Research Overview
· Last Reviewed April 28, 2026· PSI Editorial Board· IndependentCan Peptides Help Me Lose Weight?
Three drugs are FDA-approved. Two more are in late-stage trials. Five are marketed online with no human trials. Here's the honest map.
WHAT'S YOUR PRIMARY GOAL?
Indication
Animal Studies
Human Trials
Sustained weight loss
obesity, BMI 30+
Type 2 diabetes
A1C reduction, glycemic control
Cardiovascular events
MACE in CVD + obesity
Sleep apnea
obesity-associated OSA
Knee osteoarthritis
obesity-associated joint pain
MASH / liver fibrosis
metabolic-dysfunction-associated
Kidney disease
T2D-associated CKD progression
Heart failure (HFpEF)
obesity-associated HFpEF
How counts are scaled → · Tap any row to see the studies →
Quick Answer
If you're looking at peptides for weight loss, three drugs are FDA-approved right now: Wegovy, Zepbound, and Saxenda. Here's how they actually compare. And which other compounds are worth knowing about.
Zepbound is the strongest. It mimics two of your body's natural fullness signals at once. Scientists call them GLP-1 and GIP. In a 2025 head-to-head trial, people on Zepbound lost about 22% of their body weight over 72 weeks. People on Wegovy lost 15%. If you weigh 200 pounds, that's 44 pounds versus 30.
Wegovy mimics just one of those signals: GLP-1. Less weight loss in head-to-head, but Wegovy has the strongest case for heart protection. It's the only weight-loss drug with a finished trial showing it cuts heart attack and stroke risk. The trial ran 17,604 adults with existing heart disease. The benefit was 20% over about three years.
Saxenda is the older daily option in this category. It also mimics GLP-1, but it's a different molecule and you take it daily instead of weekly. About 8% weight loss, smaller than the weekly options. But it's been around longer. And daily dosing makes it easier to ramp up gently if you're sensitive to side effects.
Two more are in the pipeline. Retatrutide goes one step further than Zepbound. It mimics three signals at once: GLP-1, GIP, and glucagon. In a Phase 3 trial in late 2025, people on retatrutide lost 28.7% of their body weight. That's the biggest number ever published for this kind of drug. Orforglipron is the first oral GLP-1 to clear Phase 3. It's a daily pill instead of a weekly injection. Weight loss is about 11.2%, less than the injectables, but the convenience matters.
Then there's the other side. Peptides marketed online for fat loss that have never been tested in controlled human trials. AOD-9604, CJC-1295, ipamorelin, fragment 176-191, and MK-677. They show up in animal studies. They have not been tested in humans for weight loss the way Wegovy, Zepbound, and Saxenda have. Marketing claims that combine them with GLP-1s, like 'semaglutide stack' or 'tirzepatide plus B-12', are not backed by evidence.
Why most peptides never reach FDA approval is a separate question, covered in a dedicated PSI editorial. For current regulatory status on every peptide PSI tracks, see the FDA Status Tracker.
What's on this page. Section 1 maps which compound has evidence for which goal: heart disease, sleep apnea, knee pain, and more. Section 2 ranks the seven most-studied compounds by evidence depth. Section 3 covers the head-to-head decisions you'll actually face: Zepbound vs Wegovy, semaglutide vs tirzepatide vs retatrutide, oral vs injectable, and GLP-1s vs bariatric surgery. If you're considering any of these, the sourcing checklist at the bottom shows two things. How to verify a prescription source. And how to find a physician who knows this drug class.
Zepbound vs Wegovy
The most-asked question in the GLP-1 category. Here's what the trials actually show.
Zepbound and Wegovy are the two strongest GLP-1 options. Here's what comes up: which one wins on weight loss, which one wins on heart protection, why the mechanism difference matters.
Zepbound wins on weight loss. In the head-to-head trial that ran in 2025, people on Zepbound lost about 22% of their body weight over 72 weeks. People on Wegovy lost about 15%. If you weigh 200 pounds, that's 44 pounds versus 30. The gap held up across other trials too. Zepbound consistently does more.
Wegovy wins on heart protection. It's the only weight-loss drug with a finished trial showing it cuts heart attack and stroke risk. The trial ran 17,604 adults with existing heart disease but no diabetes. The benefit was 20% over about three years. Zepbound has its own heart trial running, but the data isn't out yet. Until it is, Wegovy is the only option in this class with proven heart benefit for people without diabetes.
The mechanism difference explains why. Wegovy mimics one of your body's natural fullness signals: GLP-1. Zepbound mimics two at once: GLP-1 and GIP. The second signal adds extra appetite suppression that GLP-1 alone doesn't. Each generation of these drugs adds another receptor and produces more weight loss. Retatrutide adds a third (glucagon) and is hitting bigger numbers in trials.
What this means in practice. If weight loss is the main goal and you don't have established heart disease, Zepbound is the stronger choice. If you have heart disease and obesity, Wegovy is the option with proven heart benefit. The other thing that often decides is access: insurance coverage, manufacturer assistance programs (LillyDirect for Zepbound, NovoCare for Wegovy). Both work. Which one fits depends on your situation.
Semaglutide vs Tirzepatide vs Retatrutide
Three GLP-1 generations. Each one hits more receptors and produces more weight loss.
Semaglutide (sold as Wegovy and Ozempic), tirzepatide (Zepbound and Mounjaro), and retatrutide are the three GLP-1s people are tracking right now. Wegovy is the established option. Zepbound is the strongest current option. Retatrutide is what's coming next. Here's how they actually stack up.
