Is ESSENCE a fair comparison of liraglutide against its comparator arm?

Concretely: ESSENCE · liraglutide.

I want to know whether there is evidence behind this or only repetition.

I have checked the obvious registries and monographs without success.

Can anyone point me at a primary source, or confirm that there is not one?

On the detail: the hazard ratio is the relative effect. What changes decisions is the absolute effect, and converting between them requires the event rate in the control arm, which is usually in the same table and rarely in the abstract.

Liver enzymes are a poor surrogate for hepatic histology in both directions: substantial steatohepatitis with normal transaminases is common, and modest enzyme elevation with minimal fibrosis is common. If the question is fibrosis, the answer comes from a non-invasive score such as FIB-4 or a stiffness measurement, not from ALT.

Headline results, principal programmes

It helps to be literal here: hbA1c is a weighted average, not a flat one: roughly half the signal comes from the most recent month. That is why a value drawn six weeks after a change already reflects most of the effect, and why a value drawn during rapid haematological turnover reflects something other than glycaemia.

The limitation is that surrogate endpoints and hard endpoints have come apart before in metabolic medicine, so a favourable biomarker is a reason for optimism rather than a conclusion.

None of this replaces a clinician who can see the whole picture, and the whole picture is usually where the answer is.

edited 1 Jan 2026 by lyoph_cake — fixed an arithmetic slip in the third paragraph

The underlying point is that read the estimand before the effect size. Almost every apparent contradiction between two published figures from the same trial resolves once you notice that one is a trial-product estimand and the other is a treatment-policy estimand.

The early fall in estimated glomerular filtration rate on treatment is haemodynamic rather than structural. Reduced intraglomerular pressure lowers the filtration rate acutely and preserves the glomerulus chronically — the same pattern seen with renin-angiotensin blockade and with SGLT2 inhibition. A dip of a few millilitres per minute in the first weeks, followed by a shallower long-term slope, is the desired trajectory, not a warning sign.

A fasting lipid panel drawn during rapid weight loss reads oddly for a mechanical reason: mobilised adipose tissue delivers free fatty acids to the liver, and hepatic triglyceride export rises. Triglycerides can transiently increase while the person is doing exactly the right thing. Draw the panel when weight has been stable for a few weeks if you want an interpretable number.

SURMOUNT-4 randomised participants after an open-label lead-in to continued tirzepatide or placebo, and the withdrawal arm regained a substantial proportion of the lost weight over the following year[1].

I would resist reading a subgroup finding as a result. Subgroups in these trials were not powered, and a striking subgroup in a large trial is the expected consequence of multiplicity.

Convert everything to an absolute effect before you compare two interventions. Relative effects are not comparable across different baseline risks.

To be exact about it, this is a question about what the trial was designed to answer, and the honest response is that it was not designed to answer this.

ApoB and LDL-C disagree because they measure different things: LDL-C is the cholesterol mass carried in the LDL fraction, ApoB is a count of atherogenic particles. Small dense particles carry less cholesterol each, so a person with many small particles has a concordantly higher ApoB than their LDL-C suggests. When they disagree, ApoB is the better risk marker.

Concretely, the rodent thyroid C-cell findings that generated the labelled warning appear to be species-specific: rodent C-cells express GLP-1 receptors at high density, human C-cells at very low density, and human calcitonin data across large trial populations has not reproduced the signal. A family history of medullary thyroid carcinoma or MEN2 is nonetheless a genuine contraindication rather than a theoretical one.

SELECT reported a hazard ratio of 0.80 (95% CI 0.72–0.90) for the primary composite major adverse cardiovascular event endpoint with semaglutide 2.4 mg in overweight or obese adults with established cardiovascular disease and without diabetes[1].

Read the confidence interval, read the estimand, and compute the absolute effect yourself. It takes two minutes and it changes how the result feels.