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The introduction of GLP-1 agonists has revolutionized the field of weight management, providing significant assistance to those struggling with obesity. These medications, like semaglutide (Wegovy and Ozempic) and tirzepatide (Mounjaro), have shown unprecedented efficacy, with clinical trials demonstrating substantial weight loss in participants. However, new research and patient experiences highlight a concerning issue: the difficulty of maintaining weight loss after stopping these drugs.
The Efficacy of GLP-1 Agonists in Weight Management
GLP-1 agonists work by mimicking the GLP-1 hormone, which promotes satiety and slows digestion. As a result, individuals feel fuller for longer periods and experience reduced hunger while taking these drugs. The weight loss was a side effect of the hormonal changes in the brain. In fact, Ozempic was not originally created for weight loss, but for adults with Type 2 diabetes because semaglutide can improve blood sugar control. Clinical trials have shown that participants can lose an average of 15% of their starting weight over 68 weeks, with some experiencing even greater reductions
Even still, GLP-1 agonists have become synonymous with weight loss—and research backs it up. According to a clinical trial published in 2021, participants on semaglutide experienced an average weight loss of 15% over 68 weeks, with some losing up to 20% of their starting weight. What’s more, a recent trial indicated that semaglutide could reduce the risk of heart attacks and strokes by 20% in patients with cardiovascular disease. This effectiveness has led to increased demand for these drugs: Novo Nordisk, the manufacturer of Ozempic and Wegovy, reports that 25,000 Americans sign up for Wegovy each week.
With all that in mind, these drugs are still fairly new to the market. And as more people sign up to take these drugs, more evidence emerges as to their potential downsides. There are numerous negative side effects that come with taking GLP-1 agonists, including nausea, stomach pain, and heartburn. Plus, they’re expensive: Without insurance, the list price of Wegovy is $1,349.02 per month, but there are discounts on the manufacturer’s website. With coverage, you could pay as low as $25, depending on your individual insurance plan.
Whether it's the shortage, side effects, lack of insurance, or high out-of-pocket costs that prompt patients to stop these drugs, they all face the same issue: how to maintain the results they got from the drug after they stop taking it, says Robert Kushner, MD, a professor and the director of the Center for Lifestyle Medicine at Northwestern University Feinberg School of Medicine in Chicago.
The Problem of Weight Regain Post-Treatment
Despite the effectiveness of GLP-1 drugs, the most prevalent issue once treatment stops is, you guessed it, regaining weight. Studies indicate that the trajectory of weight regain is often faster than the initial weight loss period, typically occurring within three to six months. A trial involving around 800 participants showed that those who stopped taking semaglutide regained 7% of the lost weight within a year, despite initial success. Similarly, the STEP 1 extension trial found that participants regained two-thirds of their prior weight loss within 12 months after stopping treatment.
Alex Miras, a clinical professor of medicine at Ulster University, explains that weight regain not only diminishes the success of the initial weight loss but also poses significant health risks.
“Weight regain is usually accompanied by accumulation of fat and less muscle. So you end up going back to a higher fat mass and a lower muscle mass,” she says. “That's not good from a metabolic perspective because having more muscle is good for reducing the risk of diabetes and heart disease.” This reaccumulation of fat, particularly around the waist, is linked to numerous problems, including cardiovascular disease and insulin resistance. Data from various studies also indicate that regaining weight can reverse improvements in cardiometabolic health achieved during treatment.
The primary theory for rapid weight regain is attributed to dysregulation in appetite-related brain regions. “What may be happening, and we don't know for sure, is that when you stop them, your body's left in a GLP-1 deficit which has a major impact on the satiety signal going to the brain," says Martin Whyte, an associate professor of metabolic medicine at the University of Surrey.
Additionally, the high doses of GLP-1 provided by these drugs may suppress the body's natural ability to secrete this hormone, leading to increased hunger once the medication is stopped. This hormonal imbalance can make it exceedingly difficult for individuals to maintain a lower-calorie diet post-treatment.
The Necessity of Ongoing Treatment and Lifestyle Changes
Because the chronic nature of obesity means that stopping treatment often leads to a relapse in weight and associated health conditions, experts agree that obesity should be treated as a chronic condition requiring long-term management.
"Obesity is not like an infection where you take antibiotics and you're done," says Domenica Rubino, director of the Washington Centre for Weight Management and Research. "It's not any different than hypertension or diabetes or the many other chronic illnesses that we deal with, where you have to use chronic medication."
Kushner underscores this, emphasizing the importance of combining medication with sustainable, healthy lifestyle changes. “Once Ozempic is stopped, all of the benefits from the medication cease,” Kushner notes, meaning the rapid feeling of satiety produced by semaglutide disappears once the medication is stopped, too. Without a holistic approach to weight management in place, one that includes diet, exercise, and behavioral changes alongside medication, patients will likely revert.
Ongoing research aims to better understand the varying responses to GLP-1 drugs and identify predictors of treatment success. Different subtypes of obesity and individual variations contribute to these differences. A European consortium known as Sophia is investigating predictors of treatment response to personalize obesity therapy effectively. Miras predicts a future where this information will help identify the most suitable weight-loss drug for a particular patient and develop strategies to prevent resistance and relapse. Understanding these nuances can help tailor treatments to individual needs, potentially improving long-term outcomes and reducing the likelihood of weight regain.
Conclusion
The challenge of maintaining weight loss after stopping GLP-1 drugs underscores the chronic nature of obesity and the need for ongoing treatment and lifestyle changes. While these medications are highly effective, their benefits diminish rapidly once treatment stops, leading to significant weight regain and associated health risks. Future research and personalized treatment strategies may offer more sustainable solutions for long-term weight management, emphasizing the importance of a comprehensive approach that includes both medication and lifestyle modifications. As obesity continues to be a major public health concern, the integration of medical and lifestyle interventions will be crucial in managing and sustaining weight loss effectively.
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