Story by Matt Windsor | UAB University Relations

Semaglutide, approved by the FDA to treat diabetes at a dose of 1 milligram per week, had impressive results in weight-loss studies testing a higher dose of 2.4 milligrams per week. "At higher doses it acts on centers in the brain and suppresses appetite," said UAB's Timothy Garvey, M.D., a co-author of the STEP 3 trial. "It is important to use this medication in conjunction with lifestyle intervention. What this medicine does is help patients adhere to a reduced-calorie diet."For decades, Americans have fought a losing battle with obesity. Between 1960 and 2010, the prevalence of adult obesity in the United States nearly tripled, to 36% from 13%, according to the Centers for Disease Control and Prevention. It isn’t as if many Americans don’t recognize the problem. According to 2018 data from the National Health and Nutrition Examination Survey, just under half of adults in the United States (49.1%) tried to lose weight in the prior 12 months. Nevertheless, according to CDC data, the obesity rate that year rose to a record 42.4%.

But a new weight-loss drug that announced jaw-dropping clinical trial results in early 2021 may be the ammunition needed to help turn the tide.

Semaglutide, an injectable drug already approved by the Food and Drug Administration as a treatment for Type 2 diabetes, had produced moderate weight loss at its dose of 1 milligram weekly. The new trials at UAB and other medical centers around the country, known as STEP, were studying the potential of a higher dose, 2.4 mg. The results, released in February, were important enough to warrant prominent placement in the New England Journal of Medicine for the STEP 1 trial results and Journal of the American Medical Association for STEP 3 trial results, and a major feature in the New York Times.

Participants lost an average 37 pounds through the combination of semaglutide and behavioral intervention in the STEP 3 trial. “This is a game-changer,” said UAB’s Timothy Garvey, M.D., co-author of the JAMA article and Butterworth Professor of Medicine in the Department of Nutrition Sciences. “We haven’t seen this degree of weight loss with any previous medication. More than 50% of trial participants are losing 15% of their body weight, and anywhere between a third and 40% of participants are losing 20% of their body weight. That is beginning to close the gap with bariatric surgery. I think this truly gives us a very powerful tool to treat obesity as a disease.”

The realization that obesity is in fact a disease is an important point, Garvey noted. “Many people among the lay public and many health care professionals as well think about obesity primarily as a lifestyle choice, even today, despite our scientific understanding of obesity as a disease,” he said. “That’s why I think these trials are important.”

The effects extend beyond weight loss. Garvey says that high-dose semaglutide (2.4 mg/weekly) could prevent and treat diabetes, cardiovascular disease and related complications including osteoarthritis and sleep apnea. That is because patients receiving semaglutide “are not just losing X amount of pounds, but really improving their health,” Garvey said. This is consistent with the Obesity Treatment Guidelines published by the American Association of Clinical Endocrinology (AACE) for which Garvey served as lead author. These guidelines advocate for a complications-centric approach. “That means treating and preventing the consequences and complications of their obesity that are responsible for impairing health: preventing progression to diabetes, sleep apnea, osteoarthritis and things like that. If approved, semaglutide 2.4 mg has the potential to really change the way we think about treating this disease of obesity.”

Novo Nordisk, the company that manufactures the lower dose for diabetes known as Ozempic, plans to apply for FDA approval of the higher dose for treatment of obesity later this year, Garvey said. And STEP 3 was not the only semaglutide trial at UAB. “We are one of the sites in a longer-term international study to see if semaglutide prevents cardiovascular events and mortality,” Garvey said. “We are also looking at this drug over two years of treatment as opposed to the one-year time course of the current study. There are more trials planned with this medication, and we are involved in several of them, in addition to other classes of promising medications in development for obesity.”

What do patients need to know about this semaglutide? Garvey explains.

What does semaglutide do?

“Semaglutide is part of a class of medications called GLP-1 receptor agonists, or glucagon-like peptide-1 receptor agonists. It increases insulin secretion, which is good for diabetes. But at higher doses it acts on centers in the brain and suppresses appetite. It is important to use this medication in conjunction with lifestyle intervention. What this medicine does is help patients adhere to a reduced-calorie diet. With obesity, you always need lifestyle plus the medicine.”

Timothy Garvey, M.D.There are other medications in this class of drugs — including liraglutide, dulaglutide, semaglutide — that are used to treat diabetes. “Usually they are used after patients fail metformin, and they are a good choice,” Garvey said. “Like some other diabetes medications, patients lose a little weight, and semaglutide has been shown to be cardioprotective — they prevent heart attacks and they protect kidney function as well. They are becoming very widely used for diabetes.”

What are the side effects of semaglutide at a higher dose for weight loss?

Participants in the STEP trials do report side effects, although they are generally mild and decrease over time as their bodies become adjusted, Garvey said. “You always have to consider nausea, vomiting, diarrhea, constipation” as potential side effects, he said. “But these are very manageable. Those tend to come on early in the course of treatment and get better over time. Only infrequently are they serious enough that patients have to stop taking the drug. In the trial we had to administer the drug over a fixed timeframe, but in practice you build up gradually to overcome symptoms.”

Who is the best candidate to receive semaglutide?

“It looks like semaglutide 2.4 mg is effective and safe across a wide spectrum of patients with obesity who might be prescribed this drug, whether you are older or younger, higher BMI or lower, and regardless of race/ethnicity,” Garvey said. “When you have a medicine that is this effective, it seems to minimize the differences among patients.”

What about insurance?

“Again I think this speaks to the bias against obesity,” Garvey said. “With many health care plans in this country, people have to pay extra for obesity care. VIVA UAB is different, however — it will cover obesity care.”

But the trial results of semaglutide may bring change, Garvey said. “That’s another thing I think this will do — insurers will be forced to cover a medication with this efficacy and safety. It could lead to more consistent coverage of this disease.”

Making a difference in Alabama

UAB’s research teams have been critical to the clinical development of semaglutide, Garvey notes. “We have very good investigators and research professional staff here,” he said. “Our university is playing an important role in the development of these obesity drugs and teaching other physicians about them and about larger issues of the treatment of obesity through continuing medical education opportunities and then presenting the data at meetings and abstracts and publications and talks.”