Each generation hits more receptors and produces more weight loss. Semaglutide mimics one of your body's natural fullness signals: GLP-1. About 15% weight loss in trials. Tirzepatide mimics two at once: GLP-1 and GIP. About 22%. Retatrutide mimics three at once: GLP-1, GIP, and glucagon. About 28.7% in Phase 3 trials. If you weigh 200 pounds, that's 30 pounds on semaglutide, 44 on tirzepatide, 57 on retatrutide. The mechanism progression is consistent. More receptors, more weight loss.
What the third receptor does. Glucagon does the opposite of insulin in one way: it raises blood sugar. But it has a second effect that matters for weight loss. Over time, it raises how many calories your body burns at rest. So retatrutide doesn't just suppress appetite the way Wegovy and Zepbound do. It adds baseline calorie burn on top. That's the new mechanism that pushed the trial number from 22% to 28.7%.
What's actually available today. Wegovy and Zepbound are FDA-approved and in pharmacies right now. Retatrutide is not yet FDA-approved. Eli Lilly's filing package is taking shape but hasn't been submitted yet. FDA approval timing depends on which indication they file first. Likely late 2026 or 2027.
What this means in practice. If you want the strongest current weight loss, Zepbound is the answer today. If you have established heart disease, Wegovy is the answer because it has the proven cardiovascular benefit. Retatrutide is the answer for two situations. People who've already tried Zepbound and hit a plateau and want what's next. Or people in the diagnostic process for severe obesity who can wait a year or two for the bigger number. Right now, retatrutide access is through clinical trial enrollment only. Compounded retatrutide is in regulatory limbo and likely to close once Lilly files.
Oral GLP-1 vs Injectable GLP-1
Daily pill or weekly injection. Here's what you give up to get the convenience.
Daily pill or weekly injection? Orforglipron is the first oral GLP-1 to clear Phase 3 trials. It's not yet FDA-approved, but the filing is in. Here's the trade-off.
You give up about half the weight loss compared to Zepbound. People on orforglipron lost about 11% of their body weight over 72 weeks in the Phase 3 trial. People on Zepbound lose about 22% over the same time. People on Wegovy lose about 15%. Orforglipron is the smallest number of the three, but it's the only one in pill form.
Why hasn't an oral GLP-1 been done before? Because GLP-1 is a peptide. Peptides break down in your stomach. The body treats them like food and digests them. Rybelsus is oral semaglutide and it gets around this by requiring you take it on an empty stomach with strict timing rules. Even then, only a small fraction of the dose actually gets absorbed.
Orforglipron solved this by not being a peptide. It's a small molecule that activates the same GLP-1 signal but survives digestion. That's why you can take it any time of day with food. The trade-off is potency. The molecular structure means orforglipron doesn't activate the receptor as strongly as the peptide versions do, so weight loss comes in lower.
What this means in practice. If maximum weight loss is the goal and you can do injections, an injectable like Zepbound or Wegovy is the right call. If injections are a non-starter (needle phobia, travel, lifestyle), orforglipron is a real option. There's also a middle path. Some people start on injectables to get the bigger initial weight loss, then switch to orforglipron to maintain it long-term. A 2025 trial called ATTAIN-MAINTAIN tested this exactly. People who switched held their weight off.
GLP-1s vs Bariatric Surgery
The other big intervention. Compared on durability, mechanism overlap, and what happens if you stop.
GLP-1 medication or bariatric surgery? This is the other big decision in the weight-loss space. Three things matter. How durable the weight loss is. Why the two approaches overlap more than they look. And what happens if you stop.
Surgery wins on durability. Roux-en-Y gastric bypass typically holds 25-30% weight loss at 5+ years. Sleeve gastrectomy holds 20-25%. Zepbound gets close in the short term: about 22% over 72 weeks. But that's on the drug. The longer-term picture for GLP-1s is different. Retatrutide just hit 28.7% in late 2025, the first GLP-1 weight-loss number that genuinely matches surgical magnitudes. We don't yet have multi-year follow-up on retatrutide.
The two approaches overlap more than they look. Surgery permanently changes how your gut works. Smaller stomach, modified hormone signaling, sometimes a rerouted intestine. After bypass surgery, your body produces more of its own GLP-1, PYY, and oxyntomodulin. These are the same hormones GLP-1 drugs mimic. So in a sense, surgery turns up your body's natural GLP-1 production, while drugs add it from outside. The mechanisms aren't identical, but they hit similar targets.
What happens if you stop. Surgery is a one-time intervention. The anatomy doesn't revert, so the weight loss largely persists. GLP-1s are different. About two-thirds of the weight you lost on a GLP-1 comes back within a year of stopping. The trial data is consistent on this. So GLP-1s are best thought of as a long-term medication. Like blood pressure or cholesterol drugs. Not a one-time treatment that fixes the issue.
What this means in practice. If you have severe obesity (BMI 40+ or BMI 35+ with serious other health issues), bariatric surgery has historically been the recommended path. The GLP-1 evidence is strong enough now that medication-first is also a reasonable choice. If you're at BMI 30-40 and considering your first intervention, a GLP-1 trial is the lower-risk starting point. Increasingly, people do both. Surgery first for the durability, then GLP-1 maintenance to hold the loss. The head-to-head trial data on combined approaches isn't out yet.
The Compounds, Ranked by Evidence
Ordered by strength of controlled human data, not popularity.
Of the 7 most-discussed peptides here, three are FDA-approved (Wegovy, Zepbound, Saxenda). Two are in late-stage trials (retatrutide, orforglipron). Five are marketed for fat loss without any controlled human weight-loss trials. Here's what each one's trials and animal studies actually show.
