The GLP-1 family, plainly

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).

Average weight loss in trials: 18–22% of body weight at the highest dose. That’s a meaningful step up from semaglutide. Common dosing: 2 mg/week starting, escalating to 10–15 mg/week. Most underground vials are 20 mg + 2 mL water = 10 mg/mL.

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 tripleagonist — GLP-1, GIP, and glucagon. The glucagon receptor angle is what sets it apart: glucagon increases energy expenditure, so retatrutide doesn’t just suppress appetite, it raises metabolic rate.

Phase 2 trial data is striking: 24% body-weight loss over 48 weeks at the highest dose, with ongoing loss at the cutoff (i.e. the curve hadn’t plateaued). The FDA has not approved it yet — it’s still in late-stage trials. For underground use, vials are commonly 10 mg + 2 mL = 5 mg/mL. Dosing ranges from 1–2 mg/week (low) up to 9–12 mg/week (high). Most people split the weekly dose across multiple injections to manage nausea.

How to choose

For most people the practical order is: start with semaglutide, escalate to tirzepatide if results stall, consider retatrutide if appetite suppression isn’t the bottleneck and you want a metabolic boost. Tirzepatide tends to have the best ratio of effect to side effects in the broader population.

If side effects are intolerable on one, switching family members often helps — they’re different molecules with different receptor binding profiles. Your gut may simply prefer one over 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.