New weight-loss drugs could shift the scales

At the end of the summer, Steve Johnson became one of the legions of Americans curious about a new weight-loss drug called Wegovy (semaglutide). The medical device salesperson had been fasting intermittently and was exercising more, but the roughly 60 lb (27 kg) he wanted to lose weren’t coming off.

He researched Novo Nordisk’s data for the drug, was impressed by the average 15% weight loss seen in clinical trial participants, and in August called his doctor.

The once-weekly shot of Wegovy might be the boost he needs, he told his physician. That is, if he could get his hands on it.

“It’s been back-ordered,” Johnson says. “At first, it was a couple of weeks, and then they drew it out, and then I heard the end of September.”

Novo Nordisk was unprepared for the demand for Wegovy, which the US Food and Drug Administration approved in early June. Social media groups are filled with people sharing tips on places that have doses in stock and people lamenting when they can’t find the drug. Company officials say it might take until the end of the year to clear the backlog.

Many industry, government, and academic scientists who study metabolism and appetite say the clamor for Wegovy demonstrates the need for safer and more-effective weight-loss drugs. In a field plagued by drugs with dangerous side effects and product recalls, doctors have been hesitant to prescribe these products—and companies have been nervous about investing in developing new ones. The emergence of Wegovy and a handful of other drugs over the past few years coincides with a shift in the medical complex's and pharmaceutical industry’s description of people who have obesity, a controversial word that is defined by the US Centers for Disease Control and Prevention as anyone with a body mass index (BMI) of 30 or higher. In the past, obesity was framed as a behavioral issue. Today, it is seen by many as a chronic disease that, because of links to other conditions like diabetes, heart disease, and high blood pressure, warrants continuous treatment.

“The problem with obesity is that it’s a chronic illness and that it’s relapsing,” says John Sharretts, an endocrinologist who is the deputy director of the FDA’s Division of Diabetes, Lipid Disorders, and Obesity. “People lose weight and they regain and it’s complicated. The goal of weight loss is the long-term reduction of excess fat with the purpose of reducing those health consequences.”

Wegovy is one of five drugs on the market for what US regulators call “chronic weight management.” Pharma companies’ pipelines, once devoid of anything related to weight loss, are now flush with drug candidates.

“It’s actually quite interesting to watch the field slowly go back into the obesity area, which was clearly for quite a few years a no-go zone, particularly with Big Pharma,” says Philipp Scherer, a metabolism scientist at the University of Texas Southwestern Medical Center.

The financial potential of a safe and effective weight-loss drug is staggering. About 42% of people in the US meet the CDC’s definition of obesity. And people with lower BMIs who have metabolic diseases are eligible for either Wegovy or a shorter-acting version of the drug called Saxenda (liraglutide) that was approved in 2014. Chronic weight management means years, if not decades, of treatment. Saxenda, which is taken daily and typically offers more modest weight loss, brought in more than $900 million in sales in 2020.

But this surge in development runs counter to another shift—one that says being fat is not a disease. A 2016 study from the University of California, Los Angeles, suggests that 29% of people who are medically defined as obese are otherwise metabolically healthy. Ragen Chastain, a public speaker and writer on the subjects of fat discrimination and the pathologizing of weight, says fat is a normal state of being and that calling it a disease is stigmatizing.

“This has become something that’s driven tremendous profit. In terms of what it’s done for the community—people who have been labeled—it’s driven stigma, oppression,” she says.

Decades of imperfect pills

The history of weight-loss drug development is a tumultuous one. From its earliest days, products have been marred by side effects ranging from high blood pressure to death.

The problems started in the 1930s, when 2,4-dinitrophenol (DNP) became one of the first chemicals used for weight loss. DNP is a mitochondrial uncoupler that works by interfering with the reactions that create and store energy in our bodies. With no place to go, the energy is released as heat, leading to weight loss.

It can also lead to uncontrolled increases in body temperature, and the drug has never been approved by modern-day regulatory authorities. People can still buy DNP on the internet, though, and between 2001 and 2010, a dozen people died after taking it, including a 28-year-old man using the drug as a bodybuilding tool. His internal body temperature peaked at 106 °F (41 °C).

In the 1960s, FDA-approved weight-loss drugs were all derivatives of amphetamine, which suppresses appetite. One of those pills, phentermine, is still widely prescribed, says physician Daniel Bessesen, a researcher at the University of Colorado Anschutz Medical Campus. People taking phentermine on average lose between 5 and 10% of their starting weight. For people whose insurance won’t cover drugs like Wegovy, it’s the best available option, Bessesen says.

