Weight & metabolic peptides: GLP-1 analogs, dual agonists, and the honest evidence map.
The GLP-1 receptor agonist class has produced the most dramatic weight-loss results in modern clinical pharmacology. Semaglutide's STEP-1 trial showed ~15% mean weight loss in 68 weeks; tirzepatide's SURMOUNT-1 pushed that to ~22.5%. The research-peptide market followed. This pillar maps thirty spokes — the approved drugs, their next-generation successors, and the grey-market compounds that shadow them — and assigns each an honest evidence tier.
- The GLP-1 receptor agonist class (semaglutide, tirzepatide, retatrutide) now has among the largest and most rigorous clinical trial databases in metabolic medicine.
- Semaglutide 2.4 mg: ~14.9% weight loss at 68 weeks (Wilding et al., STEP-1, NEJM 2021, PMID 33567185). FDA-approved as Ozempic (T2DM) and Wegovy (obesity).
- Tirzepatide 15 mg: ~22.5% weight loss at 72 weeks (Jastreboff et al., SURMOUNT-1, NEJM 2022, PMID 35658024). FDA-approved as Mounjaro (T2DM) and Zepbound (obesity).
- Retatrutide: a triple GIP/GLP-1/glucagon agonist in Phase III. Phase II showed ~24% loss at 48 weeks at 12 mg (Jastreboff et al., NEJM 2023, PMID 37358284).
- The research-chemical market sells peptide analogs as RUO — not FDA-approved, not substitutes for clinical products. The compounding landscape for semaglutide changed materially after the FDA declared the shortage resolved in October 2024.
- Older "weight loss peptides" — AOD-9604, fragment 176-191 — have thin or negative human trial records. Evidence hierarchy matters enormously in this cluster.
Why this pillar matters now
Between 2021 and 2024, GLP-1 receptor agonists moved from specialist endocrinology to general medicine to mainstream cultural conversation. Ozempic became the most searched drug name in the United States. Wegovy entered the obesity-treatment guidelines of every major medical society. Mounjaro and Zepbound extended the story to dual-receptor agonism. And Novo Nordisk and Eli Lilly's combined market caps briefly exceeded the GDP of several European nations.
The research-chemical market tracked this closely. By 2023, semaglutide and tirzepatide peptides — sold for research use only — were among the highest-revenue products at major US peptide vendors. This created a category where the stakes (and the regulatory scrutiny) are far higher than for research peptides in any other pillar. Understanding the evidence base, the regulatory position, and the sourcing landscape is not optional for anyone operating in this space.
This pillar routes all GLP-1 depth to two canonical spoke pages. If you are researching the approved drugs, start with those and come back here for the wider landscape.
Tirzepatide (Spoke 4.2) — GIP/GLP-1 dual agonist (Mounjaro / Zepbound). SURMOUNT-1, SURPASS-2, head-to-head data vs semaglutide, and the current compounded tirzepatide regulatory position.
How this cluster is organised
The thirty spokes group into four mechanistic families, each with a different evidential standing.
Family 1 — FDA-approved GLP-1 and dual agonists. Semaglutide and tirzepatide are the only compounds in this entire cluster that have passed Phase III trials and received FDA approval for obesity. Their clinical trial records run to dozens of RCTs, tens of thousands of patients, and multiple years of follow-up. For depth on semaglutide, the semaglutide research page is the pillar's canonical entry. For tirzepatide, the tirzepatide research page provides the dual-agonism mechanism and SURMOUNT trial data. The head-to-head comparison frames the clinical decision between them with honest weight-loss arithmetic.
Family 2 — Next-generation agonists (pre-approval). Retatrutide (GIP/GLP-1/glucagon triple agonist, Eli Lilly) showed ~24% weight loss at 48 weeks in a Phase II trial published in NEJM 2023. The Phase III TRIUMPH programme is ongoing. Cagrilintide (amylin/GLP-1 combination, Novo Nordisk) is in late-stage development. These are the most evidence-rich compounds in the pipeline. Our retatrutide research page covers the Phase II data in full.
