Corinne Currier was an active kid growing up in Gardner, Kansas, where she acted in plays and sang in choirs and participated in the Special Olympics, but she was always a little overweight. When the now 30-year-old artist gained more weight in high school, her mother placed some of the blame on herself for being so focused on dealing with her daughter and son’s autism that she was not paying enough attention to their eating habits. Smith bought a treadmill for her daughter, and the whole family began eating more fruits and vegetables and fewer fried and fast foods. 

But despite using the treadmill, counting her steps and changing her diet, Currier’s weight continued to creep up over the years. When it reached 288 pounds in 2021, her primary care doctor referred her to the University of Kansas Weight Management Program. In addition to recommendations for healthy nutrition and physical activity, she was prescribed semaglutide, known by its brand name, Wegovy, one of the popular, if hard to obtain, new weight loss drugs.

Anyone who has paid any attention to health news — or celebrity news — for the past couple of years can guess what happened next.

“It helped me,” Currier said. “I’ve lost 100 pounds.” 

Cathleen Beaver, M.D., Currier’s physician at the weight management program and assistant professor of medicine at the University of Kansas Medical Center, noted that while Currier worked hard on lifestyle changes to achieve her success, the drug was a critical tool.

“Although many patients are able to lose weight with lifestyle changes alone, we often see more success with the addition of these medications,” Beaver said. “That’s because medications such as Wegovy target the underlying drivers of the disease of obesity.”

Treating Weight First

Unprecedented. Revolutionary. Game-changing. These are the kinds of adjectives commonly used to describe this new class of drugs specifically approved by the U.S. Food and Drug Administration (FDA) to treat obesity, which in addition to Wegovy (semaglutide) includes Zepbound (tirzepatide).

These drugs are so effective at helping people lose weight that the drug companies that make them — Novo Nordisk for Wegovy and Eli Lilly for Zepbound — cannot keep up with the demand. Other pharmaceutical companies have dozens of similar drugs in development to try to claim a piece of the market.

It is no wonder that so many people want them. Over 30% of Americans have obesity, defined as a body mass index (BMI) of 30 or higher, according to the Centers for Disease Control and Prevention. Another 30% are overweight, defined as a BMI of at least 25. Obesity increases the risk for many diseases, including Type 2 diabetes, liver disease, stroke, heart disease, sleep disturbances, joint pain and metabolic syndrome. Linked to 13 kinds of cancer, obesity is expected to surpass tobacco use as the biggest preventable cause of malignancies.

Time spent treating chronic conditions is the reason Beaver became board-certified in obesity medicine when she was on the faculty at Dartmouth Health.

“I believed focusing on obesity first could significantly improve the health, wellbeing and metabolic disease processes of patients with underlying weight issues,” Beaver said.

A Venomous Happy Accident

Historically, treating weight issues has been mostly a matter of getting patients to eat less and move more. Bariatric surgery can be effective, but is often viewed as an invasive, last-resort measure. And the history of drug treatment for obesity is marked by inadequate effectiveness and safety problems.

In the 1940s and 1950s, diet pills containing amphetamines and diuretics caused dozens of deaths. Fen-phen, the hyped miracle drug for weight loss in the 1990s that combined two appetite suppressants (fenfluramine and phentermine) was taken off the market after being linked to heart valve damage. In 2010, the appetite suppressant Meridia (sibutramine) suffered a similar demise because it heightened the risk for cardiovascular disease and stroke. Since then, pharmaceutical companies by and large had given up on obesity medications.

Wegovy and drugs like it were, in fact, an accidental discovery — or at least their value for weight loss was. They are the result of research on Type 2 diabetes beginning in the 1980s, when a Canadian endocrinologist named Daniel Drucker found that a gut hormone known as GLP-1 (glucagon-like peptide-1) regulates blood sugar by triggering the release of insulin in the pancreas. Drucker and other researchers wanted to convert GLP-1 into a drug for Type 2 diabetes.

The problem was GLP-1 breaks up and disappears before reaching the pancreas when injected.

To solve this problem, scientists turned to a lizard. Specifically, they looked in the venom of the Gila monster, the largest lizard in the United States. Gila monsters were of interest to scientists because of their ability to go for extended periods of time without food. One hormone in their venom, Exendin-4, had been shown to regulate blood sugar. That hormone was then found to be structurally similar to GLP-1, but it did not break down quickly in the body, making it the perfect candidate for a Type 2 diabetes drug.