Tirzepatide
Sold as Zepbound. Strongest FDA-approved weight-loss drug. About 22% weight loss in the 2025 head-to-head versus 15% for Wegovy. Mimics two appetite signals at once.
Counts are PubMed-indexed papers and registered clinical trials. Scale: Strong 10+, Moderate 4–9, Limited 1–3, None 0. Methodology →
| Indication | Animal Studies | Human Trials |
|---|---|---|
Sustained weight loss obesity, BMI 30+ | 14 Reduced food intake and body weight reported in animal models of obesity. Mechanism studies established the additive effect of GIP receptor activity on top of GLP-1. | 12 SURMOUNT-1 reported 22.5% mean weight loss at the highest dose over 72 weeks in 2,539 adults. SURMOUNT-2 reported 15.7% in obesity + T2D. SURMOUNT-5 demonstrated statistical superiority versus semaglutide head-to-head over 72 weeks in 751 adults. Jastreboff 2022 SURMOUNT-1, Garvey 2023 SURMOUNT-2, Jastreboff 2024 3-yr follow-up, SURMOUNT-5 NCT05822830 |
Type 2 diabetes A1C reduction, glycemic control | 18 Glucose-dependent insulinotropic effects via dual GIP/GLP-1 receptor activation reported in animal models of T2D. | 10 SURPASS-1 reported A1C reductions of 1.87-2.07% versus placebo in tirzepatide monotherapy over 40 weeks. SURPASS-2 reported tirzepatide superior to semaglutide 1mg head-to-head in T2D over 40 weeks. |
Cardiovascular events MACE in CVD + obesity | 6 Reduced atherosclerotic burden and improved cardiac function reported in animal models of metabolic disease. | 0 SURPASS-CVOT cardiovascular outcomes trial ongoing; topline data expected 2026. Cardiovascular benefit observed as secondary endpoint in SURMOUNT and SURPASS programs but not yet established as primary outcome. SURPASS-CVOT NCT04255433 (ongoing) |
Sleep apnea obesity-associated OSA | 2 Limited animal-model data on direct OSA endpoints; weight reduction in obesity models reduces airway obstruction. | 1 SURMOUNT-OSA reported reduced apnea-hypopnea index over 52 weeks in 469 adults with obesity-associated OSA. FDA approved tirzepatide (Zepbound) for obesity-associated OSA in December 2024. |
Knee osteoarthritis obesity-associated joint pain | 1 Limited animal-model data; weight reduction in obesity models reduces joint loading. | 0 No primary tirzepatide knee OA trial has been published. STEP-9 (semaglutide) is the only completed GLP-1 knee OA primary trial. OA pain reduction reported as secondary outcome in TRIUMPH-4 (retatrutide) Phase 3. |
MASH / liver fibrosis metabolic-dysfunction-associated steatohepatitis | 8 Reduced hepatic steatosis and fibrosis markers reported in animal models of MASH. | 1 SYNERGY-NASH reported MASH resolution in 51-62% of patients on tirzepatide vs 10% on placebo at 52 weeks in 190 adults with biopsy-confirmed MASH. |
Kidney disease T2D-associated CKD progression | 4 Renoprotective effects reported in animal models of T2D-associated CKD. | 0 No tirzepatide-specific primary CKD trial has reported topline data. Renal endpoints reported as secondary outcomes in SURPASS-4. FLOW (semaglutide) is the only completed primary GLP-1 CKD trial. |
Heart failure (HFpEF) obesity-associated HFpEF | 2 Effects on cardiac function reported in animal models of obesity-associated heart failure. | 1 SUMMIT reported reduced HF events and improved KCCQ score in 731 adults with obesity-associated HFpEF over 52 weeks. |
Semaglutide
Sold as Wegovy (weight loss) or Ozempic (diabetes). Only weight-loss drug with proven heart benefit: 20% fewer cardiac events in 17,604 adults with existing heart disease.
| Indication | Animal Studies | Human Trials |
|---|---|---|
Sustained weight loss obesity, BMI 30+ | 22 GLP-1 receptor agonism reduced food intake and body weight in rodent obesity models with extensive mechanism characterization since the 1990s. | 15 STEP-1 reported 14.9% mean weight loss over 68 weeks in 1,961 adults; 86% achieved 5%+ weight loss. STEP-1 extension showed regain of approximately two-thirds of lost weight within 12 months of discontinuation. |
Type 2 diabetes A1C reduction, glycemic control | 20 Glucose-dependent insulinotropic and glucagonostatic effects via GLP-1 receptor agonism reported across animal models of T2D. | 12 SUSTAIN-6 reported A1C reductions of 0.7-1.0% versus placebo in T2D over 104 weeks. PIONEER program established efficacy of oral semaglutide. SOUL (NEJM 2025) extended cardiovascular benefit to oral semaglutide in high-risk T2D. |
Cardiovascular events MACE in CVD + obesity without diabetes | 8 Reduced atherosclerotic plaque burden and vascular inflammation reported in animal models of cardiometabolic disease. | 5 SELECT reported 20% reduction in major adverse cardiac events over 40 months in 17,604 adults with established CVD and overweight/obesity without diabetes. Also 73% reduction in incident diabetes and 22% lower renal outcomes risk. SUSTAIN-6 reported MACE reduction in T2D population. FDA approved cardiovascular indication March 2024. |
Sleep apnea obesity-associated OSA | 1 Limited animal-model data on direct OSA endpoints. | 0 No semaglutide-specific OSA primary trial has been published. SURMOUNT-OSA (tirzepatide) is the only completed primary GLP-1 OSA trial. |
Knee osteoarthritis obesity-associated joint pain | 2 Limited animal-model data; weight reduction in obesity models reduces joint loading. | 1 STEP-9 reported reduced WOMAC knee pain score and 13.7% weight loss over 68 weeks in 407 adults with obesity and knee OA. The only completed GLP-1 knee OA primary trial. |
MASH / liver fibrosis metabolic-dysfunction-associated steatohepatitis | 12 Reduced hepatic steatosis, inflammation markers, and fibrosis reported in animal models of MASH. | 2 ESSENCE Phase 3 reported MASH resolution in 62.9% of patients on semaglutide vs 34.3% on placebo at 72 weeks in 1,197 adults. |
Kidney disease T2D-associated CKD progression | 5 Renoprotective effects via reduced albuminuria and glomerular hypertension reported in animal models of T2D nephropathy. | 1 FLOW reported 24% reduction in major kidney disease events over 3.4 years in 3,533 adults with T2D and CKD. Trial halted early for efficacy. Hazard ratio 0.76 (95% CI 0.66-0.88, P=0.0003). |
Heart failure (HFpEF) obesity-associated HFpEF | 2 Effects on cardiac function reported in animal models of obesity-associated heart failure. | 2 STEP-HFpEF reported improved KCCQ score and 13.3% weight loss in 529 adults with obesity-associated HFpEF over 52 weeks. STEP-HFpEF DM replicated findings in HFpEF + T2D population. |
Retatrutide
In Phase 3 trials. People on retatrutide lost 28.7% of their body weight in late 2025. Biggest weight-loss number ever published for this drug class. Mimics three appetite signals at once.
