Evidence review
Surrogate Endpoints vs Outcomes That Matter
Most peptide claims rest on a marker moving, not on anything happening to a person. Two paired trials show what the difference costs to establish.
The distinction, in one line
A surrogate endpoint is something measurable that is expected to predict an outcome you would actually care about.
Blood pressure is a surrogate. A stroke is an outcome. Visceral fat on a CT scan is a surrogate. Living longer is an outcome.
Three tiers, and almost everything lives in the first two
Tier one — a laboratory marker. IGF-1, HbA1c, high-sensitivity C-reactive protein, interleukin-6. Cheap, fast, moves in weeks.
Tier two — a structural or functional measure. Visceral adipose tissue on imaging, liver fat fraction, MRI injury volume, body weight, grip strength. Slower, more expensive, closer to something you can feel.
Tier three — an event. Heart attack, stroke, hospitalisation, death, a return to work, a return to sport. Rare per person per year, which is why measuring it takes thousands of people and several years.
Almost every claim made about almost every peptide lives in tier one or tier two. That is not automatically wrong. It is a specific, checkable limit on what has been shown.
Worked: weight, and the trial that checked
STEP 1 randomised 1,961 adults and reported a mean weight change of −14.9% against −2.4% on placebo at week 681. Weight is tier two. It is a good tier-two measure, and it is still not an event.
SELECT then asked the tier-three question of the same drug. It enrolled 17,604 patients aged 45 or older with pre-existing cardiovascular disease, a BMI of 27 or greater, and no diabetes, and randomised them 1:1. The primary endpoint was a composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke2.
The result: a primary event occurred in 569 of 8,803 patients (6.5%) on semaglutide against 701 of 8,801 (8.0%) on placebo — hazard ratio 0.80, 95% CI 0.72 to 0.90, p<0.001, over a mean follow-up of 39.8 months2.
Notice the cost of that sentence. Roughly nine times the participants of STEP 1, and roughly three years of follow-up, to convert a tier-two finding into a tier-three one. That is the actual price of knowing. Our semaglutide page covers what each of those trials establishes separately.
Worked: visceral fat, and the trial that has not been run
Tesamorelin's pivotal phase 3 randomised 412 patients with HIV and abdominal fat accumulation. Its primary endpoint was percent change from baseline in visceral adipose tissue on computed tomography. Visceral adipose tissue decreased 15.2% on tesamorelin and increased 5.0% on placebo, with triglycerides and the total-to-HDL cholesterol ratio also improving3.
That is a clean, well-measured tier-two result. Visceral adiposity is associated with cardiovascular risk, which is why the trial was designed around it — the paper says so in its opening sentence3.
Now the bounded version of what has not happened. A ClinicalTrials.gov search for tesamorelin returned 24 studies in August 2026. The conditions listed across that set are HIV-associated lipodystrophy, abdominal obesity, non-alcoholic and metabolic dysfunction-associated fatty liver disease, mild cognitive impairment, peripheral nerve injury, chronic obstructive pulmonary disease, type 2 diabetes, sleep disorder, diabetic retinopathy, frailty and healthy volunteers4. One record in that set lists cardiac disease among its conditions: NCT03826160, a 23-participant study of growth hormone dynamics and cardiac steatosis with no phase assigned5.
So the honest statement is this. As of August 2026, that set of 24 records contains no event-driven cardiovascular outcome trial of the kind SELECT was. The tier-two evidence is strong and the tier-three question is open, and the second sentence does not cancel the first. Our tesamorelin page treats it the same way.
Surrogates for surrogates
The same phase 3 reported that IGF-1 levels increased 81.0% on tesamorelin and decreased 5.0% on placebo3.
IGF-1 is a marker that the drug is doing what it is designed to do at the receptor. It is not a marker of benefit. A compound can raise IGF-1 reliably and change nothing a person would notice, and a rise in IGF-1 is often quoted as though it were the finding rather than the mechanism check.
When a claim's strongest evidence is a hormone level, ask what that hormone level is a surrogate for, and then ask whether that has been measured.
How a surrogate goes wrong
It can move without the outcome moving. The marker responds and nothing downstream does.
It can move while the outcome moves the other way. A drug can improve a number and cause harm by another route, which is only visible if someone counts events.
It can be the wrong marker for the population. A surrogate validated in one disease does not transfer to another by analogy.
It can be one of several, chosen after the fact. This is why the primary endpoint declared on the registry record is the one that counts.
Where a peptide claim usually sits
A single-group study registered as NCT07752381 declared change in high-sensitivity C-reactive protein and change in interleukin-6 among its primary outcome measures, over eight weeks in 40 participants, with masking recorded as none6.
Even taken at face value, a change in those two markers is a tier-one result. The gap between "IL-6 fell" and "you recover from training faster" is the entire question, and it is not addressed by measuring IL-6 more carefully.
The question to ask
When you read that a peptide "reduces inflammation", "improves body composition" or "supports recovery", find the number underneath it and place it in one of the three tiers.
If it is tier one, the claim is that a marker moved.
If it is tier two, the claim is that a structure or a measurement changed.
If it is tier three, someone counted events in enough people for long enough — and that is rare, expensive, and worth naming when it exists. The rest of this reading discipline is in when a claim outruns its evidence.
Frequently asked questions
What is a surrogate endpoint?
A measurable stand-in for the outcome you actually care about — a laboratory marker such as IGF-1 or HbA1c, or a structural measure such as visceral fat on imaging. It is used because events like heart attacks are rare and slow to count, which makes trials that measure them very large and very long.
Was weight loss ever validated against a real outcome?
For semaglutide specifically, yes. STEP 1 measured weight in 1,961 adults. SELECT then enrolled 17,604 patients with pre-existing cardiovascular disease and counted events: a composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred in 6.5% on semaglutide versus 8.0% on placebo, hazard ratio 0.80 (95% CI 0.72 to 0.90) over a mean 39.8 months.
Does tesamorelin reduce cardiovascular events?
That has not been measured in an event-driven trial. Its pivotal phase 3 used visceral adipose tissue as the primary endpoint, reporting a 15.2% decrease against a 5.0% increase on placebo. A ClinicalTrials.gov search for tesamorelin returned 24 studies in August 2026, and none of them is a cardiovascular outcome trial; the one record listing cardiac disease among its conditions is a 23-participant study of growth hormone dynamics and cardiac steatosis.
Is a rise in IGF-1 evidence that a peptide works?
It is evidence that the compound is engaging its target. The same phase 3 reported IGF-1 rising 81.0% on tesamorelin against a 5.0% fall on placebo, alongside its visceral fat result. A hormone level is a mechanism check, not a benefit; treating it as the finding is the most common surrogate error in peptide marketing.
References
- Wilding JPH et al (2021). Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/33567185/
- Lincoff AM et al (2023). Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/37952131/
- Falutz J et al (2007). Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. https://pubmed.ncbi.nlm.nih.gov/18057338/
- U.S. National Library of Medicine (2026). ClinicalTrials.gov search results for tesamorelin. ClinicalTrials.gov. https://clinicaltrials.gov/search?term=tesamorelin
- U.S. National Library of Medicine (2022). NCT03826160 — Growth Hormone Dynamics and Cardiac Steatosis in HIV. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT03826160
- U.S. National Library of Medicine (2026). NCT07752381 — A Clinical Trial to Evaluate the Effects of Peptide Gummies on Markers of Inflammation, Physical Performance, and Recovery. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT07752381
Medical disclaimer: This content is for general educational purposes only and is not medical advice, diagnosis, or treatment. Always consult a licensed healthcare professional before starting, stopping, or changing any treatment.
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