And that is what happened. Exendin-1 became the basis of the synthesis of the new drugs, known as GLP-1 agonists, that mimic GLP-1 activity, including sending signals to the brain that a person is full and slowing down digestion.

The first GLP-1 agonist, Byetta, which was approved by the FDA to treat Type 2 diabetes in 2005, had to be injected twice a day. In 2010, Novo Nordisk released Victoza (liraglutide), which required just one daily injection. It also had a side effect: slight weight loss. When Ozempic, a weekly injection of another GLP-1 agonist called semaglutide, was approved to treat diabetes in 2017, the resulting greater weight loss for patients led to its off-label use for weight control. Nova Nordisk answered the call by creating a rebranded version of semaglutide for weight loss only. That was Wegovy, which the FDA approved in 2021.

On the highest dose of Wegovy, patients can expect to lose an average of 17% of their total body weight when used in combination with lifestyle changes. In the fall of 2023, the FDA approved Zepbound, which is dubbed a “dual agonist.” (Mounjaro is the same drug but approved for Type 2 diabetes.) In addition to GLP-1, Zepbound acts on a second gut hormone known as GIP (gastric inhibitory polypeptide). At the highest dose of Zepbound and with lifestyle changes, patients can expect an average weight loss of 22%.

Bariatric surgery also results in changes in gut hormones, but those effects weren’t well understood until recently.

“Twenty years ago, we did not have a complete understanding of the mechanisms of weight loss with the bariatric operations,” said Jennifer McAllaster, M.D., a bariatric surgeon and assistant professor of surgery at KU Medical Center. “We now know that the true power of these operations lies in the changes of the gastrointestinal hormones as a result of surgery.”

The Business of Medicine

Further research has shown that these medications also offer health benefits beyond weight loss. In March 2024, the FDA approved Wegovy for a new use: lowering the risk of heart attack and stroke in adults who have cardiovascular disease and are overweight.

All these benefits are remarkable, of course. They are the reason that Science magazine named these medications the Breakthrough of the Year for 2023. And if early efficacy (how well the drugs work) were the only criterion, researchers and physicians could stop right now and write off obesity as a disease cured and a public health problem solved. But the business of medicine and the disease itself are more complicated than that.

The most glaring issue is cost. These drugs, which are typically administered with a pen-injector, are very expensive, typically costing around $1,000 a month. And because of the high price, the newness of the drugs and the lack of data on their long-term effectiveness, they often are not covered by insurance. This means that low-income people and those in marginalized racial and ethnic groups, who are disproportionately affected by obesity, but not likely to have adequate insurance coverage, often cannot access them.

The cost problem is compounded by the shortages of the drug created by the demand. Around the time of the Academy Awards in 2024, Eli Lilly ran an Oscars-themed TV commercial asking people without much weight to lose, often Hollywood stars and other celebrities who can afford to spend a couple thousand dollars to drop 15 pounds, to refrain from using these drugs so that people like Currier with more serious health problems can get them.

Using these drugs for weight loss is also criticized because of the idea that doing so takes them away from people who need them for diabetes. One mitigating factor is that the FDA approvals of Wegovy and Zepbound for weight loss have reduced the off-label use of Ozempic and Mounjaro, and insurance coverage for off-label use is also less reliable. But as Beaver noted, when a manufacturer has a shortage of the drug approved for weight loss, that means they may also have a shortage of the equivalent drug approved for diabetes.

“We have patients with Type 2 diabetes receiving treatment with these medications who lose a significant amount of weight and see improvements in their diabetes, sometimes to the point of remission, and then they are unable to fill their Ozempic or Mounjaro prescriptions because of supply issues,” said Beaver. “If these patients are also insulin dependent, they may then have to resume higher doses of insulin or risk having poorly controlled diabetes, both of which can have a negative effect on their overall health. Pharmacotherapy shortages are unfortunate. We would hope patients undergoing treatment could receive their medications dose reliably.”

Clinical Considerations

Substantial weight loss also raises clinical concerns. When people shed pounds through diet and exercise without medications, lean mass accounts for 15% to 20% of their weight loss. For reasons that are not yet clear, when people take the new medications, that percentage jumps to as much as 40%. John Jakicic, Ph.D., professor of physical activity and weight management at KU Medical Center, noted that lean mass includes more than muscle, and he is conducting research to ascertain how much muscle mass is actually lost.