| Indication | Animal Studies | Human Trials |
|---|---|---|
Sustained weight loss obesity, BMI 30+ | 8 Triple GIP/GLP-1/glucagon receptor agonism reduced food intake and increased resting energy expenditure in rodent obesity models, with greater magnitude than dual or single agonists in head-to-head animal comparisons. | 2 Phase 2 reported 24.2% weight loss at 48 weeks in 338 adults with obesity at the 12mg dose. TRIUMPH-4 (December 2025) reported 28.7% mean weight loss at the highest dose. That is the largest controlled human weight-loss number ever published for a metabolic peptide. Jastreboff 2023 retatrutide Phase 2, TRIUMPH-4 NCT05929066 |
Type 2 diabetes A1C reduction, glycemic control | 4 Glucose-dependent insulinotropic effects via dual GIP/GLP-1 activation reported in animal models, with glucagon-receptor activity contributing to improved hepatic glucose handling. | 1 TRANSCEND-T2D-1 (March 2026) reported 16.8% weight loss + 2.0% A1C reduction in patients with T2D over 76 weeks. TRANSCEND-T2D-1 (Lilly press release) |
Cardiovascular events MACE in CVD + obesity | 2 Limited animal-model data on direct cardiovascular endpoints. | 0 Cardiovascular outcomes trial in TRIUMPH program ongoing. Topline data expected through 2026-2027. |
Sleep apnea obesity-associated OSA | 0 None published. | 0 No primary OSA trial has reported. Sleep apnea endpoints may be evaluated in TRIUMPH program. |
Knee osteoarthritis obesity-associated joint pain | 1 Limited animal-model data; weight reduction in obesity models reduces joint loading. | 1 TRIUMPH-4 (Phase 3 in obesity + knee OA) reported significant pain reduction alongside 28.7% weight loss in December 2025. TRIUMPH-4 NCT05929066 |
MASH / liver fibrosis metabolic-dysfunction-associated | 3 Reduced hepatic steatosis reported in animal models of MASH. | 1 Phase 2 reported reduced hepatic steatosis at 48 weeks. Phase 3 in MASH ongoing in TRIUMPH program. |
Kidney disease T2D-associated CKD progression | 1 Limited animal-model data on renal endpoints. | 0 Renal endpoints in TRIUMPH program; no completed retatrutide CKD trial. |
Heart failure (HFpEF) obesity-associated HFpEF | 1 Limited animal-model data on cardiac function in obesity-associated HF models. | 0 HFpEF trial in TRIUMPH program (TRIUMPH-HF). Topline expected 2026. |
Orforglipron
First oral GLP-1 to clear Phase 3. About 11% weight loss versus 22% for injectable Zepbound. Daily pill instead of weekly injection.
| Indication | Animal Studies | Human Trials |
|---|---|---|
Sustained weight loss obesity, BMI 30+ | 4 GLP-1 receptor activation reduced food intake and body weight in rodent obesity models. Oral bioavailability validated in pharmacokinetic studies. | 3 ATTAIN-1 reported 11.2% weight loss at 36 mg dose over 72 weeks in 3,127 adults with obesity. ATTAIN-MAINTAIN reported weight maintenance after re-randomization from injectable GLP-1s. Wharton 2025 ATTAIN-1, ATTAIN-MAINTAIN NCT06584916 |
Type 2 diabetes A1C reduction, glycemic control | 2 Glucose-dependent insulinotropic effects via GLP-1 receptor activation reported in animal models of T2D. | 1 ATTAIN-2 reported 10.5% weight loss + 1.8% A1C reduction over 72 weeks in obesity + T2D. ATTAIN-2 (Lilly press release August 2025) |
Cardiovascular events MACE in CVD + obesity | 1 Limited animal-model data on direct cardiovascular endpoints. | 0 No completed orforglipron-specific cardiovascular outcomes trial. Cardiovascular endpoints in ongoing ATTAIN program. SOUL (oral semaglutide, NEJM 2025) is the only completed CV outcomes trial for an oral GLP-1. |
Sleep apnea obesity-associated OSA | 0 None published. | 0 No primary OSA trial has reported. |
Knee osteoarthritis obesity-associated joint pain | 0 None published. | 0 No primary knee OA trial has reported. |
MASH / liver fibrosis metabolic-dysfunction-associated | 1 Limited animal-model data on hepatic outcomes. | 0 No completed MASH primary trial. Hepatic endpoints may appear in ongoing ATTAIN program. |
Kidney disease T2D-associated CKD progression | 0 None published. | 0 No primary CKD trial has reported. |
Heart failure (HFpEF) obesity-associated HFpEF | 0 None published. | 0 No primary HFpEF trial has reported. |
Liraglutide
Sold as Saxenda. Older daily option in this category. About 8% weight loss. Daily dosing makes it easier to ramp up gently.
