Weight Loss Drugs: Progress But Not Far Enough

By Sarah C.P. Williams| Illustration by AJ Golladay | Photographs by Jörg Meyer

By the time they visit her office, patients of Judith Korner, MD, PhD, often feel like they have tried everything to lose weight. The endocrinologist and founding director of the Columbia Metabolic and Weight Control Center sees people who have hundreds of pounds to lose, who cannot walk without assistance, and who have been denied vital surgeries and organ transplants because of their weight.

Dr. Korner uses prescription weight loss drugs to help these people manage their obesity and associated health challenges. Until recently, however, she and her colleagues had few prescription options, and the drugs that were available were effective only in a small percentage of people.

“Over the years, we’ve had patients who try numerous medications but don’t lose an ounce,” says Dr. Korner. “It’s only in the last couple of years that we suddenly have new medications that can really help the majority of our patients.”

Those new medications, of course, are those in the same class of drug as the uber-popular Ozempic, which sends a constant “I’m full” signal to the body, mimicking molecules usually made by the body after a meal. Clinical trials have shown that people taking these drugs consistently for a year and a half lose, on average, about 15% to 20% of their body weight. Prescriptions for Ozempic-like drugs have skyrocketed in recent years. Wegovy—the same medication as Ozempic but dosed for weight loss rather than diabetes—was approved by the FDA in 2021. It was followed by Zepbound, a weight loss formulation of the diabetes drug Mounjaro, in 2023.

For clinician-scientists like Dr. Korner, the new drugs offer not only a transformation in how they can treat their patients but also a validation that basic research into the biology of obesity has clinical benefit.

“The success of these drugs has reassured the public that obesity really is a biological issue that can be treated with pharmaceutical compounds,” says researcher Rudolph Leibel, MD. “It’s a huge step in the right direction for obesity treatment, but we also still have a lot of work to do.”

Dr. Leibel directs the New York Obesity Research Center, which was founded at Columbia in 1980, making it the oldest NIH-funded obesity research center in the country. Through the shared resources of the center, researchers, including Dr. Korner and Dr. Leibel, are striving to better understand exactly what happens in the body and brain when people gain or lose weight. They ultimately hope to develop next-generation weight loss drugs that build on the success of Ozempic but with fewer side effects and more customizable options for individual patients.

“With obesity, I don’t think there will ever be a one-size-fits-all approach,” says Dr. Korner. “There are real complex, diverse factors influencing the development of obesity and I think there will be diverse, personalized medications.”

The Path to a Miracle Drug

When you’ve just eaten a meal, your body responds with a precise choreography of molecular steps: Signals in the form of hormones zip through your bloodstream to your brain, pancreas, liver, intestines, and fat cells. You feel full and lose the desire to eat more, and your body takes advantage of the rush of nutrients it has received.

In the early 1970s, researchers discovered that one of these hormones, GLP-1, had powerful effects on blood sugar and insulin levels. This makes sense since after a meal, the body needs insulin to break down the sugars rushing into the body. This discovery led to the development of Byetta (exenatide), which used an engineered, long-lasting version of GLP-1 to treat diabetes. In the early part of the 21st century, Byetta and its successors, including Trulicity and Ozempic (semaglutide), were successful in controlling blood sugar levels in people with type 2 diabetes, the most prevalent form, but clinicians also noticed something else: People taking these drugs often lost a lot of weight.

While it increased insulin levels, GLP-1 also made people feel full and slowed the emptying of their stomach, other natural reactions to the “I just ate” signal sent by the hormone. In 2021, the FDA approved semaglutide as a weight loss drug for adults with a high BMI even if they didn’t have diabetes. After Wegovy, the version of Ozempic formulated and marketed for weight loss rather than diabetes, was approved, a flurry of other drugs targeting additional gut hormones came onto the market. The new medications not only were more effective than previous weight loss drugs, but also garnered vastly more public attention.

“There have been weight loss medications available in the past but it’s almost like no one knew they existed,” says Tirissa Reid, MD, associate director of the Metabolic and Weight Control Center. “Now there is this huge hype around drugs like Ozempic and Wegovy. That hype has both positives and negatives.”

The new drugs carry side effects that can be quite severe, and researchers have numerous questions about their effects on the body and their long-term use. Some who take the drugs experience nearly constant nausea and others develop rarer complications like gallbladder or pancreas disease.

“We’ve had at least two patients in our clinic who are taking these drugs and have ended up in the emergency room because of uncontrollable vomiting, diarrhea, dehydration, and abdominal pain,” says Dr. Korner. “While I think these drugs are amazing, they’re not easy to use for many people.”

