# Four Compounds, Four Positions on the Programme Ladder

> Comparing Four Metabolic Peptides — Metabolic & Weight Research Peptides — Semaglutide (Ozempic, Wegovy, Rybelsus), tirzepatide (Mounjaro, Zepbound), tesamorelin (Egrifta) and retatrutide, which has no brand name — compared across mechanism, evidence maturity, approval status and cautions — the four Metabolic & Weight Research research peptides on this desk, read off the trial record. No dosing advice.

**CROSS-COMPOUND BRIEFING**

Receptor count, evidence maturity and regulatory status vary independently of each other. Sorting the four on any single axis produces a different order — which is why "which is best" is the wrong question, four separate times.

## The short version

These four compounds get discussed as if they were four versions of the same product. They are not.

Most readers know three of them by a brand name: semaglutide is sold as Ozempic, Wegovy and Rybelsus; tirzepatide as Mounjaro and Zepbound; tesamorelin as Egrifta. Retatrutide has no brand name, because it has not been approved for sale anywhere. A brand name marks an approved product, so counting brand names is a rough guide to how far along a drug is — but it says nothing about how well it works.

Three of them work on gut-hormone receptors and reduce how much people eat. They differ in how many receptors they switch on: one, two, or three. More receptors has so far meant more weight lost, and also new side effects that the simpler drugs do not have.

The fourth works on a completely different system — the pituitary gland and growth hormone — and does not affect appetite at all. It shifts fat away from around the organs, and it is the only one here that *adds* muscle instead of costing some.

The other thing that separates them is how finished the evidence is. Two are approved medicines with large trials behind them. One is approved for a single narrow condition. One is experimental, with no approval anywhere and the big safety trials still running.

Those two rankings — how much weight lost, and how solid the evidence is — run in almost opposite directions.

## The comparison matrix

| Dimension | Semaglutide | Tirzepatide | Retatrutide | Tesamorelin |
| --- | --- | --- | --- | --- |
| Marketed as | Ozempic, Wegovy, Rybelsus | Mounjaro, Zepbound | **No brand name** — investigational | Egrifta |
| Class | GLP-1 receptor agonist (single incretin arm) | GIP/GLP-1 dual receptor agonist | GIP/GLP-1/glucagon triple receptor agonist | GHRH receptor agonist (not an incretin) |
| Primary lever | Reduced food intake (central appetite circuits) | Reduced food intake, amplified by dual engagement | Reduced intake **plus** increased energy expenditure | Growth-hormone-driven visceral lipolysis |
| Headline trial result | -14.9% vs -2.4% placebo at 68 weeks [4] | -20.9% vs -3.1% placebo at 72 weeks [8] | -24.2% vs -2.1% placebo at 48 weeks (phase 2) [15] | Visceral fat -27.71 cm², lean mass +1.42 kg (pooled) [17] |
| Evidence maturity | Phase 3 plus dedicated cardiovascular [3] and kidney [2] outcome trials | Phase 3 across obesity and diabetes, incl. head-to-head [1][9] | Phase 2 only; phase 3 and outcome trials ongoing [12] | Phase 3 in one population; 52-week durability data [21] |
| Regulatory status | Approved: T2D, chronic weight management, cardiovascular risk reduction, metabolic liver disease | Approved: T2D (2022) [6], chronic weight management, obstructive sleep apnoea | **Not approved anywhere** [12] | Approved 2010 for HIV-associated lipodystrophy only [18] |
| Effect on lean mass | Meaningful lean-mass loss alongside fat | Meaningful lean-mass loss alongside fat | Absolute lean-mass reduction alongside fat | **Lean mass increased** (+1.42 kg) [17] |
| Distinctive caution | Retinopathy monitoring with rapid glycaemic correction [5] | Gallbladder/biliary composite RR 1.97 (1.14–3.42) [7] | Dose-dependent heart-rate rise, peaking at 24 weeks [15] | IGF-1 elevation; active malignancy contraindicated |
| Reverses on stopping | Yes — substantial weight regain | Yes — substantial weight regain | Unknown; expected by analogy | Yes — visceral fat reaccumulates [21] |

## Mechanism: three on one axis, one on another

The incretin three sit on a single spectrum defined by receptor count, and the pharmacology at each step is better understood than the marketing suggests.

**One arm.** Semaglutide activates the GLP-1 receptor only. Its weight effect is almost entirely central — hypothalamic and brainstem appetite circuits — and it operates **without raising energy expenditure**. Whatever weight is lost is lost through intake.

**Two arms, unevenly.** Tirzepatide adds GIP. The important detail is that it is an *imbalanced* agonist, engaging the GIP receptor more than the GLP-1 receptor, and showing biased GLP-1 receptor signalling that favours cAMP over beta-arrestin recruitment [10]. It remains an intake drug, but a more effective one.

