Twenty-One Peptides, Graded

LONGEVITY LATEST ISSUE 25 · 26 AUGUST 2026

LONGEVITY LATEST · DEEP DIVE

Twenty-One Peptides, Graded

From tirzepatide to epitalon — one A-to-F scale, applied to the compounds an FDA panel has just voted to bring within reach.

By Christian Thomsen · Companion to Issue 25 · 26 August 2026 · ~7-minute read

So: why do the six D-graded compounds turn out to be, exactly, six of the seven that went before the advisory committee in July?

Because the committee and I were sorting on the same variable and drawing opposite conclusions from it. Sort twenty-one peptides by the strength of their human evidence and they don’t scatter — they stack, along a single axis, and the axis isn’t mechanism or potency or price. It is whether anybody ever ran a controlled trial. The seven nominated compounds are precisely the ones where nobody has. The committee read that absence as a gap to be closed by prescribing. I read it as the finding.

That is what happens when a market learns to price access to a molecule and nobody prices the evidence.

How the grades work

One principle first, because it drives every grade below. The popular lists grade effect size. I grade certainty. A compound that would be spectacular if it worked is not the same thing as a compound that works.

So what is graded is confidence that a compound does what it is sold to do, in humans, for the claim in question. That last clause carries weight: a grade attaches to a claim, not a molecule. Which is why three entries below hold two grades each.

A: multiple large randomised trials agreeing, on outcomes that matter. B: one or two well-designed randomised trials for the claim — B+ where a single trial is unusually good and confirmed elsewhere. C: controlled human data exists but doesn’t test the marketed claim, or pharmacology is established with no efficacy trial behind it. D: no controlled human evidence for the marketed claim at all. Uncontrolled pilots, open-label series and animal work sit here together, because none of them separates a drug effect from a placebo effect — which is why three human pilots and zero human studies land on the same rung. F: unsupported or untestable, tested and contradicted, or resting on a compromised evidence base.

Two consequences the market depends on you conflating. A high grade is not an instruction — tirzepatide earns an A and is still wrong for most people who want it. And a low grade describes what we know, not the molecule: several Ds below could grade higher in five years if anybody runs the trial.

The list

The top: what an A actually costs

Everything with an A or a B survived a trial designed to embarrass it, and they share something else: every one is a metabolic or endocrine drug, and every one but retatrutide is licensed somewhere. Retatrutide is the single exception, and being the exception is part of why it sits at B+ rather than higher — a phase 3 record most compounds would envy, but no outcomes trial, no licence anywhere, and what you can buy under that name today is not what Lilly tested.

The B tier is where the caveats live, and all three are the same caveat in different clothes: a real trial, answering a question slightly to the side of the one being sold. HCG carries decades of randomised evidence — in fertility and hypogonadism, which is exactly why it splits: an A there, a C in the wellness protocols it now appears in. Bremelanotide is licensed and works, at an effect size most people find underwhelming after the marketing. Collagen is the sharpest case. Myung and Park pooled 23 trials and 1,474 people; across all 23, collagen improved hydration, elasticity and wrinkles. Then they split by funder. Industry-funded studies showed benefit. Non-industry-funded ones did not, and neither did the higher-quality ones — exactly the pattern you'd expect if part of the effect were coming from the sponsor rather than the peptide.

The C block: one compound wearing four costumes

The C tier is really one compound in four disguises. Sermorelin, CJC-1295, ipamorelin, the GHRPs: different receptors, one destination. All end at more pulsatile growth hormone, and therefore more IGF-1.

Which is where I part company with the gym tier-list genre. In performance terms, raising IGF-1 is the entire goal. In ageing biology it is ambiguous at best: the pathway that builds tissue is the same one that, turned down, extends lifespan in essentially every model organism anyone has tested.

The human evidence for that is unusually direct. Guevara-Aguirre's team followed roughly a hundred Ecuadorians with growth hormone receptor deficiency — Laron syndrome — for 22 years. Despite being, on average, obese, not one developed diabetes, and a single non-fatal cancer occurred in the whole cohort. Among their unaffected relatives, cancer mortality ran at about 20%.

A compound whose selling point is raising IGF-1 should not be sold as an ageing intervention without somebody acknowledging the tension.

The Laron cohort is a natural experiment at one extreme, not a target, and I'm not telling anyone to suppress their growth hormone. I'm saying the lists that put it at the very top are grading a different outcome to the one they claim. In diagnosed deficiency it deserves every superlative. In a healthy forty-five-year-old chasing healthspan it's a D — and the confidence with which that gets asserted the other way round is the largest error in the genre.