What’s more, the drugs aren’t always effective. In initial studies of semaglutide, participants lost an average of 15% of their body weight over the course of more than a year. If someone who weighs 300 pounds loses 15% percent of body weight, that person still weighs 255 pounds, obese for people of most heights. Half of all participants lost less weight, with around three in every 20 people losing less than 5% of their body weight.

These downsides and limitations of the new drugs are adding incentive to obesity researchers at Columbia to pursue other options. If they can understand the complex interplay of obesity, appetite, metabolism, inflammation, mood, and genetics, they may be able to find new and better ways to provoke weight loss.

The Monotony of Maintenance

While losing weight can seem like a daunting task, maintaining the same body weight ends up being harder for many people. That is true with the new generation of weight loss drugs.

Within a year of stopping Wegovy, most people will regain about two-thirds of the weight they lost on the drug, according to a 2022 study by the drug manufacturer. Similarly, people who took Zepbound (tirzepatide) for a year lost about 20% of their body weight but regained about 15% after a year off the drug.

That is in part because the human body is programmed to fight weight loss. In the 1980s, Dr. Leibel contributed to the discovery of leptin, a hormone secreted from fat cells and intricately linked to hunger and fullness. When someone loses fat, leptin levels drop and the body responds with increased hunger, a slower metabolic rate, and even changes to the brain that make food look more enticing.

“The body perceives fat loss as a threat to survival,” says Dr. Leibel. “And lower leptin levels signal the brain to eat more and expend less energy to rectify this threat.”

Weight loss drugs like Wegovy do not change this response to fat loss; people who want to continue feeling the loss of appetite induced by the drugs need to keep taking them. As soon as they stop the drugs, low leptin levels drive increased hunger and lower energy expenditure that promote weight regain. That means that the drugs either must be taken for life—like blood pressure and diabetes drugs—or other drugs will need to be developed to promote weight maintenance.

In a large new study, Dr. Leibel and colleagues at Columbia are following more than 100 people to try to understand why, after initial weight loss, some people have an easier time keeping weight off while others quickly gain it back. They suspect factors other than just leptin are at play.

“The idea is that whatever we discover about the physiology of weight regain will, hopefully, be directly applicable to trying to prevent or mitigate that weight regain,” says Dr. Leibel.

Ironically, it can be just as hard to gain weight as to lose it. If you ask a healthy, lean person to gain a hundred pounds, they might gain the first 10 or 20 pounds easily but then struggle to keep eating as their appetite decreases over time, says Anthony Ferrante Jr., MD, PhD, chief of preventive medicine and nutrition and co-director of the Naomi Berrie Diabetes Center.

“Regardless of whether you’re lean or obese, you generally stay within the same weight range in any given year,” says Dr. Ferrante. “The human body has this seemingly magical and mysterious way of matching your energy input and output without you having to think much about it.”

In 2018, Dr. Ferrante discovered that healthy mice fed extra food gradually eat less and less, and the effect is completely independent of the leptin levels in their body. He suspects that undiscovered hormone acts in opposition to leptin, fighting weight gain in the same kind of way that leptin fights weight loss.

“If we can identify this hormone, it may be very therapeutically beneficial,” says Dr. Ferrante. “We don’t think it would make you feel nauseated or completely turned off by food. Instead, it would be like a healthy person who eats a lot over the holidays but doesn’t end up permanently gaining weight. Their body subtly adapts, speeding up their metabolism and makes them a bit less hungry.”

A Focus on the Brain

Dr. Ferrante’s belief in a still-to-be-discovered hormone mediating metabolism shows just how much is still unknown about how the human body regulates food and weight. Today, in addition to studying what puts the brakes on weight gain, Dr. Ferrante’s lab studies the role of the human immune system in obesity. His studies have shown that in healthy people, 5% or 10% of the cells within fat tissue are immune cells; in patients with the most severe degree of obesity, however, more than half the cells in fat tissue are immune cells, and they trigger constant inflammation. Much is still unknown about how this inflammation may impact the rest of the body, but ultimately, all the systems in the body that play a role in metabolism and appetite are tied together in one place: the brain.

This is especially clear when patients with obesity undergo bariatric surgery. After the surgery, they are not only limited in what they eat because of physical changes to their stomach, but also have a reduced appetite. Recently, Dr. Korner began studies of how these patients’ brains change after surgery.

“I had a patient a number of years who said to me, ‘I know they operated on my abdomen but I feel like they operated on my brain,’” Dr. Korner recalls. “If we can understand why this happens for some patients, perhaps we can mimic it with a drug.”

Equally as important as the physiological aspects of obesity and appetite are the emotional and psychological ones. “Stress always impacts eating behavior, one way or another,” says Lori Zeltser, PhD, a researcher in the Naomi Berrie Diabetes Center. Using mouse models, Dr. Zeltser confirms what is already known: Severe stress, like losing a loved one, almost always results in loss of appetite. But what about more mild stress like a looming deadline or holidays with the in-laws? “Why the same stresses cause some individuals to eat more while others lose their appetites is still elusive. Uncovering the brain circuits regulating these opposing responses is a major focus of our lab.”

