AOD-9604 vs. Semaglutide for Weight Loss

Two peptides. Two completely different stories. AOD-9604 was supposed to be the next big thing in obesity treatment — a fragment of human growth hormone that could burn fat without the side effects. Semaglutide wasn't even designed for weight loss. It was a diabetes drug that happened to make people lose 15% of their body weight.

Today, one of these peptides has FDA approval, billions in annual sales, and celebrity endorsements. The other failed its largest clinical trial and was quietly shelved in 2007. But that hasn't stopped clinics from offering AOD-9604 as a "natural alternative" to Ozempic. So what does the science actually say?

How AOD-9604 Works
How Semaglutide Works
Clinical Trial Evidence: AOD-9604
Clinical Trial Evidence: Semaglutide
Head-to-Head Comparison
Side Effects and Safety
Cost and Accessibility
Can You Combine Them?
Regulatory Status
Who Should Consider Which?
The Bottom Line
References

How AOD-9604 Works

AOD-9604 is a synthetic 16-amino acid peptide derived from the C-terminal fragment of human growth hormone (amino acids 176-191). Researchers at Monash University in Australia developed it in the 1990s with a specific goal: capture the fat-burning properties of growth hormone while leaving out everything else.

The peptide targets fat metabolism through two direct pathways. First, it stimulates hormone-sensitive lipase, the enzyme responsible for breaking down stored fat (lipolysis). Second, it inhibits acetyl coenzyme A carboxylase, which blocks the creation of new fat (lipogenesis). Both actions mirror what full-length human growth hormone does in fat tissue.

Here's what makes AOD-9604 interesting on paper: it does all this without triggering IGF-1 production or disrupting insulin sensitivity. Growth hormone therapy notoriously causes glucose intolerance and insulin resistance. AOD-9604 avoids those problems because it only contains the lipolytic portion of the hormone.

Animal studies looked promising. In obese Zucker rats and ob/ob mice, AOD-9604 reduced body weight without affecting blood sugar. The mechanism appeared to involve upregulation of beta-3 adrenergic receptors on fat cells, increasing their sensitivity to fat-burning signals. Both human growth hormone and AOD-9604 were capable of raising depressed beta-3 receptor expression in obese mice back to levels seen in lean mice.

The peptide has a very short serum half-life of approximately 4 minutes, with intact AOD-9604 becoming undetectable after 56 minutes. It's typically administered via subcutaneous injection in research settings, though oral formulations have been studied and it does show oral bioavailability.

The AOD-9604 Backstory

Metabolic Pharmaceuticals, the Australian company that developed AOD-9604, was founded specifically around this peptide. The scientific premise was sound: human growth hormone's fat-burning effects were well-documented, but the hormone itself caused diabetes-like side effects and promoted tissue growth. Isolating just the fat-metabolizing fragment seemed like an elegant solution.

The company raised significant capital, ran six clinical trials, and spent over a decade pursuing FDA approval. When the Phase IIb trial failed in 2007, it was a devastating blow — not just for the company, but for the broader concept that growth hormone fragments could be effective anti-obesity drugs. The failure raised a question that still hasn't been satisfactorily answered: why did the peptide work in animals but not in humans?

One possibility is dosing. AOD-9604's extremely short half-life (4 minutes) means systemic exposure is brief. Animal studies used intraperitoneal injection, which may have delivered the peptide more effectively to fat tissue. Human trials used oral administration at relatively low doses. The pharmacokinetics may simply not support adequate drug exposure in humans through the tested routes.

How Semaglutide Works

Semaglutide operates through an entirely different mechanism. It's a glucagon-like peptide-1 (GLP-1) receptor agonist — meaning it mimics a gut hormone that your body naturally produces after eating.

When you eat, your intestines release GLP-1, which tells your pancreas to produce insulin and tells your brain you're full. The problem is that natural GLP-1 gets broken down within minutes by an enzyme called DPP-4. Semaglutide was engineered to resist that breakdown. Its half-life is approximately 7 days, allowing once-weekly dosing.

