Does this mean these drugs cause ketoacidosis?

It means reports pairing them appear more often than the background pattern predicts, in a system that cannot establish causation. A properly designed cohort study is what would answer the question, and the signal is the reason to run one.

Why would non-diabetic patients get ketoacidosis at all?

Ketoacidosis is not exclusive to diabetes. Prolonged fasting, alcohol, and severe illness can all produce it. The relevant feature of this population is sustained large reductions in energy intake, which shifts fuel use toward fat oxidation - the same direction, from a different cause.

Is one drug safer than the other on this?

The reported ratios differ, but the two drugs differ in how long they have been marketed, how many people take them and how much attention each has had, all of which affect reporting independently of risk. A ratio difference in a spontaneous reporting database is not a risk difference.

Is this a new finding?

The clinical entity is long established, most familiar in the context of SGLT2 inhibitors, where it is a recognised and labelled concern. What is newer is the systematic comparison of these two incretin agents in a non-diabetic obesity population, which had not been done directly before this analysis.

GLP-1 & Incretin Science

The Complication That Hides Behind a Normal Glucose

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

Euglycaemic ketoacidosis is a metabolic acidosis driven by ketone accumulation without the marked hyperglycaemia that normally prompts the diagnosis. Because glucose looks near-normal, the condition can be missed. Both semaglutide and tirzepatide show disproportionality signals for ketoacidosis in non-diabetic patients.

Key facts

Defining feature: Ketoacidosis with glucose below the usual diagnostic threshold
Why it is missed: Glucose, the usual trigger for testing, appears reassuring
Population studied: Non-diabetic patients using these agents for obesity
Semaglutide signal: ROR 3.15 (95% CI 2.78-3.56); PRR 3.14 (2.78-3.54)
Tirzepatide signal: ROR 1.22 (95% CI 1.06-1.39); PRR 1.21 (1.06-1.39)
Reported cases: 261 semaglutide, 209 tirzepatide
Hospitalisation: 74.3% semaglutide, 71.3% tirzepatide
Database: FAERS, January 2021 to December 2025, 7,349,591 deduplicated reports

What ketoacidosis is, and what makes it euglycaemic

Ketoacidosis is an accumulation of ketone bodies sufficient to lower blood pH. It arises when the body shifts heavily toward fat oxidation for fuel and ketogenesis outruns the capacity to use or clear ketones. In the classical diabetic presentation, insulin deficiency drives both unrestrained ketogenesis and unrestrained hepatic glucose output, so ketosis and marked hyperglycaemia arrive together and the high glucose is what prompts the diagnostic test. Euglycaemic ketoacidosis is the same acidosis without the high glucose. The ketogenesis is present; the hyperglycaemia is not, because glucose production is suppressed or glucose is being lost or simply not being consumed.

Why the missing hyperglycaemia is the dangerous part

Clinical pathways are built around signals. A presentation of nausea, vomiting and abdominal pain with a glucose of 28 mmol/L triggers an immediate cascade of tests. The same presentation with a glucose of 7 mmol/L does not, because the number that usually raises the alarm is normal. Unless someone measures ketones or a blood gas, the acidosis is invisible. That is the entire clinical significance of the euglycaemic qualifier: it does not describe a milder illness, it describes an illness with its most recognisable sign removed.

Why a mechanistic link is plausible here

This class reduces energy intake substantially and reliably - that is what it is for - and it delays gastric emptying, which reduces carbohydrate delivery further. Sustained low carbohydrate intake shifts substrate use toward fat oxidation and raises ketone production, which is ordinary physiology and normally self-limiting. The concern is what happens when that baseline shift meets an additional stress: an intercurrent illness, vomiting, a period of not eating, surgery, or a very low carbohydrate diet adopted alongside treatment. Plausibility is not proof, and none of the data described here demonstrates causation. But the mechanism is not exotic, which is a reason to take the reporting signal seriously rather than dismiss it as noise.

What the pharmacovigilance data actually shows

Makhmutov and Qureshi analysed FAERS from January 2021 to December 2025. After deduplication, 7,349,591 unique reports were available; among non-diabetic patients they identified 48,082 semaglutide and 98,295 tirzepatide reports. Ketoacidosis appeared in 261 semaglutide cases and 209 tirzepatide cases. Semaglutide's reporting odds ratio was 3.15 (95% CI 2.78 to 3.56) and tirzepatide's was 1.22 (95% CI 1.06 to 1.39), both distinguishable from one. Hospitalisation was required in 74.3% and 71.3% of the reported cases respectively. That last figure is the one that carries the most weight: whatever the frequency, the cases that reach a report are mostly cases serious enough to require admission.

What these numbers cannot tell you

They cannot tell you how often this happens. A disproportionality analysis has no denominator of exposed people, so 261 cases is a count of reports and not an incidence. They cannot establish causation, because reports are voluntary, unverified and subject to attribution. And the difference between the two drugs' ratios should not be read as a difference in risk, because the two agents were approved at different times, have different exposure volumes and different reporting histories. The one thing the analysis does establish is that the pairing occurs more often than the background pattern predicts for both drugs, which is a reason for the question to be studied with a proper denominator.

Where this leaves a reader

With a documented signal, a plausible mechanism, and no measurement of frequency. That is an ordinary and uncomfortable position in drug safety, and it is where most safety questions sit for several years after a drug's launch. Semaglutide and tirzepatide are licensed medicines. Nothing supplied on this site is a version of them, an alternative to them, or anything a person should be taking, and any question about symptoms while using a licensed medicine belongs with the prescribing clinician, not a reference article.

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

Does this mean these drugs cause ketoacidosis?: It means reports pairing them appear more often than the background pattern predicts, in a system that cannot establish causation. A properly designed cohort study is what would answer the question, and the signal is the reason to run one.
Why would non-diabetic patients get ketoacidosis at all?: Ketoacidosis is not exclusive to diabetes. Prolonged fasting, alcohol, and severe illness can all produce it. The relevant feature of this population is sustained large reductions in energy intake, which shifts fuel use toward fat oxidation - the same direction, from a different cause.
Is one drug safer than the other on this?: The reported ratios differ, but the two drugs differ in how long they have been marketed, how many people take them and how much attention each has had, all of which affect reporting independently of risk. A ratio difference in a spontaneous reporting database is not a risk difference.
Is this a new finding?: The clinical entity is long established, most familiar in the context of SGLT2 inhibitors, where it is a recognised and labelled concern. What is newer is the systematic comparison of these two incretin agents in a non-diabetic obesity population, which had not been done directly before this analysis.

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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