But this class of drugs can be addictive and cause dangerously high blood pressure, so the drugs can be taken for only a few weeks at a time.

The 1970s and 1980s were a long dry spell for new weight-loss drugs. That ended in 1996, when the FDA approved dexfenfluramine as a stronger version of the previously approved weight-loss drug fenfluramine. Both drugs were part of a class of appetite suppressants called serotonergic anorectics, which work by lowering the amount of serotonin in the brain. Doctors had previously paired phentermine with fenfluramine, in an infamous combo dubbed fen-phen.

Then came reports of heart valve damage in people taking fen-phen. In 1997, the FDA pulled fenfluramine and dexfenfluramine off the market, marking the beginning of a merry-go-round of regulatory rejections, approvals, and withdrawals for weight-loss drugs. Meridia (sibutramine) was approved by the FDA in 1997 and then withdrawn from the market in 2010 because of side effects that included an increased risk of heart attack. Rimonabant, the first blocker of cannabinoid receptor 1 for weight loss, was approved in Europe in 2006 but pulled 2 years later after the drug was linked to thoughts of suicide. Belviq (lorcaserin), a small molecule that stimulates a serotonin receptor, was pulled in 2020 after 8 years on the market because it was shown to increase the risk of cancer.

Nadia Ahmad, the medical director for Eli Lilly and Company’s obesity product development, says this long string of safety issues and product failures is why the field has been considered such a gamble for pharma companies. “You have one drug that goes off the market for whatever reason, and it really shuts down for like a good decade any further pharmaceutical development,” she says.

The troubled history has necessarily raised the regulatory bar for weight-loss drugs. Today, on top of requiring evidence that a new drug can allow someone to maintain a weight loss of 5–10% of their starting weight for a year, the FDA also wants to see longer-term studies proving it is safe.

Safety also became more critical as the field shifted from acute to chronic use, a transition that began in 1999 with a new drug called Xenical (orlistat). The pill works by blocking fat from being absorbed by the body. While it can cause constant diarrhea for some, it was the first of several drugs allowed to be taken long term.

Older weight-loss drugs not only were prone to dangerous side effects but also didn’t work as well as people wanted. Losses were modest—around 5–10%—and people typically regained weight as soon as they stopped taking the drugs. This weight cycling is a source of mental health issues, as people internalize the failure of those products, Chastain says.

“There is something wrong with an intervention that has the exact opposite of the intended effect the majority of the time,” she says. “What the weight-loss industry has done brilliantly is to take credit for the first part of that biological response where people lose weight short term and blame their clients and get their clients to blame themselves for the second part of the same biological response—when they gain the weight back.”

Not repeating history

Companies marketing and developing new drugs think they can overcome those long-standing issues plaguing the field. Part of their confidence comes from the widespread use of their drugs for different diseases. The active compounds in Saxenda and Wegovy, for example, have been sold under different formulations to treat diabetes since 2010 and 2017, respectively. That means there is a lot of safety information already available on those products, the FDA’s Sharretts says. He uses Wegovy as an example: in the years of semaglutide use in people with diabetes, safety issues have been minor. To collect more data on the drug’s heart safety, Novo Nordisk is testing Wegovy in people who are clinically classified as obese and who have already had a heart attack, according to Jason Brett, who leads medical affairs for Novo Nordisk’s obesity and diabetes programs.

But the FDA would like more general heart data for weight-loss drugs, Sharretts says.

“I think that’s something that the FDA would like to see and, I think, that the weight-loss community would like to see,” he says.

Saxenda and Wegovy are in a class of drugs called GLP-1 agonists, which mimic glucagon-like peptide 1, a gastrointestinal hormone that helps regulate glucose. Nearly all GLP-1 agonists approved in the US for diabetes also induce some weight loss. But to date, Wegovy has performed the best: in a Phase 3 trial, people given Wegovy alongside lifestyle counseling lost about 15%, on average, of their starting weight, compared with about 2.5% weight loss in people given a placebo and counseling.

Some people in the treatment arm lost much more. At the end of the study, nearly 35% of the 1,059 people who completed the trial lost at least 20% of their body weight—a level no other weight-loss drug has achieved. These numbers motivate Johnson­—he hopes this once-weekly drug will allow him to lose as many pounds as he possibly can.

But about 20% of the people in the treatment arm didn’t finish the trial. About half those folks dropped out because of side effects like nausea, vomiting, diarrhea, and constipation. A smaller group of people reported more serious issues, like cardiovascular problems, psychiatric issues, and gall bladder and liver dysfunction.

