How is this different from an on-target effect?

An on-target effect is the mechanism taken too far. This follows from the result achieved, and would occur with any intervention producing the same change.

Would diet or surgery achieving the same change at the same speed produce it too? If yes, the drug is the vehicle rather than the agent.

Can an effect belong to more than one category?

Yes. Gallbladder events have both a rapid-weight-loss pathway and a drug-specific one through cholecystokinin suppression.

GLP-1 & Incretin Science

A Third Way an Adverse Effect Can Arise

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

Beyond off-target toxicity and on-target excess, there is a third category: effects that follow from what a treatment achieves rather than from the treatment itself. Any intervention producing the same physiological change at the same speed would be expected to produce them.

Key facts

Category 1: Off-target toxicity
Category 2: On-target effect, exceeded
Category 3: Consequence of the achievement
Example: Gallstones from rapid weight loss
Example: Retinopathy from rapid HbA1c fall
Test: Would diet or surgery do the same?

Why two categories were not enough

Adverse effects are usually divided into off-target — unrelated to the intended action — and on-target, the intended action carried too far. Neither describes gallstones after rapid weight loss. That is not an unrelated toxicity, and it is not the pharmacology exceeded; it is a consequence of the weight loss itself, which was the goal.

The test that separates the third category

Ask whether a completely different intervention achieving the same result would produce the same effect. Rapid weight loss by dieting or surgery raises gallstone risk, so the answer is yes. Rapid glycaemic improvement by any means is associated with early retinopathy worsening, so again yes. Where the answer is yes, the drug is the vehicle rather than the agent.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

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Why this changes how a signal should be read

An effect in this category cannot be engineered away by improving the molecule, and it does not distinguish between compounds achieving the same result. It also scales with effectiveness — a drug that produces a larger, faster change encounters it more, which makes better drugs look worse on the measure.

The two clear instances on this site

Gallbladder events, where rapid weight reduction is an established gallstone risk factor independent of how the weight was lost. And retinopathy, where the 2018 SUSTAIN analysis frames risk through the reduction in glycated haemoglobin rather than through the compound. Both are documented, and both are routinely reported as drug effects.

Where the categories overlap

They are not always clean. The gallbladder case has a second, genuinely drug-specific pathway — suppression of cholecystokinin reducing gallbladder emptying — running alongside the weight loss pathway. So an effect can belong to two categories at once, which is why the question is what proportion rather than which box.

And the fourth possibility, for completeness

That the association belongs to neither the drug nor its achievement but to the condition being treated — confounding by indication, as the Danish periconceptional cohort demonstrated when a preterm birth association appeared in the diabetes indication and not in weight management. Four ways to be wrong about causation, and reporting usually considers one.

Quick reference

Category	Arises from	Engineered away?
Off-target	Something other than the mechanism	In principle, by selectivity
On-target, exceeded	The mechanism itself	Not without weakening the drug
Consequence of achievement	The result, however produced	No — intrinsic to the goal
Confounding by indication	The underlying condition	Not a drug effect at all

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 is this different from an on-target effect?: An on-target effect is the mechanism taken too far. This follows from the result achieved, and would occur with any intervention producing the same change.
What is the test?: Would diet or surgery achieving the same change at the same speed produce it too? If yes, the drug is the vehicle rather than the agent.
Can an effect belong to more than one category?: Yes. Gallbladder events have both a rapid-weight-loss pathway and a drug-specific one through cholecystokinin suppression.

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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