaglutide became available. In STEP 8, semaglutide produced roughly 2.5 times as much weight loss. Liraglutide may still be appropriate for patients who prefer daily dosing, have insurance coverage issues, or cannot tolerate other options.

Investigational Peptides With Strong Trial Data

These compounds are not yet FDA-approved for obesity but have produced results in well-designed trials that suggest they may join -- or surpass -- approved options.

Retatrutide (Triple Agonist)

Retatrutide adds a third receptor target (glucagon) on top of GLP-1 and GIP agonism, making it a "triple agonist" or "triagonist." Glucagon receptor activation increases energy expenditure and promotes hepatic fat oxidation -- a metabolic boost beyond what dual agonists provide.

Phase 2 trial results (338 adults with obesity, published in the New England Journal of Medicine):

  • The 12 mg dose produced 24.2% mean weight loss at 48 weeks [3].
  • 100% of participants on the 8 mg and 12 mg doses lost at least 5% of body weight.
  • Participants had not yet reached a weight plateau when the study ended, suggesting that longer treatment may produce even greater weight loss.
  • Liver fat decreased by more than 80% at higher doses. Nine of ten patients with fatty liver disease achieved normal liver fat levels [15].
  • The safety profile was similar to existing GLP-1 medications. Most adverse events were gastrointestinal, mild to moderate, and concentrated during dose escalation.

Phase 3 trials (the TRIUMPH program) are now underway. TRIUMPH-1 and TRIUMPH-2 are expected to report results in 2026 [16]. Most recently, the Phase 3 TRIUMPH-4 trial in patients with obesity and knee osteoarthritis reported 28.7% average weight loss at the highest dose, along with major improvements in pain and physical function [17]. Seven additional Phase 3 readouts are expected in 2026.

If Phase 3 data confirms Phase 2 results, retatrutide could become the most effective pharmacological treatment for obesity ever approved.

CagriSema (Semaglutide + Cagrilintide)

CagriSema combines semaglutide with cagrilintide, a long-acting amylin analog. Amylin is a hormone co-secreted with insulin that promotes satiety through different pathways than GLP-1. The rationale is that hitting appetite through two separate mechanisms produces greater weight loss than either alone.

Phase 3 data from the REDEFINE 1 trial showed the combination produced approximately 22-24% weight loss, outperforming semaglutide alone [18]. CagriSema is currently under FDA review.

Growth Hormone Pathway Peptides

These compounds aim to reduce body fat through growth hormone-related mechanisms rather than appetite suppression. Their evidence base is dramatically weaker than the GLP-1 class.

AOD-9604

AOD-9604 is a 16-amino acid fragment of human growth hormone (amino acids 176-191) designed to isolate growth hormone's fat-burning effects without its other metabolic actions. Developed by Metabolic Pharmaceuticals in Australia during the 1990s, it underwent six human clinical trials involving over 900 participants between 2001 and 2007.

What the trials actually showed:

Early Phase 2 data was modestly encouraging. In a 12-week study of approximately 300 obese patients, the 1 mg dose group lost an average of 2.8 kg, versus 0.8 kg with placebo [19]. But the critical trial -- the Phase 2b OPTIONS study involving 536 subjects over 24 weeks -- failed to show statistically significant weight loss versus placebo [20].

Development was terminated in 2007.

AOD-9604 was later granted "generally recognized as safe" (GRAS) status for use in foods and dietary supplements, but this is a safety determination, not an efficacy one. No regulatory authority recognizes it as an effective treatment for obesity [21].

Despite this failure, AOD-9604 continues to be widely marketed by peptide clinics. This is one of the clearest examples of hype outpacing data in the peptide space. See our full guide on AOD-9604 for more detail.

Tesamorelin

Tesamorelin is a growth hormone-releasing hormone (GHRH) analog -- FDA-approved, but only for HIV-associated lipodystrophy (excess visceral fat accumulation caused by HIV treatment). It is the only growth hormone pathway peptide with solid Phase 3 evidence for fat reduction.

In clinical trials for its approved indication, tesamorelin reduced visceral adipose tissue (VAT) by 15-18% compared to placebo [22]. It also decreased liver fat and improved lipid profiles. However, overall body weight changes were modest -- tesamorelin redistributes fat rather than producing dramatic total weight loss.

Some clinicians prescribe tesamorelin off-label for general obesity, but there are no large randomized trials supporting this use. Its mechanism (stimulating the body's own growth hormone production) is fundamentally different from GLP-1 agonists and produces much smaller effects on total body weight.

MOTS-c

MOTS-c is a mitochondrial-derived peptide that has shown metabolic effects in preclinical studies, including improved insulin sensitivity and reduced fat accumulation in mice on high-fat diets. It works through AMPK activation and mitochondrial energy metabolism.