Dr. Zeltser has spent the past few years developing mouse models that reliably change how much they eat when under stress. Now, her lab is probing what cells and molecules in the brain make that happen. Her eventual goal is to find ways to manipulate those brain pathways, with implications for treating both obesity and anorexia.

“I hope the next generation of drugs can manipulate appetite and metabolism in ways that have fewer side effects throughout the body,” says Dr. Zeltser.

Similarly, Sabrina Diano, PhD, who directs the Columbia Institute of Human Nutrition, is taking a new angle to studying obesity, with the ultimate goal of drug development. Dr. Diano discovered that when mice eat a diet high in both carbohydrates and fat, immune cells in the brain get activated before nearly any other change in the body. She wants to know what triggers this change and whether altering it could treat obesity in humans.

“I want to know how the brain senses fats and sugars, how this affects brain cell function, and how that then affects whole-body metabolism,” says Dr. Diano.

Personalizing Weight Loss

For physicians at the Metabolic and Weight Control Center and elsewhere, finding the right weight loss drug for their patients can require many months of trial and error. If dozens of new drugs emerge in coming years, that trial and error could become even more drawn out—unless research also moves forward on how to hoose the best drug for each patient.

“Right now, we try the same kinds of drugs for most patients, and we can’t predict who is going to respond and who won’t,” says Sharon Wardlaw, MD, director of the neuroendocrine unit in the Department of Medicine.

Dr. Wardlaw, also a member of the New York Obesity Research Center, has collaborated with Dr. Korner to learn why certain weight loss drugs work better for some people and how to predict that ahead of time. In one study, they showed how different versions of a gene explain why some people lose weight on Contrave, an antiobesity drug approved by the FDA in 2014. They also discovered that brain proteins known to regulate body weight are present in the spinal fluid and that their levels can predict who is most likely to lose weight on Belviq (lorcaserin), a weight loss drug that was withdrawn from the market in 2020.

“There are real biological differences in terms of how people’s bodies respond to these different drugs,” says Dr. Wardlaw. “Two patients with breast cancer might get completely different treatments because of the molecular characteristics of their tumors, and I think that’s where the field of obesity treatment is heading as well.”

Dr. Korner and Dr. Wardlaw hope to apply some of their studies of Contrave and Belviq to the newer generation of weight loss drugs, including semaglutide, to pin down whether genetic or molecular differences in patients could guide treatment approaches.

Access for Everyone

At the Metabolic and Weight Control Center, Dr. Reid says, about 40% of the prescriptions she writes for weight loss drugs are denied by patients’ insurance.

“It’s incredibly frustrating,” she says. “We’re not treating patients who want to lose five pounds for a wedding. These are people who are dealing with significant extra weight and often have other medical conditions and risks related to it.”

Obesity is a major contributor to diabetes, hypertension, dyslipidemia, and cancer. “Even modest weight reduction reduces the first three and probably cancer as well,” says Dr. Leibel. “This alone is rationale for increasing access to effective drugs.”

Today, Medicaid and Medicare, as well as many private insurance plans, do not cover weight loss drugs for obesity alone, which is considered a cosmetic issue, although insurance covers many of the same drugs to treat diabetes. One of her patients, Dr. Reid says, weighs more than 500 pounds and has a variety of health issues including severe reflux, high cholesterol, and sleep apnea, but not diabetes. His insurance denied coverage of Wegovy.

Since the drugs cost about $1,000 per month, most people cannot afford the out-of-pocket cost.

The New York Times reported last year that prescriptions for Ozempic and similar drugs were highest in New York’s wealthiest and whitest neighborhoods. Dr. Reid suspects those inequities largely stem from the cost and poor insurance coverage of the drugs but could also relate to other challenges in treating obesity. People with lower socioeconomic status tend to have less access to primary care medicine and, when they do seek health care, they often have more urgent issues to deal with, leaving little time to discuss weight loss.

These inequities, researchers stress, are another reason that more effective and diverse weight loss drugs, like those in the basic research pipeline at Columbia, are needed. The more evidence-based drugs exist, the more likely policies can help promote insurance coverage and price caps. Drugs with fewer side effects and clearer prescription guidelines also can make it easier for physicians who do not specialize in obesity medicine to prescribe the drugs and quicker for patients to find the right drug.

“We’re just at the tip of the iceberg,” says Dr. Reid. “We have just a few prescription obesity drugs now, which pales in comparison to the hundreds of hypertension or cholesterol drugs that exist. We need to keep growing the armamentarium so we can help more patients.”