# GLP-1 agonists (semaglutide, tirzepatide, retatrutide)

Most effective weight-loss drugs ever; powerful systemic drugs, not 'clean' wellness peptides.

- Page: https://peprank.xyz/peptides/glp-1-agonists
- Category: Metabolic & weight (Research peptide)
- Also known as: Ozempic/Wegovy; Mounjaro/Zepbound; reta; tirz; sema
- Routes: Injection
- Sequence: HAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (class: native GLP-1(7-37) shown; semaglutide = Aib8, Arg34, C18 diacid-linker on Lys26; liraglutide = Arg34, palmitoyl-Glu on Lys26; tirzepatide/exenatide differ)
- Safety tier: Strict: Avoid · Balanced: Avoid · Evidence only: Avoid
- Risk axes (0 none to 3 severe): Seen harm 3, Mechanism 3, Data gap 1, Silent harm 2, Product 3
- Positive: 50% of 56 graded reports glowing or positive, shrunk toward the 49% all-report average by 8 reports' weight
- Rank: #35 of 61 research peptides
- Graded reports: 56 (Glowing 19, Positive 9, Mixed 8, Nothing 6, Negative 5, Bad reaction 9)
- Evidence: Approved drug — (semaglutide, tirzepatide) with large outcome RCTs; retatrutide in phase 3
- Access: Approved drug
- Onset: Appetite and 'food noise' drop within hours to a few days of the first shot; meaningful weight loss shows over the first month, and full effect takes months of dose titration.
- Lasts: One weekly injection (half-life about 7 days for semaglutide, 5 for tirzepatide, 6 for retatrutide); some users feel appetite return in the last day or two before the next dose.
- Cost per month: ≈ €27–1210 (researchers' estimate)
- Dose users report: 0.35–1 mg/day (median 640 mcg, n=12)
- Updated: 2026-10-30

**Why Avoid under the strict bar:** Potent drugs with real serious-harm paths (pancreatitis, gallbladder, GI, heart rate, NAION). Worth it for obesity/diabetes under a doctor, but outside a 'clean general-health peptide' list.

## What users report

Highest real-world sentiment of anything here ('saved my life', 100 lb lost, drinking urges gone). Under 10% feel nothing, though dose response varies. But ER physicians' threads list pancreatitis, gallstones, severe vomiting, AKI from dehydration and euglycaemic DKA, mostly from grey-market retatrutide and over-fast titration. Sleep disruption on reta is a common complaint, and r/Retatrutide carries a cluster of heart-rhythm reports (SVT needing adenosine, AFib after one dose, ER visits for tachycardia and low blood pressure), one of them inside a Lilly trial.

**Effects:** large fat loss; appetite and 'food noise' suppression; reduced alcohol craving; improved glucose, liver fat, BP, apnoea

**Downsides:** nausea, vomiting, constipation; fatigue; loss of lean mass without resistance training; sleep disruption (reta)

**Risks:** Pancreatitis and gallbladder disease; Gastroparesis / severe GI events; dehydration-driven AKI; NAION (very rare, EMA 2025 for semaglutide); Heart-rate increase; retatrutide is unapproved (phase 3) and sold grey-market with unknown dose/purity

**Typical use:** Sema 0.25 mg/wk up to 2.4 mg; tirz 2.5 mg/wk up to 15 mg; reta (grey) 1-12 mg/wk, titrated slowly.

**Getting it:** Semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) are prescription drugs; US telehealth also sells compounded versions. Retatrutide is still in phase 3 and is only available as grey-market research vials.

**Stacked with:** Resistance training and high protein intake (The standard advice across the GLP-1 subreddits to limit lean-mass loss during rapid weight loss.); Ondansetron (Zofran), stool softeners and electrolytes (Commonly prescribed or self-managed to get through nausea, constipation and dehydration during titration.); Ursodiol (Some doctors add it during rapid loss to lower gallstone risk; a two-year tirzepatide user took it until reaching goal.); TRT, HGH, MOTS-c, 5-amino-1MQ or tesamorelin (Common in r/Retatrutide and Biohackers stacks for lean mass and energy; untested combinations that confound any attribution.); Metformin (Tried by Mounjaro users to break stalls or by non-responders as a fallback.)

## Risk profile

- **Seen harm 3/3:** Deaths and multiple well-documented serious harms: 19 fatal UK pancreatitis reports by October 2025, label warnings for pancreatitis, gallbladder disease, kidney injury, aspiration under anaesthesia and anaphylaxis, NAION as a confirmed very rare effect, compounded-dosing overdoses needing hospital, and a Victorian liver-injury cluster with grey-market 'retatrutide'.
- **Mechanism 3/3:** Dangerous pathways are demonstrated in vivo: slowed gastric emptying behind aspiration and ileus, pancreatitis and gallstones in humans, and thyroid C-cell tumours in rodents at clinical exposures (a boxed warning); retatrutide also raises heart rate.
- **Data gap 1/3:** Semaglutide and tirzepatide alone would score 0 (outcome trials such as SELECT with 17,604 patients, years on the market); retatrutide, sold grey-market, has large phase 3 trials but no approval, so the entry scores 1.
- **Silent harm 2/3:** Most serious harms present with symptoms, but gallstones, lean-mass loss and retinopathy build up over months and need tests to catch; the human relevance of the rodent thyroid tumours is unresolved.
- **Product 3/3:** Pharmacy semaglutide and tirzepatide would score 0, but the entry includes retatrutide, which is only grey-market; Australian testing found only one of 18 vials matched its label, and one 'retatrutide' vial held semaglutide at eight times the approved strength.
- **Never if:** Personal or family history of medullary thyroid carcinoma or MEN 2 (label); History of pancreatitis; Pregnancy (label); Upcoming surgery under anaesthesia without telling the anaesthetist

