When GLP-1 drugs first entered clinical practice nearly two decades ago, few could have predicted how quickly they would escape the confines of endocrinology and enter everyday conversation. Today, medications like Ozempic and Wegovy are discussed not just in clinics and conferences, but on social media, red carpets, and group chats — often framed as lifestyle enhancers rather than powerful, lifelong medications.
For Jody Dushay, an endocrinologist at Beth Israel Deaconess Medical Center and an Assistant Professor of Medicine at Harvard Medical School, the current moment feels both exhilarating and unsettling. She has been studying GLP-1 drugs since the very beginning, long before they became cultural shorthand for weight loss.
“I worked on exenatide during my fellowship,” she told DDN, referring to the first GLP-1 drug approved for treating type 2 diabetes in 2005. “At the time, we were asking basic questions: could this help with weight loss at all, and if so, in whom?”
That early work enrolled 41 obese women without diabetes in a 35-week randomized, double-blind trial to investigate the effect of exenatide on weight loss. The results were striking — not just because participants lost weight, but because the responses varied so markedly. Around 30 percent of participants lost at least five percent of their body weight, while others showed more modest losses, or no benefit at all.
There’s a general consensus that we don’t really understand this drug yet. We’ve only seen a few years of data, and we don’t know how people will respond after 10, 15, or 20 years. At the same time, the message from industry is clear: once you start, this is a medication you’re expected to stay on for life.
—Hyung Heon Kim, MetaVia
Nearly twenty years later, clinicians still cannot reliably predict who will respond dramatically, who will tolerate treatment long-term, and who will struggle to stay on therapy at all. And yet, millions of people are now taking these medications. GLP-1s are being used at the population scale while fundamental questions remain unanswered: why do some patients respond so robustly while others barely at all? Why do side effects cluster so differently? And what does long-term use mean when appetite, reward, and metabolism are being pharmacologically reshaped?
As Hyung Heon Kim, CEO and President of MetaVia, told DDN, “There’s a general consensus that we don’t really understand this drug yet. We’ve only seen a few years of data, and we don’t know how people will respond after 10, 15, or 20 years. At the same time, the message from industry is clear: once you start, this is a medication you’re expected to stay on for life.”
What we still don’t know about GLP-1 drugs
Even as GLP-1 drugs are reshaping obesity and diabetes care, researchers are only beginning to map their full effects on the body — and the brain. The first comprehensive sex-specific atlas of GLP-1 in mouse brains has now revealed that GLP-1’s activity is not uniform. It operates in dozens of brain regions, and these patterns differ between males and females. Scientists are uncovering sex-specific circuits that influence appetite, insulin signaling, and even reward pathways, suggesting that the same dose can have very different effects depending on the patient.
Moreover, GLP-1 interacts with a web of other hormonal and neural systems — leptin, ghrelin, estrogen, anorexigenic neurons, and more — creating a complex, dynamic network that governs hunger, satiety, and metabolism. While clinical trials can measure outcomes like weight loss or blood sugar reduction, they cannot yet fully capture how these networks are being reshaped with chronic drug exposure.
As research uncovers new indications for GLP-1s, understanding the variability in individual responses is more important than ever. For example, GLP-1s have demonstrated consistent neuroprotective effects in preclinical models of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). However, when these drugs are tested in clinical trials, the outcomes are often highly variable, largely owing to the heterogeneity in the study population.
Beyond efficacy, questions remain about long-term use and tolerability. Combined with differences in sex, genetics, and baseline metabolic health, this means that millions of people are now taking these drugs at a population scale while key mechanisms and outcomes remain unclear.
Improving tolerability
GLP-1 drugs are designed to be ongoing therapies — stop them, and the disease often returns. Tolerability, adherence, and durability may become the real differentiators as the field evolves.
Dushay emphasized that these medications are not benign. Side effects can include nausea, constipation, diarrhea, osteoporosis, kidney damage, gallstones, and pancreatitis. Rapid weight loss can also obscure underlying disease. “These drugs affect receptors all over the body,” she noted. “You shouldn’t feel terrible and assume that’s just the deal. That could be something serious.”
This shift is reshaping how some companies think about the next wave of obesity medicines. Rather than optimizing for maximal short-term weight loss, developers are increasingly asking what sustainable success actually looks like in the real world, particularly in regard to tolerability and adherence.
At MetaVia, that question has become central to drug design. The company’s lead program, DA-1726, is a dual GLP-1/glucagon receptor agonist intended to provide Wegovy-level weight loss with a shorter titration period and a milder gastrointestinal side effect profile. Originally conceived as a type 2 diabetes therapy rather than a pure obesity drug, DA-1726 was optimized less for maximal appetite suppression and more for metabolic control, which Kim believes may underlie its comparatively better tolerability.
