Transaminases above 3× the upper limit of normal, total bilirubin above 2×, with no alternative explanation such as biliary obstruction.

Why does bilirubin matter so much?

It reflects impaired function rather than mere cell damage. Damage plus loss of function predicts severe outcomes; damage alone usually does not.

Can a Phase 2b trial rule out liver injury?

No. Idiosyncratic injury may occur in one in several thousand exposures, which a few hundred participants cannot exclude.

GLP-1 & Incretin Science

Hy's Law: How Trials Decide a Drug Hurt the Liver

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

Trials use a combination rule usually called Hy's Law: transaminases above three times the upper limit of normal, total bilirubin above twice the upper limit, without an alternative explanation such as biliary obstruction. Enzyme elevation alone does not meet it.

Key facts

Named after: Hyman Zimmerman
Component 1: ALT or AST above 3× upper limit of normal
Component 2: Total bilirubin above 2× upper limit
Component 3: No alternative cause; ALP not markedly raised
Significance: Predicts risk of severe outcome
Enzyme rise alone: Common, usually not meaningful

Why one measurement is not enough

Transaminases leak from damaged liver cells, so a rise indicates injury to hepatocytes. But mild rises are extremely common, occur with many drugs and with none, and usually resolve without consequence. A threshold on enzymes alone would flag enormous numbers of clinically irrelevant events.

What bilirubin adds

Function rather than damage. Bilirubin is cleared by the liver, so a rise means the organ's capacity to do its job has been compromised, not merely that some cells were injured. Damage plus loss of function is a fundamentally more serious combination than damage alone, and requiring both is what makes the rule discriminating.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

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Why the exclusion matters

Bilirubin also rises when bile cannot drain — a gallstone, a stricture, a tumour. That is obstruction rather than drug toxicity. Checking that alkaline phosphatase is not disproportionately elevated distinguishes hepatocellular injury from a blocked biliary tree, and without that step the rule would capture the wrong patients.

Why the combination is taken so seriously

Zimmerman's observation was that patients meeting these criteria had a substantial risk of progressing to liver failure or death. That empirical association is what gives the rule its weight — it is not an arbitrary regulatory threshold but a pattern that predicted severe outcomes.

The detection problem this creates

Idiosyncratic drug-induced liver injury is rare, often around one in several thousand exposures or rarer. A Phase 2b trial of a few hundred participants is simply too small to observe such an event reliably, so a clean liver result at that stage is genuinely reassuring and genuinely not conclusive. This is why the danuglipron case — one participant — was treated as significant despite being a single observation.

How to read a safety statement

No cases of drug-induced liver injury is a specific claim about this rule being met by nobody. Liver enzyme elevations were in line with approved agents is a quite different and much weaker statement. Both appeared in the recent oral GLP-1 literature, attached to different compounds, and the difference between them is the whole story.

Quick reference

Finding	What it means	Weight
ALT/AST raised only	Hepatocyte damage	Common, often unimportant
Bilirubin raised too	Function impaired	Serious in combination
ALP also high	Suggests obstruction	Points away from drug injury

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

What is Hy's Law?: Transaminases above 3× the upper limit of normal, total bilirubin above 2×, with no alternative explanation such as biliary obstruction.
Why does bilirubin matter so much?: It reflects impaired function rather than mere cell damage. Damage plus loss of function predicts severe outcomes; damage alone usually does not.
Can a Phase 2b trial rule out liver injury?: No. Idiosyncratic injury may occur in one in several thousand exposures, which a few hundred participants cannot exclude.

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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