Appetite control drugs have made it possible for many people to overcome obesity. However, after stopping therapy, many patients regain most of the weight they had lost. Because of this, the question of what effect such a pattern has on long-term health is increasingly being asked.
Domenica Rubino, director of the Washington Center for Weight Management and Research, points out that in the last few years she has noticed the belief that drugs such as Ozempic and Wegovy by Novo Nordisk, as well as Mounjaro by Eli Lilly, represent a permanent solution to obesity. However, according to her, such an understanding is not in accordance with the nature of this disease.
Rubino explains that obesity, as a disease, does not work like an acute infection that resolves with short-term therapy. On the contrary, it is comparable to chronic conditions, including hypertension or diabetes, in which long-term or continuous treatment is often necessary to control the condition.
In the last few years, the field of obesity treatment has been significantly changed by the introduction of a new class of drugs, the GLP-1 receptor agonists. These drugs mimic the effects of the natural hormone GLP-1, which is crucial for regulating appetite and satiety.
American agency U.S. In June 2021, the Food and Drug Administration approved the drug Wegovy, with the active ingredient Semaglutide, for long-term weight management. The high demand for these therapies led to the emergence of new options, so at the end of 2023, Tirzepatide arrived on the market under the brand name Mounjaro, while a new drug, Retatrutide, is currently in development.
Scientific research confirms that drugs in the GLP-1 receptor agonist class are highly effective in treating obesity. In one of the most significant clinical trials that studied the effect of the drug Semaglutide, published in 2021, participants lost an average of about 15% of their initial body weight over 68 weeks.
On the other hand, patients who received a placebo recorded a significantly smaller decrease in body weight, on average about 2%. In some patients who used the therapy, weight loss was even more pronounced, reaching approximately a fifth of their initial weight.
In addition to effects on body weight, research also suggests possible health benefits. The results of the SELECT trial study from 2023 showed that the use of Semaglutide can reduce the risk of cardiovascular risks, such as heart attack and stroke, by about 20% in patients who already have a history of cardiovascular disease. However, the application of these therapies also raises certain questions.
One of the challenges is the high price – monthly therapy with this drug can reach a price of around 1,350 US dollars. In addition, some patients experience side effects, the most common of which are nausea, stomach pain, and heartburn. Therefore, what happens after these drugs are stopped is often considered.
Research results so far indicate a similar trend: after stopping therapy, body weight often increases again. In one study, about 800 participants received weekly injections of Semaglutide along with dietary changes and planned psychological support.
This combination of interventions enabled patients to lose approximately 11% of their initial body weight over 4 months. However, when a third of the subjects were later switched to a placebo during the following year, some of the lost weight was regained, averaging about 7%.
Similar results were reported in a large clinical study from 2021, the STEP 1 trial. During 68 weeks of Semaglutide therapy, participants lost an average of more than 15% of their initial body weight. However, in the following year after stopping the treatment, a large part of this effect is weakened.
Patients regained, on average, about two-thirds of the weight they had lost. At the same time, certain indicators of cardiometabolic health began to return to their initial values. These parameters include factors associated with conditions such as diabetes and cardiovascular disease, including heart attack.
Similar experiences are reported by doctors who apply therapy with drugs from the group of GLP-1 receptor agonists on a daily basis. According to Ulster University’s Alex Miras, only a small number of patients manage to maintain their weight loss after stopping treatment. Estimates indicate that such cases are relatively rare, accounting for no more than 10% of patients.
It is also noted that body weight is often regained faster than it was lost. According to Miras’ observations, most weight regain occurs during the first three to six months after stopping therapy. However, many experts point out that such a result is not surprising. In the case of numerous chronic diseases such as rheumatoid arthritis, asthma, or hypertension, stopping therapy leads to a worsening of the condition.
Therefore, understanding the mechanisms behind weight regain after drug use is of great importance. Such findings may help in understanding their long-term health effects and in defining the most effective ways to apply them in the future treatment of obesity.
The Regain Problem
Most experts believe that the rapid weight regain after stopping GLP-1 drugs is explained by the continued weakened function of the brain centers that control appetite. Drugs like Semaglutide or Tirzepatide temporarily reduce hunger, but when therapy is stopped, old patterns of overeating return.
“People often don’t realize how chronic this need for therapy is,” Rubino points out. “Patients think: “I’m different, when I reach the desired weight, everything will be fine.” But the brain is strong and quickly returns to old habits. “
Another possible explanation is given by Martin Whyte, associate professor of metabolic medicine at the University of Surrey. According to him, the doses of GLP-1 drugs used in therapy exceed what the body naturally produces. This can lead to a decrease in your own GLP-1 production. When the medication is stopped, you may feel hungrier than before.
“It is possible, although there is no definitive evidence yet, that the body remains in a deficit of GLP-1, which significantly weakens the satiety signal that goes to the brain,” explains Whyte.
This weight regain effect is of great concern to scientists, as it can have severe physiological consequences. In one study, patients who switched to placebo injections not only regained body fat but also saw their waistline increase.
Excess fat in this body part is linked to several health issues, including heart disease, insulin resistance, and fatty liver. Miras points out that many patients who regain weight after stopping medication or dieting experience changes in their body composition, which can be even more harmful than if they had just maintained their previous weight.
