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Pharmacotherapy for Obesity

Five drugs are now approved by the US FDA for long-term weight management in adults: orlistat, phentermine/topiramate, naltrexone/bupropion extended release, liraglutide, and semaglutide. However less than 1% of US adults with obesity use one. Watch this video to learn why obesity is best thought of as a chronic condition that might benefit from ongoing drug therapy and to learn about the role of medication to help people lose weight, including semaglutide, most recently approved by the FDA and possibly more effective than the other options.

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[Presenter:] In the US, more than 40% of adults are classified as having obesity, based on a body mass index (BMI) of 30 or greater. This represents a really heterogeneous group. While some individuals who fall into this category might be otherwise healthy, a BMI over 30 is a risk factor for developing other health conditions.

Medications for weight management are available, but only a small percentage of people trying to lose weight use them. Let's take a look at pharmacotherapy of obesity, and review data on semaglutide, the newest addition to the list of US FDA-approved medications for long term weight management in adults.

Obesity has been increasingly recognized as a disease, but the idea that it is an individual lifestyle choice is ingrained in the way society views it.

[Yanovski:] Unfortunately, many healthcare professionals, as well as patients, consider obesity to be a lifestyle disease, that people are just lacking in willpower. And if they could just push away from the table, they wouldn't have a problem. But obesity is really a very complex disease.

[Presenter:] Obesity has many diverse causes. Research has demonstrated that there is a significant genetic contribution to body weight. And genetic predisposition interacts with factors such as the environment the person lives in, access to good quality food, what medications the person takes, culture, and more. Once a person develops obesity, if they want to lose weight, their body may undergo physiologic changes that keep them from doing so or from maintaining a lower weight.

[Ard:] And then we add in the other sort of line of research that really starts to get at, well, what controls body weight? It's a process that starts in the brain, and then affects or is impacted by feedback from organs, including the gut, the pancreas, the muscles, the fat cell itself. That is a complex system. And when there is dysregulation of that system, when some part of that system is not working in an ideal way, that's the definition of a disease.

[Presenter:] The disease of obesity is complex, chronic and progressive, which means that it should also be treated like other complex, chronic, progressive diseases. One of the most important implications of this is that treatments should be continued on a long term basis.

[Yanovski:] You can't treat obesity like an infectious disease, where you treat short term with an antibiotic and then expect that the patient's infection is going to go away, and that you can then forget about it.

[Presenter:] Of course lifestyle intervention, including exercise and nutrition, in an essential part of any obesity treatment program. And some patients will be able to lose and maintain weight without medication or surgery. But for those patients who have been unable to lose weight or who continue to regain weight, even with various lifestyle interventions, these additional treatment options should be considered.

Bariatric surgery is the gold standard in terms of obesity treatment. But not all patients are interested in surgery, and many are not good candidates. Medications are available for those patients.

A total of five medications are currently approved by the FDA for long term weight management in adults. Semaglutide is the newest addition, and was approved in June 2021. First let's look at these four medications, which have been in use longer.

The mean placebo-subtracted 1-year weight loss has ranged from 3.4 to 8.9 kg, with the greatest weight loss associated with use of high-dose phentermine plus topiramate. Currently, monotherapy with phentermine is the most prescribed obesity medication. It's approved for short-term use, but is often used off-label as a long term treatment. Overall, these medications help patients lose an average of about 5% to 10% of their body weight when used with lifestyle intervention—which is clinically meaningful, even if it isn't as much as many patients are looking to lose.

And this is why the recently published data from four double-blind, randomized, placebo-controlled clinical trials that tested semaglutide, 2.4 mg, have generated increased attention. The data suggest that patients could lose an average of 15% to 16% of their body weight while taking this medication.

Semaglutide is an analogue of the hormone GLP-1, which is a naturally occurring hormone that is released by the body when you eat.

[Wadden:] And the GLP-1 does really three things. First, it's going to signal the pancreas to release some insulin to pick up the carbohydrate that you've consumed. Two, GLP-1 is going to travel to the brain, and signal the brain that you're getting full, it's time to stop eating, and it's also going to do that by a third thing, that GLP-1 slows gastric emptying.

[Presenter:] Semaglutide is about 94% similar to native GLP-1; it's been modified to stay in the body longer, and the medication also contains a much greater amount than would be released during a meal. Patients in semaglutide trials have reported very noticeable effects on appetite.

