AOD-9604 vs Semaglutide: Head-to-Head Comparison

AOD-9604 and semaglutide work through entirely different biological pathways, reflecting their different origins and development histories.

AOD-9604: Growth Hormone Fragment

AOD-9604 is a modified synthetic peptide corresponding to the C-terminal fragment (amino acids 177–191) of human growth hormone, with an added tyrosine residue. The theoretical mechanism proposes that this specific fragment retains the fat-metabolizing properties of growth hormone without its growth-promoting, diabetogenic, or IGF-1-raising effects:^[1]

• Proposed lipolytic activity: AOD-9604 is hypothesized to stimulate lipolysis (fat breakdown) in adipose tissue by mimicking the fat-burning region of growth hormone.
• No IGF-1 elevation: Unlike full-length HGH, AOD-9604 does not increase insulin-like growth factor 1 (IGF-1) levels, avoiding the cancer risk concerns associated with elevated IGF-1.
• No glucose impairment: AOD-9604 does not appear to impair glucose tolerance, unlike growth hormone which can cause insulin resistance.

However, it is important to note that the precise mechanism by which AOD-9604 might promote fat loss in humans has never been conclusively demonstrated. The lipolytic activity observed in animal and in vitro studies did not clearly translate to human fat loss in clinical trials.

Semaglutide: GLP-1 Receptor Agonism

Semaglutide’s mechanism is well-characterized and proven in humans:^[2]

• Appetite suppression: Central GLP-1 receptor activation reduces hunger and increases satiety, leading to a sustained ~20–35% reduction in caloric intake.
• Delayed gastric emptying: Slowed stomach emptying prolongs fullness after meals.
• Metabolic improvement: Enhances glucose-dependent insulin secretion, suppresses glucagon, and improves multiple cardiometabolic markers.
• Cardiovascular benefit: The SELECT trial demonstrated a 20% reduction in major adverse cardiovascular events.^[3]

The evidence gap between AOD-9604 and semaglutide is vast and represents the most important factor in comparing these two compounds.

AOD-9604: Promising Preclinical Data, Failed Clinical Validation

AOD-9604 completed six human clinical trials involving over 900 participants, but the results were disappointing:^[1]

• Early pilot studies: Small IV and oral dosing studies showed some initial promise, with the 1 mg oral dose producing 2.8 kg mean weight loss over 12 weeks (compared to 0.8 kg with placebo).
• Phase IIb trial (n=536): The largest study failed to meet its primary endpoint. When an intensive diet and exercise regimen was incorporated, AOD-9604 did not produce statistically significant weight loss above placebo.
• Development terminated: Metabolic Pharmaceuticals terminated AOD-9604 development in 2007 after the failed Phase IIb results.
• Current status: AOD-9604 has been repositioned as a nutraceutical/supplement ingredient rather than a pharmaceutical, and was granted GRAS (Generally Recognized as Safe) status by the FDA for use as a food ingredient—not as a weight loss drug.

Semaglutide: Gold-Standard Clinical Evidence

Semaglutide has one of the most robust clinical evidence bases of any obesity medication:^[2]

• STEP 1 (n=1,961): 14.9% mean weight loss at 68 weeks, with 50.5% losing at least 15%.
• STEP 2–5: Replicated results across different populations (diabetes, behavioral therapy, long-term maintenance).
• SELECT (n=17,604): 20% reduction in major cardiovascular events—the only obesity medication to demonstrate cardiovascular benefit.^[3]
• Real-world confirmation: Post-marketing data generally confirm clinical trial efficacy.

The Evidence Verdict

Semaglutide has conclusively demonstrated efficacy in large Phase III trials with tens of thousands of participants. AOD-9604 failed to demonstrate efficacy in its most rigorous trial. This is not a difference of degree—it is a fundamental difference in whether the compound works for weight loss in humans at all.

Interestingly, AOD-9604’s safety profile may be its strongest attribute, while semaglutide’s side effects are its most notable limitation.

AOD-9604 Safety

Across six clinical trials involving over 900 participants, AOD-9604 demonstrated a favorable safety profile:^[1]

• Well-tolerated: Adverse events were generally mild and comparable to placebo.
• No IGF-1 effects: Unlike growth hormone, AOD-9604 did not elevate IGF-1 levels.
• No glucose impairment: No negative effects on glucose tolerance or insulin sensitivity.
• GRAS status: The FDA granted GRAS status for oral AOD-9604, indicating acceptance of its safety as a food ingredient.

Semaglutide Safety

Semaglutide’s side effects are well-characterized but more pronounced:^[2]

• Nausea: ~44% (most common during dose escalation)
• Diarrhea: ~30%
• Vomiting: ~24%
• Constipation: ~24%
• Discontinuation: ~7% stopped due to adverse events
• Serious warnings: Pancreatitis risk, thyroid C-cell tumor warning (rodent studies), gallbladder events

The Trade-Off

AOD-9604 is very well-tolerated—but produces minimal demonstrated weight loss. Semaglutide has significant GI side effects—but produces substantial, proven weight loss and cardiovascular benefit. In clinical medicine, tolerability without efficacy provides no meaningful advantage.

AOD-9604 and semaglutide occupy very different positions in terms of availability and cost.

AOD-9604

• Dosing: Typically 250–500 mcg/day via subcutaneous injection; oral formulations also available
• Availability: Sold by peptide suppliers as a research compound or supplement ingredient; not prescription-required
• Cost: Substantially less expensive than semaglutide, typically $50–$150/month depending on source and form
• Quality concerns: Without pharmaceutical manufacturing standards, peptide purity and consistency vary between suppliers

Semaglutide

• Dosing: 2.4 mg once weekly (Wegovy); gradual escalation over 16–20 weeks
• Availability: Prescription-only; available at pharmacies
• Cost: ~$1,300–$1,400/month list price; insurance coverage and manufacturer programs can reduce costs
• Quality: Pharmaceutical-grade manufacturing under FDA oversight

AOD-9604’s lower cost and easier access make it appealing, particularly for individuals who cannot afford or access semaglutide. However, spending less on a compound without proven efficacy is not necessarily a bargain—it represents a different kind of cost, measured in time and missed opportunity for effective treatment.

The comparison between AOD-9604 and semaglutide ultimately comes down to one question: do you prioritize proven clinical evidence, or are you willing to use a compound based primarily on theoretical mechanisms and early-stage data?

The Case for Semaglutide

Semaglutide has demonstrated, in rigorously controlled Phase III trials with thousands of participants:

• Consistent, reproducible weight loss of approximately 15%
• A 20% reduction in heart attacks, strokes, and cardiovascular death
• Sustained efficacy over 2+ years of treatment
• A well-characterized safety profile

The Case for AOD-9604

AOD-9604’s primary attributes are:

• Favorable safety profile with minimal side effects
• Lower cost and easier access
• Theoretical lipolytic mechanism that does not raise IGF-1 or impair glucose metabolism
• However, its largest clinical trial failed to demonstrate significant weight loss

For individuals who cannot access semaglutide due to cost, insurance, or medical contraindications, AOD-9604 is sometimes considered as an alternative. However, it is essential to understand that the evidence supporting AOD-9604 for weight loss is weak compared to semaglutide’s robust clinical validation.