The Loudest Drug In The Room

Part one: We have spent three years talking about GLP-1s as a celebrity accessory. The clinicians using them properly are watching something else entirely, and the evidence backs them.

Words by Kris Abbey

There is a version of this story you already know. A red carpet, a jawline that has changed, a denial, a magazine cover. Somebody’s weight, discussed in public, by strangers.

And there is the version almost nobody is writing. A man in his fifties who has come off two blood pressure medications. A woman who has spent eleven years being told to lose weight by people who never asked her why she could not, and who has stopped hearing the noise about food for the first time since she was a teenager. A clinician looking at a set of trial results and quietly recalculating how many of her patients will still be alive in five years.

Both versions are true. Only one of them has been getting airtime.

This is an attempt at the other one. What these drugs actually are, what the evidence shows, and why the clinicians working with them are having a very different conversation to the one happening in the media.

First, what a GLP-1 actually is

Glucagon-like peptide-1 is not a drug. It is a hormone you already make.

It is produced by specialised cells in the lining of your small intestine and colon, called L-cells, and it is released in response to food arriving. It is one of a family of gut hormones known as incretins, and its job is essentially to co-ordinate the body’s response to a meal. It tells the pancreas to release insulin, but only when blood glucose is actually elevated, which is why it does not tend to cause hypoglycaemia the way older diabetes drugs can. It suppresses glucagon, the hormone that tells the liver to release stored glucose. It slows the rate at which the stomach empties, so food arrives in the small intestine more gradually. And it signals to the brain, in the hypothalamus and in the brainstem, that you have eaten.

That last part matters more than the rest of it combined, and it is the part the public conversation has largely missed.

Natural GLP-1 has a half-life of a couple of minutes. An enzyme called DPP-4 breaks it down almost as fast as you make it. Which is elegant biology for a body that eats three times a day, and useless as a treatment.

The breakthrough, and it took decades, was in building molecules that do the same job but survive in the bloodstream for days rather than minutes. Semaglutide, the compound in Ozempic, Wegovy and Rybelsus, is one. Tirzepatide, sold here as Mounjaro, is another, and it works on two receptors rather than one, adding GIP, a second incretin hormone, to the GLP-1 effect. There are more coming, including triple agonists and oral versions.

What they all do is take a signal your body sends briefly after a meal and make it more or less continuous.

These drugs do not make people eat less through willpower. They make the body stop asking.

The part that should have been the headline

If GLP-1s only caused weight loss, they would be interesting. What has made the last three years significant in medicine is what they do to outcomes that have nothing to do with the number on the scale..

The SELECT trial is the one to know. More than 17,500 adults across 41 countries, all with established cardiovascular disease and overweight or obesity, and none with diabetes. Followed for an average of 40 months. The result: a 20 per cent reduction in the risk of heart attack, stroke or death from cardiovascular causes in the semaglutide group compared with placebo. Mean weight loss over four years was 10.2 per cent against 1.5 per cent for placebo.

The framing matters here. This was not a weight loss trial that happened to measure hearts. It was a cardiovascular outcomes trial, and it is the first time a weight management medication has been shown to reduce cardiovascular events in people without diabetes. Analyses also suggested the cardiovascular benefit was not fully explained by how much weight people lost.

Then the FLOW trial, in 3,533 people with type 2 diabetes and chronic kidney disease, followed for a median of 3.4 years. A 24 per cent reduction in the primary composite of kidney failure, substantial loss of kidney function and death from kidney or cardiovascular causes. An 18 per cent reduction in major cardiovascular events. And a 20 per cent reduction in death from any cause.

Death from any cause. That is the number clinicians discuss among themselves, and it rarely makes the coverage.

It keeps going. In the ESSENCE trial, in people with metabolic dysfunction-associated steatohepatitis, the liver disease formerly called NASH, 62.9 per cent of those on semaglutide achieved resolution of steatohepatitis without worsening fibrosis at 72 weeks, against 34.3 per cent on placebo. Fibrosis itself improved in 36.8 per cent versus 22.4 per cent. This is a condition that was, until very recently, heading towards being a leading cause of liver transplant with no approved drug treatment at all.

In SURMOUNT-OSA, in 469 people with moderate to severe obstructive sleep apnoea and obesity, tirzepatide improved sleep-disordered breathing alongside 18 to 20 per cent weight loss, with systolic blood pressure falling by up to 7.9 mmHg more than placebo and high-sensitivity C-reactive protein, a marker of systemic inflammation, dropping by between 29 and 45 per cent.

