METABOLIC & WEIGHT RESEARCH / MATRIX
Four Metabolic Peptides, Side by Side
Where they converge on mechanism, where they diverge on evidence maturity, and what the regulatory record says about each one.
The short version
This page lines up the four compounds on this desk — semaglutide, tirzepatide, retatrutide, and tesamorelin — on the dimensions that matter most when reading the metabolic-peptide literature: receptor class, evidence quality, regulatory status, WADA standing, and the defining caution for each.
The headline is simple: three of these are incretin-class compounds with broad metabolic evidence; one approaches visceral fat through a completely different axis. Two are fully approved medicines; one is investigational; one is approved only for a narrowly defined population. None should be approached without understanding exactly which column it sits in.
The comparison matrix
| Dimension | Semaglutide | Tirzepatide | Retatrutide | Tesamorelin |
|---|---|---|---|---|
| Receptor class | GLP-1R agonist | GIPR + GLP-1R dual agonist | GIPR + GLP-1R + GCGR triple agonist | GHRH-R agonist (pituitary) |
| Primary mechanism | Incretin: appetite suppression, insulin secretion, gastric slowing | Dual incretin: amplified appetite suppression and glucose effects | Triple incretin + energy expenditure via glucagon arm | GH-axis stimulation → IGF-1 → visceral lipolysis |
| Key efficacy finding | -14.9% weight at 68 wk (STEP 1) [4] | -20.9% weight at 72 wk (SURMOUNT-1) [10]; superior to semaglutide [1] | -24.2% weight at 48 wk (Phase 2) [15]; -82.4% liver fat [14] | -27.71 cm² VAT (HIV-lipodystrophy meta-analysis) [17] |
| Evidence maturity | Very high — multiple large Phase 3/4 RCTs, CV and kidney outcomes trials | High — multiple Phase 3 RCTs, head-to-head vs. semaglutide | Moderate — Phase 2 only; Phase 3 ongoing | Moderate — approved indication well-evidenced; off-label thin |
| Regulatory status | FDA-approved (T2D, obesity, CVD risk, MASH) | FDA-approved (T2D, obesity, sleep apnea) | Investigational — not approved anywhere | FDA-approved for HIV-associated lipodystrophy ONLY |
| WADA status | Not specifically prohibited | Not specifically prohibited | Not specifically prohibited | Prohibited S2 (in- and out-of-competition) |
| Key caution | Weight regain on stopping; lean-mass loss; retinopathy in rapid glycemic correction [5][7] | Higher discontinuation rate from GI events vs. GLP-1 class; gallbladder disease [9] | Unapproved; unverified supply outside trials; dose-dependent heart-rate increase [15][12] | Narrow indication; off-label evidence thin; WADA prohibition [18] |
Receptor class and mechanism
Three of the four are incretin-class compounds — they target the gut-hormone receptors that regulate energy homeostasis after meals. Semaglutide agonizes the GLP-1 receptor alone [6]. Tirzepatide adds the GIP receptor — the "dual incretin" strategy [8]. Retatrutide adds a third: the glucagon receptor, whose activation raises energy expenditure through thermogenic mechanisms and drives hepatic lipid mobilization [12][13]. Each additional receptor contributes incremental metabolic effect.
Tesamorelin operates outside this framework entirely. It agonizes the GHRH receptor on pituitary somatotrophs, stimulating pulsatile growth-hormone release, which drives IGF-1 production and preferential visceral lipolysis [17][20]. Different axis, different tissue target, different approval basis.
Evidence maturity
Semaglutide has the deepest human evidence base: multiple large Phase 3 RCTs across multiple outcomes (weight, cardiovascular events, kidney disease) [2][3][4], including the SELECT trial (n=17,604) and the FLOW trial (n=3,533).
Tirzepatide has strong Phase 3 data for weight and glycemic endpoints [10][11], plus a head-to-head trial against semaglutide [1]; cardiovascular outcomes data are emerging.
Retatrutide is Phase 2. Its weight-loss and liver-fat numbers are the largest in the class, but the TRIUMPH Phase 3 program is ongoing and no long-term outcomes data exist [12][15].
Tesamorelin is well-evidenced in its approved population — a 2026 meta-analysis of five RCTs supports its visceral-fat and hepatic-fat effects in HIV-associated lipodystrophy [17]. Outside that population, the evidence is sparse.
Regulatory and WADA status
Semaglutide is FDA-approved for type 2 diabetes, chronic weight management, cardiovascular-risk reduction in established CVD with overweight/obesity, and (2025) metabolic steatohepatitis.
Tirzepatide is FDA-approved for type 2 diabetes, chronic weight management, and moderate-to-severe obstructive sleep apnea in adults with obesity.
Retatrutide has no regulatory approval anywhere as of mid-2026. It is investigational [15].
Tesamorelin is FDA-approved for one indication: HIV-associated lipodystrophy in adults. All other uses are off-label. It is prohibited by WADA under S2 in- and out-of-competition — the only one of the four explicitly on the Prohibited List [18].
None of the three incretin compounds appear on the current WADA Prohibited List, though athletes should independently verify current status.
Key caution per compound
Each compound carries a defining caveat.
For semaglutide: the weight regain after stopping (STEP 1 extension showed mean regain of roughly 11.6 percentage points within one year), lean-mass loss with rapid weight reduction, and the retinopathy-complication signal in people with pre-existing retinopathy undergoing rapid glycemic correction [5][7].
For tirzepatide: the higher discontinuation rate due to GI adverse events versus comparators in meta-analysis, and the significantly elevated composite gallbladder/biliary-disease risk [9]. The power comes with a tolerability cost.
For retatrutide: the compound is not approved, and material obtained outside a clinical trial has no verified identity, purity, or sterility [15]. The dose-dependent heart-rate increase is a signal without long-term cardiovascular data to contextualize it [12].
For tesamorelin: the narrowness of its indication. Everything outside HIV-associated lipodystrophy is off-label, investigational, and not backed by Phase 3 RCTs. Its WADA prohibition also applies to any athlete under testing [18].