The complete research reference for GLP-1 receptor agonists — covering all three generations of the drug class, from semaglutide through retatrutide.
GLP-1 (glucagon-like peptide-1) is an incretin hormone secreted by L-cells in the small intestine in response to food intake. It acts on receptors in the pancreas to stimulate insulin secretion, suppress glucagon, slow gastric emptying, and signal satiety to the hypothalamus.
GLP-1 receptor agonists are synthetic peptides engineered to mimic and extend this action. Unlike native GLP-1 (half-life ~2 minutes), pharmaceutical GLP-1 agonists are modified to resist enzymatic degradation — semaglutide achieves a ~7-day half-life through fatty acid conjugation, enabling once-weekly dosing.
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Each generation expands receptor coverage to produce progressively greater metabolic effects.
The most clinically studied GLP-1 agonist. Approved for T2D (Ozempic) and obesity (Wegovy). Extensive cardiovascular outcome data from the SELECT trial.
Dual GLP-1/GIP agonism produces ~22% weight loss — significantly greater than semaglutide. Approved for T2D (Mounjaro) and obesity (Zepbound) since 2022–2023.
Triple agonism adds glucagon receptor activation, increasing energy expenditure alongside appetite suppression. Phase 2 data shows ~24% weight loss at 48 weeks — the highest of any GLP-1 agent in trials.
All GLP-1 content on CompoundReview, organized by topic.
Nausea is the most common side effect across all three GLP-1 class agents. Rates vary by compound and dose — here is a summary from Phase 3 clinical trial data.
| Agent | Nausea Rate | Onset | Key Management Tip | Full Guide |
|---|---|---|---|---|
| Semaglutide | 30–44% | Weeks 1–4 of each dose increase | Eat small, low-fat meals; avoid lying down after injection | Full Guide → |
| Tirzepatide | 33–45% | Weeks 1–4 of each dose increase | GIP co-agonism may reduce severity vs pure GLP-1; same dietary rules apply | Full Guide → |
| Retatrutide | 47–58% | Weeks 1–6 of each dose increase | Highest nausea rate; slower titration (every 4–6 wks) is critical | Full Guide → |
Average weight loss varies significantly across the three GLP-1 class agents. Here is a summary of mean body weight reduction from pivotal Phase 2 and Phase 3 clinical trial data at maximum approved (or tested) doses.
| Agent | Mean Weight Loss | Trial | Duration | Full Guide |
|---|---|---|---|---|
| Semaglutide | ~15% | STEP 1 (Wegovy 2.4 mg) | 68 weeks | Full Guide → |
| Tirzepatide | ~22.5% | SURMOUNT-1 (Zepbound 15 mg) | 72 weeks | Full Guide → |
| Retatrutide | ~24.2% | Phase 2 (NCT04881760, 12 mg) | 48 weeks | Full Guide → |
Every head-to-head comparison across the three GLP-1 class agents — weight loss and nausea — in one place.
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GLP-1 (glucagon-like peptide-1) peptides are a class of incretin hormone analogues that activate GLP-1 receptors in the pancreas, brain, and GI tract. They suppress appetite, slow gastric emptying, and improve insulin secretion. The class includes semaglutide, tirzepatide, and retatrutide.
GLP-1 is the endogenous incretin hormone produced naturally in the gut. GLP-1 receptor agonists are synthetic peptides that mimic GLP-1's action at its receptor but with longer half-lives — semaglutide has a ~7-day half-life versus GLP-1's ~2 minutes.
Semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) are FDA-approved as prescription drugs for type 2 diabetes and obesity. Retatrutide is in Phase 3 trials and not yet approved. Research-grade versions are available for laboratory research use only.
Clinical trials show 15% (semaglutide), 22% (tirzepatide), and ~24% (retatrutide, Phase 2) mean body weight reduction. Results vary based on dose, duration, diet, and individual response.
The most common side effects are gastrointestinal: nausea, vomiting, diarrhea, and constipation. These are typically dose-dependent and most pronounced during titration. Rare but serious risks include pancreatitis and thyroid C-cell tumors (in animal studies).