Family 3 — Compounding and access. The regulatory mechanics of 503A/503B compounding, the FDA's October 2024 shortage-resolution declaration for semaglutide, and the legal skirmishes between compounders and brand manufacturers are covered in the compounded semaglutide vs Ozempic spoke. This is the most commercially sensitive spoke in the cluster and the one most likely to change as regulations evolve.
Family 4 — Older metabolic peptides (weaker evidence). AOD-9604, a fragment of growth hormone (hGH 176-191), was studied as an anti-obesity drug in the 2000s; human Phase III trials did not confirm the weight-loss effects seen in rodents. Fragment 176-191 is sold as an RUO research chemical but lacks meaningful human evidence. MOTS-c and other mitochondrial peptides are metabolically interesting but substantially preclinical.
Evidence hierarchy across the cluster
The table below assigns the principal compounds in this pillar to translational stages. Stage definitions mirror the Muscle & Recovery pillar: (1) in vitro; (2) rodent; (3) veterinary; (4) human Phase I; (5) human Phase II; (6) human Phase III / equivalent RCT; (7) regulatory approval.
| Compound | Best evidence stage | FDA status | Key trial / data point |
|---|---|---|---|
| Semaglutide | Stage 7 — approved | Ozempic (T2DM), Wegovy (obesity) | STEP-1: −14.9% body weight at 68 weeks (Wilding, NEJM 2021) |
| Tirzepatide | Stage 7 — approved | Mounjaro (T2DM), Zepbound (obesity) | SURMOUNT-1: −22.5% at 72 weeks (Jastreboff, NEJM 2022) |
| Retatrutide | Stage 5–6 — Phase II/III | Not approved (Phase III ongoing) | ~24% at 48 weeks, 12 mg (Jastreboff, NEJM 2023) |
| Cagrilintide | Stage 5–6 — Phase II/III | Not approved | CagriSema combination in development |
| AOD-9604 | Stage 5 — Phase III failed | Not approved | Phase III did not replicate rodent weight loss |
| MOTS-c | Stage 1–2 — preclinical | Not approved (RUO) | Mitochondrial peptide; metabolic effects in mouse; no human weight data |
| Fragment 176-191 | Stage 2 — rodent | Not approved (RUO) | hGH lipolytic fragment; no published human RCT |
The practical implication is stark: the gap between semaglutide/tirzepatide and everything else in this cluster is not a gap of degree but of kind. Every other compound listed above either failed human trials, hasn't reached them, or is preclinical. Researchers approaching this cluster should begin with the Phase III-anchored literature — the semaglutide vs tirzepatide comparison and the GI side-effects overview — before engaging with lower-evidence compounds.
The SELECT trial and cardiovascular relevance
One dimension of the GLP-1 literature that goes underdiscussed in the research-peptide world is the cardiovascular outcome data. The SELECT trial (Lincoff et al., NEJM 2023) randomised 17,604 patients with established cardiovascular disease and obesity to semaglutide 2.4 mg vs placebo. At a mean follow-up of 39.8 months, composite MACE (CV death, non-fatal MI, stroke) occurred in 6.5% vs 8.0% — a 20% relative risk reduction (HR 0.80, 95% CI 0.72–0.90, p<0.001). This is the first anti-obesity drug to demonstrate a MACE benefit independent of diabetes status.
The STEP-5 trial (Wilding et al., Nature Medicine 2022) extended the evidence to 2-year durability, showing that weight loss was maintained at 104 weeks with continued semaglutide therapy and largely regained after cessation — a finding that frames the discussion of treatment duration and "off-ramps" in clinical practice.
The STEP-3 trial (Wadden et al., JAMA 2021) added intensive behavioural counselling on top of semaglutide, achieving a mean weight loss of ~16%, and is the reference point for discussions about whether GLP-1 agonists work best combined with structured lifestyle programmes.
The compounding and RUO landscape
The compounding market for GLP-1 analogs is the most regulated topic in any PeptideRadar pillar. The short version: during periods of FDA-declared drug shortage, section 503A and 503B of the FD&C Act permit compounding pharmacies to produce copies of shortlisted drugs. The FDA declared semaglutide in shortage in 2022; this enabled large-scale 503A and 503B compounding. The FDA announced resolution of the semaglutide shortage in October 2024, which — under the statute — removes the shortage-compounding authorization and triggers FDA enforcement against ongoing compounders.