The weight loss from semaglutide comes primarily from appetite suppression. It acts on GLP-1 receptors in the hypothalamus and brainstem to reduce hunger, increase satiety, and slow gastric emptying. People on semaglutide consistently report that they simply think about food less.

But semaglutide does more than just reduce appetite. It also improves insulin sensitivity, lowers blood pressure, reduces inflammation, and has demonstrated cardiovascular benefits. The SELECT trial showed a 20% reduction in major adverse cardiovascular events in people with obesity taking semaglutide.

Clinical Trial Evidence: AOD-9604

This is where the AOD-9604 story gets complicated. Metabolic Pharmaceuticals, the Australian company that developed the peptide, ran six randomized, double-blind, placebo-controlled clinical trials involving over 900 participants.

The early results seemed encouraging. In a 12-week trial, subjects taking 1 mg per day of oral AOD-9604 lost an average of 2.6 kg compared to 0.8 kg in the placebo group. That's a statistically significant difference, but the absolute amount of weight lost was small.

Then came the definitive trial. A 24-week Phase IIb study enrolled 536 subjects — a much larger and longer study designed to confirm whether AOD-9604 could produce meaningful weight loss. It failed. The drug did not induce statistically significant weight loss compared to placebo.

After this result, Metabolic Pharmaceuticals terminated AOD-9604's development in 2007. The peptide has never been submitted for FDA approval. It has no regulatory approval from any major health authority anywhere in the world.

To be fair to AOD-9604, the six trials did establish an excellent safety profile. The peptide showed no effect on serum IGF-1 levels, no insulin resistance, and no impaired glucose tolerance. It received GRAS (Generally Recognized As Safe) designation from the FDA as a food ingredient — but that's very different from being approved as a drug.

AOD-9604 Trial Summary

Trial	Duration	Subjects	Dose	Result
Phase I	Short-term	Small cohort	Various	Safe, well-tolerated
12-week RCT	12 weeks	~100	1 mg/day oral	2.6 kg vs. 0.8 kg (placebo)
Phase IIb	24 weeks	536	Various doses	Failed — no significant weight loss
Additional trials	Various	900+ total	0.25-1 mg	No consistent efficacy demonstrated

Clinical Trial Evidence: Semaglutide

The contrast with semaglutide couldn't be sharper. Novo Nordisk ran the STEP (Semaglutide Treatment Effect in People with obesity) trial program — one of the most thorough clinical programs in obesity medicine.

STEP 1 enrolled 1,961 adults with BMI 30+ (or 27+ with weight-related conditions) who didn't have diabetes. After 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle counseling, participants lost an average of 14.9% of their body weight. The placebo group lost 2.4%. That's a 12.5 percentage point difference.

The numbers are striking: 86% of semaglutide participants lost at least 5% of body weight (vs. 32% on placebo). Over half — 51-64% across trials — lost 15% or more.

STEP 3 combined semaglutide with intensive behavioral therapy and a low-calorie diet. Average weight loss reached 16.0%, compared to 5.7% with the behavioral program alone.

STEP 5 provided long-term data over 104 weeks (two years). Weight loss was sustained at 15.2% vs. 2.6% with placebo. The drug kept working.

And then came the STEP UP trial, testing a higher 7.2 mg dose. Participants lost an average of 20.7% of their body weight after 72 weeks. One-third of participants in the high-dose group lost 25% or more — a number that was essentially unheard of before GLP-1 drugs arrived.

STEP Trial Results Summary

Trial	Duration	n	Mean Weight Loss (Semaglutide)	Mean Weight Loss (Placebo)
STEP 1	68 weeks	1,961	14.9%	2.4%
STEP 3	68 weeks	611	16.0%	5.7%
STEP 5	104 weeks	304	15.2%	2.6%
STEP UP	72 weeks	~700	20.7% (7.2 mg dose)	2.4%

Head-to-Head Comparison

No study has ever directly compared AOD-9604 and semaglutide. But the indirect comparison tells a clear story.

