As GLP-1 receptor agonists continue expanding across obesity, diabetes, fatty liver disease, and cardiometabolic care, clinicians are increasingly confronting a pressing question: Does long-term use lead to tolerance, or do apparent “diminishing returns” reflect predictable physiology? It’s a conversation that is evolving quickly as millions of patients move from early weight-loss phases into long-term maintenance.
The study generally referred to as the baseline in this area was published online in 2017. The analysis of just 10 individuals concluded that liraglutide had the same effect when administered in chronic treatment — in this case, over 21 days — as it did in acute treatment. These medications are prescribed for much longer periods, though, and there is a gap in research around significant long-term use.
“We still don’t fully understand how GLP-1s reach and affect the brain, which makes it difficult to define true tolerance mechanistically,” said Hyung Heon Kim, CEO of Cambridge, Massachusetts-based MetaVia, which is currently developing a novel antiobesity medication.
Plateaus Are Not Drug Failure
Clinically, most providers say what patients describe as “the medication stopped working” is almost always something else: a natural plateau, metabolic adaptation, inconsistent dosing, or behavioral drift. GLP-1s typically induce rapid early weight loss followed by slower, steadier progress — a trajectory seen across nearly all obesity treatments, including bariatric surgery.
Primary care clinicians, now responsible for much of the long-term oversight, begin with a straightforward assessment.“When a patient’s results slow down, I start by checking the basics: Are they taking the right dose and staying consistent? Has their eating or activity level shifted?” said Hayley Miller, MD, medical director of Nurx Weight Management, an online obesity management platform. “Seasonal changes can play a big role, depending on where they live. Now’s a good moment to assess symptoms and rule out other factors like thyroid issues, medications, or hormonal shifts.”
Once these potential contributors are addressed, Miller said that tapering weight loss typically reflects physiology, not medication failure.
“If everything checks out and progress is just gradually tapering off, that usually points to the body adapting to a lower weight and not the medication ‘stopping’ working,” Miller said.
Many patients benefit from a structured behavioral reset before any pharmacologic changes are made.
“Reassess the basics first,” Miller said. “Confirm your dose and how consistently you’re taking it, evaluate your food intake and activity level, and consider any new medications or health issues. A lot can happen on the days between doses.”
“A brief, guided session with a registered dietitian, along with an exercise plan that incorporates resistance training, can boost your energy balance and help maintain lean muscle,” she added.
If a true plateau persists despite behavioral recalibration, clinicians may explore treatment adjustments.
“This could involve changing your dosage, adding a new medication, or exploring a different approach,” Miller said. “Every change should be tailored to you, ensuring safety and guided by a licensed clinician experienced in metabolic health.”
Real-World Behavior Data and Tolerance
Digital health data may provide another window into long-term usage patterns. Aja Beckett, founder of Shotsy — a GLP-1 companion app with more than 250,000 monthly active users — says real-world behavior aligns strongly with the view that plateaus are physiologic, not pharmacologic.
“I see no solid evidence that true pharmacologic tolerance develops with long-term GLP-1 use,” Beckett said. “Clinical trials and large real-world datasets show a pattern of rapid early weight loss followed by a plateau. If the medications genuinely stopped working, we would not see the significant weight regain that often occurs when someone discontinues them.”
Most perceived “diminishing returns,” she said, can be traced to predictable variables.
“What many people describe as diminishing returns appears more consistent with known factors such as natural plateaus, metabolic adaptation, changes in habits, missed or inconsistent doses, switching between products, and exposure to unstable compounded formulations,” Beckett said. “We still need longer and more detailed mechanistic studies before anyone can determine whether something like classic receptor-level tolerance is occurring.”
Why Some Patients Regain
For Michael Kyle, MD, senior vice president and chief medical officer at Currax Pharmaceuticals, the question of tolerance cannot be disentangled from the broader biology of obesity — a chronic, relapsing disease that often pushes back against weight loss.
“We have seen some data showing that people start regaining weight on GLP-1s over time,” Kyle said. “We also see that with bariatric surgery, where patients start to regain weight as well.”
One factor, he said, is the speed of early weight loss.
“When you lose weight really fast, your body thinks it’s in a semi-starvation state,” he said. “Metabolic rate, adaptive thermogenesis — all these things change. We have to think about whether the speed of weight loss and the amount of weight loss are the right way to approach obesity in every case.”
Kyle pointed to modern reinterpretations of the Minnesota Starvation Experiment, which showed that regain often exceeds baseline weight — and disproportionately as fat mass.
“It follows the same curve we see in some of the GLP-1s and in some bariatric surgery data,” he said.
Risk of Cycling On and Off GLP-1s
Another concern is medication cycling. Stopping GLP-1 use, whether due to cost, tolerability, supply issues, or unrealistic expectations, can destabilize long-term outcomes.
“What we see right now are patients who cycle on their medicines for obesity,” Kyle said. “They’ll take it for a while, they’ll stop it, and then they’ll restart. That tells me it worked the first time, and the side-effect profile didn’t stop them. But they’re not using it in a way that reflects the need for long-term therapy.”
“When you cycle, your body has a preference when it starts to regain weight by accumulating fat before muscle,” he said. “Cycling actually sets you up for worsening obesity later in life.”
Where Long-Term Evidence Is Still Missing
Kim and Kyle agree that the field urgently needs better long-term data, not only on durability but also on sequencing: when to adjust doses, when to combine agents, and how to support long-term maintenance after initial success.
“We’re at the beginning of a new era, and we need extensive long-term data,” Kim said. “Most patients with type 2 diabetes who take GLP-1s are also on metformin, SGLT2 inhibitors, or DPP-4 inhibitors. We need to understand sequencing — when to move from metformin plus GLP-1 to SGLT2 plus GLP-1.”
Kyle emphasized that no single therapy can address the complexity of obesity. His company, Brentwood, Tennessee-based Currax Pharmaceuticals, for example, makes Contrave, an oral medication that combines naltrexone and bupropion.
“We need lots of different options for patients,” he said. “Just like hypertension and diabetes, obesity requires an arsenal of medications.”
He sees a clear role for oral, non-GLP-1 options as long-term maintenance tools, particularly for patients who cannot tolerate injections or who regain weight after bariatric surgery.
“There are many surgeons who have come to us and said, ‘Do a study with this product because we need to help these patients maintain weight loss,’” he said. “As a long-term maintenance option for patients who can’t tolerate a GLP-1 or who have regained weight after bariatric surgery, I think there’s a real opportunity.”
New agents may further expand the landscape, including dual- and triple-hormone compounds that target multiple metabolic pathways.
The study reported having no disclosures.
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