The D floor, and a coincidence that isn't one

Six compounds sit at D, and here is what I only noticed once the table was laid out: they are, precisely, six of the seven that went in front of the advisory committee in July. The seventh, epitalon, I graded lower still.

What unites them isn't that they're useless — it's that nothing in the file can settle the question. FDA reviewers found no human safety studies at all for four. Where there was human data, the longest anyone has been followed is fifteen days, for conditions people intend to treat for years.

The F tier holds three different failures, worth telling apart. Epitalon fails because its central claim can’t practically be tested in a living person. Dihexa fails because the evidence base is compromised: two of the papers establishing its mechanism were retracted by the Journal of Pharmacology and Experimental Therapeutics in April 2025, after a Washington State University investigation found falsified or fabricated figure data, and a third carries an expression of concern.

AOD-9604 fails in the most honourable way available to a drug. 536 subjects, 24 weeks, placebo-controlled, primary endpoint missed, development halted in 2007. One caveat I’ll flag rather than bury: that trial dosed orally, and peptides survive the gut badly, so its defenders argue the delivery failed rather than the molecule. Nobody has run the injectable version in the twenty years since, which tells you what the people who owned it concluded.

Three places I disagree with the consensus

By consensus I mean the tier lists that circulate on YouTube and in gym forums, which are usually better informed than their critics assume and wrong in three consistent ways.

First, effect size against certainty — the principle at the top of this article. Collapsing the two is how a market gets built on mouse data. Same discipline we applied to the lipid drugs in Issue 24: bempedoic acid is the cleverer molecule and still graded below atorvastatin, because one outcomes trial is one outcomes trial.

Second, growth hormone, for the reason above.

Third — the one that genuinely bothers me — grey-market availability keeps getting framed as a feature, phrased as a triumph: you can get the best drug in the class from a website before your doctor may prescribe it. That sentence should end a conversation, not open one. It describes an uncontrolled trial with a sample size of one and nobody reading the outcome.

The frontier

Retatrutide has seven further phase 3 readouts due and a filing expected next year; watch whether the glucagon arm delivers liver benefit beyond the weight loss, which the phase 2 data hinted at strongly. The FDA's rulemaking on the six endorsed peptides will take a year or more, unless it is accelerated politically rather than scientifically. And the next advisory committee, due before the end of February 2027, takes up five more: LL-37, GHK-Cu, dihexa acetate, melanotan II and pegylated mechano growth factor.

Read that last list again. Dihexa is on it, with a retracted evidence base behind it. That will be the clearest test yet of whether the committee is weighing evidence or weighing demand.

What this means for you

This isn’t a protocol and I’m in no position to write you one. It is a way of deciding, and it will disappoint anybody hoping for a stack.

If you have a metabolic condition a GLP-1 drug is licensed to treat, that conversation belongs with a doctor — and take the cardiovascular numbers from Issue 23 into the room, because the same drugs move both. If you have an injury: load the tissue progressively, sleep, eat enough protein. Unglamorous, nearly free, better evidenced than anything in the D tier. And if what you want is what the secretagogues advertise, the strength work we graded in Issue 21 raises your own growth hormone more reliably than sermorelin does, and gives you the muscle growth hormone alone doesn't.

And if you're going to ignore all of that — some of you will, and I'd rather you did it with the numbers in front of you — hold on to three. 41.6% of independently tested vials failed a basic quality bar. Purity certificates tell you nothing about endotoxin. And “research use only” is the seller's legal protection, not yours.

The most expensive item on that list is the protein. The most valuable one is the sleep.

Sources and further reading

Where a table entry is not separately cited below, it rests on the FDA briefing documents and the independent analysis of them at [1] and [2], which set out the human evidence identified for each nominated compound.

1. FDA Pharmacy Compounding Advisory Committee, meeting of 23–24 July 2026; Docket FDA-2025-N-6895; briefing documents released 29 June 2026 — FDA scientific staff recommended against all seven nominated peptides; the committee voted to recommend six (BPC-157, KPV, TB-500, MOTS-c, Semax, epitalon) and rejected emideltide 7–6.

2. Analysis of the PCAC briefing documents, Health Affairs Forefront, August 2026 — no human safety studies identified for KPV, TB-500, MOTS-c or epitalon; for BPC-157, emideltide and Semax the studies were small, incompletely reported and no longer than 15 days.