The tirzepatide compounding story is adjacent but distinct: Eli Lilly challenged compounders in court and won rulings in 2024 that accelerated FDA's move to remove tirzepatide from shortage status, curtailing 503B outsourcing-facility compounding. The compounded semaglutide vs Ozempic spoke covers the 503A vs 503B distinction and what the shortage resolution means for access and cost in 2025–2026.
Research-chemical semaglutide and tirzepatide occupy a third, legally distinct tier. Sold as RUO materials with no clinical intent, they sit outside the FDA drug and compounding frameworks entirely. Quality varies enormously; the USP published a semaglutide monograph in 2024 that provides a reference standard against which COAs can be compared.
Cross-cluster connections
The Weight & Metabolic pillar connects to two other clusters in ways that researchers frequently encounter. First, the Longevity & GH-axis pillar contains tesamorelin — the only FDA-approved GHRH analog — which is approved specifically for HIV-associated lipodystrophy (visceral fat reduction). Tesamorelin lives primarily in the Longevity cluster but is cross-referenced here because its mechanism (GH-axis-driven lipolysis) is adjacent to the GLP-1 mechanism (central satiety + gastric motility) and the two are sometimes combined in body-recomposition protocols. Our tesamorelin research page covers the Falutz NEJM 2007 and Stanley JAMA 2014 trial data.
Second, the Muscle & Recovery pillar is relevant because GLP-1 agonist-associated weight loss includes ~30–40% lean-mass loss. The GLP-1 muscle loss mitigation spoke addresses what the research says about preserving lean mass during GLP-1 therapy — an increasingly high-priority clinical question.
The spoke articles, by sub-topic
Core GLP-1 and dual-agonist spokes
The highest-volume spokes in the pillar are the compound-level research pages. The semaglutide research page (spoke 4.1, 450,000 searches/month) is the cluster's anchor: it covers the full STEP program, the SELECT MACE trial, and the COA-vs-USP-monograph guidance for RUO sourcing. The tirzepatide research page (spoke 4.2, ~246,000/month) covers the dual GIP/GLP-1 mechanism and the SURMOUNT-1 and SURPASS-2 trial data. The head-to-head comparison (spoke 4.3, ~49,500/month) is the cluster's highest-intent commercial spoke — readers at this URL have already decided to use one of the two; they want the honest weight-loss differential.
Next-generation pipeline spokes
The retatrutide research page (spoke 4.4) covers Eli Lilly's triple agonist, LY3437943, which targets GIP, GLP-1, and glucagon receptors simultaneously. The Phase II NEJM 2023 publication (Jastreboff et al.) is the central citation; the Phase III TRIUMPH programme is ongoing as of April 2026. Retatrutide is not approved and is not available as an FDA-authorized product. Spoke 4.6 (cagrilintide) will cover the amylin analog and the CagriSema combination programme.
Compounding and sourcing spokes
The compounded semaglutide vs Ozempic spoke (spoke 4.9, ~27,100/month) is the cluster's most sensitive commercial page. Spoke 4.10 (compounded tirzepatide vs Mounjaro) will parallel it for tirzepatide. Both pages carry FTC disclosure, clear RUO framing, and current-as-of dates because the regulatory picture changes rapidly.
Clinical management spokes
Spokes covering dosing schedules (semaglutide dosing, tirzepatide dosing), side-effect management (GI side effects, nausea management), and plateau strategies (Ozempic plateau) address the informational needs of readers who are already on these drugs or researching their use cases.
Older and alternative metabolic compounds
The AOD-9604 spoke covers the hGH fragment whose Phase III programme failed to replicate rodent weight-loss findings — a useful case study in translation failure. The MOTS-c metabolic spoke covers the mitochondrial peptide's role in insulin sensitivity and metabolic health, without overclaiming human weight-loss data that doesn't yet exist.