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How comparable are tirzepatide and liraglutide on the evidence available?

Asked 16 Feb 2025Modified 17 months agoViewed 16k times
6

For reference: tirzepatide · liraglutide.

I am trying to choose between two options that are usually discussed as though only one exists.

I am not optimising for price, but I am not indifferent to it either.

Which axes does this decision turn on?

clinical-trials
clinical-trials

Reading the primary literature properly: estimands, intention-to-treat versus per-protocol, confidence intervals, absolute versus relative…

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semaglutide
semaglutide

A GLP-1 receptor agonist with a fatty-acid-acylated backbone and a roughly one-week half-life, marketed for type 2 diabetes and for weight…

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tirzepatide
tirzepatide

A dual GIP and GLP-1 receptor agonist. Questions here cover the SURPASS and SURMOUNT programmes, the practical differences from a pure GLP-1…

162 questions
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TM
askedtwo_two_micron15k1716 Feb 2025
5Adding for future readers: the certificate should carry the lot number, not just a batch code. – e_dziedzic 2 months ago
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3 Answers

Accepted answer first, then by votes
87

Accepted answer

Put another way, 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.

The relevant detail is that 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.

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.

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DA
answered · acceptedDr_Yusuf_Adeyemi95k24815 Mar 2025
4The distinction between purity and content cannot be repeated often enough here. – plate_count_9k 2 months ago
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35

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 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.

Put another way, 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].

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

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DB
answeredDr_Aoife_Brennan50k483 Mar 2025
5This should probably be in the site help pages rather than buried in an answer. – j_wierzbicki 9 months ago
4Good answer, but the confidence interval in the cited trial is wider than implied. – Dr_Sara_Kuusela 7 months ago
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24

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.

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.

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.

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

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

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answeredstopper_core50k13820 Feb 2025
2Useful. I have added the accept threshold suggestion to my own notes. – nkem_obiora 2 months ago
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Your answer

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.

Not medical advice. Research-use-only compounds are not approved for human use.