The GLP-1 system is one of many metabolic targets that researchers have explored for weight loss. Significant effort has gone into exploiting hormones known to modulate appetite, most notably PYY (peptide tyrosine tyrosine), leptin, and ghrelin. So far, targeting the GLP-1 receptor has been the most effective strategy. Few drugs based off the other targets have made it into clinical trials.

The failures to develop drugs to modulate other hormones reflect the complexity and redundancy of the biochemical signals that control our need to eat, says Linda Shapiro, the chief medical officer of Rhythm Pharmaceuticals, a company that specializes in weight-loss drugs for people who have genetic mutations that cause weight gain. “There’s not one single highway because, of course, if there was a breakdown in that highway, we could all starve to death,” she says. “We’re really at the infancy of understanding obesity and, certainly, understanding genetic obesity.”

Rhythm’s weight-loss drug Imcivree (setmelanotide) is a peptide that modulates the activity of another metabolic target, the melanocortin receptor 4. The drug is for people with serious genetic defects in the pathways that signal that a person is full, including people with leptin receptor deficiencies. People with these mutations have what amounts to an uncontrollable physiological need to eat, because their bodies cannot register that they are full.

Some of the most interesting targets in potential weight-loss drugs are analogs of hormones that act in hunger- and satiety-related metabolic pathways, says Indiana University Bloomington chemist Richard DiMarchi, a former Lilly researcher who sold his diabetes start-ups to Novo Nordisk. He develops small proteins for weight loss and to treat metabolic diseases.

These proteins include glucose-dependent insulinotropic polypeptide (GIP), an incretin that, like GLP-1, spurs insulin secretion. Another is amylin, a satiety hormone missing in some people with diabetes. And Brett says that Novo Nordisk has begun safety studies of a combination of the amylin analog cagrilintide with the highest approved weight-loss dose of semaglutide.

Lilly and Pfizer both have small molecules in development to stimulate the GLP-1 receptor. And a few companies are exploring small-molecule mitochondrial uncouplers despite the health risks of DNP, another drug in that class. Josua Jordi, CEO of the start-up EraCal Therapeutics, which is focusing on weight-loss drugs, calls these risks the “dark cloud” of DNP.

And with the popularity of drugs like Wegovy, scientists are trying to engineer novel combination peptides that could promise equal or greater weight loss.

Among the most promising, DiMarchi and others say, is Lilly’s tirzepatide, a single molecule that modulates the receptors for two hormones, GIP and GLP-1. Lilly’s Ahmad says the peptide appears to affect more than one food-related pathway: in preclinical studies, animals given tirzepatide are less hungry and seem to use more energy. “Most of the pharmacological therapies, they have all been focused on food-intake reduction. And there hasn’t been a focus on energy expenditure,” she says.

Lilly is developing the peptide for both type 2 diabetes and weight loss. Although the company has yet to show late-stage data from its weight-loss trials, studies in people with type 2 diabetes suggest that tirzepatide can elicit twice the weight loss as those taking the drug Ozempic, the formulation of semaglutide used to treat diabetes. But those results come with the caveat that participants were taking semaglutide doses for diabetes, not the much higher dose prescribed for weight loss.

AstraZeneca is also developing a dual-agonist drug for diabetes that industry experts are watching because studies suggest it, too, spurs weight loss. Called cotadutide, the molecule works on both the glucagon and GLP-1 receptors. Lutz Jermutus, who leads the team at AstraZeneca focused on metabolic diseases, downplays that effect and says the company isn’t looking to turn the drug toward weight loss right away. Instead, the company’s focus is on expanding into diseases like nonalcoholic steatohepatitis (NASH) and chronic kidney disease.

Wegovy isn’t the end of the road for Novo Nordisk, Brett says. The company is also testing whether its oral version of semaglutide, marketed as Rybelsus, can cause weight loss, and it is heavily invested in combination drugs, including semaglutide and an amylin analog. Brett, like others, says that the burst of activity in the development of weight-loss drugs is promising.

“The future’s bright for drug development, I think, for new projects and new targets,” he says.

In addition, at least two start-ups are focusing on weight loss. Rivus Pharmaceuticals is trying to tackle mitochondrial uncoupling safely and effectively. And EraCal is looking for completely new appetite-related pathways to drug.

DiMarchi agrees with Brett. “I think this is going to be one of the greatest successes of the pharmaceutical industry, of academics, of biotechs,” he says of weight-loss drugs like Wegovy and what is coming down the pike. “It was not that long ago when some very respectable, informed individuals were telling us this is not achievable, that you’re fighting survival mechanisms.”

