By Saima Sidik, Nature magazine on July 5, 2023
Coloured scanning electron micrograph (SEM) of a sample of fat tissue, showing fat cells (adipocytes, red yellow) surrounded by fine strands of supportive connective tissue. The lipid-storage cells called adipocytes enlarge during the development of obesity. Credit: Steve Gschmeissner/Scence Photo Library/Getty Images
Two new drugs for treating obesity are on course to become available in the next few years — and they offer advantages beyond those of the highly effective blockbuster drugs already on the market. The first, called orforglipron, is easier to use and to produce, and it will probably be cheaper than existing treatments. The second, retatrutide, has an unprecedented level of efficacy, and could raise the bar for pharmacological obesity treatment.
“They’re both breakthroughs,” says endocrinologist Daniel Drucker at the University of Toronto in Canada, who was not involved in the recent research on either drug.
Results from phase II clinical trials of both drugs were announced at a meeting of the American Diabetes Association this month and in the New England Journal of Medicine. Phase II trials provide data on a drug’s efficacy and ideal dosage in a small group of participants.
ACTING ON APPETITE
Orforglipron and retatrutide both mimic hormones produced by the lining of the gut in response to certain nutrients. These hormones help to slow the passage of food through the digestive tract and lower appetite by acting on receptors in the brain — both effects that reduce people’s desire to eat and help them to lose weight.
The drugs are part of a class called glucagon-like peptide-1 (GLP-1) receptor agonists. Similar drugs were first created to combat diabetes, with weight loss as a welcome side benefit. In the past five years or so, two GLP-1 receptor agonists that lead to substantial weight loss have come on the market, amid much fanfare. One of the drugs, tirzepatide (marketed as Mounjaro), has been approved by US regulators only for treating diabetes. The other approved drug, semaglutide, is sold under two brand names: Ozempic, a diabetes treatment, and Wegovy, an obesity treatment. Both tirzepatide and semaglutide have helped people with obesity to gain the potentially life-saving benefits of weight loss, such as lowered blood sugar and reduced hypertension.
Both Wegovy and Mounjaro require weekly injections, which many people find unpleasant. What’s more, the drugs both belong to a group of molecules called peptides, which are expensive and labour-intensive to produce. The list prices for Wegovy and Mounjaro are more than US$1,000 per month, and supply shortages have sometimes made the drugs hard to find.
Orforglipron, however, is a non-peptide molecule that’s easy to produce and package into a pill. The drug’s price has not yet been set, but it will probably be much cheaper than existing weight-management drugs, says internal-medicine physician Sean Wharton at McMaster University in Hamilton, Canada. “I see it as a game changer, myself,” says Wharton, who co-authored the orforglipron study.
RESETTING EXPECTATIONS
Whereas orforglipron could bring pharmacological weight management to a wider population, retatrutide could provide an unprecedented level of weight loss. At the highest dose used in the trial, participants lost an average of 24.2% of their body weight over 11 months of treatment. Currently approved drugs tend to yield around 15–20% weight loss over a similar time period. Retatrutide “will likely reset our expectations for what we consider an efficacious obesity drug”, says neurobiologist Amber Alhadeff at the Monell Chemical Senses Center in Philadelphia, Pennsylvania, who was not involved in either study.
What’s more, all participants in the retatrutide study who received higher doses lost at least 5% of their body weight. The currently approved drugs, by contrast, work in about 90% of the people who take them. “This is great, but when you’re a clinician seeing 60–80 patients per week, 10% of them will come back disappointed,” says obesity-medicine specialist Beverly Tchang at Weill Cornell Medicine in New York City. Retatrutide interacts with three receptors that determine appetite, which is probably why it’s so effective, she adds. Wegovy interacts with one receptor, and Mounjaro interacts with two.
THE DOWNSIDES
Wegovy and Mounjaro can have unpleasant side effects, such as nausea and vomiting, and the new drugs seem poised to follow suit. Wharton isn’t too concerned — he thinks clinicians can use techniques, such as increasing the dosage of the drugs slowly, to mitigate side effects. “We can manage it,” he says.
Tolerable side effects will be key because people who take orforglipron or retatrutide are likely to regain the lost weight if they ever stop taking the drugs. That’s unavoidable because of the biology underlying obesity, Wharton says. The human brain seems to have a ‘set point’ for how much fat the body stores, and drugs simply mask that set point rather than changing it. “The idea that you could stop the medication and not have the weight regain is a non-biological idea, which doesn’t make any sense,” Wharton says.
Other specialists are willing to dream big. Drucker thinks research into what causes the body to choose a certain weight set point could lead to treatments that help people to shed pounds permanently.
Even long-acting drugs will not address root causes of the obesity epidemic, such as the fact that healthy food and exercise are difficult for many people to access. But for people who need to find relief from obesity soon, the new drugs could be the answer. “Medications are not and will not be the only solution, but they are one revolutionary step forward in countering the epidemic,” Tchang says.
This article is reproduced with permission and was first published on June 26, 2023.
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