**Three arms, more unevenly still.** Retatrutide adds glucagon, and that changes the category of the drug rather than its magnitude. Structural work puts it at roughly 8.9 times native potency at the GIP receptor but only 0.3 and 0.4 times at the glucagon and GLP-1 receptors [13] — the glucagon arm is deliberately weak, because a fully potent one would be dangerous. That arm contributes energy expenditure and lipid mobilisation, making this the only compound here with a second lever.

**A different axis entirely.** Tesamorelin does not appear on that spectrum. It stimulates pituitary release of the body's own growth hormone, which raises IGF-1 and drives lipolysis preferentially in visceral tissue [20]. No appetite effect, no incretin receptor, no gastrointestinal profile in common.

## Evidence maturity: the ranking that inverts

Sorted by headline weight reduction, the order is retatrutide, tirzepatide, semaglutide. Sorted by depth of evidence, it is almost exactly reversed.

**Semaglutide** is the only compound here with dedicated hard-outcome trials in two organ systems beyond weight: a cardiovascular outcomes trial in 17,604 participants reporting a hazard ratio of 0.80 [3], and a kidney outcomes trial in 3,533 participants reporting a hazard ratio of 0.76 [2]. Those are the most expensive and most informative trials in this entire field, and no other compound on this desk has completed one.

**Tirzepatide** has phase 3 data across obesity [8] and diabetes [9] and, uniquely, a completed head-to-head trial against the class benchmark [1]. It has no completed cardiovascular or renal outcome trial.

**Retatrutide** has phase 2 data only [15][16], plus a phase 2 liver-fat substudy [14]. Phase 3 and the dedicated cardiovascular and kidney outcome trials are ongoing [12]. Its numbers are the largest and its evidence is the thinnest, and both of those statements are correct simultaneously.

**Tesamorelin** is a different case again: mature evidence including 52-week durability data [21], but confined to one population — HIV-positive adults on antiretroviral therapy [17][19]. Depth without breadth.

One methodological warning, because it is the most common error made about this class: **the -24.2% and the -20.9% figures cannot be compared directly.** Different trials, different populations, different durations, different designs, different placebo arms. Only SURMOUNT-5 [1] compared two of these compounds under the same protocol, and retatrutide was not in it.

## Safety: shared class profile, distinct outliers

The three incretin compounds share most of their caution list, which is unsurprising given the shared mechanism. Gastrointestinal intolerance during dose escalation dominates all three [5][8][15]. Lean-mass loss accompanies weight loss in all three. Weight regain on discontinuation is documented for the approved two and expected for the third. The boxed thyroid warning attaches to the approved incretins on the strength of rodent data, with human confirmation absent [5][6].

Where they diverge:

- **Semaglutide** carries the retinopathy caution — monitoring is advised where glycaemia is corrected rapidly in people who already have diabetic retinopathy [5] — and, on the strength of the safety review, an increased risk of biliary disease.
- **Tirzepatide** carries the most precisely quantified biliary signal: a gallbladder-or-biliary composite relative risk of 1.97 (95% CI 1.14–3.42) across nine trials and 9,871 participants, in the same analysis that found pancreatitis *not* significantly increased at 1.46 (95% CI 0.59–3.61) [7].
- **Retatrutide** carries a caution the other two do not have at all: a dose-dependent increase in resting heart rate, peaking around 24 weeks [15], driven by the glucagon arm. It is also the only compound here with no verified supply outside a trial, which makes identity and purity a live safety issue rather than a theoretical one.
- **Tesamorelin** shares essentially none of the above. Its caution list is IGF-1 elevation with limited long-term oncologic data, active malignancy as a labelled contraindication, modest glucose perturbation warranting monitoring in dysglycaemia, and prohibition in sport. Its liver-injury likelihood score is E — unlikely [18].

The pattern is worth naming: **greater potency has not bought a cleaner profile.** It has bought a larger effect with the same profile, plus one new mechanism-specific problem at each step up the receptor count.

## The convergence nobody planned

The most interesting thing on this page is not a difference but an overlap.

Retatrutide's phase 2 liver substudy reported relative liver-fat reductions reaching -82.4% at 24 weeks, with 86% of participants reaching normal liver fat, sustained to -86.0% at 48 weeks [14]. Tesamorelin's pooled data report a hepatic fat fraction reduction of -4.28% [17], and its randomised trial a net hepatic lipid-to-water reduction of -2.9% [19].

The magnitudes are not comparable — different measures, different populations, different scales — and no inference should be drawn from putting the numbers next to each other. What *is* notable is that two compounds sharing no receptor, no hormone family and no side-effect profile both move hepatic fat substantially. Either both are simply reducing adiposity and the liver follows, or hepatic fat sits downstream of several independent levers. The literature has not resolved which, and this desk is not going to pretend otherwise.

For the individual briefings, see [semaglutide](/semaglutide), [tirzepatide](/tirzepatide), [retatrutide](/retatrutide) and [tesamorelin](/tesamorelin). Every figure above traces to the [references list](/references).

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A clinical-literature briefing on metabolic peptides: it reports what the trials measured and names what they left unresolved, and it neither practises medicine nor sells anything.