What interval makes sense for repeating creatinine on mazdutide?

Stated plainly: creatinine · mazdutide.

I would like to set this up properly once, rather than adjust it repeatedly.

My budget is real but not tight, and my tolerance for uncertainty is low.

What would you do, and what would make you change course?

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.

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.

Headline results, principal programmes

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.

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].

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.

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.

To be exact about it, 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.

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.

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.

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.

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.

Mechanically, 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.

The caveat is the population. Trial participants were screened, monitored and supported; the effect size in an unmonitored setting is not the trial effect size, and it is not obvious in which direction the difference runs.

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

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-1 reported mean weight reductions of approximately 15, 19 and 21 per cent at tirzepatide 5, 10 and 15 mg respectively at 72 weeks[1].

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 22 Dec 2024 by dead_volume — added the method parameters