How comparable are cagrilintide and tirzepatide on the evidence available?

What I am working with: cagrilintide · tirzepatide.

I want to know what the trade-off actually is rather than which option is fashionable.

I would rather have a defensible reason than a marginal improvement.

So which one, and on what grounds?

Answer first: read the primary endpoint, the comparator and the population before you read the effect size. Almost every argument on this site about a trial is really an argument about one of those three.

Intention-to-treat and per-protocol analyses answer different questions. ITT asks what happens if you offer the treatment; per-protocol asks what happens if it is taken as directed. The gap between the two is a measure of how tolerable the protocol was.

Relative to absolute, worked

The last two rows describe the same finding. Only one of them is used in headlines.

The part that matters: confidence intervals matter more than point estimates when two trials disagree. Two studies reporting fifteen and twenty per cent whose intervals overlap heavily have not disagreed about anything.

The cardiovascular outcome programme in this class runs to several large randomised trials — LEADER for liraglutide, SUSTAIN-6 and SELECT for semaglutide, REWIND for dulaglutide — and they are the reason the class is discussed as more than a weight intervention.

Be careful about generalising from a trial population to yourself. The exclusion criteria are usually the most informative page in the supplement.

Read the protocol and the statistical analysis plan if the result matters to you. Both are usually published alongside.

In practice, the trial answers a narrower question than the headline suggests, and the narrowing is where the useful information is.

Trial populations are selected. Exclusion criteria in this class routinely remove people with significant renal impairment, prior pancreatitis and unstable psychiatric illness, which is exactly the population the results are then quoted for.

The underlying point is that non-inferiority and superiority designs are not interchangeable. A non-inferiority result says the new agent is not meaningfully worse against a pre-specified margin — it does not say it is as good, and it certainly does not say it is better.

Registry entries at ClinicalTrials.gov carry the pre-specified primary endpoint with a timestamp, which is the cheapest available check on whether an endpoint was changed after the data were seen.

One qualification: absence of a signal in a trial of this size is not evidence of absence for a rare event. It is evidence that the event is rarer than the trial could detect.

The short version: check the endpoint, check the comparator, check who was excluded, then look at the number.

edited 15 Feb 2025 by Dr_Ingrid_Baumgartner — expanded the table to cover the lower concentration

Specifically, this is answerable from the published record, but only if you take the placebo arm seriously rather than reading the active arm alone.

A composite endpoint is only as informative as its least serious component. Where a cardiovascular composite combines death, infarction and stroke, ask which component moved, because they are not interchangeable outcomes.

Duration decides what can be seen. A 68-week trial can measure weight and glycaemia; it cannot measure anything whose event rate is one per cent per year without enrolling tens of thousands.

The caveat is that trial evidence is about licensed product administered under supervision. None of it transfers automatically to research-grade material of unverified content.

If a claim cannot be traced to a named trial with a named endpoint, treat it as a claim rather than as evidence.

The short version: the effect is real, the magnitude depends on the population, and the population is usually the part that gets dropped when a result is quoted second-hand.

Placebo arms in this class are not nothing. Lifestyle-intervention placebo arms in the major obesity trials commonly lose two to three per cent of body weight, so an active-arm figure quoted without its comparator overstates the drug effect by roughly that much.

I am not a clinician and this is not medical advice; it is a reading of a published protocol.

Quote the interval alongside the estimate and half the disagreements on this site would not start.

Start with what the trial was powered for. Everything else in the publication is secondary, exploratory, or a subgroup, and those three words mean three different things.

Open-label extensions are not the same evidence as the randomised phase. Once everyone knows what they are taking, the reported outcomes acquire a bias that no analysis fully removes.

When two sources disagree, the answer is almost always in the methods section of the one you have not read.