For a Publications of the Week article discussing the use of semaglutide in overweight and obesity, click here.
James Douketis, MD: Hello everyone. This is another edition of [McMaster Perspective referring to] the Paper of the Week [of April 6]. This week we’ll be talking about the STEP 1 (Semaglutide Treatment Effect in People with Obesity) trial, which is a randomized controlled trial looking at semaglutide as a weight-loss intervention in overweight and obese people. I am delighted to have with me today Dr Megha Poddar, who is a community-based endocrinologist, has expertise in obesity management, and is an adjunct associate professor of medicine at McMaster University. Welcome, Megha.
Megha Poddar, MD: Thank you. Thank you for having me.
James Douketis: It’s our pleasure. Let’s start off by talking about this very important trial. Tell us a little bit about semaglutide and where it falls into the treatment options for management of overweight and obesity.
Megha Poddar: Absolutely. Semaglutide is a weekly glucagon-like peptide-1 (GLP-1) receptor analogue. Many of us are familiar with the GLP-1s in the management of type 2 diabetes. We have daily and weekly injectables to help in the management of blood sugar [levels]. In the management of obesity, we also have liraglutide at the 3-mg dose, which is a daily subcutaneous GLP-1, called Saxenda. That’s already used in weight management today and already approved. The data around the STEP 1 trial was looking at semaglutide, which is a weekly GLP-1 receptor analogue, at a higher dose than the [dose] that’s usually used for type 2 diabetes. You’re probably familiar with Ozempic, which is semaglutide at the 1-mg dose. The STEP  trial looked at semaglutide at the 2.4-mg dose, so [a] much higher dose. That study looked at just <2,000 patients; specifically those with a body mass index (BMI) >30 [kg/m2] or a BMI >27 [kg/m2] with the comorbidity related to weight; importantly, those were patients without diabetes. So [the study was] looking really at a different group of patients than we see in other semaglutide trials.
James Douketis: Thank you, that’s a nice introduction. And the trial itself: It looked like it had very impressive results in terms of weight reduction. Do you think that and other aspects of this… What would you consider the strengths of this trial for practicing clinicians?
Megha Poddar: Absolutely. I think, certainly in the obesity space, this is something we’re all very excited about in terms of the overall percentage of weight loss. At the end of the trial, which was at ~68 weeks, the average weight loss in patients on semaglutide was just <15% of the total body weight compared with placebo, [in the case of] which [it] was just <2.5%. And just to give you an idea of what we see with the average antiobesity medication: On average we see ~5% to 8% weight loss with medications thus far. So this is sort of much, much greater than [what] we’ve seen in terms of success with weight loss [in the case of] any other pharmacotherapy agent that we have. But, more importantly, the number of patients who lost >15% to 20% of their total body weight was quite high; ~1/3 of patients lost ~20% of their body weight. And when we look at the benefit of that, certainly, from a cardiometabolic standpoint, there was a significant improvement in blood pressure and blood sugar [levels], quality of life, exercise capacity—various… different aspects of both overall health consequences as well as quality of life. And bariatric surgery presented weight losses [that] are closer to 20% to 30%. So now we are starting to see medications actually approaching the weight loss similar to [that associated with] bariatric surgery and it’s certainly a more accessible tool for our patients than surgery is from a population perspective. I think it is going to be a game changer in terms of our options for the treatment of obesity.
James Douketis: Well, that’s really good to hear. I have to say, though, that… I think it may be fair to say that pharmacologic therapy for weight management has had a bit of a checkered past. And not to go into the details too much but… What do you see as potential weaknesses of this trial and, you know, how safe do you think this drug will be, particularly in the long term?
Megha Poddar: Yes, absolutely. I think that’s a top-of-the-mind question that a lot of physicians and a lot of patients have as well. Obesity is a chronic disease, just like type 2 diabetes and high blood pressure. A lot of our patients have tried medications before that have been taken off the market, so it’s certainly something that is an important conversation. I think with semaglutide the benefit is that we have experience with GLP-1s. We’ve been using them in the type 2 diabetes world for over a decade, so our comfort level is sort of extrapolated from the type 2 diabetes management. When we look at the side-effect and the adverse-event profile in the STEP 1 trial, really it was what we would expect.