Shifting the burden

Kerrie Cliett is a housekeeper and gig worker in Tennessee who says that because of her job, she is literally climbing stairs all day. She started gaining weight when she started a family, lost some of it on one drug, and then gained it back. After having her last child, she weighed more than she ever had in her life. Her doctor put her on something different over the summer. It didn’t work.

It’s that roller coaster of weight loss and regain that Chastain says is so harmful to people.

Now, Cliett is taking Wegovy. She lost 13 lb (5.9 kg) in the first month.

Cliett says that since she’s gained weight, she’s felt people are less kind to her than they used to be.

“I’ve said time and time again, one of the main motivators for me wanting to lose weight is that people treat you differently. Obviously, feeling better and being healthier is a wonderful thing, but it’s very difficult when people treat you like a different person,” she says.

Ahmad, Bessesen, and other doctors who spoke to C&EN about treating people who want to lose weight say that these feelings, along with the health issues affecting people who are at higher weights, are why they think it’s important to consider clinically defined obesity a disease. Calling it a disease shifts the blame from a person’s behaviors to dysfunctional biochemistry, Ahmad says.

But Chastain disagrees and says that pathologizing fat is the issue. “The fact that people who are higher weight get a health issue more often cannot be led to say, ‘Well, then their body size is the problem and then making them thin will solve the problem,’ ” she says.

These two views create a disconnect, and it’s one that is exacerbated by our body image–obsessed culture, says Sarah Nutter, a weight stigma and body image researcher at the University of Victoria. She agrees that weight is not a good proxy for health and is frustrated by the number of researchers and doctors who tell their patients that losing weight will alleviate other metabolic diseases. She says that for as many people who will feel stigmatized by calling fat a disease, there are those who won’t be.

“I think that declaring obesity a disease can feel freeing for some people to feel like it’s not their fault, and I think other people do feel incredibly stigmatized by it. And that’s the nuance right?” Nutter says. “People aren’t going to feel the same way about it. And until we are able to have messy conversations about this, do a better job of bringing in multiple perspectives and multiple truths into the conversation, people are going to be left out.”

In the meantime, people like Cliett say they might stop taking Wegovy when they reach their goals. Doctors argue that losing just 5–10% of starting weight leads to health benefits for clinically obese people, which Cliett can attest to. And Wegovy, tirzepatide, and potentially newer drugs are pushing average weight loss to 15% and higher. But for many people, that’s not enough—their goal is to be thin. That’s something Bessesen and other doctors who spoke to C&EN say they think about regularly.

“People want to look like they did when they were 16. And there’s no treatment, short of bariatric surgery, that’s going to give them that,” Bessesen says. “If they lose 5% of their weight, only 5%, their risk of developing diabetes goes down by 60%. But people aren’t excited by that.”

Chastain goes back to the prickly issue of maintenance. People in the Phase 3 study of Wegovy saw their weight loss taper significantly around week 60. And when people stopped taking the drug, they started regaining weight, Novo Nordisk’s Brett says. The company is testing longer treatment periods and will release more data on maintenance in a few weeks.

Why weight comes back after therapies and lifestyle changes is the big black box of the field, UT Southwestern’s Scherer says. “No one has been able to touch that dial or to even define it in molecular terms—what the set point is and why is the set point so firm.”

For these long-term drugs like Wegovy, the coming years will be key to understanding whether people can safely maintain their weight loss.

After weeks of trying to get the entry-level dose of Wegovy, Johnson, the medical device salesperson, ended up asking his doctor to prescribe Ozempic instead. It’s still semaglutide. He’s been on a very low dose of Ozempic for 3 weeks, and so far, he’s lost 1 lb (0.45 kg). Johnson says he hasn’t experienced fat stigma the way Cliett says she has, but for him, losing weight isn’t a health issue alone, even if it’s his primary reason for trying to lose weight.

“Both parents died at 68 from [myocardial infarction]. Neither was overweight,” he says via text after a long spate of work travel. “A big thing is to fit in clothes better. A lot of people will call you ‘big guy.’ Not my favorite thing to be called.”

The question of whether being fat is a disease will continue to rage, even as new drugs hit the market and people jump to them as they have Wegovy. The drugs seem to be getting safer, but Nutter says our thin-at-all-costs society still drives people to tolerate some of the miserable side effects of Wegovy—nausea, vomiting, and constipation—day after day, in order to lose weight. And on top of that are Chastain and the growing movement to end fat discrimination who question why these drugs have to exist at all.

“Because of the way obesity has been created,” Chastain says, “we see a situation where it’s reasonable to risk people’s lives and quality of life to make us thin.”