Did the SUSTAIN programme show a retinopathy signal?

It produced retinopathy data warranting a dedicated pooled analysis, published by Vilsbøll and colleagues in 2018.

Why does the title mention HbA1c reduction?

It places the glycaemic improvement between the drug and the outcome, framing the question as whether risk follows from that improvement rather than from the drug itself.

Is the question settled?

No. Vujosevic's 2025 overview title ends in a question mark, which accurately reflects that it remains live.

GLP-1 & Incretin Science

What the SUSTAIN Programme Data Showed

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

Vilsbøll and colleagues evaluated diabetic retinopathy data from across the SUSTAIN clinical trial programme, published in Diabetes, Obesity and Metabolism in 2018 under a title linking the reduction in glycated haemoglobin to retinopathy risk.

Key facts

Analysis: Vilsbøll 2018 (PMID 29178519)
Journal: Diabetes Obes Metab, April 2018
Source data: SUSTAIN clinical trial programme
Title frames risk via: Reduction in glycated haemoglobin
Later review: Marchand 2021, Diabet Med (PMID 32799379)
Recent overview: Vujosevic 2025 (PMID 40586870)

Why a retinopathy signal was examined at all

Diabetic retinopathy is among the most consequential microvascular complications of diabetes, so any signal in a large trial programme of a diabetes medicine warrants dedicated analysis. Pooling across a programme rather than reporting one trial gives enough events to describe the pattern rather than count a handful.

What the paper's title is doing

It reads semaglutide, reduction in glycated haemoglobin, and the risk of diabetic retinopathy. That places the HbA1c reduction between the compound and the outcome, framing the question as whether the risk follows from the glycaemic improvement rather than from the drug acting on the eye. Titles are chosen carefully, and this one states a hypothesis.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

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Why that framing is biologically motivated

Rapid improvement in glycaemic control has long been associated with transient worsening of retinopathy, observed across intensive-control studies well before any incretin existed. A compound that lowers HbA1c substantially and quickly would be expected to encounter that phenomenon, and encountering it would say nothing specific about the compound.

Why the distinction matters clinically

If the association follows from the speed and magnitude of glycaemic improvement, then it is a known property of treating hyperglycaemia effectively rather than a property of one drug. It is managed by awareness and monitoring in those at risk, and it does not transfer as an argument against the class.

What the later literature added

Marchand and colleagues reviewed GLP-1 receptor agonists and long-term complications with a focus on retinopathy in Diabetic Medicine in 2021. Vujosevic and colleagues published on new generation glycaemic agents and retinopathy progression in Acta Diabetologica in 2025, under a title ending in a question mark — an accurate signal that the question remains live.

What this concerns

Licensed medicines studied in registered trials in people with diabetes under clinical supervision. Nothing supplied on this site is semaglutide, affects glycaemic control, or has any bearing on eye health in any person.

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

Did the SUSTAIN programme show a retinopathy signal?: It produced retinopathy data warranting a dedicated pooled analysis, published by Vilsbøll and colleagues in 2018.
Why does the title mention HbA1c reduction?: It places the glycaemic improvement between the drug and the outcome, framing the question as whether risk follows from that improvement rather than from the drug itself.
Is the question settled?: No. Vujosevic's 2025 overview title ends in a question mark, which accurately reflects that it remains live.

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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