The findings from a new clinical trial released Wednesday may point the way to an elusive goal: a safe and effective drug that helps reduce obesity in people.
The study found that people with obesity given a treatment currently used for type 2 diabetes lost significantly more weight than a control group, with one-third losing 20% or more of their body weight. Those in the experimental group also experienced greater improvements in other markers of health. However, the long-term health effects of the treatment are not yet known, meaning we do not yet know how effective or safe it is as an obesity treatment.
The drug is called semaglutide, and it’s been approved in the U.S. since 2017 to help people with type 2 diabetes. Semaglutide helps increase the body’s production of insulin, the hormone that plays a big role in controlling our blood sugar (people with type 2 diabetes either stop making enough insulin or stop responding to it as normal, which causes the unstable blood sugar levels that characterize diabetes). It does this by mimicking the human glucagon-like peptide-1 hormone, also called GLP-1.
GLP-1 is one lever of the body’s system that regulates our sense of hunger and metabolism. After eating, it’s usually released into the gut at high enough levels to curb our appetite. That’s likely why one commonly reported side effect of semaglutide in patients with diabetes has been reduced appetite and weight loss. And because obesity, a common risk factor of type 2 diabetes, often involves a dysfunctional metabolism, it’s also why some scientists have hoped that the drug could be retooled into a genuine obesity treatment.
This new Phase III trial (called STEP-1) was funded by Novo Nordisk—the makers of semaglutide—and involved nearly 2,000 patients over the age of 18 recruited in 16 countries from June to November 2018. The volunteers had all reported trying to lose weight unsuccessfully at least once and either had a body mass index over 30—the cut-off for obesity—or a BMI of 27 along with health complications likely related to their weight, but not including diabetes. (BMI, it should be noted, has been criticized as too imprecise to be a reliable marker of health). The findings were published Wednesday in the New England Journal of Medicine.
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All of the volunteers were encouraged to take on a reduced-calorie diet and exercise more. They also all received individualized counseling from dietitians once a month, either in-person or over the phone. But about half were randomized to receive a weekly injected dose of semaglutide, while the other received a placebo shot. Each dose of semaglutide was 2.4 milligrams, higher than the 1 milligram dose used for diabetes treatment.
By the end of the 68-week trial (which nearly all participants completed), the results were clear. Those on semaglutide experienced an average weight loss of 33 pounds, while the placebo group experienced an average loss of six pounds. Two-thirds of the treatment group lost at least 10% of their baseline weight, while one-third lost at least 20%. They also saw more substantial improvements in waist circumstance, blood pressure, and self-reported quality of life.
On the face of it, the findings are nothing short of tremendous, given the relative lack of options for people who seek to address their obesity with pharmaceuticals. (There are several drugs currently approved in the U.S. for obesity, but none have shown the degree of success seen here.)
“The findings of this study represent a major breakthrough for improving the health of people with obesity,” said Rachel Batterham, an obesity researcher at the University College London in the UK who helped lead one arm of the trial, in a statement released by the university. “No other drug has come close to producing this level of weight loss—this really is a gamechanger. For the first time, people can achieve through drugs what was only possible through weight-loss surgery.”
Despite the promising news, at least some outside experts are more cautious about the study’s implications. In an accompanying editorial, Julie Ingelfinger and Clifford Rosen—both medical doctors and editors with NEJM—called the results a “good beginning.”
In the trial, semaglutide was well-tolerated overall, even at a higher dose, with symptoms like nausea, diarrhea and vomiting more common in the treatment group. But Ingelfinger and Posen point out that other research has suggested that it could raise the risk of more serious health problems like pancreatitis. In mice, it’s been associated with certain thyroid tumors when taken as a pill, which is why the drug isn’t currently recommended for people with multiple endocrine neoplasia type 1, a hereditary condition that raises the risk of thyroid cancer.
They also note that obesity is a chronic condition. And despite the length of the 68-week trial, we still don’t know how effective, safe, or practical it would be for someone to take a weekly injected dose of semaglutide over the long term. These potential risks and limitations don’t mean that the drug can’t be used for obesity, but it does mean that scientists will need to keep evaluating whether its benefits outweigh its harms if it wins regulatory approval. Some health experts and activists have also questioned the value of obesity treatment in general, arguing that doctors should strive to improve people’s health at any size, while recognizing that weight loss may not be the optimal goal for some.
“In sum, we have a long way to go to control the obesity epidemic, but STEP 1 serves its name well,” they wrote.
Regulatory health agencies like the Food and Drug Administration will soon have to weigh these questions themselves, since Novo Nordisk is already planning to submit the drug for approval as an obesity treatment in Europe, the UK, and the U.S.