The case in front of me: SURMOUNT-2 · oral semaglutide.
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?
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.
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.
Concretely, 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.
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].
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.
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.
edited 24 Oct 2024 by coldpack_88 — fixed an arithmetic slip in the third paragraph
Analytical standards and reagents with traceable certificates. Every quantitative result you read inherits the accuracy of the standard behind it.
Shop standardsConcretely, 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.
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.
None of this replaces a clinician who can see the whole picture, and the whole picture is usually where the answer is.
edited 23 Nov 2024 by mateo_iglesias — added the placebo-arm figures
Stated carefully, 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.
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.
Concretely, 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 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.
Convert everything to an absolute effect before you compare two interventions. Relative effects are not comparable across different baseline risks.
The underlying point is that 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.
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.
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].
The papers are readable. Read the paper rather than the summary of the paper, especially where the summary is enthusiastic.
The relevant detail is that 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.
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.
Read the confidence interval, read the estimand, and compute the absolute effect yourself. It takes two minutes and it changes how the result feels.
Ask PeptideStack is a static archive. Posting is closed, but the norms are worth stating: answer the question that was asked, show your working, cite the trial or the certificate, and say plainly where the evidence runs out.