You know, with most GLP-1s it’s gastrointestinal (GI) upset—typically nausea, diarrhea, and constipation—and those were certainly most commonly seen with semaglutide as well. Fortunately, those GI upset issues are [observed] initially and are often just related to the titration phase and mild. So, most patients, I think… The [percentage of] patients who stayed on semaglutide by the end of the trial was about 90%, so, certainly, I think, those GI issues tend to be mild and [occur] just initially.
Other things to look out for with GLP-1s are things like acute pancreatitis and gallbladder issues across this class of medications. So semaglutide really didn’t stand out as having its own issues compared with the other classes of medications. I think the interesting thing that’s going to come out soon is the SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial, looking at semaglutide at the 2.4-mg dose in nondiabetic patients and their cardiovascular outcome data. And that’s something that we don’t have with antiobesity medications. And in terms of comfort with prescribing these medications [for] long-term [use], I think that trial will be very, very helpful.
James Douketis: Thank you. That’s actually very reassuring. If a practitioner in the community is assessing an obese person for the first time, what would you advise them in terms of where this medication in this trial fits into the care path of obesity management?
Megha Poddar: For sure. You know, I think that an important thing to acknowledge is that all medication treatments are on top of lifestyle modification. So I think an important conversation is what are the behaviors that are challenges for our patients and what are the tools and resources [with which] we can help to improve behavior around nutrition as well as physical activity. But to be honest, most patients have struggled with weight for a long time and often diet and exercise are not effective enough because of metabolic adaptation, genetics, [and] biology, which all play a role in dictating our weight. So I would say, you know, evaluating the patient’s journey in the past: what has worked, what hasn’t worked, what are their comorbidities related to weight.
If they have multiple medical issues that are weight related and they meet the BMI criteria, I think [that] adding pharmacotherapy on top of behavioral modification helps more patients do better and I think they do better for longer. So, often, as long as you stay on these medications, your weight is better maintained than with diet and exercise alone. That’s sort of, you know, the general approach to it. In terms of semaglutide, it is not yet approved by Health Canada, but hopefully by the end of the year we will have this tool available and I think it’s going to be an important one. Many of our patients with insulin resistance and metabolic syndrome would certainly benefit from a tool like this and I think a lot of us as physicians will start to use it almost as [the] first-line [drug] if pharmacotherapy is indicated.
James Douketis: Thank you again. My final question is: Do you think this will obviate or reduce the need for surgical intervention given the magnitude of its efficacy?
Megha Poddar: It’s a great question. I think that it’s… I think many patients who need surgery don’t get surgery for lots of different reasons. Fortunately, in Ontario, it’s OHIP-funded [covered by the Ontario Health Insurance Plan], but certainly the number of referrals compared with the number of surgeries that actually happened per year [shows that] there is a huge gap there. So I think it is going to help us, help more patients. I think there is going to be a group of patients who are gonna decide [on] semaglutide versus surgery. That is probably the reality, but bariatric surgery is gold standard. I don’t think that’s going anywhere. I think that’s an important tool for many patients and it’s really the only tool that has shown mortality benefit in obesity management. So, you know, I definitely think that it should be considered as part of the treatment paradigm, but I think that pharmacotherapy is going to help more patients across the board, because we will just have more access to it. And the presented weight loss seen in something like semaglutide is very, very reassuring that these patients will be able to achieve similar outcomes, hopefully, as they would with surgery.
James Douketis: Dr Poddar, I want to thank you very much for this very lucid and incisive comment on the STEP 1 trial. For those of you who want more information on it, please refer to the McMaster Textbook of Internal Medicine, Paper of the Week, and we will join you for our next installment. Dr Poddar, once again, thank you very much.
Megha Poddar: Great, thanks for having me. Take care.