What does REDEFINE-1 tell me about dizziness at the 20 mg dose?

The case in front of me: REDEFINE-1 · dizziness · 20 mg.

The figures are clear enough; the question is what they mean and what they do not.

I can supply the numbers if the specifics change the answer.

What can I legitimately conclude from this figure?

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.

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.

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.

More usefully, 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.

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.

It helps to be literal here: a network meta-analysis can rank agents that were never compared directly, but only under a transitivity assumption — that the trials being linked are similar enough in population, duration and endpoint definition for the indirect comparison to hold. In this field that assumption is often visibly violated, which is why indirect rankings should be read as hypotheses.

The PIONEER programme established oral semaglutide’s efficacy and the constraints on its administration, and the bioavailability figure of roughly one per cent is what drives the fasting and water-volume requirements[1].

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

edited 21 Feb 2026 by lyoph_cake — added the placebo-arm figures

A single laboratory value is a point on a noisy curve. What you want is a trend across at least three draws under comparable conditions, and "comparable" is doing a lot of work in that sentence.

Estimated average glucose from HbA1c: eAG in mg/dL = 28.7 × A1c − 46.7, or in mmol/L, 1.59 × A1c − 2.59. An A1c of 6.5 per cent is therefore about 140 mg/dL or 7.8 mmol/L. The relationship is a population regression, so an individual can sit well off the line.

Worth being explicit that this is interpretation of published data and not medical advice. Laboratory results belong in a conversation with whoever ordered them.

The papers are readable. Read the paper rather than the summary of the paper, especially where the summary is enthusiastic.

More usefully, 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.

Absolute risk reduction, worked: if the control-arm event rate is 8.0 per cent over the follow-up period and the hazard ratio is 0.80, the treated rate is approximately 6.4 per cent, the absolute risk reduction is 1.6 percentage points, and the number needed to treat is 1 ÷ 0.016 ≈ 63 over that period. A 20 per cent relative reduction and a number needed to treat of 63 are the same finding stated two ways, and only one of them sounds impressive.

SURMOUNT-OSA reported reductions in the apnoea-hypopnoea index with tirzepatide in adults with obesity and moderate-to-severe obstructive sleep apnoea, both with and without concurrent positive airway pressure therapy[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.