# Compare Semaglutide, Tirzepatide, Retatrutide & Tesamorelin — Booking Peptides

> Side-by-side comparison of four metabolic research peptides — semaglutide, tirzepatide, retatrutide, and tesamorelin — across mechanism, approval status, evidence maturity, and key cautions.

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](/semaglutide), [tirzepatide](/tirzepatide), [retatrutide](/retatrutide), and [tesamorelin](/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].

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A literature digest — what the studies found, in the species studied, stated plainly and stopped.