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Researchers are still studying the impact of going off a GLP-1 medication.
Alessandra (Ale) Vignola
President, cardiovascular & metabolic
Worldwide Clinical Trials
As glucagon-like peptide-1 (GLP-1) agonists become cornerstone therapies in treating obesity, an important question looms: What happens when treatment stops?
Although a lot of data exists about using GLP-1 medications to treat diabetes, there isn’t as much data yet supporting their long-term use for obesity. What we do know is that patients appear to experience a fairly rapid rebound effect once they stop GLP-1 use. In one extension study,1 for example, patients regained about two-thirds of the weight they lost during the trial within one year. They also lost many of the cardiometabolic benefits they gained while on the GLP-1 medication.
This pattern not only threatens the durability of therapeutic outcomes but also raises key considerations for clinical trials involving GLP-1 agonists. It’s important to proactively address these realities to help patients navigate the study process and to design sustainable interventions that resonate with patients, regulators, and payers.
To address the rebound effect, patients and researchers must first understand that obesity is a chronic, complex disease2 that GLP-1 agonists alone will not quickly fix.
Obesity is a central component of metabolic syndrome3 and is influenced by a diverse mixture of genetic, lifestyle, behavioral, and emotional factors. Most patients living with obesity have comorbidities such as diabetes, cardiovascular conditions, metabolic dysfunction-associated steatohepatitis (MASH), depression, or anxiety. However, that’s not always the case. One research study4 has found that about 25% of European patients with a high body mass index (BMI) were otherwise metabolically healthy.
This means that both the root causes and consequences of obesity are different for every patient.
GLP-1 agonist medicines have shown promise by lowering not only weight, but also blood sugar, blood pressure, cholesterol, and inflammation. They appear to decrease food cravings and offer some neurological benefits. These factors may affect obesity, fatty liver disease, cardiovascular disease, sleep apnea, kidney disease, dementia, and more. Still, we don’t yet fully understand how various GLP-1 agonists work, their durability, or their impact over time.
Given the intricacies involved, it’s unlikely that any single therapeutic intervention or pathway will work for all patients. Instead, clinical trials testing GLP-1 agonists may increasingly entail medication combinations designed to treat obesity plus other conditions. We are already seeing many studies that pair GLP-1 medications with investigational products (IPs) for treating fatty liver, heart disease, and other diseases.
At a recent conference, a French bariatric surgeon told an interesting anecdote about starting to see more patients who had previously used a GLP-1 but stopped because they couldn’t tolerate it physically. They then regained much of their previous weight. Psychologically, though, these patients had learned what it was like to be lean while on the GLP-1. That knowledge fueled their commitment to finding a long-term solution; they were more willing to undergo bariatric surgery to recapture the positive experience.
GLP-1 agonist medicines have many implications in addition to their physical effects because weight loss is not just a physical transformation; it is also a mental and emotional one. Some psychological impacts may be positive, while others may be negative. Therefore, amidst all the encouraging data and glowing media stories illustrating phenomenal results, research teams must set realistic patient expectations. Solid support systems should be in place to assist patients during and after any GLP-1 study. Before patients enroll, they should be aware that:
To set up patients for long-term success, sponsors can connect study participants with advocacy groups capable of nurturing their lifestyle changes. Sponsors should also ensure patients understand how their metabolism works. Education must go beyond explaining the medications and instead help patients manage their metabolism effectively. Relatable advice, such as eating protein before drinking orange juice to minimize blood sugar spikes, can go a long way toward fostering sustainable lifestyle changes.
However, patient education must be appropriate for patients’ health literacy and other social determinants of health (SDOH). For instance, counseling patients to buy fresh, organic produce is unrealistic if they live in food deserts or lack the resources to afford such options. Tailoring education to patients’ realities helps ensure that interventions are actionable.
Lifestyle counseling is almost always integrated into GLP-1 study protocols, partly because existing prescribing information advises exercise and diet along with the medication. But that is only one piece of the picture.
There is beauty in the holistic approach that’s emerging in GLP-1 trials. It’s not uncommon to have endocrinology, cardiology, behavioral health, and other specialties collaborating on a single study. The key question increasingly being asked is: Besides weight loss, what additional value can the medication deliver for patients?
Until recently, clinical trials testing GLP-1 agonists tended to focus on BMI reduction. Now, this collaborative environment offers opportunities for innovation. Sponsors and research teams may want to take advantage of multidisciplinary approaches to consider:
Extension studies and/or long-term studies. Data collection is paramount given the relative newness of GLP-1 medications for treating obesity. Studies that evaluate patients a year or more after the conclusion of their initial GLP-1 clinical trial are needed to gather valuable “post-GLP-1” data. Data from long-term studies is likewise necessary to better understand the consequences of long-term GLP-1 use.
Combined and/or exploratory endpoints. Combined endpoints are becoming more common, such as obstructive sleep apnea (OSA) and metabolic dysfunction-associated steatohepatitis (MASH) as a secondary endpoint in studies for obesity. Sponsors are also gathering data on inflammation markers, whole-body composition, type of fat being lost, and other exploratory endpoints.
Personalization. Evidence is mounting that a patient’s genetic makeup may influence their response to different GLP-1 therapies. Genetics may even play a more prominent role than lifestyle factors, so sponsors and research teams should be prepared to triage patients based on genotype.
Patient verification and retention. Few GLP-1 studies have problems enrolling patients; the challenge is keeping them engaged if they don’t tolerate the study drug or achieve desired results. Since most qualified patients have comorbidities, the same patient population may be targeted in clinical trials for obesity, diabetes, MASH, or other conditions. Dozens of different GLP-1 therapies are currently in development, so patients have an abundance of clinical trials from which to choose. In fact, it’s not uncommon for patients to enroll in several studies at once. Therefore, sponsors may want to use services that verify whether patients are enrolled in other clinical trials. In addition, they should take steps to strengthen engagement by making patients feel respected and welcome. This can be accomplished by using inclusive language (e.g., “patients living with obesity” rather than “obese patients”), confronting obesity bias, and accommodating patients' needs (for example, having wheelchairs available for patients with limited mobility).
Advocacy. The reality is that it’s difficult to conduct completely blinded studies of GLP-1 agonist medicines for treating obesity because patients and providers alike quickly suspect they’re in the placebo arm of a study if the patient doesn’t experience weight loss and side effects. Although the U.S. Food and Drug Administration (FDA) may prefer studies with a placebo arm, the industry may soon need to advocate for obesity studies without one. Patient outcomes reports could be powerful motivators, as the voice of the patient may influence regulatory acceptance, payer acceptance, and provider prescribing habits.
Obesity is more than a weight issue; it is a chronic, multi-dimensional disease. For patients, treatment is a lifelong journey.
Hopefully, one day we will realize the aspiration to deliver personalized treatment options. Until then, staying patient-focused is the industry’s best strategy for long-term GLP-1 study success. Sponsors and research teams must proactively plan to manage patient expectations, support their mental and behavioral health, and help them maintain lifestyle changes. Multidisciplinary collaboration, patient-centered education, and robust data collection will be the keystones of progress.
In that light, the GLP-1 rebound effect is not an obstacle but an opportunity to chart a new, holistic course in obesity care. By rising to its challenges, we can discover solutions that resonate with regulators, payers, and, most importantly, patients.
Alessandra (Ale) Vignola is President of Cardiovascular & Metabolic at Worldwide Clinical Trials.
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