What did FLOW measure?

Hard clinical events — kidney failure, substantial loss of kidney function, and death from kidney or cardiovascular causes. Not a surrogate endpoint.

3,533 participants with type 2 diabetes and chronic kidney disease. The trial is completed.

Was the benefit just from weight loss?

Not separable within one trial. The Nature Medicine analysis of participants with and without SGLT2 inhibitor use addresses part of the question.

GLP-1 & Incretin Science

FLOW: A Kidney Outcome Trial, Stopped Early

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

FLOW, registered as NCT03819153, was a completed Phase 3 trial of semaglutide against placebo in 3,533 participants with type 2 diabetes and chronic kidney disease. Perkovic and colleagues published results in the New England Journal of Medicine in July 2024.

Key facts

Trial: FLOW, NCT03819153
Phase: 3
Enrolment: 3,533
Status: Completed
Population: Type 2 diabetes with chronic kidney disease
Published: NEJM 2024 (PMID 38785209)
Endpoint type: Clinical events, not a surrogate

Why this is stronger evidence than a weight trial

The endpoint is events people care about — kidney failure, substantial loss of kidney function, death from kidney or cardiovascular causes. That is not a surrogate. A trial that counts hard clinical events over years is a fundamentally more demanding and more informative exercise than one measuring percentage change in body weight over 68 weeks.

Why kidney disease was a plausible target

Diabetic kidney disease progresses through glomerular injury driven by hyperglycaemia, raised intraglomerular pressure and inflammation. A drug improving glycaemic control and reducing weight addresses several of those upstream, and incretin effects on inflammation and haemodynamics have been proposed as additional contributors.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

View — £59.99

The question the trial could not answer alone

Whether benefit came from glycaemic control, weight reduction, or a direct renal effect. Those travel together in the same participants, so a single trial cannot separate them. Mann and colleagues addressed part of this in Nature Medicine in 2024 by examining effects with and without concomitant SGLT2 inhibitor use — a class with established renal benefit through a different mechanism.

Why the SGLT2 comparison matters

If semaglutide's benefit were simply duplicating what SGLT2 inhibitors already do, the effect would shrink substantially in participants already taking one. Examining that subgroup is how a trial team interrogates its own mechanism rather than asserting it, and it is the kind of analysis worth looking for in any outcome trial.

How this reframes the drug class

A compound with a cardiovascular outcome trial, a kidney outcome trial and a liver histology trial is no longer straightforwardly a weight-loss drug. It is a metabolic agent with several indications, which is why the regulatory and prescribing picture has become considerably more complicated than the public conversation suggests.

What none of this concerns

Research material. FLOW studied a licensed medicine in a defined patient population under clinical supervision. Nothing supplied here is semaglutide or an alternative to any prescribed treatment for kidney disease.

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 did FLOW measure?: Hard clinical events — kidney failure, substantial loss of kidney function, and death from kidney or cardiovascular causes. Not a surrogate endpoint.
How large was it?: 3,533 participants with type 2 diabetes and chronic kidney disease. The trial is completed.
Was the benefit just from weight loss?: Not separable within one trial. The Nature Medicine analysis of participants with and without SGLT2 inhibitor use addresses part of the question.

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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