Factor	AOD-9604	Semaglutide
Mechanism	Fat metabolism (lipolysis/lipogenesis)	Appetite suppression (GLP-1 agonist)
Best trial result	2.6 kg in 12 weeks	~15 kg in 68 weeks (14.9% of body weight)
Largest trial outcome	Failed (no significant weight loss)	Consistent 15-20% weight loss
Total participants studied	~900	10,000+
FDA approved	No	Yes (Wegovy for weight loss; Ozempic for diabetes)
Administration	Subcutaneous injection or oral	Once-weekly subcutaneous injection
Half-life	~4 minutes	~7 days
Research status	Development terminated 2007	Active, ongoing trials
WADA status	Banned substance	Not banned (used medically)

The weight loss difference is not subtle. Semaglutide produces roughly 5-8 times more weight loss than AOD-9604 showed in its best trial — and AOD-9604 failed to replicate even those modest results in its larger study.

Side Effects and Safety

AOD-9604 Side Effects

AOD-9604 has a remarkably clean safety profile — perhaps its only genuine advantage over semaglutide. Across six trials and 900+ participants:

No effect on IGF-1 levels
No insulin resistance or glucose intolerance
No significant adverse events reported
Mild injection-site irritation in some users
Occasional headaches and fatigue

The safety data is real and consistent. AOD-9604 simply doesn't do much of anything to the body beyond a modest effect on fat cells, which is both its safety advantage and its efficacy problem.

Semaglutide Side Effects

Semaglutide's side effect profile reflects a drug that powerfully affects multiple body systems:

Common (affect 10-40% of users):

Nausea (the most frequent, at ~13%)
Diarrhea (~9%)
Vomiting
Constipation
Abdominal pain

Most GI side effects are mild to moderate, occur during the dose-escalation phase, and fade as the body adjusts. But they can be significant enough to cause some patients to discontinue treatment.

Serious (rare but documented):

Pancreatitis: Pharmacovigilance data shows a reporting odds ratio of 20.27, though a causal link remains debated. Case reports of severe pancreatitis exist.
Gallbladder disease: Increased risk of gallstones with rapid weight loss
Thyroid concerns: A boxed warning exists based on rodent studies showing thyroid C-cell tumors. Human relevance is uncertain, but semaglutide is contraindicated in people with personal or family history of medullary thyroid carcinoma
Acute kidney injury: Linked to dehydration from persistent nausea/vomiting

Semaglutide is clearly the more potent drug with more side effects. That trade-off makes sense — drugs that produce large physiological effects almost always carry more risk than ones that don't.

Cost and Accessibility

AOD-9604 Costs

AOD-9604 is available through compounding pharmacies and research peptide suppliers. Typical costs for subcutaneous injectable formulations run $50-$150 per month, depending on the source and dosage. Because it's not FDA-approved as a drug, insurance never covers it.

Semaglutide Costs

Brand-name semaglutide has been expensive. The list price of Ozempic runs about $998 per month, while Wegovy lists at $1,349 per month. However, Novo Nordisk has recently introduced aggressive self-pay pricing:

New patients: $199/month for the first two months (introductory offer through March 2026)
Ongoing self-pay: $349/month for Ozempic (0.25-1 mg), $499/month for the 2 mg dose
Wegovy tablets: $149-$299/month depending on dose
With commercial insurance: potentially $0-$25/month through savings programs

Compounded semaglutide has been available at lower prices ($200-$400/month), though the FDA has been cracking down on this market.

Can You Combine Them?

Some clinics offer AOD-9604 alongside GLP-1 agonists. The theory: semaglutide suppresses appetite while AOD-9604 directly boosts fat metabolism, creating complementary effects.

There's no published research supporting this combination. No studies have examined safety or efficacy of using both together. The biological rationale is plausible — the two work through completely different pathways — but "plausible" and "proven" are very different things.

Given AOD-9604's failure to produce significant weight loss on its own, adding it to semaglutide is unlikely to produce meaningful additional benefit. But this remains an open question.

Regulatory Status: Approved Drug vs. Research Compound

The regulatory status of these two compounds could hardly be more different, and it matters for anyone considering either option.

