As a functional and longevity doctor, I’m constantly evaluating new treatments and their long-term impact on health, and we have been running our metabolic reset programme for well over a year. Few topics are as prominent right now as GLP-1 receptor agonists (like liraglutide and semaglutide) for weight loss. The results can be dramatic, but a crucial question remains: what happens when the medication stops? Do you have an exit strategy? How do you stop the medication and keep the benefits?
A fascinating 2024 paper from the Lancet group, following up on the S-LITE trial, provides a sobering answer and a powerful insight into what truly creates sustainable change.
The message is clear: if GLP-1 therapy is used in isolation, a significant weight rebound is not just possible but highly probable. But, there is a way to avoid it.
The S-LITE trial: a tale of two outcomes
So with any research, it is important to look at the details, and there are some nuances as to how this trial was done.
They took 195 adults with obesity and first initiated significant weight loss (an average of 13kg) with an eight-week very low-calorie diet. This is a key point: participants were already undergoing major physiological changes before the main trial began.
They were then randomised into four groups for one year (52 weeks):
Placebo
Supervised exercise alone
Liraglutide (a daily GLP-1 medication) alone
A combination of liraglutide and supervised exercise.
At the end of that year, the results were impressive, particularly for the medication groups. The combination therapy group led the way, losing an average of 16kg from their randomisation weight. The liraglutide-only group wasn’t far behind, losing around 13.5kg. Exercise alone resulted in a 7kg loss.
But here’s the critical part of the experiment. At week 52, all treatments stopped. No more medication, no more supervised training, no more behavioural support. The researchers then waited another full year to see what would happen.
So both medication groups were impressive, but the difference in what happened in the following year was fascinating.
The snapback
The findings from week 104 are where the real lesson lies.
The group that had been on liraglutide alone regained a staggering 9.6kg on average. In fact, when all was said and done, they ended up heavier than they were at the start of the 52-week trial period. The powerful pharmacological brake on their appetite was released, and without another system in place, the weight returned, and it returned quickly. On top of that, all of the metabolic benefits they had seen, like improved HbA1c and fasting glucose, also disappeared. The metabolic changes were supericial
However, the story was very different with the groups that incorporated exercise. The exercise-only group regained a modest 3.9kg.
The big insight, however, was the combination group, while they did regain some weight (around 5.5kg), their net weight loss after two years was still a remarkable 10.7kg below their randomisation weight.
The conclusion is inescapable. GLP-1 medications are incredibly effective tools for initiating weight loss. But it is a structured exercise that stabilises it for the long term.
This is why I tell my patients that exercise is the non-negotiable anchor
So, what’s the mechanism here? Why did exercise provide such a durable protective effect, even after the supervised sessions ended?
The study offers a vital clue.
A year after all interventions ended, participants in the exercise arms reported and demonstrated significantly higher levels of moderate-to-vigorous physical activity.
The supervised exercise wasn’t just a temporary fix; it had successfully installed a lasting behavioural habit. It gave them a tool they could continue to use independently with no support.
On DEXA scan they has also maintained a higher amount of muscle, the metabolic engine that buffers any excess calories. They had used the medication to kick start the process and then laid down metabolic changes that lasted with exercise.
I feel that this fundamentally reframes how we should view these therapies and should be a key consideration for any patient that is considering them.
The medication provides a window of opportunity. It controls appetite and facilitates initial weight loss, creating the headroom for new, healthier habits to be built and solidified, but alone does not bring about biological, metabolic and behavioural change that is required for long-term results.
Exercise becomes the ‘exit strategy’, the anchor that prevents the ship from being swept back out to sea once the engine is cut.
Furthermore, from a clinical perspective, we must look beyond the scales, weight alone is a poor indicator as to what is going on. The study used DEXA scans to assess body composition, measuring fat mass and lean mass. The combination therapy group achieved superior outcomes in reducing fat percentage and preserving vital muscle mass compared to liraglutide alone. This is the hallmark of healthy, sustainable weight loss: losing fat, not just weight.
My clinical takeaway: a strategy for sustainable success
This research powerfully validates the approach we take in functional medicine: we use all effective tools at our disposal, but always within a holistic framework aimed at creating lasting behavioural and biological change.
Using a GLP-1 agonist without a concurrent, robust exercise programme is like building a beautiful house on foundations of sand. The results might look good for a while, but they won’t hold up to the test of time.
If you are considering or currently using a GLP-1 medication, my advice is to view exercise not as an optional add-on, but as the most critical component of your long-term success. It is the non-negotiable lever that turns a temporary intervention into a lasting transformation. Medication can start the journey, but it’s the habits you build along the way that will carry you to your destination and keep you there.
Have you discussed your strategy for making health changes stick for good? Have you discussed what your exit plan looks like before you start?
All opinions are my own and should not be taken as medical advice. Discuss any strategy with your practitioner and educate yourself before starting any medication.
A link to the full paper can be found here:
Healthy weight loss maintenance with exercise, GLP-1 receptor agonist, or both combined followed by one year without treatment: a post-treatment analysis of a randomised placebo-controlled trial eClinicalMedicine Lancet Feb 2024
