Why do gastrointestinal effects persist across every generation?

They follow from receptor pharmacology rather than from any particular molecule, so improved design does not remove them.

Can an on-target effect ever be separated?

Only if the wanted and unwanted effects turn out to run through different pathways — which the 2024 work on dissociable hindbrain circuits suggests may be possible.

GLP-1 & Incretin Science

The Same Effect, Past the Point of Benefit

JMWritten & reviewed by Jack Muncaster · Founder, UK PeptidesLast reviewed 2026-08-233 cited sources

Adverse effects divide into two kinds: those arising from something other than the intended action, and those that are the intended action carried too far. The second cannot be engineered away without weakening the drug, which makes it a different problem entirely.

Key facts

Type 1: Off-target or unrelated toxicity
Type 2: The intended mechanism, exceeded
Type 1 example: Idiosyncratic liver injury
Type 2 example: Gastroparesis from delayed emptying
Type 1 remedy: Improve selectivity
Type 2 remedy: Dose, titration, patient selection

Why the distinction is not academic

It determines whether the problem is soluble by chemistry. An off-target effect can in principle be engineered out by making a compound more selective, leaving the wanted action intact. An on-target effect taken too far cannot — reducing it means reducing what the drug does, because they are the same thing.

How to tell which you are looking at

Ask whether the adverse effect would disappear in a hypothetically perfect version of the drug. Drug-induced liver injury would; it is not part of how any GLP-1 agonist is supposed to work. Gastroparesis would not, because delayed gastric emptying is the mechanism. That thought experiment separates the two reliably.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

View — £59.99

Why on-target effects define a class

They appear across every compound sharing the mechanism, at every generation, regardless of design improvements. Gastrointestinal effects have persisted through liraglutide, semaglutide, tirzepatide and retatrutide and will persist in anything engaging the same receptor, because they follow from receptor pharmacology rather than from any particular molecule.

What can be done about them anyway

Dose, titration schedule and patient selection. If an effect scales with exposure, lower exposure reduces it. If it attenuates with time, gradual escalation limits the peak. If it affects some people much more, identifying them in advance helps. None of these removes the effect; they manage where on the curve someone sits.

The one route that could genuinely separate them

Finding that the wanted and unwanted effects run through different pathways after all. The 2024 Nature work on dissociable hindbrain circuits for satiety and aversion is exactly this — if appetite suppression and nausea are separable rather than one signal, then what looked like an inseparable on-target cost becomes a selectivity problem, which chemistry can address.

Why this framing helps in reading safety claims

A claim that a new compound has better tolerability means something different depending on the type. Improved selectivity against an off-target effect is a real advance. A lower rate of an on-target effect may simply reflect lower exposure or slower titration, which is a dosing statement rather than a molecular one.

Quick reference

	Off-target	On-target, exceeded
Arises from	Something other than the mechanism	The mechanism itself
Example	Idiosyncratic liver injury	Gastroparesis
Engineered away?	In principle, by selectivity	Not without weakening the drug
Managed by	Better molecules	Dose, titration, selection

Extended research context

The GLP-1 & Incretin Science deep dive

Deep dive: the two routes to a bigger effect

Every compound trying to beat GLP-1 alone has taken one of two routes. The first adds more receptors from the same hormone family — GIP in tirzepatide, GIP and glucagon in retatrutide. The second adds a non-incretin satiety hormone, which in practice means amylin: CagriSema combines cagrilintide with semaglutide, and amycretin engages both receptors from one molecule. Both routes work, because they recruit signalling pathways that do not fully overlap. Neither has escaped the constraint that binds all of them, which is that gastrointestinal tolerability worsens as effect size grows.

Deep dive: why a percentage is not a result

The most-quoted numbers in this field are the least comparable. REDEFINE 1 reported 22.7% and 20.4% for the same compound in the same trial — the first among participants who adhered to treatment, the second across everyone randomised. TRIUMPH-1 reported 28.3% in an uncomplicated obesity population while TRIUMPH-3 reported up to 22.6% in adults with established cardiovascular disease, using the same compound. Before any two figures can be compared they have to match on estimand, population, duration, comparator and whether the number is placebo-adjusted. Most published comparisons match on none of them.

Deep dive: what happens after the trial stops

Every headline figure describes weight while treatment continues. The STEP-1 extension found that a year after semaglutide was stopped, participants had given back roughly two-thirds of what they lost, moving from 17.3% mean reduction to a net 5.6% — though average weight remained below baseline and nearly half stayed at least 5% down. Meta-analysis puts regain at around 0.8 kg per month. This is why maintenance studies such as TRIUMPH-6 matter more to the field's future than another two points of peak reduction.

Research applications

▸Comparing incretin and amylin compounds on a like-for-like basis
▸Interpreting estimands, thresholds and placebo-adjusted figures in trial reports
▸Tracking the obesity pipeline across sponsors and jurisdictions
▸Understanding receptor pharmacology behind GLP-1, GIP, glucagon and amylin
▸Distinguishing licensed medicines from investigational compounds

Handling checklist

✓Identify which estimand a quoted percentage comes from before citing it
✓Check the trial population and baseline BMI against the comparison you are making
✓Confirm the duration and whether the reduction curve had plateaued
✓Read discontinuation rates alongside efficacy figures
✓Verify every NCT identifier against ClinicalTrials.gov rather than secondary reporting

Common research-handling mistakes

Learnt from thousands of researcher orders across our UK labs.

✗ Comparing headline percentages across different trials

Fix: Population, duration, estimand and comparator all differ; the numbers are not interchangeable.

✗ Quoting the larger of two figures from the same trial

Fix: Name the estimand. Efficacy and treatment-policy answer different questions.

✗ Treating peak reduction as a durable outcome

Fix: Substantial regain follows cessation across the class; peak figures describe a maintained state.

✗ Assuming an oral route means a weaker mechanism

Fix: Route and receptor count are independent. Orforglipron is weaker because it hits one receptor, not because it is a tablet.

✗ Reading investigational compounds as available treatments

Fix: Most of this pipeline holds no authorisation anywhere; mazdutide is approved only in China.

Continue researching

Peer-reviewed guides, comparators and matched reference materials.

Frequently asked questions

How do I tell the two apart?: Ask whether the effect would disappear in a hypothetically perfect version of the drug. If it is the mechanism, it would not.
Why do gastrointestinal effects persist across every generation?: They follow from receptor pharmacology rather than from any particular molecule, so improved design does not remove them.
Can an on-target effect ever be separated?: Only if the wanted and unwanted effects turn out to run through different pathways — which the 2024 work on dissociable hindbrain circuits suggests may be possible.

Primary sources & clinical trials

Peer-reviewed research and registered trials from PubMed, ClinicalTrials.gov, PubChem, FDA and NIH. All links open in a new tab and point to the primary source, so every claim can be verified at origin.

Written and reviewed by

Jack Muncaster · Founder, UK Peptides

Jack founded UK Peptides in Manchester after repeatedly receiving research compounds with missing or recycled paperwork. He is responsible for supplier selection, batch release decisions and the content published in this research library. Every article here is sourced to primary literature and every product page to a signed third-party certificate.

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