Sheree had maintained a healthy weight for 15 years, thanks to a surgery that wrapped a silicone ring around the top of her stomach. But when the gastric band repeatedly slipped and had to be removed, the weight came back — fast. She gained nearly 20 kilograms in just 2 months.
Frustrated, she turned to the latest generation of anti-obesity medications, hoping to slow the rapid weight gain. She cycled through various formulations of the blockbuster therapies semaglutide (sold under the brand name Wegovy) and tirzepatide (Zepbound), finding some success with higher doses of these drugs, which mimic the effects of the appetite-suppressing hormone GLP-1. But each time, drug shortages disrupted her treatment, forcing her to start again with a new formulation or to go without the drugs for weeks.
Tired of the uncertainty around the therapies, she decided to try something different. Sheree, who asked that her middle name be used to protect her privacy, underwent two minimally invasive procedures designed to reduce the size of her stomach and to blunt hunger cues.
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Developed over the past two decades, these ‘endoscopic’ procedures — performed using flexible tubes inserted through the mouth, and no scalpels — are just one part of a growing toolkit to help people who want to move away from GLP-1 therapy. More-conventional bariatric surgeries, used routinely since the 1980s to reroute the flow of food through the gut or to restrict the stomach’s size, might also gain wider appeal. And the search is picking up for other drugs that could offer lasting alternatives for a post-GLP-1 population.
That momentum is driven by a convergence of factors: chronic shortages of GLP-1 therapies, high costs, insurance barriers and debilitating side effects. As a result, many people who start the drugs ultimately stop — with discontinuation rates in clinical trials ranging from 37% to 81% in the first year1. And once treatment ends, the weight lost often piles back on.
As demand grows for complementary strategies, the landscape of weight-loss treatment, which has been overtaken in recent years by semaglutide and tirzepatide, is now broadening again. In this way, says Ricardo Cohen, a weight-loss specialist at the Oswaldo Cruz German Hospital in São Paulo, Brazil, GLP-1 drugs are not just reshaping treatment — they’re pulling more people into often-overlooked avenues of support.
“The new drugs are a gateway for people seeking obesity care,” he says.
Surgical solution
During their early ascent, GLP-1 drugs were often viewed not as a gateway, but as a pharmaceutical fix that might render older weight-loss strategies obsolete.
For decades, bariatric surgery had been the gold standard in obesity care. In its various forms, including the gastric-band surgery that Sheree first had, the treatment induces substantial and sustained weight loss and improves obesity-related health conditions. And it has a strong safety record, with rates of serious complications and mortality that are comparable to, or even lower than, those of common procedures such as gallbladder removal and knee replacement.
Still, many people with obesity view bariatric surgery as a last resort. The proportion of eligible individuals who undergo the procedures has remained stubbornly low — around 1% in the United States, and not much higher in any other country.
The arrival of semaglutide and tirzepatide offered a way to reach the other 99% — promising to achieve similar weight reductions without the invasiveness, recovery time or stigma often associated with surgical intervention. “The hype generated by the drugs put surgery in a second tier,” acknowledges Cohen, president of the International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) in Naples, Italy, a global professional organization for bariatric surgeons. But he hopes to shift that perception.
In 2022, the IFSO and its US counterpart revised their guidelines, lowering the recommended body mass index thresholds for surgery eligibility, aiming to make the procedure available to more people who could benefit2. Cohen now sees opportunities to expand the surgery’s reach to people who discontinue GLP-1 therapy or who fail to achieve results with medication alone — and he’s hoping to build the case with clinical data.
At his clinic in Brazil, for example, Cohen will soon begin enrolling participants for a randomized trial in which people who first lose weight on semaglutide will be assigned to receive bariatric surgery, continued semaglutide injections or undergo both treatments.
Tummy techniques
Regardless of whether opinions of bariatric surgery shift, there are other ways to shrink the stomach. Starting in the late 2000s, weight-loss specialists began developing non-surgical approaches that achieve similar results (see ‘Shrinking the stomach’). As an added bonus, these techniques tend to be less expensive and simpler to deploy than are surgical methods, because they require fewer hospital resources and involve shorter recovery times.