Human data is limited to observational studies showing that circulating MOTS-c levels are lower in people with obesity and type 2 diabetes [23]. No randomized clinical trials have evaluated MOTS-c for weight loss in humans. It remains a research compound at this stage.

Comparing the Evidence

The following table puts the clinical data side-by-side. Pay attention to the sample sizes and trial quality -- a Phase 2b failure in 536 patients tells you more than a promising Phase 1 in 15 volunteers.

PeptideHighest Trial PhaseParticipantsWeight Loss (%)DurationFDA Status
Semaglutide 2.4 mgPhase 3 (STEP)1,96114.9%68 weeksApproved (Wegovy)
Semaglutide 7.2 mgPhase 3 (STEP UP)1,500+20.7%72 weeksUnder review
Tirzepatide 15 mgPhase 3 (SURMOUNT)2,53922.5%72 weeksApproved (Zepbound)
Liraglutide 3.0 mgPhase 3 (SCALE)3,7318.0%56 weeksApproved (Saxenda)
Retatrutide 12 mgPhase 233824.2%48 weeksInvestigational
CagriSemaPhase 3~3,400~22-24%68 weeksUnder review
AOD-9604Phase 2b (failed)536Not significant24 weeksNot approved
TesamorelinPhase 3 (lipodystrophy only)800+VAT -15-18%26 weeksApproved (Egrifta; HIV only)
MOTS-cPreclinicalN/AN/AN/AResearch only

The pattern is unmistakable. Peptides that suppress appetite through incretin pathways produce 8-25% weight loss in large trials. Peptides that target fat metabolism through growth hormone pathways either produce minimal effects or have failed their trials entirely.

The Lean Mass Problem

One legitimate concern about GLP-1-based obesity treatments is lean mass loss. When you lose a significant amount of weight, some of that weight comes from muscle and other lean tissue -- this is true regardless of the method.

What the data shows:

In semaglutide trials, approximately 25-40% of total weight lost was lean mass [24]. The 2025 SEMALEAN study, which tracked 115 patients on semaglutide 2.4 mg using DXA scans, found that lean mass initially dropped by about 3 kg at 7 months but then stabilized, while fat mass continued to decrease through 12 months [25].

Tirzepatide shows a similar pattern. DXA substudy data from SURMOUNT-1 confirmed that both fat mass and lean mass decreased, though the ratio was consistent with expected changes during significant weight loss [11].

Why this matters for obesity treatment:

Lean mass loss during weight loss is not new or unique to peptides. It happens with diet, exercise, and bariatric surgery. The question is whether the overall health benefits of substantial fat loss outweigh the lean mass reduction -- and for most people with obesity, they clearly do. Excess fat drives inflammation, insulin resistance, cardiovascular disease, sleep apnea, and joint damage.

What can be done about it:

Research from Regeneron's Phase 2 COURAGE trial showed that combining semaglutide with anti-myostatin antibodies preserved 50-80% of the lean mass that would otherwise be lost [26]. On the lifestyle side, a 2025 case series documented that patients who combined GLP-1 therapy with resistance training (3-5 days per week) and protein intake of 1.2-1.7 g/kg/day preserved or even gained lean mass during treatment [27].

For more on peptides that target muscle preservation, see our guides on best peptides for muscle growth and best peptides for athletic performance.

Regulatory and Access Issues

The regulatory picture for obesity peptides is complicated and has shifted rapidly.

FDA-approved options (semaglutide, tirzepatide, liraglutide) require a prescription and are manufactured to pharmaceutical standards. Their primary barrier is cost -- without insurance coverage, these medications can exceed $1,000 per month. Insurance coverage varies widely and many plans still do not cover anti-obesity medications, though this is gradually changing as more payers recognize obesity as a chronic disease.

Compounded peptides occupy a legal gray area that the FDA has been tightening. In January 2025, the FDA finalized new guidance on compounding under Section 503A, ending the previous categorization system and restricting compounding of substances without USP monographs [28]. Most popular non-approved peptides (AOD-9604, CJC-1295, ipamorelin, BPC-157) remain restricted for compounding. Legal challenges from compounding pharmacies are ongoing, but the trend is toward tighter regulation.

The WHO's December 2025 guideline acknowledged that while GLP-1 therapies are effective for obesity, their recommendation is conditional due to limited long-term data, high cost, and "inadequate health-system preparedness" [29]. The WHO added GLP-1 therapies to its Essential Medicines List in September 2025, and is working on prioritization frameworks to ensure equitable access globally.