## Top reports

- Glowing, metabolic: “🌷 my reta update 🤍 started: february 10, 2026 240lbs vs 133lbs (108 kg vs 60kg) 107lbs lost (48kg lost)” — [@ilavakgsi on X](https://x.com/ilavakgsi/status/2100422069787783317)
- Glowing, metabolic: “Zepbound (tirzepitide) saved my life. PCOS (now PMOS) made me legitimately suicidal. I gained 50 lbs in a year in 2024. Lost my hair a little. Was prediabetic (it harms your insulin levels). It would yo-yo and back again. I tried surgery, peels, everything just to maintain. The drug is a miracle.” — [@GeauxGabrielle on X](https://x.com/GeauxGabrielle/status/2091511798197326289)
- Glowing, metabolic: “In 2022 I was given ozempic, I was on it for 2 years and not one pound lost. In mid 2024 I was given ozempic Mounjaro and in 2025 the weight finally started coming off so slowly that I didn’t even notice.” — [r/Mounjaro](https://www.reddit.com/r/Mounjaro/comments/1wks9a0/100_pounds_down/)
- Glowing, metabolic: “I've been trying Retatrutide for 3 weeks. It is insane. I experience zero "food noise" during the day. No desire to eat sugar or drink alcohol. Just don't want it. Food is just fuel. That is the extent of it. My mental clarity is v high.” — [@Danhightower on X](https://x.com/Danhightower/status/2111959871042015677)
- Glowing, metabolic: “I had prayed to a god I don’t believe in that this medicine would work for my alcoholism and for weight loss. Since that first shot, I haven’t had a single craving. I’ve also lost 110lbs.” — [r/tirzepatidecompound](https://www.reddit.com/r/tirzepatidecompound/comments/1v9zvyi/for_those_asking_does_it_get_better/)

## Cheapest in Europe

- [Europa-Peptide](https://europa-peptide.de/en/shop/retatrutide-pills-3mg/) (PL): Retatrutide pills, 30 x 3mg, €199, €2.21/mg
- [Europa-Peptide](https://europa-peptide.de/en/shop/retatrutide/) (PL): Retatrutide 30mg, €149, €4.97/mg
- [Europa-Peptide](https://europa-peptide.de/en/shop/retatrutide/) (PL): Retatrutide 40mg, €199, €4.97/mg
- [Europa-Peptide](https://europa-peptide.de/en/shop/retatrutide/) (PL): Retatrutide 50mg, €249, €4.98/mg
- [Europa-Peptide](https://europa-peptide.de/en/shop/retatrutide/) (PL): Retatrutide 60mg, €299, €4.98/mg

## Studies

- [Wilding et al. 2021 (STEP 1): once-weekly semaglutide in adults with overweight or obesity](https://pubmed.ncbi.nlm.nih.gov/33567185/) (rct, n=1961, 2021): Semaglutide 2.4 mg/week cut body weight 14.9% at 68 weeks versus 2.4% on placebo; GI side effects were the main reason for stopping.
- [Wilding et al. 2022: weight regain after withdrawal of semaglutide (STEP 1 extension)](https://pubmed.ncbi.nlm.nih.gov/35441470/) (rct, n=327, 2022): One year after stopping, participants had regained about two-thirds of the weight they lost, and cardiometabolic gains largely reverted.
- [Jastreboff et al. 2022 (SURMOUNT-1): tirzepatide once weekly for the treatment of obesity](https://pubmed.ncbi.nlm.nih.gov/35658024/) (rct, n=2539, 2022): Tirzepatide 5, 10 and 15 mg/week cut body weight 15.0%, 19.5% and 20.9% at 72 weeks versus 3.1% on placebo.
- [Aronne et al. 2025 (SURMOUNT-5): tirzepatide compared with semaglutide for obesity](https://pubmed.ncbi.nlm.nih.gov/40353578/) (rct, n=751, 2025): Head to head at maximum tolerated doses, tirzepatide cut weight 20.2% at 72 weeks versus 13.7% for semaglutide.
- [Jastreboff et al. 2023: triple-hormone-receptor agonist retatrutide for obesity, a phase 2 trial](https://pubmed.ncbi.nlm.nih.gov/37366315/) (rct, n=338, 2023): Retatrutide 12 mg/week cut weight 24.2% at 48 weeks versus 2.1% on placebo; heart rate rose dose-dependently, peaking at 24 weeks.
- [Lincoff et al. 2023 (SELECT): semaglutide and cardiovascular outcomes in obesity without diabetes](https://pubmed.ncbi.nlm.nih.gov/37952131/) (rct, n=17604, 2023): Semaglutide 2.4 mg cut major adverse cardiovascular events 20% over about 3.3 years in people with established cardiovascular disease.

## Sources

- [EMA PRAC: NAION a very rare side effect of semaglutide (June 2025)](https://www.ema.europa.eu/en/news/prac-concludes-eye-condition-naion-very-rare-side-effect-semaglutide-medicines-ozempic-rybelsus-wegovy)
- [r/emergencymedicine: peptides and their side effects (Australia ER experience)](https://www.reddit.com/r/emergencymedicine/comments/1x26730/peptides_and_their_side_effects/)