| Indication | Animal Studies | Human Trials |
|---|---|---|
Sustained weight loss obesity, BMI 30+ | 18 GLP-1 receptor agonism reduced food intake and body weight in rodent obesity models with extensive characterization across the original GLP-1 receptor agonist development era. | 6 SCALE-1 reported 8.0% mean weight loss over 56 weeks in 3,731 adults with overweight/obesity. SCALE-Maintenance and SCALE-Diabetes extended findings to specific populations. |
Type 2 diabetes A1C reduction, glycemic control | 22 Glucose-dependent insulinotropic effects via GLP-1 receptor agonism reported across animal models of T2D. | 8 LEAD-1 through LEAD-6 established A1C reductions of 0.8-1.5%. FDA approved as Victoza for T2D in 2010. LEAD program (Buse, Pratley, Russell-Jones et al.) |
Cardiovascular events MACE in CVD + obesity | 6 Reduced atherosclerotic plaque and vascular inflammation reported in animal models of cardiometabolic disease. | 1 LEADER reported 13% reduction in major adverse cardiac events over 3.8 years in 9,340 adults with T2D and high CV risk. The first dedicated GLP-1 cardiovascular outcomes trial. |
Sleep apnea obesity-associated OSA | 0 None published. | 0 No primary OSA trial completed for liraglutide. Older first-generation drug; subsequent OSA trials prioritized weekly tirzepatide. |
Knee osteoarthritis obesity-associated joint pain | 0 None published. | 0 No primary knee OA trial completed for liraglutide. |
MASH / liver fibrosis metabolic-dysfunction-associated | 4 Reduced hepatic steatosis reported in animal models. | 0 No primary MASH trial completed for liraglutide. Hepatic endpoints in LEADER were secondary. |
Kidney disease T2D-associated CKD progression | 3 Renoprotective effects reported in animal models of diabetic nephropathy. | 0 No primary CKD trial completed for liraglutide. Renal endpoints in LEADER were secondary; FLOW (semaglutide) is the only completed primary GLP-1 CKD trial. |
Heart failure (HFpEF) obesity-associated HFpEF | 1 Limited animal-model data on HF endpoints. | 0 No primary HFpEF trial completed for liraglutide. STEP-HFpEF (semaglutide) and SUMMIT (tirzepatide) are the completed primary GLP-1 HFpEF trials. |
AOD-9604
Reached a Phase 2 human obesity trial that was never published. Did not advance to FDA approval. The FDA voted against allowing legal compounding in late 2024.
| Indication | Animal Studies | Human Trials |
|---|---|---|
Sustained weight loss obesity, BMI 30+ | 6 Fat oxidation and weight loss reported in obese mice with chronic AOD-9604 treatment. Lipid metabolism effects characterized in rats. | 0 Reached Phase 2b per developer (Metabolic Pharmaceuticals); did not advance to FDA approval; primary Phase 2b RCT data not published as peer-reviewed paper. The FDA voted against legal compounding (December 2024). |
Type 2 diabetes A1C reduction, glycemic control | 1 Limited animal-model data on glycemic endpoints. | 0 None published. |
Cardiovascular events MACE in CVD + obesity | 1 Limited animal-model data on cardiovascular endpoints. | 0 None published. |
Sleep apnea obesity-associated OSA | 0 None published. | 0 None published. |
Knee osteoarthritis obesity-associated joint pain | 1 Limited animal-model data on cartilage repair via separate mechanism unrelated to weight loss. | 0 No completed obesity-OA primary trial. |
MASH / liver fibrosis metabolic-dysfunction-associated | 0 None published. | 0 None published. |
Kidney disease T2D-associated CKD progression | 0 None published. | 0 None published. |
Heart failure (HFpEF) obesity-associated HFpEF | 0 None published. | 0 None published. |
Marketed Without Weight-Loss Evidence
Four compounds marketed online for fat loss. Zero controlled human weight-loss trials. The FDA voted against allowing legal compounding for CJC-1295, ipamorelin, and MK-677 in late 2024.
| Indication | Animal Studies | Human Trials |
|---|---|---|
CJC-1295 + Ipamorelin GH-releasing peptides; often marketed stacked | 25 Growth hormone secretion effects reported in animal models. Evidence base is for GH-axis pharmacology, not weight-loss outcomes. | 0 No controlled human weight-loss trials. The FDA voted against legal compounding for CJC-1295 (December 2024) and ipamorelin (October 2024). The Sigalos & Pastuszak 2018 review documented GH-axis effects in healthy adults but noted absence of weight-loss trial data. Sigalos & Pastuszak 2018 review, FDA compounding committee December 2024 outcomes |
Fragment 176-191 16-amino-acid GH fragment (same molecule as AOD-9604) | 11 Animal-only fat metabolism studies. Same molecule as AOD-9604 with shared evidentiary status. | 0 No published Phase 2+ controlled human obesity trial of fragment 176-191 specifically. |
MK-677 (ibutamoren) Non-peptide oral GH secretagogue | 14 GH secretion effects reported in animal models. Discontinued by Merck after Phase II (early 2000s). | 2 Phase II trials by Merck did not advance. No controlled human weight-loss trials. The FDA voted against legal compounding in October 2024. FDA has issued warning letters identifying MK-677 products as unapproved new drugs (2021, 2022, 2023). Sigalos & Pastuszak 2018 review, FDA warning letters 2021-2023 |
What's Marketed vs What's Studied
8 common claims, corrected.