For patients, the practical implication is clear: FDA-approved options have known quality, dosing, and safety profiles. Non-approved peptides obtained from compounding pharmacies or research vendors carry risks of contamination, inaccurate dosing, and unknown purity. This is not a theoretical concern -- studies have found that 12-58% of nutritional and peptide supplements contain undisclosed or contaminated substances.

Frequently Asked Questions

What is the most effective peptide for obesity?

Based on current evidence, tirzepatide (Zepbound) at the 15 mg dose produces the highest weight loss among approved treatments -- 22.5% of body weight over 72 weeks in the SURMOUNT-1 trial [2]. In head-to-head comparison, tirzepatide outperformed semaglutide by about 6.5 percentage points [10]. Among investigational compounds, retatrutide showed 24.2% weight loss in Phase 2, with Phase 3 results pending.

Are GLP-1 peptides safe for long-term use?

The STEP 5 trial showed semaglutide's effects were maintained over two years [5]. The SELECT trial followed patients on semaglutide for four years and showed a 20% reduction in major cardiovascular events on top of sustained weight loss [30]. Gastrointestinal side effects are the most common issue and tend to lessen over time. However, longer-term data (10+ years) does not yet exist for any GLP-1 obesity medication. The WHO's 2025 guideline noted this as a key knowledge gap [29].

What happens when you stop taking GLP-1 medications?

Weight regain is the norm. In SURMOUNT-4, participants who switched from tirzepatide to placebo regained an average of 14% of body weight over 52 weeks [9]. This is consistent with the understanding of obesity as a chronic condition requiring ongoing management -- similar to how blood pressure medications control but do not cure hypertension.

Does AOD-9604 work for weight loss?

No. While early smaller trials showed modest results (2.8 kg over 12 weeks), the largest and most rigorous trial -- the Phase 2b OPTIONS study of 536 subjects over 24 weeks -- failed to show statistically significant weight loss versus placebo [20]. Development was terminated in 2007. Despite this, it continues to be marketed by peptide clinics. See our full AOD-9604 profile.

Will I lose muscle on GLP-1 medications?

Some lean mass loss occurs during any significant weight loss. With GLP-1 therapies, lean mass can account for 25-40% of total weight lost [24]. Resistance training and adequate protein intake (1.2-1.6 g/kg/day or higher) can substantially reduce this. Pharmacological approaches to preserve muscle during GLP-1 therapy -- like adding anti-myostatin antibodies -- are in clinical trials [26]. See our guide on best peptides for muscle growth and recovery.

Can peptides cure obesity?

No current peptide cures obesity. GLP-1 medications manage it effectively while you take them, similar to how statins manage cholesterol. Stopping treatment typically leads to weight regain. Researchers are exploring whether lower maintenance doses, combination therapies, or intermittent dosing schedules can sustain results with less medication, but this remains an active area of investigation.

How do I choose between semaglutide and tirzepatide?

Both are effective. Tirzepatide produces more weight loss on average (20-22% vs. 15-17% for semaglutide 2.4 mg) [10]. Semaglutide has a longer safety track record and more post-market data. In practice, the choice often depends on insurance coverage, prescriber preference, and individual response. Some patients do better on one than the other.

The Bottom Line

The clinical evidence for peptide-based obesity treatment sorts into three tiers, and the gaps between them are enormous.

Tier 1: Strong evidence, FDA-approved. Semaglutide and tirzepatide produce 15-22% weight loss in large Phase 3 trials, with well-characterized safety profiles and cardiovascular benefits. Liraglutide produces more modest results (8%) but has the longest track record. These are the standard of care.

Tier 2: Promising evidence, not yet approved. Retatrutide and CagriSema have produced striking results in Phase 2 and Phase 3 trials, respectively. If their regulatory paths proceed as expected, they could expand the options available within the next few years.

Tier 3: Weak or negative evidence, not approved. AOD-9604 failed its pivotal trial. Tesamorelin is approved only for HIV-associated lipodystrophy and has not been tested for general obesity in large trials. MOTS-c remains preclinical. Growth hormone pathway peptides as a class have not demonstrated meaningful total body weight loss in controlled human studies.

If you are living with obesity and considering peptide therapy, the data points in one direction: talk to a physician about FDA-approved GLP-1 medications. The evidence base is deep, the results are reproducible, and the safety data spans years and tens of thousands of patients. Compounds sold outside this framework may come with appealing price tags or marketing claims, but they do not come with the evidence to back them up.

This article is for educational purposes only and does not constitute medical advice. Peptide therapies should only be used under the supervision of a qualified healthcare provider. Do not start, stop, or change any medication without consulting your doctor.

References

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  19. BioSpace. Metabolic Pharmaceuticals's obesity trial update: first 100 subjects complete the Phase 2b trial of AOD9604. December 2004.

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