The hotel ballroom was packed to near capacity with scientists when Susan Yanovski arrived. Despite being 10 minutes early, she had to manoeuvre her way to one of the few empty seats near the back. The audience at the Obesity Week conference in San Diego, California, in November 2022, was waiting to hear the results of a hotly anticipated drug trial.

The presenters – researchers affiliated with pharmaceutical company Novo Nordisk, based in Bagsværd, Denmark – did not disappoint. They described the details of an investigation of a promising anti-obesity medication in teenagers, a group that is notoriously resistant to such treatment.

The results astonished researchers: a weekly injection for almost 16 months, along with some lifestyle changes, reduced body weight by at least 20 per cent in more than one-third of the participants. Previous studies had shown that the drug, semaglutide, was just as impressive in adults.

The presentation concluded like no other at the conference, says Yanovski, co-director of the Office of Obesity Research at the US National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland. Sustained applause echoed through the room “like you were at a Broadway show”, she says.

This energy has pervaded the field of obesity medicine for the past few years. After decades of work, researchers are finally seeing signs of success: a new generation of anti-obesity medications that drastically diminish weight without the serious side effects that have plagued previous efforts.

These drugs are arriving in an era in which obesity is growing exponentially. Worldwide obesity has tripled since 1975; in 2016, about 40 per cent of adults were considered overweight and 13 per cent had obesity, according to the World Health Organization (WHO). With extra weight often comes heightened risk of health conditions such as type 2 diabetes, heart disease and certain cancers.

The WHO recommends healthier diets and physical activity to reduce obesity, but medication might help when lifestyle changes aren’t enough. The new drugs mimic hormones known as incretins, which lower blood sugar and curb appetite. Some have already been approved for treating type 2 diabetes, and they are starting to win approval for inducing weight loss.

The ability to melt weight away by tweaking biology gives credence to the idea that obesity is a disease. In the past, scientists and the public often thought that those with obesity simply lacked the willpower to lose weight. But evidence is growing that most people’s bodies have a natural size that can be hard to change.

“The body will defend its weight,” says Richard DiMarchi, a chemist at Indiana University Bloomington.

However, some researchers worry that these drugs play into some societies’ obsession with being thin. Body size isn’t always a good predictor of health.

“I’m really hesitant to be excited about something that I think is potentially harmful from a weight stigma perspective,” says Sarah Nutter, a psychologist at the University of Victoria in Canada, who specialises in weight stigma and body image.

Research questions abound, including who will respond to treatment and whether people will have to take these drugs for life – a huge barrier to access, given that they also carry a hefty price tag: the injections often cost upwards of $1,000 each month.

Still, obesity researchers are celebrating these developments. For the first time, scientists can pharmacologically alter weight safely, says physician-scientist Matthias Tschöp, chief executive of Helmholtz Munich in Germany. “It indeed is ‘the’ transformative breakthrough.”

The seeds of today’s success were sown decades ago, when Jeffrey Friedman was racing to figure out which gene mutation was making the mice in his laboratory eat until they became obese. In 1994, Friedman, a molecular geneticist at The Rockefeller University in New York City, discovered that the faulty gene encoded leptin, a hormone that is produced by fat tissue and induces a feeling of fullness. Giving leptin supplements to mice that lacked it reduced their hunger and body weight.

“That really revolutionised our thinking about the biological basis of obesity and appetite regulation,” Yanovski says.

An explosion of research into obesity’s underpinnings followed, alongside research into pharmacological treatments. But these early drugs led to only modest weight loss and serious side effects, especially on the heart.

Even before leptin’s discovery, researchers had been looking for hormones that regulate blood glucose levels, and had found one called GLP-1 (glucagon-like peptide 1). It seemed to have the opposite effect of type 2 diabetes – GLP-1 enhanced insulin production and reduced blood sugar – making it an appealing approach to treating obesity, says Jens Juul Holst, a medical physiologist at the University of Copenhagen, who discovered and characterised GLP-1.

In the 2000s, the US Food and Drug Administration (FDA) began approving drugs that mimicked GLP-1 as type 2 diabetes treatments. But scientists noticed that participants in clinical trials also lost weight, owing to GLP-1’s effect on receptors in the brain that govern appetite and those in the gut that slow digestion.

Over time, companies began to trial these diabetes medications for weight loss. By the mid-2010s, one such drug, liraglutide, was capable of eliciting a loss in body weight of about 8 per cent on average, 5 percentage points more than for people taking a placebo – clinically relevant, but not astonishing.

But in early 2021, scientists were wowed by a phase III clinical trial investigating a new drug of the same type: semaglutide. The molecule, a modified version of liraglutide, acts on the same pathways but remains intact and active in the body for longer, says DiMarchi. It might also have better access to brain regions that regulate appetite, he adds.

Those receiving weekly injections of semaglutide lost, on average, 14.9 per cent of their body weight after 16 months of treatment; those who received a placebo lost 2.4 per cent on average. In 2021, four years after approving it for diabetes, the FDA approved semaglutide for weight loss for adults with obesity.

Historically, it hasn’t been possible to safely decrease body weight by more than 10 per cent through pharmacological methods, says Timo Müller, a biologist and director of the Helmholtz Munich Institute for Diabetes and Obesity. But these newer treatments also improve cardiovascular health, he adds – the opposite of past iterations.

• A Nature report