Early data from an eight-week Phase 1 study showed that patients receiving a 48 mg dose of DA-1726 achieved rapid and statistically significant weight loss, alongside pronounced reductions in waist circumference without treatment-related discontinuations. By Day 26, patients had lost an average of 6.1 percent of body weight, deepening to 9.1 percent by Day 54, while waist circumference fell by nearly four inches over the same period. Gastrointestinal side effects were mild to moderate, and no patients stopped treatment due to tolerability issues.
For Kim, the challenge is not simply how much fat patients lose, but which fat they lose. “Everyone talks about fat loss and lean mass preservation,” Kim said. “But they rarely specify where the fat is being lost. Fat on the arms and legs isn’t the same as fat around the waist, which drives many metabolic issues.” MetaVia is placing particular emphasis on reductions in visceral and abdominal fat — the depots most strongly associated with insulin resistance, cardiovascular disease, and fatty liver — and is using full-body MRI imaging to capture changes that conventional metrics like BMI or total weight cannot.
Maintenance, not just momentum
In addition to making therapies more targeted and tolerable, it’s important that patients are supported beyond the prescription itself. GLP-1s do not operate in isolation; they act on appetite, reward, and metabolism within the context of a person’s daily life. Without guidance on nutrition, movement, side-effect management, and expectations, even the most effective drug can fall short of delivering lasting benefit.
Most outcomes don’t fail in the clinic. They fail in the months between visits, when people are left to manage side effects, behavior change, and expectations on their own.
—Wei-Li Shao, Omada Health
This is where virtual care models are beginning to play a larger role. For Wei-Li Shao, President of Omada Health and a former Eli Lilly executive, the biggest gap in obesity care has never been the doctor’s visit itself — but everything that happens in between.
“Most outcomes don’t fail in the clinic,” Shao said. “They fail in the months between visits, when people are left to manage side effects, behavior change, and expectations on their own.”
Omada was founded on that premise more than a decade ago, initially focusing on diabetes and hypertension. As GLP-1s began reshaping obesity treatment, the company launched a dedicated GLP-1 care track, designed to sit alongside pharmacotherapy rather than replace it. The goal is not just to support initiation, but to address the less visible challenges that often derail long-term use.
In the real world, patients frequently discontinue GLP-1s within a year, often due to side effects, cost, or lack of support. Omada’s internal data suggest that pairing GLP-1 therapy with continuous virtual coaching, nutrition guidance, and remote monitoring meaningfully changes that trajectory. At 12 months, persistence rates for patients using GLP-1s alongside Omada’s program were above 60 percent, compared with roughly 40 percent in usual care. More strikingly, a 16-week analysis showed that patients who stopped medication after six or twelve months regained little to none of the weight they lost — a sharp contrast to published data showing double-digit percentage regain in most cohorts.
A cultural phenomenon
Beyond medicine and economics, GLP-1 drugs are reshaping body norms. The speed and visibility of weight loss — especially among celebrities — have revived a cultural ideal of extreme thinness that many clinicians find troubling. “These medications are changing what people think is normal,” Dushay said. “That’s scary, especially for women and girls.”
Fernando Ovalle Jr., a double board-certified plastic surgeon and obesity medicine specialist, told DDN, “These medications should be used where there’s a clear medical indication and a defined benefit. Right now, social media and aesthetic use may be outpacing the data. GLP-1s are not casual wellness drugs; they meaningfully alter appetite, gastric emptying, and body composition.”
He continued, “The biggest risk I see is applying data from patients with obesity or metabolic disease to populations where we don’t have good evidence, namely, lean patients, cosmetic use, or medically complex individuals. The risk-benefit profile is completely different in those groups.”
Food, Dushay emphasized, is not tobacco. Appetite is not inherently pathological. While some individuals experience a pathological drive to eat, many do not — and suppressing hunger in people without that pathology may carry psychological costs.
“We have to eat,” she said. “We should enjoy food. Treating appetite as the enemy is dangerous.”
A smarter way forward
Despite the hype and rapid adoption, the consensus among experts is that GLP-1 therapy must be deployed thoughtfully. Structured programs, frequent follow-ups, dietary support, and realistic messaging are critical. “If you’re covering a very expensive medication, it’s fair to provide support and accountability,” Dushay said. “It’s not just the drug — it’s how you use it.”
Nearly twenty years after she first studied GLP-1s, Dushay sees the current moment as a crossroads. The drugs are here to stay. The question is whether medicine, policy, and culture can catch up.
“We’re still at the beginning of this story,” she concluded. “But how we handle this phase will shape everything that comes next.”