“Weight regain usually goes hand in hand with an increase in fat mass and a decrease in muscle mass,” he explains. That means the body comes back with more fat and less muscle. This kind of change is not good from a metabolic standpoint, as more muscle mass helps reduce the risk of diabetes and heart disease.”
However, there is currently no direct evidence that a person’s body composition after stopping weight loss drugs is worse than before they started treatment in the first place.
Understanding Obesity
The response to GLP-1 drugs can vary significantly from person to person. Not everyone is equally sensitive to their effectiveness. For example, in a 2021 clinical study of Semaglutide, nearly 14% of participants failed to lose even 5% of their body weight, even though they used the drug for more than a year.
Although studies show that weight loss can be sustained while taking the drug, some people regain weight even before they stop taking the drug. Miras cites data on earlier GLP-1 formulations such as Sazenda or Liraglutide: “After one year, the average weight loss is about 8%, but after three years it drops to 6%. A similar trend is seen with bariatric surgery.”
Rubino explains that some patients may regain weight after stopping Semaglutide, but that metabolic gains may still persist. One example is better regulation of blood sugar levels, which, according to some research, occurs years after stopping therapy.
The reasons for this can be different. She believes that people who lose significant body weight often become more physically active, sleep better, and have fewer episodes of sleep apnea (a condition associated with a higher risk of developing Type 2 Diabetes). These lifestyle changes can continue to positively impact metabolic health even after medication is stopped.
Variations in the effects of therapy can also be explained by the fact that obesity is not a uniform condition. It was once thought to be a single disease, but research increasingly indicates that there are several different forms or subtypes of obesity, which respond differently to treatment.
On the other hand, some studies indicate the possibility of longer-lasting positive effects. In one study, women with polycystic ovary syndrome (PCOS) and obesity received Semaglutide for 16 weeks in combination with metformin therapy.
During that period, there was a decrease in body weight, an improvement in cardiometabolic parameters, and a drop in testosterone levels, which is often elevated in women with this syndrome. Two years after stopping therapy, body weight and free testosterone levels were still lower than at the beginning of the study, while cardiometabolic indicators returned to baseline values.
However, the sudden increase in the popularity of GLP-1 drugs on the market has opened up a new opportunity for scientific research. According to Novo Nordisk, about 25,000 people in the United States are being treated with Wegovy each week.
The large number of users gives researchers the opportunity to better understand the different forms of obesity, analyzing the reaction of patients to these drugs, during their use, but also after the cessation of therapy.
Novo Nordisk, the manufacturer of the drugs Ozempic and Wegovy, stated in a BBC interview that there is currently no valid evidence that patients will necessarily regain all the weight they lost after stopping therapy.
The results of the STEP 1 extension trial showed that, one year after stopping the weekly subcutaneous administration of Semaglutide at a dose of 2.4mg with lifestyle changes, participants regained about two-thirds of the weight they had previously lost. These results further emphasize the fact that obesity is a chronic condition and that long-term weight maintenance often requires continuous therapy.
Meanwhile, the new European research project Sophia (Stratification of Obese Phenotypes to Optimize Future Obesity Therapy) was launched by University College Dublin. The aim of this project is to examine in more detail the different types of obesity and their response to available therapies.
According to Miras, researchers are trying to identify indicators, including laboratory findings and psychological assessments, that could help predict the drug’s effectiveness in individual patients.
“Currently, we prescribe therapy to the patient for a few months, and if there is weight loss, we can say we were lucky,” Miras explains. “To a large extent, we are still choosing therapy without clear guidelines.”
He believes that in the future, such data could enable a much more precise approach to treatment. Based on the patient’s individual characteristics, it can be assessed in advance which drug is the most effective, how likely it is to lose its effect over time, and which combinations of therapies could help with long-term weight maintenance.
Still, according to experts, one thing is pretty clear: Many people with obesity will likely need to use therapy long-term to prevent weight gain again. As Whyte explains, in many patients, discontinuation of treatment can lead to a return of previous problems with appetite and body weight regulation.
Rubino states that new clinical trials are currently being planned that would examine a different approach to administering GLP-1 drugs. One idea is that in the initial phase of treatment, higher doses are used to achieve significant weight loss, while after that, the therapy continues with a smaller dose, the so-called maintenance dose.
These lower doses would have a lower risk of side effects and would be more suitable for long-term use. A big challenge in the treatment of obesity with these drugs is their price. For example, in the United Kingdom, the National Health Service currently covers treatment with Wegovy for 2 years. However, it is expected that the situation could change with the arrival of cheaper generic versions of these drugs.
Novo Nordisk’s Saxenda patent is about to expire, and Teva, Pfizer, and Mylan plan to introduce generic versions of Liraglutide in 2024. On the other hand, generic alternatives to Ozempic are expected in the coming years.
According to Whyte, although Liraglutide is not as effective as Semaglutide, falling prices after the patents expire are expected to make these therapies more affordable. As costs come down, it is highly likely that GLP-1 drugs will become a more realistic option for long-term, chronic obesity treatment.
