Calling the Shot: Could a Hormonal Approach Be a Key to Treating Obesity?

A higher dose of a well-known diabetes drug has led to twice the weight loss seen with previous medications. While endocrinologists are hopeful about this new treatment, the drug may not be widely adopted since most insurers will not cover such therapies.

A JAMA news article called the new formulation of semaglutide a potential “new dawn for obesity treatment.” But it could take years for that sun to rise high enough to shine on many patients who could benefit.

The drug represents an exciting breakthrough in using hormonal pathways to treat an intractable condition, obesity specialists tell Endocrine News, but is too expensive to see widespread adoption soon.

In June, the U.S. Food and Drug Administration approved semaglutide under the brand name Wegovy as a once-a-week, 2.4-mg injection for chronic weight management in adults with obesity or with overweight accompanied by at least one weight-related condition, such as high blood pressure, type 2 diabetes, or hyperlipidemia. Sold under the brand name Wegovy, the drug should be used in addition to a healthy lifestyle regimen of a reduced-calorie diet and increased physical activity.

STEP Up the Performance

The approval came on the heels of the publication earlier this year of the first four STEP (Semaglutide Treatment Effect in People with obesity) clinical trials. The 68-week STEP 1 trial tested 2.4-mg semaglutide versus placebo in patients with overweight or obesity but not type 2 diabetes (along with healthy diet and lifestyle intervention in both groups). The participants who received the drug lost 15% of their body weight on average, compared with 2.4% in the placebo group. But even better, about a third of the patients lost 20% or more of their body weight, with 10% achieving a 30% weight loss, approaching the range of bariatric surgery.

“Some of the other medications that are used have a lot of off-target effects because they are small molecules. If they work well in the brain for one thing, you can bet they are also doing something else that you don’t want them to do. This is a lot more specific, and I think the specificity is really helpful.” – Michael D. Jensen, MD, professor of medicine, Mayo Clinic, Rochester, Minn.

The results are exciting because of the long-sought double-digit percentage of lost body weight that should get the attention of patients, physicians, and decision-makers, according to Robert Kushner, MD, a professor at the Northwestern University Feinberg School of Medicine, Chicago, Ill., who worked on the STEP 1 and STEP 2 trials, and is a consultant to the drug’s manufacturer, Novo Nordisk. He also served on the committee that created the Endocrine Society scientific statement, “The Science of Obesity Management.”

An Amount that Counts

“A 20% weight loss is likely to improve patients’ overall health, functional ability, quality of life, and whatever associated medical problems they may have, like type 2 diabetes, hypertension, arthritis of the knees, reflux disease, and overall disease burden,” Kushner says.

Michael D. Jensen, MD, professor of medicine at the Mayo Clinic in Rochester, Minn., who also worked on the Endocrine Society scientific statement on obesity management, agrees: “Now we are talking about amounts that not just physicians find interesting, but patients find interesting.” Physicians may be impressed with the improvements in blood tests that a 10% weight loss brings, but patients aren’t impressed until they start feeling the results. “That really gets their attention, so now you’ve got buy in from the patient,” he says.

“Everyone who entered the trial wanted to lose weight and did so over the first 20 weeks. But when the drug was replaced with a placebo injection, they regained their weight. That really demonstrates the biological power of this drug very nicely. It is not just the will of wanting to lose weight or the effect of continuing to see a registered dietitian every week. It really was the medication.” – Robert Kushner, MD, professor, Northwestern University Feinberg School of Medicine, Chicago, Ill.

Another significant aspect was the durability of the weight loss compared with older drugs, says Jennifer L. Kirby, MD, PhD, associate professor in the Division of Endocrinology and Metabolism at the University of Virginia in Charlottesville: “The weight loss continued beyond the one-year mark, so that is impressive.”  She adds that another important benefit of that level of weight loss is that it gets patients “to a place where they can really be physically active.”

New Paths to Treatment

These endocrinologists were just as excited by the relatively new treatment approach the drug represents. “My hope is that this is the first in a series of medicines that can make a significant difference in treating patients with obesity,” Kirby says.

Semaglutide is already familiar to endocrinologists under the brand name Ozempic, a glucagon-like peptide-1 (GLP-1) receptor agonist given in a 1-mg weekly dose to treat diabetes. GLP-1 agonists increase insulin secretion, help regulate appetite, and are associated with weight loss. Kushner says that this use of an incretin hormone illustrates “the new direction that we are going in obesity treatment, treating it more as an endocrine disease, treating it hormonally,” even though the exact pathways are not clear.