“Compounded semaglutide and tirzepatide from telehealth platforms are the same as Wegovy/Zepbound, just cheaper.”
Same molecule, different rules. The shortage windows that allowed broad telehealth compounding ended by May 2025. The legal path that's still open is much narrower than what most pre-2024 services were doing.
“Retatrutide produces 24.2% weight loss based on Phase 2 data from 2023.”
That number is out of date. The Phase 3 trial that read out in late 2025 hit 28.7%. That's the biggest weight-loss number ever published in this class. Six more Phase 3 readouts coming through 2026.
“Once goal weight is reached on a GLP-1, treatment can stop and the loss persists.”
It doesn't work that way. About two-thirds of the lost weight comes back within a year of stopping. The trial data is consistent on this. GLP-1s are long-term medications, not short-term treatments.
“GH fragments like AOD-9604 and CJC-1295 produce fat loss similar to GLP-1s.”
They don't. AOD-9604 made it to a Phase 2 trial that was never published. CJC-1295, ipamorelin, MK-677, and fragment 176-191 have no controlled human weight-loss trials at all. In late 2024, the FDA voted against allowing any of these to be legally compounded for human use.
“Tirzepatide and semaglutide produce similar weight loss; cost decides.”
Cost matters, but the trials don't show 'similar.' In the 2025 head-to-head, Zepbound clearly beat Wegovy on weight loss. About 22% versus 15% over 72 weeks. Earlier head-to-head trials in diabetes showed the same gap. The drugs work, but they don't work to the same magnitude.
“Oral GLP-1 pills now produce the same weight loss as injections.”
Not yet. Orforglipron is the first oral GLP-1 to clear Phase 3, and it produces about 11% weight loss. Injectable Zepbound produces about 22%. Wegovy produces about 15%. Orforglipron is a real new tool for people who can't or won't do injections. It's a convenience trade-off, not an efficacy match.
“Semaglutide is just a diabetes drug; the weight-loss claims are off-label.”
Semaglutide has two on-label uses, depending on the brand name. Ozempic is the diabetes brand. Wegovy is the weight-loss brand. Same molecule. The FDA approved Wegovy specifically for chronic weight management in 2021. The FDA also approved it for cardiovascular protection in 2024 based on a 17,604-person trial. Same molecule, different label, different indication.
“GLP-1s cause muscle loss, so they're not safe for fitness-focused people.”
Some lean-tissue loss happens, but the framing is misleading. About a quarter to a third of the weight you lose on a GLP-1 is lean mass rather than fat. That ratio is roughly the same as any major weight-loss intervention, including just eating less or having bariatric surgery. Resistance training and adequate protein (around 1.0 to 1.6 grams per kilogram of body weight) substantially reduce the lean-tissue portion. There's also some evidence of bone-density loss roughly proportional to weight loss. Worth tracking if you're already at higher fracture risk.
If Considering Use, Here Is How to Be Safe
How to evaluate sources, verify quality, and find qualified physicians.
Get a prescription from a doctor who actually knows this drug class.
Weight management with GLP-1s is a medical decision. It needs evaluation of your BMI, your health history, and any contraindications. The contraindications include personal or family history of medullary thyroid cancer or a rare condition called MEN-2 syndrome. A real prescribing visit covers what drug fits, what dose to start, and how to monitor as you ramp up. Endocrinologists, obesity-medicine specialists, and primary care physicians who regularly prescribe these are the right starting points. Telehealth services that prescribe without a comprehensive evaluation should be approached with caution.
Use the FDA-approved branded products when you can.
Wegovy, Zepbound, Saxenda, Ozempic, Mounjaro, and Rybelsus all have full purity, stability, and clinical-trial documentation. The manufacturer assistance programs (LillyDirect, NovoCare) bring monthly cost down to $25 to $200 if you qualify, even without commercial insurance. Coverage for weight-loss indications varies by insurer and is improving but inconsistent. Coverage for diabetes is more uniform.
If you're considering a compounded GLP-1, verify three things before any prescription is filled.
First: the compounding pharmacy's state license, and whether it's registered as 503A (patient-specific) or 503B (outsourcing facility). Second: third-party purity and sterility testing, with batch certificates of analysis available on request. Third: the prescribing doctor's medical license and DEA registration. Important context. The 2024-2025 FDA enforcement-discretion windows have closed. Legitimate compounding now requires documented clinical justification for why the FDA-approved version doesn't meet your specific needs. The court that ruled on this (Northern District of Texas, March 2025) sided with the FDA. The broad shortage-window framework is over.
Avoid online marketplaces selling AOD-9604, CJC-1295, ipamorelin, fragment 176-191, or MK-677 for fat loss.
The FDA's compounding advisory committee voted against legal compounding for all of these in late 2024. They can't legally be made for human use. They're sold as 'research chemicals,' which is not a legal pathway for human therapy. There are no controlled human weight-loss trials supporting any of them. Marketing claims that combine them with GLP-1s ('semaglutide stack', 'tirzepatide plus B-12') aren't backed by clinical evidence.
