How comparable are mazdutide and retatrutide on the evidence available?

What I have: mazdutide · retatrutide.

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.

Which axes does this decision turn on?

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.

Creatinine is a muscle-derived metabolite, so a substantial loss of lean mass lowers serum creatinine and mathematically raises estimated GFR without anything happening to the kidney. If you have lost twenty kilograms, your creatinine-based eGFR is flattering you. Cystatin C is not muscle-dependent and is the measure to use when the two disagree.

Relative to absolute, worked

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

On the detail: 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.

STEP 1 reported a mean weight change of approximately −14.9 per cent with semaglutide 2.4 mg versus −2.4 per cent with placebo at 68 weeks[1]; the difference between the figures quoted from this trial in different places is an estimand difference.

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

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.

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.

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.

If the trend across three draws is flat, the difference between draws one and two was noise. Most of what people react to is noise.

Start with the population. The inclusion criteria of the trial determine what its result can be extrapolated to, and the extrapolation people want is usually to a population the trial excluded.

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.

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.

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

edited 2 Aug 2026 by tandem_gradient — added the placebo-arm figures

The confidence interval is the informative part. A point estimate with an interval spanning no effect is a different object from the same point estimate with a tight interval, and the abstract presents them identically.

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.

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].

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