Is creatinine a better monitoring choice than cystatin C on ecnoglutide?

Stated plainly: creatinine · cystatin C · ecnoglutide.

I suspect the honest answer is that it depends, in which case I would like to know on what.

Assume I can obtain either option without difficulty, so availability is not the deciding factor.

Under what conditions does the answer flip?

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.

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.

To be exact about it, 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.

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].

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.

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.

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.

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].

One qualification: a trial that demonstrates an endpoint at a given dose has demonstrated it at that dose. Extrapolating the endpoint down the dose ladder is an assumption, not a finding.

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 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.

edited 22 Mar 2026 by g_paskevicius — added the placebo-arm figures

To be exact about it, 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.

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.

FLOW tested a composite renal endpoint — kidney failure, sustained 50 per cent eGFR decline, or renal or cardiovascular death — in type 2 diabetes with chronic kidney disease, and was stopped early for efficacy[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.