Semaglutide is FDA-approved under two brand names: Ozempic (for type 2 diabetes, approved 2017) and Wegovy (for chronic weight management, approved 2021). It's also approved by the EMA and regulatory authorities worldwide. This means it has undergone the full gauntlet of Phase I-III clinical trials, manufacturing quality standards, and post-market surveillance. When you get a prescription for semaglutide, you know exactly what's in the vial.

AOD-9604 exists in a regulatory gray zone. It received GRAS (Generally Recognized As Safe) designation from the FDA — but only as a food ingredient, not as a therapeutic drug. GRAS status means the substance is considered safe when consumed at typical dietary levels. It says nothing about efficacy for weight loss or any medical condition. The peptide is classified as a research compound, and WADA bans it as a performance-enhancing substance.

In practice, AOD-9604 is available through compounding pharmacies and research chemical suppliers. Quality control varies significantly between sources. Without FDA pharmaceutical manufacturing standards, purity, potency, and sterility cannot be guaranteed to the same degree as an approved drug.

Who Should Consider Which?

This isn't really a close call based on current evidence, but context matters.

Semaglutide may be appropriate if you:

Need significant weight loss (BMI 30+, or 27+ with complications)
Want a treatment backed by large-scale clinical trials
Can tolerate or manage GI side effects
Have access through insurance or can afford the cost
Are working with a physician who can monitor your progress

AOD-9604 is sometimes considered by people who:

Cannot tolerate GLP-1 side effects
Are looking for a gentler, lower-risk option
Understand the limited evidence for weight loss
Are interested in its potential joint health benefits (a newer area of research)
Prefer a peptide that doesn't affect appetite or hormonal systems

But here's the honest truth: if meaningful weight loss is the goal, the evidence overwhelmingly supports semaglutide. AOD-9604 failed its most important clinical trial. Recommending it as an alternative to semaglutide for weight loss is not well-supported by the available research.

For a broader look at fat-loss peptides, see our guide on best peptides for fat loss.

The Bottom Line

AOD-9604 and semaglutide both target weight loss, but they exist in different universes of clinical evidence. Semaglutide has been tested in over 10,000 participants across multiple Phase III trials, consistently producing 15-20% body weight reduction with a clear mechanism and FDA approval. AOD-9604 completed six smaller trials, showed modest results in one short study, and failed its largest and longest trial.

AOD-9604's safety profile is genuinely excellent — no metabolic side effects, no hormonal disruption, well-tolerated across all trials. But safety without efficacy isn't enough. A treatment that doesn't cause side effects but also doesn't produce the desired effect isn't a medical solution.

If you're considering either of these peptides for weight management, talk to a physician. Semaglutide is a prescription medication that requires medical supervision and monitoring. AOD-9604 remains an unapproved research compound. Neither should be self-administered without professional guidance.

References

Heffernan, M. et al. (2001). "The effects of human GH and its lipolytic fragment (AOD9604) on lipid metabolism following chronic treatment in obese mice and beta(3)-AR knock-out mice." Endocrinology, 142(12):5182-5189. PubMed
Stier, H. et al. (2013). "Safety and Tolerability of the Hexadecapeptide AOD9604 in Humans." Journal of Endocrinology and Metabolism, 3(1-2):7-15. Link
More, M.I. et al. (2014). "Safety and Metabolism of AOD9604, a Novel Nutraceutical Ingredient for Improved Metabolic Health." Journal of Endocrinology and Metabolism, 4(3):66-78. Link
Thompson, D. (2004). "Obesity Pharmacotherapy: Current Perspectives and Future Directions." PMC. Link
Wilding, J.P.H. et al. (2021). "Once-Weekly Semaglutide in Adults with Overweight or Obesity." New England Journal of Medicine, 384:989-1002. NEJM
Garvey, W.T. et al. (2022). "Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial." Nature Medicine, 28:2083-2091. Link
STEP UP Trial (2025). "Semaglutide 7.2 mg Achieves Superior Weight Loss vs. 2.4 mg, Placebo." Applied Clinical Trials Online. Link
Semaglutide Safety Review. PMC. Link
Gastrointestinal adverse events associated with semaglutide: A pharmacovigilance study. PMC. Link
Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide. PMC. Link

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