New anti-obesity drugs already outperform Ozempic

For decades, people who are overweight have been given simple advice: move more and eat less. However, in more than 80% of cases, this approach only works in the short term. A 2023 article published in Science highlighted that, despite what popular culture and many doctors believe, there is little consensus on the causes of the obesity pandemic. “Although it is often asserted that increasing sedentary behavior is a major cause of the obesity pandemic, this is far from clear, and present evidence does not support this conclusion,” the authors wrote. An editorial in The Lancet in February lamented the lack of consensus on a clear definition of obesity, despite it affecting nearly an eighth of the world’s population.

In 2017, the U.S. Food and Drug Agency (FDA) approved the use of semaglutide, the popular drug Ozempic, which was originally intended for diabetes. It quickly became a miracle solution to obesity by reducing the uncontrollable desire for food and achieving weight loss of up to 15% in 68 weeks. It was the first in a series of drugs that are, for the first time, effective against obesity and can help lessen the moral judgment that accompanies it.

Semaglutide’s main competitor is tirzepatide, produced by the U.S. pharmaceutical company Eli Lilly. While semaglutide mimics GLP-1 (glucagon-like peptide), a hormone that suppresses appetite and regulates metabolism, tirzepatide adds an analog of another gastric hormone, GIP (gastric inhibitory peptide), which increases insulin release and reduces blood sugar. This combination of hormone imitators has led to an average weight loss of 20% in 72 weeks in clinical trials.

The pharmaceutical industry is not stopping there. There are already 100 new drug candidates in trials, all vying for a slice of the obesity treatment market, which could reach $100 billion by 2030. Nearly all of the major pharmaceutical companies are making their bets on the weight-loss business.

Retatrutide, also from Eli Lilly, adds glucagon — a hormone that regulates blood sugar levels — to GLP-1 and GIP. Although it is not yet approved, this compound has shown a reduction of nearly a quarter of the participants' weight (24%) in its trials and could be approved as early as 2027.

Meanwhile, at Novo Nordisk, the most valuable European company thanks to its anti-obesity drugs, they are testing a range of drugs, including Cagrisema, which combines GLP-1 with an analog of amylin, a hormone that slows gastric emptying and reduces appetite. In an advanced clinical trial presented last December, Cagrisema showed an average weight reduction of 22.7% after 68 weeks of treatment. While the difference might seem small to patients and doctors, the market viewed these results as a disappointment, with the stock falling 29% in a single day. This data underscores the intensity of the competition and raises questions about whether the push for even greater weight loss could lead to health problems. Cagrisema could be approved next year.

When we eat, our intestine, pancreas, and fatty tissue release peptides (the hormones that most weight-loss drugs aim to imitate) that inform the brain when we’ve eaten enough. These hormones are synthesized throughout the digestive tract so that, as the meal progresses, satiety signals are delivered at the right time and food is processed correctly.

What’s more, this system regulates the response of the liver, fatty tissue, and muscles to the arrival of nutrients. This mechanism is far more complex than simply calculating the calories burned versus the calories consumed, as not everyone experiences hunger in the same way, nor do we all store calories the same. As in many other fields, obesity medicine aspires to become precision medicine, and this is where the vast array of drugs in development could prove useful.

“Until now, we have worked by trial and error, but we are now close to having tools to measure which hormone our patient is lacking,” explains Andreea Ciudin, coordinator of the Comprehensive Obesity Treatment Unit at Vall d’Hebron Hospital in Barcelona. “Our unit participates in trials with these molecules, and we are seeing that some patients respond very well to the triple agonist [such as retatrutide], but it is possible that they do not need three hormones — one or two could be enough,” she explains. “That would allow us to give each one what they need, or to propose a sequential treatment, first the triple agonist, first the triple agonist, then tapering to double, and finally to a single hormone.”

Manuel Tena, professor of Physiology at the University of Córdoba in Spain, notes that with these drugs, “too much emphasis is placed on weight loss, but the effects go far beyond that, from improving the metabolic profile to enhancing insulin resistance or even reversing type 2 diabetes.”

However, he cautions that “there is a therapeutic consensus that the application of these drugs must be paired with lifestyle changes, and the therapeutic arsenal must be reserved for cases where obesity doesn’t respond to other, more common measures,” such as dietary improvements or increased physical activity. “Even with medications, comprehensive obesity treatment must continue,” he adds.

Ciudin agrees that diet is important, but stresses its role more in quality than in caloric restriction, “because the drugs already handle the quantity aspect.” In this case, one of the goals of diet is to prevent muscle mass loss, which must also be supported by exercise.

Cristóbal Morales, an endocrinologist at Virgen Macarena University Hospital in Seville, points out that, “now, in the announcements that companies make to investors [for new drugs], it seems that the emphasis is on weight loss, when what we really need to focus on is healthy weight loss and maintaining muscle mass.” For the specialist, the key is “not to rush, but to monitor weight loss and maintain it.”

Despite the importance of exercise and good nutrition, which also benefits healthy people or those suffering from conditions other than obesity, doctors remind us of their limitations. “We talk about obesity as if it were a single problem that comes from people eating too much and not moving, but we must move past that idea,” says Ciudin. “Insulin is a pancreatic peptide like glucagon and amylin [whose imitators are found in new drugs], and in many cases, these peptides are not produced. No matter how much you diet, if you lack the hormone that regulates your appetite, you won’t be able to succeed.”

When obesity develops, the hormonal mechanism that tells us when to eat and when to stop goes awry, making it very difficult to regain health simply by changing habits, much like what happens with diabetes. Moreover, a low-calorie diet triggers a response from the body, which is programmed to maintain a certain weight.

“The more restrictive the diet, the more the body will resist and the worse the metabolic adaptation will be, which is why people who have followed many diets, eating little, gain weight, because the basal metabolism burns a third of what it has to burn,” explains Ciudin. “This makes it very difficult to treat people with obesity, because they have followed many uncontrolled diets, without medical supervision.”

Morales points out that people in the placebo groups of anti-obesity drug trials receive excellent support, with nutritionists, exercise assistance, and close monitoring far beyond what conventional healthcare can provide. “With these healthy lifestyle habits, they manage to maintain a weight loss of 3 or 4%,” says the specialist. The new drugs, however, aim for a weight loss of around 25%.

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