Answering the narrow version, because the broad one does not have a single answer. HbA1c reflects roughly three months of average glycaemia weighted toward the most recent weeks, which is why repeating it at six weeks tells you very little. The improvement on this class comes from two directions — direct glucose-dependent insulin secretion and glucagon suppression, plus the indirect effect of weight loss on insulin sensitivity — and the second continues after the first has plateaued.

Happy to go further on any of that.

Dr.CardioMD said:

HbA1c reflects roughly three months of average glycaemia weighted toward the most recent weeks, which is why repeating it at six weeks tells you very…

That is correct as far as it goes, and here is where it stops going. Orforglipron is a small molecule rather than a peptide, which is the whole point: no SNAC absorption enhancer, no fasting window, no cold chain, and oral bioavailability in the tens of percent instead of around one. Phase 2 put it near 14.7% weight loss at 36 weeks on the top dose with a side-effect profile that looks like the injectables.

Correct me if the detail matters more than I have assumed.

roxy_nash said:

I have been following the oral non-peptide data since phase 2 and I am trying to work out how much of the enthusiasm here is about efficacy and how…

Agreed, with the caveat that HbA1c is unreliable in anaemia, haemoglobinopathies and recent blood loss, all of which are commoner than people assume. If it disagrees with fasting glucose or a CGM, that is worth chasing.

Clinical perspective, offered as context rather than as advice. It helps to say which part of this you are uncertain about. A precise question gets a precise answer; a general one gets everybody’s favourite anecdote.