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02-25-2021 | Semaglutide | Commentary | Article

STEP 3: Semaglutide plus intensive lifestyle therapy for weight loss

Thomas Wadden explains the rationale behind STEP 3 trial, and why semaglutide is the “breakthrough people with overweight and obesity have been waiting for.” (7:41)

Keep up with the latest results from the STEP trials


Interviewer: If you could just lay out the rationale for this – why did you want to test semaglutide in the setting of intensive lifestyle therapy?

Thomas Wadden: Well we wanted to give people a large dose of lifestyle modification and to see how much weight semaglutide could add on top of that. Very often with intensive medications, the lifestyle intervention is pretty moderate – people maybe get a monthly counseling session in the group that gets placebo, and monthly counseling just loses 2–3% of their weight. We thought, well let’s see if we give people a more aggressive behavioral counseling program, and can lose 6, 7, 8% of their weight – how much additional weight loss can semaglutide add on top of that? So that was the rationale for it.

Interviewer: And how did the weight loss that you got with semaglutide compare to what you would get with a currently approved obesity medication plus lifestyle treatment?

Thomas Wadden: Weight loss with semaglutide as compared to currently approved medications was about double the effectiveness of most medications. So if you look at it in relationship to medications such as Contrave, which is naltrexone bupropion, that produces a 5 kg weight loss and in this case semaglutide is producing a weight loss upwards of 16 kg or so. So it’s triple the weight loss of many of these medications.

Probably the most effective medication next to semaglutide is Qsymia – that’s phentermine topiramate. It’s not approved in many countries in the European Union – I’m not sure if it’s approved in Great Britain or not. It is the most successful weight loss – it produces about an 8.8 kg loss greater than placebo, but you can see that semaglutide is clearly more effective than it is, as well. Semaglutide produced an absolute weight [loss] of 16.8 kg.

Interviewer: How does that compare to liraglutide?

Thomas Wadden: Again, it’s substantially greater than liraglutide. So liraglutide produces a weight loss 5.3 kg greater than placebo, and total weight loss of about 8 kg, so again semaglutide is about twice as effective as liraglutide 3.0 mg.

I think this is really the breakthrough in weight management that people with overweight and obesity have been waiting for. Patients are excited when they can lose more than 10% of their weight. A recent survey done back in 2016 said that people would like to lose about 20% of their initial bodyweight – that figure actually was much higher 20 years ago, when they wanted to lose 35%. And now we’ve got a medication that’s going to take the average weight loss from 7 or 8%, where very few people get to a 15% weight loss, and now this medication is going to allow about 50% of people to lose 15% and about 35% are going to lose 20% of their bodyweight, or more.

So you’re going to find that people will be more satisfied with their weight loss than with just behavioral treatment, or other weight loss medications. And second, and more important, is that people are going to achieve larger improvements in their health in terms of cardiometabolic risk factors. So greater improvements in their blood sugar and control of type 2 diabetes, greater improvements in blood pressure. They’ll be improvements in their lipid profile, particularly triglycerides. In addition, if you have sleep apnea, weight loss of 15% is really going to have an impact on your sleep apnea, whereas a loss of 5% you may not see much change.

So I think you’re going to see larger categorical weight losses, people will be happier with them, they’ll improve their health and mobility, and it may make the process of losing weight just a lot easier for many people.

Interviewer: In the JAMA paper you were speculating about whether intensive lifestyle treatment is actually necessary for people taking semaglutide - can you expand on that?

Thomas Wadden: Yeah, I think it’s a good question. It may well be that semaglutide is such a robust medication that it’s going to help people on average to lose about 15% of weight, and that you potentially don’t need as much behavioral counseling to modify your food intake. So much of behavioral counseling is about recording your food intake and your calories, doing that daily. And part of what semaglutide does is it really remarkably decreases people’s hunger – decreases cravings. We know that it decreases food intake by about 35%; when you look at people having an ad libitum lunch, where they can eat as much as they want, and after they get on semaglutide they decrease their calorie intake by about 35% on this ad libitum lunch.

So I think part of what semaglutide does is it decreases people’s urge to eat – hunger, the initiation of eating – and when you do eat, you feel full more quickly and therefore stop eating sooner and eat less food. So semaglutide may help people make the behavioral changes that we try to help them with, with intensive behavioral therapy. The drug is going to make people less responsive to the food environment, less vulnerable to all the ads for eating high-fat, high-sugar foods. So I think it does help the behavioral treatment, and you may not need as much intensive behavioral treatment as we provided in this study.

Interviewer: Do you feel that semaglutide could be a useful treatment for people who just really struggle to engage in lifestyle for whatever reason?

Thomas Wadden: I think it could be. And there are different reasons that people struggle with lifestyle modification. Some people will just report that they’re extremely food preoccupied – they’re always thinking about their next meal as soon as they eat this one – and semaglutide, to my experience with a patient I treated, seems to turn down the volume of the desire to eat – that background noise about “I’m hungry, I’m thinking about food.” So it turns that down, and people are able to sort of focus on their work and other activities, rather than thinking about their next meal. It’s important to realize that while semaglutide helps people with their appetite, you still obviously want people to continue to engage in physical activity. So, critical that folks continue to get out there and try to walk 150 minutes, 200 minutes per week, because physical activity is going to have benefits for your cardiovascular health and fitness above and beyond just weight loss. So the study doesn’t mean we shouldn’t have people trying to modify their lifestyle, but it may be the drug will make it easier to modify food intake and they can focus even more on increasing their physical activity.

About the speaker

Thomas A. Wadden

Thomas A. Wadden, PhD, is the Albert J. Stunkard Professor of Psychology in Psychiatry at the Perelman School of Medicine at the University of Pennsylvania and former director of the Center for Weight and Eating Disorders.

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