[Ard:] So from a patient perspective, people will notice that, "Hey, I feel fuller earlier." The other thing that people will notice is that they feel full a little bit longer. So, as a result of delaying gastric emptying, the amount of time that people go before they need to eat again, or feel the urge to eat again, gets a little bit longer.

[Presenter:] The FDA's approval of semaglutide for chronic weight management is based, in large part, on four clinical trials called the STEP trials.

In the first trial, called STEP 1, over 1900 participants were randomly selected to receive either semaglutide or placebo. Both groups also received lifestyle counseling with a dietician. This study found that at the end of the 68-week study period, participants who had received semaglutide had lost 15.3kg on average. By contrast, patients who received placebo had only lost 2.6kg. This translates to an average 14.9% body weight loss for the semaglutide group and 2.4% for the placebo group, for an estimated treatment difference of 12.4%.

Another finding in this study that has generated attention are the proportions of participants who lost at least 10, 15, and 20 percent of their body weight. [Wadden:] When you get to a 20% loss, you are approaching what bariatric surgeons can produce with sleeve gastrectomy. The average weight loss with sleeve gastrectomy is about 25% after one year.

[Presenter:] The medication is self-administered as a subcutaneous injection once a week. Importantly, this medication is not meant to be used short-term. One of the STEP trials, published in JAMA, looked at what happens if patients discontinue the medication. After an initial 20-week run-in period, during which 803 participants achieved a mean weight loss of 10.6%, they were randomized to either continued treatment or placebo for an additional 48 weeks.

[Wadden:] The patients who had lost 10% of weight and discontinued the drug, they regained about 7 percentage points of their body weight in the ensuing 48 weeks. By contrast, the patients who continued on the medication lost an additional 7.9 percentage points of their weight. That is the lesson, that obesity is a chronic condition, and to my mind and other practitioners' mind, it's going to require chronic care similar to other health conditions.

[Presenter:] Across all four STEP trials, gastrointestinal side effects were common: typically nausea, constipation, diarrhea, and vomiting. The researchers reported that most GI events were mild to moderate and of relatively short duration, and the majority of participants recovered without treatment discontinuation. However some participants did discontinue due to adverse events.

While the results from the STEP trials have generated enthusiasm, there are some important unknowns. One is that these studies were not designed to detect adverse effects that may arise with long term use, or in larger populations.

[Yanovski:] If you have a relatively small number of people, even if it's several thousand, in phase three studies, sometimes adverse effects don't come out until large numbers of people have been on a medication for a long time. So we do need to really look at longer-term safety and efficacy.

[Presenter:] More clinical trials of semaglutide are ongoing, including one that examines cardiovascular outcomes.

[Yanovski:] We always want to know is this actually improving the way patients feel, the way they function, their medical conditions, and, ultimately, their cardiovascular morbidity and mortality, or prevention of diabetes.

[Presenter:] And, importantly, in order to make a difference for patients, medications for weight management need to be accessible.

The cost of obesity medications is prohibitive for many patients who would most benefit from their use. Currently, Medicare, many state Medicaid programs as well as many private insurers specifically exclude obesity medications from coverage.

A government report examining 2012 to 2016 found that of an estimated 71.6 million US adults with obesity, only an estimated 660,000 per year, on average, used an obesity drug. 68% paid for these drugs out of pocket.

Beyond insurance coverage, physicians might hesitate to prescribe medications for weight management. There are a few different reasons for this. One is that the history of obesity medications is riddled with medications being pulled from market due to post-approval safety signals.

[Yanovski:] They've had a very checkered history. And physicians, of course, we take an oath to do no harm. So I think there's a feeling that, well, I'm afraid that there may be -- you know, I may be doing something bad for my patients if I prescribe these medications. The other thing is a feeling, and this is true for both patients and physicians, is that, well, these drugs don't work very well.

[Presenter:] And this is why the higher efficacy of semaglutide reported in the STEP trials is key. Since it appears to be more effective than other currently approved medications, physicians may be more inclined to prescribe semaglutide and patients to take it. But this hinges on several important, but as yet unanswered questions. Among these is whether the efficacy and safety of semaglutide reported in the STEP trials will be confirmed in clinical practice settings. Additionally there are not yet enough data to determine what effect, if any, semaglutide has on patients' cardiovascular outcomes. Look out for data on these and other questions over the next few years.


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