Peptide basics

Who the GLP-1 weight-loss trials did not enrol

This page does not tell you whether you would have qualified for a trial, and it is not eligibility advice for any study now recruiting. It contains no dose, schedule or route. It reads the published exclusion criteria to show what the resulting evidence does not cover.

Why an exclusion list is worth reading

A randomised trial answers a question about the people it enrolled. The eligibility criteria are the definition of those people, written before anyone was recruited, and published alongside the result. Reading them is the cheapest way to find out whether a headline is about anyone like you.¹

FDA guidance to sponsors makes the same point from the regulator's side, recommending that eligibility criteria be broadened where they are not needed for safety or scientific validity, precisely because narrow criteria limit what can be learned about the people who will eventually use a product.⁶

What STEP 1 excluded

STEP 1's registry entry lists two main-phase exclusions in its summary. The first is a glycated haemoglobin at or above 48 mmol/mol (6.5%) at screening, which removes people who meet a diabetes threshold. The second is a self-reported change in body weight of more than 5 kg in the 90 days before screening.¹

The posted protocol is longer. It carries 31 numbered exclusion criteria, covering among other things prior participation in the trial, participation in another clinical trial within 90 days of screening, known or suspected abuse of alcohol or recreational drugs, and — separately — anyone from the same household as another participant in a semaglutide trial.²

That gap between the registry summary and the full protocol matters. If you only read the registry page, you will see two exclusions and conclude the trial was broad. The protocol document, posted on the same page, tells a different story.¹²

What the other obesity trials excluded

SURMOUNT-1's registry entry lists diabetes mellitus, a weight change greater than 5 kg in the three months before starting, obesity induced by other endocrine disorders or by monogenic or syndromic causes, a history of pancreatitis, family or personal history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, significant active or unstable major depressive disorder or other severe psychiatric disorder within the previous two years, and any lifetime history of a suicide attempt.³

The SCALE obesity trial excluded known type 1 or type 2 diabetes, a screening calcitonin at or above 50 ng/L, a history of acute or chronic pancreatitis, obesity induced by drug treatment, use of approved weight-lowering pharmacotherapy, previous surgical treatment of obesity, a history of major depressive disorder or suicide attempt, and uncontrolled hypertension.⁴

• People with diabetes were excluded from the main obesity trials of all three compounds.
• People who had already had weight-loss surgery were excluded from SCALE.
• People with a history of pancreatitis were excluded from SURMOUNT-1 and SCALE.
• People with severe or recent psychiatric illness, and in SURMOUNT-1 anyone with a lifetime suicide attempt, were excluded.
• People whose weight had recently moved by more than 5 kg were excluded from STEP 1 and SURMOUNT-1.¹³⁴

Age: no ceiling, but a thin record at the top

None of STEP 1, SURMOUNT-1 or SCALE set an upper age limit. Each required participants to be 18 or older and left the top end open. That is consistent with ICH E7, the international guideline on geriatric populations, which states that protocols should not ordinarily include arbitrary upper age cutoffs.¹³⁴⁷

No ceiling is not the same as representation. The same guideline defines the geriatric population as 65 and over, asks sponsors to seek patients aged 75 and above where possible, and says that for diseases present in but not unique to older people, a minimum of about 100 geriatric patients would usually allow clinically important differences to be detected.⁷

Against that benchmark, the approved US labeling for semaglutide in weight management records 233 treated patients (8.8%) aged between 65 and 75, and 23 (0.9%) aged 75 or over. The first number clears the guideline's threshold. The second does not come close.⁷⁸

Pregnancy, and who carried the requirement

The STEP 1 protocol's exclusion criterion 30 covers a woman who is pregnant, breastfeeding, intends to become pregnant, or is of childbearing potential and not using a highly effective contraceptive method. Becoming pregnant, or intending to, were also grounds for discontinuing trial product.²

The same protocol states that no contraception measures were required for male participants, on the stated basis that transfer of semaglutide in seminal fluid was considered unlikely to cause harm. So the participation requirement fell on one sex and not the other.²

SELECT's registry summary carries the equivalent criterion in its public listing: a female who is pregnant, breastfeeding, intends to become pregnant, or is of childbearing potential and not using a highly effective contraceptive method was excluded.⁵

SURMOUNT-1 is the tirzepatide obesity trial whose results are most often quoted. Its exclusion list — diabetes, pancreatitis history, certain endocrine histories, recent severe psychiatric illness, any lifetime suicide attempt — defines the boundary of what that trial can be said to cover.

How to use this when reading a claim

Open the registry page for the trial being cited, read the exclusion criteria, and then open the protocol PDF if one is posted. If a group you care about appears on that list, the trial has nothing to say about them, and any claim that it does is being stretched.¹²

Common questions