Hello everyone. My name is Dr Alice Cheng, an endocrinologist from the University of Toronto.

What were the key findings from STRIDE?

So the study was a prospective randomised control trial involving individuals living with type 2 diabetes and peripheral arterial disease and randomised them to receive either semaglutide titrated up to 1 milligramme a week versus placebo on top of standard of care, with the question being asked of whether semaglutide could improve the functional outcome or the functional capacity of these individuals with type 2 diabetes and peripheral arterial disease. In other words, could they walk farther based on a structured validated test whereby they walk on a treadmill at a 12% incline at a speed of 3.2 kilometres per hour.

At the end of 52 weeks, it turned out that the semaglutide treated group was in fact able to walk farther compared to baseline and a greater difference compared to baseline compared to those who received placebo.

And just to put it into real terms for the audience, it turned out that the mean absolute improvement in terms of the distance that could be walked was an additional 39.9 metres or 40 metres, which translates into about 140ft. So therefore, people were able to walk farther in terms of their maximum walking distance.

What clinical criteria should be used to identify patients most likely to benefit from semaglutide based on STRIDE data?

Well, in the STRIDE study, the inclusion criteria were individuals, adults living with type 2 diabetes who had peripheral arterial disease. But the definition of peripheral arterial disease, the group that was included, was quite specific. So specifically, they wanted individuals who were classified as Fontaine Class 2A. So what does that mean?

What that means is that those individuals were able to walk more than 200 metres still and also had an ankle-brachial index less than 0.9 or a toe-brachial index of less than 0.7. So true peripheral arterial disease but still functional, which I think is important because you want to help a population that is experiencing functional decline but is not end stage per se. So a group where you can still intervene.

So these were individuals with established PAD who were still able to walk more than 200 metres using the structured test of a treadmill, 3.2 kilometres per hour speed at a 12% incline and could still walk greater than 200 metres.

But an important exclusion criteria was that they did not include individuals who had other reasons to limit their walking so that they could be more pure in the assessment, in that any improvement that was seen would in fact be related to the PAD component as opposed to improvements in heart failure or improvements of osteoarthritis, for example.

How might clinical teams collaborate to integrate semaglutide into a comprehensive PAD treatment pathway?

Well, I think first and foremost, if we think about a team approach to type 2 diabetes, which we always should, is that we need to first of all think about peripheral arterial disease because I think that's been a bit of a forgotten complication of type 2 diabetes. We spent a lot of time talking about microvascular complications for decades, then macrovascular in the form of atherosclerotic cardiovascular disease, and then recently around heart failure.

But I think PAD has been forgotten in the mix, partly because we have not had effective treatments for PAD other than surgical intervention. And even on the surgical side, especially individuals living with diabetes, there may be a lot of smaller vessel disease which may or may not benefit from the larger vessel revascularisation that can occur.

So I think step one is we need to be looking for it. And who's we? It's actually individuals who are not the vascular surgeons, but primary care, endocrinology, diabetes educators, anybody who is seeing individuals early on in their type 2 diabetes journey. So that's number one.

Number two in terms of then incorporating therapies, I mean, we have many reasons to be using semaglutide and GLP1 receptor agonists already in the type 2 diabetes space, but I think this adds to that information as to benefits functionally that patients can experience which may have more immediate meaning to them.

And then I think educating and helping our vascular surgery colleagues who may be referred these individuals because of their symptomatic intermittent claudication and letting them know about the value of semaglutide in this group. They may or may not be comfortable actually initiating the semaglutide, but we need to educate about it so that they can educate the patient who could then potentially come back to another member of the team to actually start the medication and discuss side effects.

So I think we all need to know about it. We all need to be asking about peripheral arterial disease and then we all need to be aware that treatment is available. And then we need to figure out within our respective local teams who would actually be responsible for the specific initiation.

How do the STRIDE results compare with existing studies investigating the effects of semaglutide in similar patient populations?

So the role of semaglutide and GLP-1 receptor agonists as a class is very well established now in type 2 diabetes management. There have been numerous randomised control trials over the last 10 years or less that have really shown a lot of positive results for those living with type 2 diabetes from a metabolic perspective in terms of lowering A1C, lowering body weight, lowering blood pressure.

And then from an organ protection or outcome perspective of reducing cardiovascular endpoints, meta analyses, even showing reductions in hospitalisation for heart failure, reductions in cardiovascular death, protection for those who also have chronic kidney disease.

So we have lots and lots of reasons to be using semaglutide and GLP-1 receptor agonists. And I think what STRIDE does is it adds yet another reason for utilising it in this population to improve functional outcomes in those with PAD.

But I think on top of that, what was interesting in STRIDE was that there was actually an improvement in the ankle-brachial index, the ABI, which then is suggestive that this is an atherosclerotic mechanism, slash anti inflammatory or a little bit of both, which I think then helps inform or feed into the other results that we've seen with semaglutide in the type 2 diabetes space. So I think STRIDE adds yet another reason to use it clinically but also provides some potential insights into mechanistic reasons for the benefits we see.

How might the findings from STRIDE influence current guidelines or recommendations for treating patients with PAD and T2D?

Well up until the STRIDE trial the only approved medical therapy for peripheral arterial disease was cilostazol, which I'm probably mispronouncing to be honest. It is not available in Canada where I work. It is available in the United States and my understanding is it's not commonly used because of potential side effects that it can bring.

Now it was approved by the FDA as a medical treatment for peripheral arterial disease based on functional outcomes and the functional outcomes seen in STRIDE are similar as well. So therefore, I would expect that semaglutide would then be incorporated into clinical practise guidelines for the treatment of peripheral arterial disease in those living with type 2 diabetes as a therapy to provide functional outcome benefit for individuals living with these chronic diseases.

And I think we need to remember the importance of functional outcomes because those mean something for individuals living with the disease and have immediate results because they'll feel it, they'll feel it and see it, that they're able to walk farther without pain and be able to do more.

So I anticipate that the STRIDE study would change clinical practise guidelines around vascular disease and peripheral arterial disease to support the use of semaglutide in this population.

What additional studies would help clarify the long-term benefits of semaglutide for patients with PAD and T2D?

Now the STRIDE study focused on functional outcomes which are extremely important, extremely important for the individual. And I think as a clinician, when we're trying to convince a patient to take a therapy, for me to tell them that it reduces long-term effects may be a bit of a nebulous concept, but for me to be able to say, hey, you're going to be able to walk farther and you're going to be able to walk farther without pain, that is meaningful.

Having said that though, I think we would still want to see longer-term study. I'd like to see what we quote unquote call hard outcomes, meaning I would like to see outcomes such as amputations or acute limb ischemia, and be able to show reductions in those hard outcomes or the major adverse limb events as they've been referred to.

I would also like to see this study being conducted in those who do not live with diabetes but have peripheral arterial disease to see if in fact semaglutide may be a treatment for the larger PAD population, not just those living with diabetes.

So those are some of the studies that I would love to see happen so that we can really broaden our understanding of semaglutide's role but also potentially broaden its reach in terms of the people that it can in fact help.