Plan for the long term.
GLP-1s work best alongside structured nutrition and exercise. About two-thirds of the weight loss reverses within a year of stopping, so 'staying on' is the realistic plan unless something changes. Resistance training and 1.0 to 1.6 grams of protein per kilogram of body weight reduce the lean-mass portion of weight loss. Modest bone-density loss tracks with weight-loss magnitude in people without diabetes. Bone monitoring is worth considering if you're at higher baseline fracture risk. Cardiovascular and kidney benefits build with both dose and duration. If you do want to discontinue, do it under physician supervision with a structured maintenance plan.
The legal landscape shifted hard in 2024 and 2025. FDA declared the tirzepatide shortage resolved in October 2024, and the semaglutide shortage in February 2025. The enforcement windows that allowed broad telehealth compounding closed by May 2025. The Outsourcing Facilities Association sued the FDA over the change. The court (Northern District of Texas) ruled in FDA's favor in March 2025. The FDA's compounding advisory committee voted against legal compounding for AOD-9604, CJC-1295, ipamorelin, and MK-677 in late 2024. Retatrutide is currently still listed as compoundable under review. If Eli Lilly files for FDA approval and the agency approves, retatrutide compounding will close the same way semaglutide and tirzepatide did. PSI updates this page as the landscape changes.
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Zepbound or Wegovy: which is better for weight loss?
Zepbound wins on weight loss. In the 2025 head-to-head trial, people on Zepbound lost about 22% of their body weight over 72 weeks. People on Wegovy lost about 15%. The gap held in other trials too. Wegovy has one thing Zepbound doesn't yet. A finished trial showing it cuts heart attack and stroke risk by 20%. The trial enrolled people with existing heart disease. Zepbound's heart trial is still running. So if maximum weight loss is the goal, Zepbound. If you have established heart disease, Wegovy is the option with proven heart benefit.
What is retatrutide and when will it be FDA-approved?
Retatrutide is the next generation. It mimics three of your body's natural fullness signals at once: GLP-1, GIP, and glucagon. Zepbound mimics two. Wegovy mimics one. In a Phase 3 trial that read out in late 2025, people on retatrutide lost about 28.7% of their body weight. That's the biggest weight-loss number ever published for this kind of drug. If you weigh 200 pounds, that's about 57 pounds. Six more Phase 3 trials are reading out through 2026. FDA approval timing depends on which indications Eli Lilly submits first. Likely late 2026 or 2027.
How much weight will I lose on Zepbound?
In the FDA-approval trial, people on the highest dose of Zepbound lost about 22% of their body weight over 72 weeks. Lower doses gave 16-19%. About 9 in 10 people lost at least 5% of their starting weight. About 1 in 3 lost at least 25%. If you weigh 200 pounds, the average is about 44 pounds. Real-world results vary based on starting weight, dose tolerance, lifestyle changes, and how consistently you take it. The 3-year follow-up data shows the loss generally holds while you're on the drug.
How much weight will I lose on Wegovy?
In the FDA-approval trial, people on the highest dose of Wegovy lost about 15% of their body weight over 68 weeks. About 86% of people lost at least 5%. If you weigh 200 pounds, the average is about 30 pounds. The diabetes version of semaglutide (Ozempic) uses a lower dose and produces less weight loss, around 6%. Real-world results vary. Long-term follow-up data is more limited for Wegovy than for Zepbound.
Is compounded semaglutide still legal in 2026?
The legal landscape changed substantially in 2024 and 2025. FDA declared the semaglutide shortage resolved in February 2025. The enforcement-discretion windows that allowed broad telehealth compounding ended by May 2025. The earlier 'shortage exception' that let compounding pharmacies make copies of Wegovy is no longer in effect. There is one path that's still legal. Patient-specific compounding by a 503A pharmacy with documented clinical justification. Where the patient has a specific need that the FDA-approved version doesn't meet. That path is narrow and most pre-2024 telehealth services don't qualify under it.
What happens when I stop taking a GLP-1?
About two-thirds of the weight you lost typically comes back within a year. The largest follow-up trial showed people who stopped semaglutide regained most of their loss over 12 months. The same pattern happened in the tirzepatide stopping trial. This is why GLP-1s are usually thought of as long-term medications, not short-term treatments. The signals that suppress your appetite go away when the drug clears your system. Your body returns to its earlier hunger and food-reward patterns. There's also evidence that people who switch from injectable Wegovy or Zepbound to oral orforglipron can hold the loss. The pill route is lower-effort to maintain.
Does Wegovy reduce heart attack risk?
Yes, in people who already have heart disease. The largest cardiovascular trial in this class enrolled 17,604 adults with prior heart attack, stroke, or peripheral artery disease. They had overweight or obesity but no diabetes. People on Wegovy had 20% fewer major cardiac events over about three years compared to placebo. The trial also showed Wegovy reduced new diabetes cases by 73% and reduced kidney problems by 22%. The oral version of semaglutide (called Rybelsus) showed similar heart benefits in a separate 2025 trial. Wegovy is currently the only weight-loss drug with proven heart benefit in adults without diabetes.
Is there an oral alternative to weekly GLP-1 injections?