"The difference between these medications and previous weight loss medications is that they target the hormonal abnormalities that are associated with excess weight, in addition to providing appetite suppression."

- Cathleen Beaver, M.D.

The drugs also carry a small risk of pancreatitis and are not recommended for people with a history of that disease. These medications are also contraindicated in patients who have a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2 (MEN2) syndrome, which can cause tumors in the endocrine system. Beaver said she also would not prescribe them for people with moderate to severe gastroparesis, which impairs the function of stomach muscles.

There is also a small percentage of people who lose very little weight on these drugs. Beaver said in her experience, the vast majority of people who do not lose weight on the drugs have some other contributing factor, such as taking medications that have weight gain as a side effect. Most of the time, though, the problem is that the patient cannot tolerate the medications’ most common side effects, which are nausea and constipation. These side effects, which typically get better over time, usually can be avoided or lessened by consuming smaller portions, avoiding fatty and processed foods, and focusing on lean proteins, whole grains and fruits and vegetables.

Bradley J. Newell, Pharm.D., assistant dean and clinical associate professor at KU School of Pharmacy, pointed out that these drugs are not necessarily appropriate for everyone looking to lose weight and must be considered on an individual basis.

“If there is a patient with a BMI, of, say, 28, and no additional risk factors, but they haven’t really looked at modifying their diet, but they do have concerns about binge eating or something of that nature, there are other medications that we can use in those scenarios,” said Newell, who also manages these obesity drugs for patients as an ambulatory care pharmacist. “Another thing we like to do is find out what the patient can achieve on their own before trying these medications. And if we do prescribe these medications, we can’t stop doing these other things. We always have to be mindful of our diet, we always have to be mindful of exercise, we have to be mindful of the other medications we're taking.”

This raises an important point often missed by the public about these drugs. They were never intended to be a panacea, but a tool. What people eat and how much they move still matters. As Jakicic noted, the FDA did not approve these drugs to be used in place of lifestyle changes.

“If you read the insert with these medications, it says that they should be used as an adjunct to lifestyle. And that lifestyle includes diet and activity,” he said.

Newell puts it more bluntly: "You can't out-medicate poor exercise or diet choices. If those are not fixed, the medications won't really help."

The Blame Game

In addition to being the most effective non-invasive treatments ever devised to fight obesity, these drugs have the potential to do something even more fundamental to obesity care: changing the narrative on body weight and bringing the idea that obesity is a chronic condition, just like high blood pressure and diabetes, into the mainstream.

Obesity as a chronic disease is not a new idea, at least not for the medical community. The American Medical Association recognized obesity as a chronic disease in 2013. The public, however, as well as insurers, have been slower to change their view. It wasn’t until March 2024 that Medicare announced it would cover weight loss drugs for the first time, but only if the patient has another condition in addition to the obesity. Meanwhile, people with obesity are still subject to public judgment. Being overweight is often regarded as the result of a lack of willpower, a behavioral problem if not a downright character flaw.

"Obesity is a disease, and there would be no other disease where we would say treatment is a cop-out."

- John Thyfault, Ph.D.

These attitudes are why some people are dismissing these drugs as a lazy cop-out, an easy way to lose weight without getting off the couch and onto the bike and just saying no to the Oreos and Chicken McNuggets. They are also the reason that Oprah Winfrey, who takes a GLP-1 agonist (she won’t reveal which one), titled her primetime TV special on these drugs, “Shame, Blame, and the Weight Loss Revolution.”

Felicia Steger, Ph.D., an assistant professor of dietetics and nutrition at KU School of Health Professions who teaches a course on obesity, said that she even encounters this bias in her classroom.

“Everyone immediately thinks of the lifestyle contributors to obesity,” she said. “But in reality, there's also a strong genetic contribution, a strong environmental contribution and hormonal contributions, which are mostly outside the control of the individual.”

John Thyfault, Ph.D., exercise physiologist, director of the KU Diabetes Institute and co-principal investigator for the Kansas Center for Metabolism and Obesity Research, objected to the idea that taking these drugs is a cop-out.

“It’s ridiculous. Obesity is a disease, and there would be no other disease where we would say treatment is a cop-out,” he said.

Beyond Our Control

To be sure, many people with a bias against the drugs on principle are simply reacting according to what they have been taught for decades, that weight is a simple function of two things: calories taken in by eating, and calories expended via exercise. But it turns out that there are aspects of obesity that a person cannot control.

