Daily Briefing

Weight-loss drugs: The 'how,' the 'who,' the risks, and what they could mean for obesity

As new weight-loss drugs, such as semaglutide, grow in popularity, researchers and clinicians are "overwhelmed with curiosity" about these medications. Writing for Nature, McKenzie Prillaman outlines four key questions researchers are asking about this new wave of weight-loss drugs.  

1. How do these new weight-loss drugs work?

Semaglutide is a drug that mimics a hormone called glucagon-like peptide-1 (GLP-1) to target areas of the brain that regulate appetite and food intake. The drug, which is made by Novo Nordisk, is available in two forms: Ozempic, a diabetes treatment, and Wegovy, a higher dose of the drug approved for weight loss.

Compared to older medications on the market, semaglutide results in more weight loss for patients. In a clinical trial of Wegovy, patients lost an average of 15% of their body weight over 68 weeks, leading many experts to call it a "game-changer" for obesity treatments.

Aside from Novo Nordisk, other drug manufacturers are also trying to enter the weight-loss market. For example, Eli Lilly is currently testing an experimental drug called tirzepatide, which has already been approved by FDA to treat diabetes under the name Mounjaro.

Tirzepatide mimics both GLP-1 and another hormone called glucose-dependent insulinotropic polypeptide (GIP). In a late-stage clinical trial of the drug, researchers found that patients who took the highest dose for almost 1.5 years lost an average of 21% of their body weight.

Aside from GLP-1 and GIP, some researchers are also exploring the effects of glucagon, another gut hormone. By activating glucagon receptors in the liver, energy expenditure will increase and fat will be burned in the organ.

According to Matthias Tschöp, CEO of Helmholtz Munich, a research center in Germany, imitating individual hormones can lead to weight loss, but targeting multiple hormones at once can allow them to work synergistically and boost the potential health benefits.

Currently, several drug manufacturers are developing drugs that mimic more than one hormone. So far, at least 10 compounds are being tested in clinical trials and could soon enter the market.

2. Who will benefit from these drugs?

Although new weight-loss drugs have performed well in clinical trials, not all patients will benefit from their use.

"There is a small population of patients that lose very little body weight when you give them GLP-1," said Timo Müller, acting director of the Institute for Diabetes and Obesity at Helmholtz Munich. "Why this is the case is not entirely clear."

According to Prillaman, several factors that contribute to obesity, including genetics, poor nutrition, sedentary lifestyle, and chronic stress, can also impact a person's response to weight-loss treatments. Comorbidities, such as type 2 diabetes, may also affect how well someone responds to certain weight-loss drugs.

Gitanjali Srivastava, an internist and director of the obesity medicine program at Vanderbilt University Medical Center, said there may be "a blunting of response particularly in patients with type 2 diabetes that have been prescribed a GLP-1 agonist."

"Typically, the people that are non-responders tend to be sicker," she said. "They tend to have more complicated metabolic derangements. They have a lot of complications [like] psychosocial issues that may be going on in their life."

3. Are there long-term risks from these drugs?

Although gastrointestinal side effects are common with GLP-1 drugs, there are also many other side effects that may not be as well-known.

For example, semaglutide could lead to unintended muscle mass loss. In a subset of trial participants, lean body mass, which includes muscle and bone, made up almost 40% of the weight they lost.

Semaglutide may also potentially increase the risk of miscarriage or birth defects among patients. Currently, FDA recommends people discontinue use of semaglutide at least two months before getting pregnant due to these potential risks.

Aside from potential side effects of these drugs, obesity experts note that patients will likely have to be on them indefinitely to keep weight off.

"Bodies like to gain weight; they don't like to lose it," says Arya Sharma, an obesity specialist formerly at the University of Alberta.

Although patients can keep weight off while on these drugs, an extension study of Wegovy published in 2022 found that participants regained two-thirds of weight loss achieved while using the medication after one year of withdrawal.

Currently, many researchers believe weight-loss drugs will be safe in the long-term, but there is still a risk of negative health impacts later on.

Risks "may be rare, so you only see them when [the drugs] start being used by millions of people," said Susan Yanovski, co-director of the Office of Obesity Research at the U.S. National Institute of Diabetes and Digestive and Kidney Diseases. "Or they may require a long time, like several years, to actually become evident."

4. Are these drugs changing how we think about obesity?

According to Prillaman, many researchers and clinicians are excited about the potential impact of these new weight-loss drugs on patients and obesity care.

"I'm just delighted for patients," Tschöp said. "There's light at the end of the tunnel now."

Separately, Müller said these drugs show that obesity isn't due to "a lack of willpower." In general, lifestyle changes, such as exercising more and eating less, are not enough to help people lose weight. Because the brain tells people when and how much to eat, there may be a biological imbalance that certain drugs can treat.

Currently, insurers do not cover weight-loss drugs, but researchers hope that showing that obesity has a biological basis and is a chronic condition will help convince them to provide coverage in the future.

Although many health experts are excited about these new weight-loss drugs, some are also concerned about how the drugs could influence diet culture and societal pressure to lose weight.

"There are people who are really worried about the uptake and the excitement around these medications," said Sarah Nutter, a psychologist and weight-stigma researcher at the University of Victoria in Canada. In particular, Nutter said some people are worried the drugs could worsen eating disorders and weight stigma.

"What we need to do is develop a better understanding of health as being independent of weight," Nutter said.

Advisory Board researchers have also compiled the six key questions that providers and payers need to answer when it comes to these drugs. You can see what our experts posit here .  (Prillaman, Nature, 8/2)


What the headlines get wrong about weight-management medications

Weight-management drugs are big news for healthcare and mainstream media outlets alike, but the articles don't always tell the whole story. Are these drugs an end to the obesity epidemic or a dangerous vanity fad? Are they here to stay? Who pays for them? Read on to find out Advisory Board's take on what healthcare leaders really need to know.







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