The most widely adopted has been endoscopic sleeve gastroplasty (ESG), a procedure performed under anaesthesia that internally folds and stitches the stomach into a narrow tube. This reduces the stomach’s volume by up to 70% — to about the size of a banana — limiting food intake and promoting a feeling of fullness, although the weight-loss results are generally more modest than with surgery.
Pichamol ‘Sigh’ Jirapinyo, a bariatric endoscopist at Brigham and Women’s Hospital in Boston, Massachusetts, says that nearly half of the people who underwent ESG last year at her hospital or at Bariendo, a US-based network of eight non-surgical weight-loss clinics where she serves as medical director, had previously taken a GLP-1 drug. That’s up from about one in six just two years earlier.
ESG systems are approved as obesity treatments in the United States, the United Kingdom and beyond, but the procedure doesn’t work consistently for everyone. Sheree, who is from North Carolina and in her 50s, learnt that first-hand in 2022. When she didn’t get the results she desired from the ESG procedure, her physician recommended an experimental endoscopic method that uses a medical device authorized for other applications.
Known as gastric mucosal ablation (GMA), the procedure uses argon gas and an electrical current to generate ionized plasma, rapidly raising tissue temperatures in the upper portion of the stomach. The result is a controlled thermal injury that creates scar tissue along the gastric lining.
Vivek Kumbhari, a bariatric endoscopist at Mayo Clinic Florida in Jacksonville, and his colleagues have shown in studies in rats, pigs and human tissue that this targeted tissue-burning technique can reduce the upper stomach’s secretion of ghrelin, a hormone that stimulates hunger. It also makes the stomach stiffer, effectively shrinking its capacity (see, for example, ref. 3).
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Early recipients of GMA, an outpatient procedure done under anaesthesia, have experienced some side effects, including cramping, nausea and bloating. But these have generally been mild and temporary, and are more than offset by the weight-loss benefits, according to Christopher McGowan, a gastroenterologist who co-founded the True You Weight Loss clinic in Cary, North Carolina.
McGowan, in collaboration with Kumbhari and others, published a clinical trial of GMA last year4. The study involved ten people with obesity who had tried to lose weight with diet and exercise, but explicitly excluded anyone who had taken weight-loss medications. Now, the researchers aim to fill that gap with a trial targeting individuals who have discontinued GLP-1 therapy, which is more representative of real-world patients navigating multiple treatment options. Demonstrating the effectiveness of GMA in this population could help to persuade more physicians and potential candidates to consider the procedure, says McGowan — and might pave the way for reimbursement by insurers and health-care systems.
Individual experiences such as Sheree’s could prove anecdotally persuasive, too. Months after undergoing GMA at McGowan’s clinic — where she paid around US$6,000 for the procedure — she has reached a weight that she feels comfortable with, has had no adverse reactions and is maintaining her weight without GLP-1 drugs. “It gave me an outlet to stop chasing these medicines,” Sheree says.
Gut reset
In a mock surgical suite in an industrial park on the outskirts of Boston, Harith Rajagopalan is testing a proprietary device developed explicitly for post-GLP-1 weight maintenance. When he switches it on, a slender, squid-like catheter shimmers to life. Near the tip, a tiny balloon gently inflates with water that is heated to near-boiling point.
This tool, inserted endoscopically through the throat, creates a precisely controlled tissue burn much as GMA does, but is targeted at the duodenum, the upper portion of the small intestine, rather than the stomach. Called Revita, it aims to minimize tissue damage and promote regeneration, potentially rewiring how the gut senses nutrients and regulates metabolism.
Such changes could reverse the harm that chronic high-fat and high-sugar diets do over time, restoring “a more normal physiologic state”, says Rajagopalan, who is co-founder and chief executive of the firm Fractyl Health in Burlington, Massachusetts. “The duodenum is not designed to see Coca-Cola and McDonald’s,” he says.
