The introduction is also posted on Spotify as a podcast by “Gerry at The Health Equation”
You can search Spotify for “Gerry at The Health Equation”
Or use the link below
https://podcasters.spotify.com/pod/show/gerrygaj
Below is the specific link
Gerry Gajadharsingh writes:
“The rise of GLP-1 receptor agonists—Ozempic, Wegovy, Mounjaro and others—has transformed the landscape of metabolic medicine. These medications are delivering powerful shifts not only in weight, but in appetite regulation, blood pressure, glucose metabolism, and even reward-based behaviours such as alcohol intake or compulsive snacking. For many people, they feel like the long-awaited “miracle drugs.”
Yet as more patients reach the point of stepping off GLP-1s, a crucial question emerges: what comes back when the medication stops?
New analysis from the SURMOUNT-4 trial, highlighted by Dr Perry Wilson at Yale, offers the clearest view yet—and the results are sobering. For the vast majority, weight, waist circumference, blood pressure, and metabolic markers rebound once the drug is withdrawn, despite continued advice around diet and exercise. The physiological “set point” proves remarkably persistent.
This brings us to an important but often overlooked reality: medication alone cannot anchor long-term metabolic stability. To maintain the gains achieved during GLP-1 therapy, patients need a structured nutrition framework that supports metabolic regulation, stabilises insulin dynamics, and re-establishes internal cues for hunger and satiety.
This is where programmes such as Metabolic Balance become highly relevant. I’ve discussed this before, but it’s worth emphasising:
Metabolic Balance provides a personalised, clinically grounded nutritional plan designed to re-train metabolic pathways—supporting liver function, glucose and insulin balance, hormonal balance, and sustainable appetite regulation. For individuals transitioning off GLP-1s, it can be an essential bridge, helping prevent rebound physiology and re-establishing a healthy metabolic “baseline.”
You can learn more about how this works on my Metabolic Balance page here
https://www.thehealthequation.co.uk/metabolic-balance-nutritional-programmes/
You might also like to read my iBook based on the principles of Metabolic Balance
https://www.thehealthequation.co.uk/ibook/
As we move deeper into the GLP-1 era, the emerging evidence asks us to rethink how we guide patients:
Are GLP-1s a short-term intervention, or will many people require long-term metabolic support?
Who rebounds, who maintains progress, and why?
And how can we pair medical therapy with nutrition and behavioural frameworks that make the results truly sustainable?
Medscape
F Perry Wilson MD MSCE
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson from the Yale School of Medicine.
I’ve referred to GLP-1 agents like Ozempic and Mounjaro as “miracle drugs”— a cure not just for the obesity epidemic but for the epidemic of overconsumption that drives so much early death in the United States: overconsumption of alcohol, cigarettes, drugs, gambling, and so on all of which have been found in studies of varying quality, to be positively affected by the GLP-1s.
But there is a problem, and if I’m honest, something that makes these drugs less miraculous: They stop working when you stop taking them.
The clinical trials of these drugs — the blockbuster papers appearing in The New England Journal of Medicine and the like — tend to run for about a year. And over that year, for those lucky enough to be randomized to the treatment group instead of the placebo group, the effects are dramatic, even life changing. Tirzepatide (Mounjaro) boasts around a 20% body weight loss in a year, and with it a slew of other benefits: reduced blood pressure, improved haemoglobin A1c levels, better cholesterol. And, of course, those odd, off-target effects like a reduction in compulsive shopping.
But the duration of the randomized trials, 1 year or a bit more, is — let’s face it — arbitrary. And they leave open this really important question of what you do when that first year is over.
The data that have emerged so far are pretty clear: If you want to keep the weight off, you keep taking the drug. But what about those other benefits — the cholesterol, the blood pressure, the glucose control? What happens to all those when the drug is stopped? We finally have the answer. And you’re not going to like it.
We have the most detailed picture yet of what happens when you stop a GLP-1 drug, thanks to a paper appearing in JAMA Internal Medicine.
It’s a post hoc analysis of the SURMOUNT-4 trial, which was a really interesting study that specifically evaluated what happens when you stop a GLP-1 drug. Here’s how it worked.
Six hundred and seventy participants were given tirzepatide (Mounjaro or Zepbound) for 36 weeks. The effects were, as we have come to expect, pretty impressive, with about a 20% weight loss over that time period.
To be fair, they didn’t only get Mounjaro. They were given a pretty intense lifestyle-modification program as well, which included 150 minutes of exercise a week, and guidance to reduce intake by about 500 calories per day.
