Why did SELECT exclude people with diabetes?

So any cardiovascular benefit could not be attributed to improved glucose control — the participants were not hyperglycaemic to begin with.

Why did it need 17,604 participants?

Cardiovascular events are relatively rare even in high-risk populations, and detecting a real difference requires enough of them.

Was the benefit caused by weight loss?

Not separable. Weight reduction and cardiovascular benefit occurred in the same participants, so attribution remains difficult.

GLP-1 & Incretin Science

SELECT: The Trial That Changed What the Class Was For

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

SELECT enrolled 17,604 participants with overweight or obesity and established cardiovascular disease but without diabetes, testing semaglutide against placebo on major adverse cardiovascular events. Lincoff and colleagues published it in the New England Journal of Medicine in December 2023.

Key facts

Enrolment: 17,604
Population: Obesity + established CV disease, no diabetes
Endpoint: Major adverse cardiovascular events
Published: NEJM 2023 (PMID 37952131)
Weight analysis: Ryan 2024, Nat Med (PMID 38740993)
Significance: Outcome benefit outside diabetes

Why excluding diabetes was the whole design

Cardiovascular outcome trials of diabetes drugs had already shown benefit, but in people with diabetes any cardiovascular effect could plausibly be explained by better glucose control. Removing diabetes from the population removes that explanation. Whatever SELECT found could not be attributed to glycaemic improvement, because the participants were not hyperglycaemic to begin with.

Why the size was necessary

Counting heart attacks, strokes and cardiovascular deaths requires enough events to distinguish a real difference from noise, and those events are relatively rare even in a high-risk population. 17,604 participants followed for years is what it takes. That scale is why outcome trials cost what they do and why most compounds never get one.

Research material referenced

Retatrutide 10mg — third-party HPLC tested

View — £59.99

What it established for the category

That the benefit extends beyond glucose and beyond weight as a number. A drug demonstrating reduced cardiovascular events in people without diabetes is being assessed as a cardiovascular agent, which is a different regulatory and clinical proposition from a weight-management product.

The question it left open

How much of the effect ran through weight reduction and how much through other mechanisms. Ryan and colleagues examined the long-term weight outcomes in SELECT separately in Nature Medicine in 2024. Weight and cardiovascular benefit travel together in the same participants, so attribution remains genuinely difficult.

Why it sits beside FLOW and ESSENCE

Three large trials, three organ systems, one compound: cardiovascular events in SELECT, kidney events in FLOW, liver histology in ESSENCE. Read together they describe a metabolic agent rather than an appetite suppressant, and that reframing is the most consequential thing to have happened to this drug class since the weight results themselves.

And what it says about research material

Nothing. SELECT studied a licensed medicine in 17,604 patients under clinical supervision with ethics approval and event adjudication. No research compound is covered by those findings or is an alternative to a prescribed cardiovascular treatment.

Quick reference

Trial	Organ system	Enrolment	Endpoint type
SELECT	Cardiovascular	17,604	Clinical events
FLOW	Kidney	3,533	Clinical events
ESSENCE	Liver	1,205	Histological surrogate

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

Why did SELECT exclude people with diabetes?: So any cardiovascular benefit could not be attributed to improved glucose control — the participants were not hyperglycaemic to begin with.
Why did it need 17,604 participants?: Cardiovascular events are relatively rare even in high-risk populations, and detecting a real difference requires enough of them.
Was the benefit caused by weight loss?: Not separable. Weight reduction and cardiovascular benefit occurred in the same participants, so attribution remains difficult.

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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