Three peptides dominate the weight-loss conversation right now: semaglutide, tirzepatide, and retatrutide. They’re related — each one is more aggressive than the last — and they get conflated constantly. Here’s what each one does, plainly.
The shared mechanism
All three are agonists of GLP-1 (glucagon-like peptide 1), a hormone the gut releases after eating. GLP-1 does three useful things for weight loss: slows gastric emptying (you feel full longer), reduces appetite via signaling in the brainstem, and improves insulin sensitivity. The natural hormone has a half-life of two minutes. These peptides are engineered to last for days.
Semaglutide (Ozempic, Wegovy)
The original blockbuster. Pure GLP-1 agonist. Once-weekly injection. Approved by the FDA for type 2 diabetes (Ozempic) and chronic weight management (Wegovy). Average weight loss in trials: 12–15% of body weight over a year at the highest dose.
Reconstitution is straightforward — most underground vials are 5 mg, dissolved in 2 mL of BAC water. Common dosing escalates from 0.25 mg/week to a max of 2.4 mg/week, increasing every four weeks to manage the gut side effects (nausea, mostly).
Tirzepatide (Mounjaro, Zepbound)
Semaglutide’s younger, stronger sibling. Tirzepatide is a dual agonist — it hits both GLP-1 and GIP receptors. GIP is another gut hormone that, paired with GLP-1, produces a synergistic effect on satiety and metabolism. Once-weekly injection. Approved for type 2 diabetes (Mounjaro) and obesity (Zepbound).
The SURMOUNT-1 trial (72 weeks of continuous use) showed 15% body-weight loss at 5 mg/week, 19.5% at 10 mg/week, and 20.9% at 15 mg/week. That’s a meaningful step up from semaglutide. Common dosing: 2 mg/week to start, escalating to 10–15 mg/week. Most underground vials are 20 mg + 2 mL BAC water = 10 mg/mL. Half-life is approximately 5 days, so splitting the dose into multiple weekly injections — rather than one large shot — gives steadier plasma levels and fewer GI side effects.
Side effects are similar to semaglutide — nausea, occasional vomiting, fatigue at higher doses. Splitting the weekly dose into two or three injections per week often helps tolerability without changing the total.
Retatrutide
The newest and most aggressive of the three. Retatrutide is a triple agonist — GLP-1, GIP, and glucagon. The glucagon receptor angle is what sets it apart: glucagon directly stimulates lipolysis in adipose tissue and drives hepatic gluconeogenesis from the glycerol released by fat breakdown. In plain terms, it mobilizes fat through a different pathway than appetite suppression alone, which is why its fat-loss results outpace tirzepatide even when calorie intake is similar. The tradeoff is that appetite suppression is weaker per milligram than tirzepatide — the fat-loss edge comes from metabolic acceleration, not just hunger control.
Phase 2 trial data: 25–30% body-weight loss over 48 weeks at 12 mg/week, with the curve still trending down at the cutoff (loss hadn’t plateaued). The FDA has not approved it — it’s in late-stage trials with completion expected around 2029, and approval likely later. It has been removed from most US gray-area research-peptide sites as of late 2025. For underground use, vials are commonly 10 mg + 2 mL BAC water = 5 mg/mL. Half-life is approximately 6 days, so splitting the weekly dose into three equal injections (e.g., 1 mg Mon/Wed/Fri) is preferred over a single large shot — steadier plasma levels, fewer peak-dose GI side effects. Community sweet spot is 3 mg/week split this way.
How to choose
The practical progression many users follow is semaglutide first, tirzepatide second, retatrutide third — but this isn’t the only order, and community experience has shifted. A lot of people who started on tirzepatide have moved to retatrutide for better fat loss at equivalent appetite suppression. Retatrutide is not a last resort — it’s the current community preference for total fat loss, especially when running protocols that blunt GLP-1 effectiveness (heavy anabolics, high appetite).
Tirzepatide wins if appetite suppression is the primary bottleneck. Retatrutide wins if appetite is manageable but fat loss has stalled — the glucagon arm mobilizes fat through a different route that tirzepatide doesn’t have. The two can also be stacked: retatrutide as the base for fat mobilization, tirzepatide added on top when appetite needs reinforcement.
If side effects are intolerable on one, switching often helps — they’re different molecules with different receptor binding profiles. Your gut may simply respond better to one than another.
Caveats that matter
- All three can cause significant lean mass loss alongside fat loss if protein intake and resistance training aren’t protected. Eat protein. Lift.
- All three can affect blood glucose. If you’re not diabetic, watch for hypoglycemia symptoms in the first few weeks.
- Stopping abruptly often causes rebound appetite. Plan a taper, or expect to stay on a maintenance dose.
- Pancreatitis is a rare but real risk across the class. If you develop persistent severe abdominal pain, stop and see a doctor.
- Get bloodwork at least once a year on any of these.
For the math on whichever you’re running, use the reconstitution calculator. For full protocols, get the free Peptide Guide.