And many of those are the hormonal changes that happen when a person becomes overweight or obese. When people have enough excess weight, their gut hormones, including GLP-1, stop working properly, and metabolic function becomes dysregulated.

“And then the body really tries to defend whatever weight it's at,” said Thyfault. “So, it's really hard to lose weight and to maintain weight loss.”

Currier would understand this.  Through the KU weight management program, she was diagnosed with insulin resistance, which means that her body did not respond as it should to insulin, a hormone in the pancreas that is essential for regulating blood sugar levels. This was one reason it was hard for her to lose weight by diet and exercise alone.

These drugs are the first medications to address this kind of metabolic dysregulation in people who are overweight.

“The difference between these medications and previous weight loss medications is that they target the hormonal abnormalities that are associated with excess weight, in addition to providing appetite suppression,” Beaver said.

There is another intriguing thing these drugs seem to do, and that is silence food noise, the internal chatter that drives many people to make brownies at 10 o'clock at night. Newell said he has had patients report to him how much easier it is to stop eating once they are on the drug.

“One of my patients told me, ‘I would just eat and eat, but now with the medication, I’m like, I don’t need to eat; I’m good.’ So it’s like the drug turned on a switch that says, ‘you’re regulated with your food intake, and you don’t need any more,’” he said.

“Our appetite regulation system in our brain is pretty complex,” Beaver said. “There’s the part of the brain that controls the appetite and drives our hunger, but we have another area in our brain that regulates pleasure or reward-seeking behavior. These two areas communicate with each other to manage hunger, cravings and appetite. That’s why with patients on the medication, we may see an improvement in not just appetite, but also the cravings that drive unhealthy food choices.”

By addressing the biological drivers to eat that are different in people who don't have that same drive, these drugs help to level the playing field, Jakicic noted. “And then lifestyle changes can do what they need to do.”

This doesn’t mean that after that playing field is leveled and weight is lost, the game is over. For one thing, statistics already show that once people are off the drugs, many regain the weight. That is one reason that some people may need to take these medications indefinitely.

It is yet another aspect of these medications that is uncertain. It’s not yet clear if insurers will pay for these drugs for life, to say nothing of the clinical effects of these drugs when they are taken for life.

“We don't have data yet on the long-term effects of this newer generation of medications for weight loss in patients with obesity,” said Beaver, who also noted that GLP-1 drugs have been taken safely for diabetes for nearly 20 years. “These medications are very popular. There are very few medications that come out of the starting gate like this and just take off. As a physician, that does concern me.”

Science Marches On

Researchers are investigating other weight loss drugs as well, including a "triple-agonist" drug that targets a third hormone and promises even more weight loss is in the pipeline, as is a GLP-1 agonist in pill form.

Despite their effectiveness, there is still much left to learn about these drugs. As Thyfault points out, it is believed these GLP-1 agonists do more than researchers know, but it isn't known what those mechanisms are yet. As Beaver noted, it is an unusual situation in which the clinical world is outpacing scientific data.

But science marches on. Trials are underway to see how effective these drugs are in treating conditions such as fatty liver disease, sleep apnea, kidney disease and Alzheimer’s disease. And the ability of these drugs to quell the pleasure-seeking portion of the brain has sparked an interest in using them to treat drug, alcohol and other addictions.

How do
GLP-1 drugs work?

BRAIN
Reduces hunger signals and reduces food cravings

STOMACH
Delays gastric emptying and promotes a feeling of being full

PANCREAS
Decreases blood sugar and
increases insulin production

LIVER AND INTESTINE
Mimics natural gut hormones and decreases glucose release

Beaver is also conducting research with Carol Fabian, M.D., and Kristy Brown, Ph.D., at The University of Kansas Cancer Center to look at the effect of these medications on lowering the risk of breast cancer in patients at high risk for the disease through the drugs’ ability to reduce inflammation. Jakicic and his colleague, senior scientist Renee Rogers, Ph.D., are launching a study that will measure muscle mass and muscle quality in response to weight loss induced by GLP-1 weight loss medications and determine what effect adding exercise has on the muscle.

And in Gardner, Currier continues to take her Wegovy and make healthy food choices. For exercise, she especially enjoys dancing, especially to old music videos.

“I just turn on MTV Classics and start dancing,” she said.

She also enjoys getting to buy new clothes, including a pink dress she wore at a party for her 30th birthday. More importantly, both her asthma symptoms and her bloodwork have improved markedly already since she started losing weight.

“She’s just so much healthier,” her mother said.