Two options exist. Rybelsus is an oral version of Wegovy. It's the same active ingredient (semaglutide) but in pill form. The catch: you have to take it on an empty stomach with strict timing rules. Even then, only a small fraction gets absorbed. Weight loss on Rybelsus is meaningfully less than on injectable Wegovy. Orforglipron is the newer one. It's the first oral GLP-1 that's not a peptide, so it survives digestion without strict timing rules. In a 2025 Phase 3 trial, people on orforglipron lost about 11% of their body weight. That's less than injectable Zepbound's 22% or Wegovy's 15%. The trade-off is convenience: a daily pill you can take any time. Eli Lilly filed for FDA approval in 2025.
Do AOD-9604 or other 'fat-loss peptides' actually work?
There's no evidence they work for weight loss in humans. AOD-9604 has fat-burning data in mice and rats. It made it to a Phase 2 human trial with the developer Metabolic Pharmaceuticals. The trial was never published as a peer-reviewed paper. The drug never advanced to FDA approval. CJC-1295, ipamorelin, MK-677, and fragment 176-191 are all in the same category. They have effects on the growth-hormone system in animal studies, but no controlled human weight-loss trials. In late 2024, the FDA's Pharmacy Compounding Advisory Committee voted against allowing any of these to be legally compounded for human use. They're sold online as 'research chemicals.' That's not a legal pathway for human therapy. The growth-hormone-fragment fat-loss idea makes mechanistic sense in animal models. It just hasn't translated to humans in any of the compounds tested.
How much do GLP-1s cost without insurance?
Brand-name Wegovy and Zepbound run about $900 to $1,500 per month at retail. The manufacturer assistance programs (LillyDirect for Zepbound, NovoCare for Wegovy) can bring that to $25 to $200 per month if you qualify. Medicare doesn't currently cover these drugs for weight loss. It does cover them for diabetes (under different brand names: Ozempic, Mounjaro). Commercial insurance coverage for weight loss is improving but inconsistent. Compounded versions through 503A pharmacies historically ran $200 to $500 per month. Most of those operations have shut down or pivoted since the FDA shortage exception ended in mid-2025.
What are the side effects of GLP-1s?
The most common side effects are gut-related: nausea, vomiting, diarrhea, constipation, and stomach pain. Most are dose-dependent and improve as your body adjusts, especially if you ramp up slowly. Less common but more serious: pancreatitis, gallbladder disease, and (in rodent studies) thyroid C-cell tumors. The thyroid finding has not been seen in humans. The largest safety dataset is the 17,604-person Wegovy heart trial. It ran for over three years. No new safety signals beyond the gut effects. There's also evidence of modest bone-density loss roughly proportional to weight-loss magnitude, especially in people without diabetes.
Can peptides be combined for better weight loss?
There's no controlled human trial supporting any peptide stack for weight loss. The 'semaglutide stack', 'tirzepatide plus B-12', or 'GLP-1 plus growth-hormone fragment' combinations marketed online are not backed by clinical evidence. The trial-validated approach is one drug at a time, with the most effective option you can access. Right now, Zepbound is the strongest. Retatrutide is in trials for people who have tried first-line drugs and need more. Stacking unapproved peptides on top of an FDA-approved drug adds risk without adding evidence-supported benefit.
Is GLP-1 use appropriate for cosmetic weight loss if I'm not obese?
FDA approval for weight loss requires a BMI of 30 or higher. That's the obesity threshold. There's also approval at BMI 27 or higher if you have a weight-related health condition. Like high blood pressure, high cholesterol, sleep apnea, or heart disease. Use outside those criteria, including for cosmetic weight loss in people at a normal BMI, is off-label. Off-label use hasn't been studied in controlled trials at meaningful scale. The safety and effectiveness data we have is from people who started at obesity-range BMIs. The risk-benefit picture in normal-weight people isn't well characterized. Some doctors will prescribe in those situations; others won't.
What questions should I ask my doctor before starting a GLP-1?
Six things worth asking. First: based on my BMI, my health history, and my goals, am I a good candidate for this drug class? Second: which specific drug fits my situation given cost, dosing, and what I'm trying to do? Wegovy, Zepbound, or Saxenda? Third: what's the dose schedule and how slowly will we ramp up to manage side effects? Fourth: what baseline labs should I get first (lipids, A1C, kidney, thyroid)? Fifth: how often will we check in once I'm on it, and what are we tracking? Sixth: if I want to stop later, what's the plan to manage regain?
Are GLP-1s addictive or do they cause dependence?
No, not in the way addictive drugs work. GLP-1s don't activate the brain's reward circuits the way alcohol, opioids, or stimulants do. There's no high. There's no compulsive use pattern. There's no withdrawal in the medical sense when you stop. Some research actually points the other direction. GLP-1s seem to reduce reward-driven eating, and there's interest in studying them for alcohol use disorder. What people sometimes call a 'rebound' after stopping is just weight regain because your appetite returns to baseline. That's not the same as withdrawal. The drug doesn't have a hold on you. The hunger does.
Can I drink alcohol on GLP-1s?
Moderate drinking isn't typically off-limits, but a few things change. GLP-1s slow down how fast your stomach empties. So alcohol can hit differently. Some people report stronger effects from less alcohol, or more nausea than usual. If you have type 2 diabetes and you're on insulin or another diabetes drug, watch out. Adding alcohol to the GLP-1 can increase your low-blood-sugar risk. Worth a heads-up. There's also early research suggesting GLP-1s might reduce alcohol cravings. Some people on these drugs say they just don't want to drink as much. That part is still being studied. Talk to your prescriber about your specific situation.
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Medical Disclaimer
This content is for educational and informational purposes only and does not constitute medical advice. The information presented reflects published research as indexed by PSI and should not be used to make treatment decisions. Always consult a qualified healthcare provider before starting, stopping, or modifying any treatment.