He says that imaging studies in animals appear to show a deeper penetration into different receptors in the brain than previous drugs, with semaglutide hitting more areas that regulate appetite.

Jensen says that because it is a peptide, it is not likely to affect as many off-target pathways as other drugs. “Some of the other medications that are used have a lot of off-target effects because they are small molecules,” he says. “If they work well in the brain for one thing, you can bet they are also doing something else that you don’t want them to do. This is a lot more specific, and I think the specificity is really helpful.”

Kirby says that it may take some time to understand exactly how the drug is working, just as the understanding of bariatric surgery has evolved: “We used to think that bariatric surgery’s effect was simply based on creating a small stomach. But it turns out it is probably regulating changes at the level of the hypothalamus in those appetite and satiety centers. That complexity is important. I think we diminish it by saying that these are appetite suppressants. This is much more complex than that.”

In the STEP 4 trial, all participants were given 2.4-mg semaglutide for 20 weeks, and they lost an average of 11% of their body weight. Some participants were then randomly and blindly switched off the drug and onto placebo. Those on the drug lost an additional 8%, whereas those on placebo regained 7% of their weight. Kushner says these results show the peril of the belief that weight loss is simply a matter of willpower.

“Everyone who entered the trial wanted to lose weight and did so over the first 20 weeks,” Kushner says. “But when the drug was replaced with a placebo injection, they regained their weight. That really demonstrates the biological power of this drug very nicely. It is not just the will of wanting to lose weight or the effect of continuing to see a registered dietitian every week. It really was the medication.”

Not for Everyone

But as with other weight-loss and obesity drugs, there was a very large amount of patient-to-patient variation. In the STEP 1 trial, 13% of participants failed to achieve even a 5% weight loss. And in contrast to STEP 1, the STEP 2 trial tested semaglutide in patients with diabetes. Participants in this trial lost considerably less weight — averaging about 10% — than in the STEP 1 trial, and more than 30% of patients with diabetes lost less than 5%.

“All of our obesity medications have a fairly large nonresponder group, and that is when you just say, OK, looks like this is not working for you,” Jensen says.

“It is similar to any other chronic disease, Kushner says. “No drug works in every patient. We have to pick a drug that we think is the most useful.”

“We used to think that bariatric surgery’s effect was simply based on creating a small stomach. But it turns out it is probably regulating changes at the level of the hypothalamus in those appetite and satiety centers. That complexity is important. I think we diminish it by saying that these are appetite suppressants. This is much more complex than that.” – Jennifer L. Kirby, MD, PhD, associate professor, Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, Va.

There are more obesity medications in the pipeline in various stages of clinical trials, including combinations of GLP-1 receptor agonists with glucose-dependent insulinotropic polypeptide (GIP) or an amylin analogue. As more options become available, obesity treatment could become more like treatment of hypertension as clinicians try different medications in a hunt to see what works.

And as with hypertension and other chronic conditions, if a medication works, patients should expect to continue on it indefinitely.

Questions of Access

But getting semaglutide into the arms of patients faces a huge cost barrier. GLP-1 agents for diabetes are expensive, and a web search for Wegovy prices found an average retail price of almost $1,400 for a monthly supply. And weight-loss drugs are currently not covered by Medicare and many insurance plans.

“I am hoping it will get the attention of insurers to see that, by treating underlying obesity, you have an effect on multiple other co-morbid conditions, with the ability to get people off some of these other medications, increase productivity, and reduce absence from work,” Kushner says.

But Jensen says that, unless there is some breakthrough to make it cheaper, “there is no possible health benefit you’re going to get that is going to save enough money to pay for this by cutting other drugs and co-morbidities. I checked with our pharmacist, and he said we are just not going to make it available. It’s just too expensive. Basically they are telling people on our health insurance plan that if you want it, you are pretty much going to pay for it yourself, because they can’t justify the cost. If you had to pay full price, you would be better off financially having bariatric surgery, because you could practically pay for it with a couple of years of treatment.”

Regardless of the financial obstacle, semaglutide is advertised heavily on TV as a diabetes drug, so when patients Google it, they also learn about Wegovy. “There has been a lot of interest from patients about it,” Jensen says.

Seaborg is a freelance writer based in Charlottesville, Va. In the September issue, he wrote about how machine learning technology can predict hypoglycemic events in hospitalized patients with diabetes.