IGF-1 as a surrogate endpoint and its limitations — the long version

On the subject in the title: IGF-1 as a surrogate endpoint and its limitations — the long version Working notes rather than a conclusion.

A narrow question about IGF-1, deliberately narrow, because the broad version has been asked here four times and produced four long threads and no answer.

One question, stated units, stated method, and what I have already ruled out.

On analysis: these are short peptides and generally straightforward chromatographically, which means a poor purity result is more likely to reflect the synthesis than the method.

That holds under the stated conditions and I have stated them.

Agreed on all of that, and I have nothing to add to it.

The opening post and I disagree about the size of the effect, not about the direction.

What a well-designed human trial of a secretagogue would look like: randomised, placebo-controlled, adequate sample size, IGF-1 as primary outcome, muscle and strength as secondary outcomes, adequate follow-up duration. Very few secretagogue trials meet that description.

The honest answer is that it depends, and here is what it depends on.

Pulsatile secretion matters because growth hormone is secreted in pulses, not continuously. A single post-dose growth hormone level is nearly uninterpretable. Assessing this class properly requires serial sampling or an integrated measure like IGF-1, and almost nothing published online does either.

That has held every time I have looked, which is not the same as always.

The failure mode on IGF-1 is boring rather than dramatic. It is almost always the step everyone assumes was done correctly because it is too simple to get wrong.

Injection-site reactions are reported more often in this family than for the incretins. Whether that is the compounds or the preparations they are typically supplied in is not established.

That holds for the case as described. Change the assumptions and it may not.

Confirming post #6 from a second method, which matters more than confirming it from a second person.

IGF-1 as a surrogate: it is a better integrated measure than a spot growth hormone level and it is still a surrogate, with all the caveats that come with surrogates. Stable or rising IGF-1 is not the same as "this is working" in any health-related sense.

I had written a reply contradicting post #8 and deleted it. Here is what survived.

IGF-1 as a downstream marker is more informative than a single growth hormone measurement because it integrates over a longer period. It is still a proxy, and proxies in this area have a mixed record.

Distinguishing three things in the IGF-1 discussion that keep getting used interchangeably: the observation, the proposed mechanism, and the recommendation that gets attached to both.

Effects reported at the level of appetite are the most consistently described and the most mechanistically direct for the ghrelin-receptor compounds, which is not what most people are taking them for.

I had read the opposite somewhere and cannot now find where, which tells me something.