On blood pressure specifically, an ambulatory monitoring substudy of SURMOUNT-1 found placebo-adjusted 24-hour systolic reductions of 7.4 to 10.6 mmHg depending on dose. For context, that is in the range you would expect from adding a blood pressure medication.

Real-world data is starting to agree with the trials. A 2025 analysis in Nature Medicine, using insurance claims across more than 450,000 people, found semaglutide associated with a lower risk of heart attack or stroke than an older comparator drug, with tirzepatide performing comparably.

Why clinicians are talking about deprescribing

This is the part that does not fit into a headline about a celebrity.

When someone loses 15 or 20 per cent of their body weight and their blood pressure falls by 8 or 10 points and their HbA1c comes down and their triglycerides drop by 30 per cent and their liver inflammation resolves, the practical consequence is that they start coming off things. The second antihypertensive. The insulin. In some cases the oral diabetes medications, one at a time.

A clinician who has spent fifteen years watching patients accumulate prescriptions does not experience that as a cosmetic outcome. They experience it as a reversal of direction, and they know what the alternative trajectory looked like, because they have watched it play out in hundreds of people.

There is a reasonable counter-argument, and it should be said plainly. Deprescribing is not risk-free, it has to be done deliberately and under supervision, and the benefits described above hold while the person is on the drug. Part two deals with what happens when they stop.

The habit window, and why “cheating” is the wrong word

The most interesting claim being made by clinicians right now is not about hearts or kidneys. It is about behaviour.

Practitioners who work in this area describe a pattern that goes something like this. They can spend years with a patient on the things we all know work. Food environment, sleep, movement, stress, portion awareness, the slow business of changing what somebody reaches for at nine o’clock at night. Progress is real but fragile, and it is repeatedly undone by a physiology that is actively fighting the change, because weight loss triggers hormonal adaptations that increase hunger and reduce energy expenditure. The body defends its previous weight with considerable enthusiasm.

Then the same patient starts a GLP-1, and within weeks the habits they could not establish in years simply establish themselves. Not because the person suddenly found discipline. Because the signal they were fighting has been turned down.

Patients describe this as the quieting of what has come to be called food noise: the constant, intrusive, low-level negotiation with food that runs in the background of daily life for a great many people and is close to absent in others. It is not a scientific term, but it describes something real, and the pharmacology explains it. GLP-1 receptors are found not only in the appetite centres of the hypothalamus but in areas involved in reward and motivation.

Which is why the effect does not appear to stop at food. In a randomised controlled trial published in JAMA Psychiatry in 2025, 48 adults with alcohol use disorder received low-dose semaglutide or placebo for nine weeks. Those on semaglutide drank significantly less on the days they drank and reported significantly lower cravings, although the drug did not change how often they drank. It was a small, short, early trial, and the researchers and independent experts were clear that it is nowhere near a licence to prescribe for addiction. But the signal is there, and larger trials are running.

The framing that follows from all of this matters for how we talk about people who use these drugs. If obesity is substantially a disorder of appetite regulation, then a medication that corrects the signal is not a shortcut around effort. It is the thing that makes effort work. Nobody says a person with poor eyesight is cheating at reading by wearing glasses.

The drug does not replace the behaviour change. It opens a window in which behaviour change is finally possible.

That window framing is the useful one, and it carries an obligation. If the medication is what makes new habits establishable, then the period on the drug is precisely when the strength training, the protein intake, the sleep and the food skills need to be built, because they are what the person will be standing on later. And in my view, should be a compulsory part of the prescription. 

Which brings us to everything this piece has not yet dealt with. Who is actually taking these drugs and why, the side effects we are only now beginning to see, what happens when people stop, and what the options look like for the many people who cannot or would rather not take them. That is part two.

EDITORIAL NOTE

This article is general information and is not medical advice. GLP-1 receptor agonists are prescription medicines with significant benefits and significant risks, and decisions about them belong with a qualified medical practitioner who knows the individual’s history. Anyone experiencing disordered eating should speak with their GP or contact the Butterfly Foundation.

How they work, in sixty seconds

• GLP-1 is a hormone your gut already releases when you eat. It tells the pancreas to release insulin when glucose is high, suppresses glucagon, slows stomach emptying and signals fullness to the brain.
• Your own version breaks down within minutes. The drugs are engineered to last for days.
• Semaglutide targets the GLP-1 receptor. Tirzepatide targets both GLP-1 and GIP, a second gut hormone, which is part of why it produces greater weight loss.
• The appetite effect is not only in the stomach. GLP-1 receptors sit in brain regions governing reward and motivation, which is why people describe cravings and intrusive thoughts about food quieting rather than simply feeling full.

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