Semaglutide in people without diabetes: what the evidence base looks like

Semaglutide in people without diabetes: what the evidence base looks like Writing it up because I had to work it out twice and would rather nobody else did.

Session topic: SUSTAIN 6 (N Engl J Med, 2016). Please read it before posting; the discussion is much better when everyone has.

The question I would like us to start with is what the trial set out to estimate, rather than what it found. Once that is on the table we can talk about whether the design could have answered it, and only then about the numbers.

Specific things I would like covered: the population and how far it generalises, how discontinuation was handled, whether the comparator was a fair one, and what the absolute rather than relative effect looks like.

I will summarise at the end and the summary will feed the relevant digest page.

For anyone arriving from a search: the marked solution above is the direct answer, and the replies underneath it add the caveats that make it safe to use.

The 165 to 184 hour range: that is roughly 7 to 7.6 days, which is why the weekly schedule works. Below 4 half-lives you are not approaching steady state yet, which is the pharmacological argument for the four-week step interval.

This follows post #2 rather than contradicting it.

Is there a ceiling dose beyond which the effect plateaus? The trials did not study that because they stopped at 2.4 mg. Some people report trying higher doses, but trial data is absent and off-label dosing enters territory this site does not advise on.

On the opening post — agreed on the reasoning, with one qualification.

Two things before anyone answers the substance.

First, the context in the first post is clear and specific. Second, the question is framed so that an answer can actually address it. Both are the norm here and both matter more than they sound.

post #5 answers the question as asked. The question underneath it is different.

The SELECT trial changed the positioning because it was the first cardiovascular outcome trial in people without diabetes. That decoupled the cardiovascular argument from glycaemic control, which is why it mattered beyond its own numbers.

On alcohol: the labelling does not contraindicate it, but it raises gastric irritation risk and semaglutide already does that. There is no published interaction study and the conservative position is to limit it if you are titrating or if gastrointestinal symptoms are troublesome.