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02-11-2021 | Semaglutide | Commentary | Article

STEP 1: Semaglutide for weight loss


Lead author of the STEP 1 trial, John Wilding, discusses the findings and what they may mean for the treatment of people with obesity. 

Keep up with the latest results from the STEP trials


John Wilding: So this study with semaglutide uses a dose of 2.4 milligrams weekly, which is somewhat more than the standard diabetes dose of 1 milligram weekly. And what we saw in this trial is an average weight loss of just under 15% or just over 15 kilograms in the people taking the semaglutide type 2.4 milligrams, compared to just over 2 and 1/2 kilograms in people taking placebo.

So it's a very big effect in terms of weight loss. And we actually had more than 85% of people achieving a 5% weight loss, nearly 70% achieving a 10% weight loss, 50% achieving 15% weight loss, and just under a third achieving a 20% weight loss. We've not seen anything like that with any other obesity treatment.

This is about twice as effective as the liraglutide.

Interviewer: And what about the gastrointestinal side effects? How did they compare with lower doses?

John Wilding: Yeah, so a little bit more than we see in the lower doses, but certainly not anything that would mean that it would be not used. And in fact, over 90% of people actually stayed in the trials, so most people were actually able to get over that initial feeling of nausea and stay in the trial for a year on the full dose.

So the GI side effects are pretty much in line with what we've seen with other GLP‑1 analogs.

Interviewer: And can you say anything about the durability of the response compared with existing options?

John Wilding: So at the moment, we only have data for the 68 eight weeks of the trial. And of course, that includes quite a long titration period of 12 weeks. Sixteen weeks, rather. So it's 52 weeks on the full dose. There are ongoing trials that are going out to two years, and there is also the select trial, which is a cardiovascular outcome trial, with 17,500 thousand people to be recruited, which will follow people up for a median of somewhere around three or four years.

It's an eventual trial so it's hard to be exactly precise about what the duration of treatment will be. But the primary outcome of that trial isn't weight loss. It's actually cardiovascular events.

Interviewer: Do you think that people will need to continue taking this drug to maintain the weight loss, or would they be able to be weaned off it?

John Wilding: That's again, a really interesting question. What we've seen with other obesity treatments and with some of the preliminary data from other trials in the step trial series, is that if you stop taking the drug then the weight gain will occur and people will eventually gradually put that weight back on. So this would really be considered to be a long term treatment.

Much as the way that we treat any other chronic disease, we require a long term treatment. We don't expect blood pressure to stay down if we stop the anti-hypertensive. We don't expect cholesterol to stay down if we stop the statin.

Interviewer: So in this trial people were taking their medications and they also had a lifestyle program. What do you think is likely to happen to your average person in the real world who may not have access to a lifestyle program, wouldn't be a highly motivated person in a clinical trial, or may not stick to their lifestyle program?

John Wilding: I mean, I think what these medicines do is actually help people to stick to a lifestyle program more effectively. So the way that these drugs are approved, any obesity medication is approved, is as an adjunct to lifestyle support. And so the way it should be used in clinical practices, is with lifestyle support.

And certainly, in the UK, for example, in the NHS, where the liraglutide has been approved, it's only approved for use within specialist weight management services, where that lifestyle support is being provided.

Interviewer: And finally, what questions are there remaining and how will these be addressed by the rest of the step program?

John Wilding: So I think, I mean, some of the important questions are ones that we've already discussed. So I think the cardiovascular outcome data is really important. That's being addressed in the select trial. I think that there are-- this trial only included people without diabetes. There is another trial in the step program that looks at this dose in people with diabetes.

And that's going to be very interesting. I think we will see the results of that very soon. And clearly, we've already got some data to show that it improves, that semaglutide treatment in this trial improved risk factors, it improved quality of life. But we can start to ask questions about other conditions that are associated with obesity, like arthritis, like whether it might prevent progression to diabetes in people with pre-diabetes which we will be able to address with the data that we have from step one, along with some of the other trials.

And also other conditions, like sleep apnea and so on. So I think there is still a lot more to do, but this is certainly a first step in the program.

About the speaker

John Wilding

John Wilding, DM FRCP, leads Clinical Research into Obesity, Diabetes and Endocrinology at the University of Liverpool, UK.

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