3. Mendias CL, Awan TM. Evaluation of research grade peptides marketed directly to consumers reveals extensive variability in purity and measured abundance. Preprints.org, 24 April 2026. doi:10.20944/preprints202604.1748.v1 — 6,487 samples, 203 vendors, 14 peptides; 41.6% to 71.1% failed quality criteria; 156 samples contained none of the stated peptide; endotoxin measurable in 15% of the tested subset. Preprint, not peer-reviewed.

4. Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with tirzepatide versus dulaglutide in type 2 diabetes (SURPASS-CVOT). N Engl J Med. 2025;393:2409–2420 — n=13,165; 3-point MACE HR 0.92.

5. Cardiorenal outcomes with tirzepatide compared with dulaglutide: a post hoc analysis of the SURPASS-CVOT randomized clinical trial. PMID: 41903177 — 6-component composite 23.7% vs 27.4%; HR 0.84 (0.79–0.90); median treatment 46.9 months.

6. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med. 2022;387:205–216.

7. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes (SELECT). N Engl J Med. 2023;389:2221–2232 — n=17,604; MACE HR 0.80.

8. Eli Lilly and Company. TRIUMPH-1 topline results, 21 May 2026 — n=2,339; 25.0% mean weight reduction at 80 weeks on 12 mg; up to 30% at 104 weeks in a pre-specified extension.

9. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007;357:2359–2370.

10. Stanley TL, Feldpausch MN, Oh J, et al. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA. 2014;312(4):380–389. PMID: 25038357 — VAT −34 cm² vs +8 cm²; net liver fat effect −2.9 percentage points.

11. Body composition, hepatic fat, metabolic and safety outcomes of tesamorelin in HIV-associated lipodystrophy: a meta-analysis of randomised controlled trials. Diabetes Metab Syndr. 2026 — five RCTs; visceral adipose tissue −27.71 cm² (95% CI −38.37 to −17.06).

12. Baker LD, Barsness SM, Borson S, et al. Effects of growth hormone-releasing hormone on cognitive function in adults with mild cognitive impairment and healthy older adults. Arch Neurol. 2012;69:1420–1429.

13. McGuire FP, Martinez R, Lenz A, et al. Regeneration or risk? A narrative review of BPC-157 for musculoskeletal healing. Curr Rev Musculoskelet Med. 2025;18:611–619.

14. Vasireddi N, Hahamyan H, Salata MJ, et al. Emerging use of BPC-157 in orthopaedic sports medicine: a systematic review. HSS J. 2025;21:485–495.

15. Myung S-K, Park Y. Effects of collagen supplements on skin aging: a systematic review and meta-analysis of randomized controlled trials. Am J Med. 2025 — 23 RCTs, n=1,474; effects on hydration, elasticity and wrinkles absent in non-industry-funded and higher-quality subgroups.

16. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13. PMID: 21325617 — 22-year follow-up of the Ecuadorian Laron cohort; no diabetes and a single non-fatal cancer, against roughly 20% cancer mortality in unaffected relatives.

17. Morton RW, Murphy KT, McKellar SR, et al. A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med. 2018;52:376–384 — 49 studies, n=1,863; benefit plateaus at approximately 1.6 g/kg/day.

18. Retraction notices, J Pharmacol Exp Ther, April 2025 — Kawas LH, et al. (2011;339:509–518) and Benoist CC, et al. (2014), both retracted following a Washington State University investigation that found falsified and/or fabricated figure data. A third foundational paper (McCoy et al., 2013) carries a 2021 expression of concern.

19. Misra A. Anti-obesity drugs: a review of current status. Curr Cardiol Rev. 2013 — records termination of AOD-9604 development in 2007 after a 24-week phase 2b trial in 536 subjects failed to produce significant weight loss. The pivotal trial was never published in a peer-reviewed journal.

20. Teichman SL, Neale A, Lawrence B, et al. Prolonged stimulation of growth hormone and IGF-I secretion by CJC-1295. J Clin Endocrinol Metab. 2006;91:799–805.

21. Beck DE, Sweeney WB, McCarter MD. Prospective, randomized, controlled proof-of-concept study of ipamorelin for the management of postoperative ileus. Int J Colorectal Dis. 2014;29:1527–1534.

22. Eli Lilly and Company. Lilly calls on online platforms, payment companies and regulators to shut down the illegal retatrutide black market, 12 August 2026 — six federal lawsuits; more than 14,000 listings reported across over 100 countries; 200-plus referrals to regulators and law enforcement.