At week 36, it got interesting. At that point, at random, half of the people continued the tirzepatide, and half got switched to an identical placebo. The lifestyle stuff? That continued in both groups; everyone was still encouraged to eat less and exercise and whatnot. The only difference was whether the drug was in their system or not.
And you may have seen these results before. There is an immediate separation between the two arms of the study in terms of weight. The placebo group, despite diet and exercise, starts gaining right away. The group that stayed on the drug actually continues to lose weight over the course of the next year.
But the new analysis digs into the group that was switched to placebo in more detail than we have ever seen before.
To start off, we need to realize that when you see a graph like this, you are seeing the average weight gain once tirzepatide was switched to placebo. But obviously, not everyone is average. This chart shows you the actual, person-by-person change in weight among those who got switched to placebo.
I find this incredibly dramatic. Without the drug, almost no one could keep the weight off over the next 12 months. Despite all we say about diet and exercise, it just seems completely ineffective for the vast majority of individuals.
You could imagine a drug that sort of “resets” your baseline body weight somehow. Like, you take it for a year and lose all this weight, and that’s just your new body weight from that point on — like resetting the thermostat in your house. The GLP-1 drugs do not appear to work that way. Our body-weight thermostat is still there and rapidly pushes us back toward our starting weight once the medication is out of our system.
The authors divided the placebo group into four categories: people who only gained a little weight back (less than 25% of the weight they had lost) all the way through people who gained more than 75% of their lost weight back over the course of the year.
And here’s the thing that shocked me most about this.
There was almost no difference, at baseline, between these groups. Based on data when the participants started tirzepatide, it was essentially impossible to predict who would regain weight fast and who would be able to keep it off when they stopped the drug. All four groups were similar in terms of age, sex, race, ethnicity, duration of obesity, body mass index, waist circumference, fasting glucose, and so on.
In fact, the only thing that could predict whether or not you’d regain weight off of tirzepatide was how much weight you lost on tirzepatide. Those who lost more weight were more likely to keep it off than those who lost less weight.
So, I’ll put this together for you. Basically, if you’re starting a patient or yourself on tirzepatide, there is basically no way to know if you will need to keep taking it in the long term. After you’ve taken it for a year, people who get a more dramatic effect tend to hold on to that weight loss a bit better. Which, I thought at first, was a bit odd, because if anything, these are the people for whom the drug worked best; you’d think they’d suffer the most without it. But maybe these are the people who are more motivated to lose weight to begin with — that’s a hard variable to measure — and thus are more motivated to keep it off when the drug goes away.
But weight loss is not the only things these drugs do. They shrink waist circumference, they lower blood pressure, they improve glucose control. What would happen to these factors when the drug is removed?
Well, some things, like waist circumference, are so closely tied to body weight that what happens is directly proportional to what happens to body weight.
If you are in that group that regains a lot of weight after stopping the drug, you also regain a lot of waist circumference. If you’re one of the rare people who can keep the weight off, you keep your waist slimmer as well.
But that’s not true of all the factors. Take a look at the graph of systolic blood pressure here.
Sure, people who regained more weight had greater increases in blood pressure after stopping the drug. But the people who were able to keep the weight off had increases as well. This suggests weight-independent effects of these drugs. We knew they were there, of course. These drugs have clear off-target effects, like their ability to reduce alcohol consumption. The nephrologist in me wonders if they reduce salt intake by a similar mechanism, and with that resistance removed, salt intake increases and the blood pressure rises.
That’s just speculation, of course.
But what’s not speculation is that the data are very, very clear that it is the rare individual indeed who can take these drugs for a defined period of time, achieve the result they desire, and then stop taking the drug. For most people, stopping the GLP-1s means an eventual return to their baseline state. And that appears to be true for weight, waist circumference, blood pressure, and the other markers that improve during treatment.
The next steps here, I think, are to figure out how to manage the drugs in the long term. There are already people microdosing GLPs in order to maintain weight instead of losing more. That’s an interesting strategy but it has not been studied in any detail yet.
It seems that, for now, after the first year or so of therapy, we are flying blind. That’s OK. We are in a new paradigm of weight-loss treatment, and figuring this stuff out takes time. In the meantime, I remain convinced that this class of drugs has something very special to offer us, both as individuals and as a community. But perhaps I need to reevaluate my “miracle” moniker.
- Perry Wilson, MD, MSCE,is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape.