[00:00.5]
Hello friends, I'm Professor Subodh Verma from the University of Toronto at St. Michael's Hospital. I'm a cardiac surgeon, and I was involved in the STRIDE trial, a trial that we presented earlier this year at the ACC meeting.

[00:17.9]
STRIDE was a randomised double blind controlled trial in people living with type 2 diabetes and prevalent peripheral arterial disease. As you know, peripheral arterial disease remains a growing and recalcitrant problem. We have no solutions for peripheral arterial disease in terms of improving symptoms or progression.

[00:39.4]
The last available therapies that were approved were about a quarter of a century ago. So it's really been an area of intense interest and investigation to try to find solutions to improve functional outcomes and hard outcomes in people with peripheral arterial disease.

[00:56.2]
So we hypothesise that the GLP1 receptor agonist semaglutide may actually be effective in this population, based on a lot of data suggesting an anti inflammatory role of these agents in addition to the emerging body of evidence that linked semaglutide to atherosclerosis.

[01:16.5]
Now so we did a really robust trial involving just short of 800 patients globally and asked the question of whether GLP1 receptor agonists could improve this outcome. And we were pleasantly surprised that functional outcomes, as evaluated by maximum walking distance on a constant load treadmill, pain free walking distance - these are so called gold standard ways of evaluating outcomes in PAD - were favourably affected by semaglutide.

[01:48.0]
We also had a inbuilt anchor measure which was a measure that was informed by patients. So, you know, it's really important in functional studies to not only evaluate what is statistically significant but whether that was clinically meaningful through the lens of a patient is probably of much greater significance.

[02:10.4]
So these results were not only statistically significant but highly clinically significant from a patient standpoint by using the so called anchor measure. So maximum walking distance improved, pain free walking distance improved over 52 weeks.

[02:28.0]
These curves separated quite early after treatment was initiated and continued to give the appearance of ongoing separation even beyond 52 weeks. In addition to that, quality of life metrics as studied by Vascular Quality of Life Questionnaires were improved, and most notably ankle brachial indices which are a measure of hemodynamics, was also improved with semaglutide.

[02:55.4]
So you know, this thesis was all supporting the concept that GLP1 receptor agonists now emerge as one of the first therapies after 25 years to potentially treat symptoms of claudication in people with PAD and type 2 diabetes. And also, we demonstrated a reduced rate of progression to either rescue therapy or major adverse limb events.

[03:24.2]
Now what we presented as a late breaking clinical trial analyses from stride at the ESC meeting, published simultaneously in JACC, was the sex-specific differences. And you may ask the question, why did you do that? One, because there's limited sex-specific data in people with PAD.

[03:45.4]
There's very little data in females to inform baseline characteristics and overall sort of natural history of PAD in this population. There has been a loud sort of and clear message from guidelines that we need to make this a research priority to generate more sex-specific data in PAD.

[04:07.4]
Furthermore, GLP1 receptor agonists have some exhibit sexual dimorphism with respect to their efficacy on cardiometabolic events or cardiometabolic parameters in that, you know, females tend to lose more weight than males, they have greater anti- inflammatory effects than males.

[04:26.1]
So the question was, you know, are the benefits seen consistently or to a greater or lesser extent in this population? And finally, we wanted to underscore really, you know, what are the risk factors at baseline in females compared to males that actually lead to, you know, early symptomatic peripheral arterial disease?

[04:47.4]
So all important questions, and we're very grateful to JACC for actually publishing this simultaneously. So what we found is that a quarter of the patients were female. Females tended to be younger and females had some unique demographic differences compared to males, even though the entry criteria was similar between males and females.

[05:12.2]
There was a markedly lower rate of current or past smoking history, and smoking is known to be one of the most important risk factors for peripheral arterial disease. And we found almost a 50% lower rate of prevalent smoking or past smoking in females compared to males.

[05:33.1]
And that's really important because it tells us that our perceptions of what the dominant risk factor for PAD is across the board may not apply to females in the same way it does to males. We also found that females tended to be undertreated with respect to background therapies, antiplatelet therapies, anti-diabetic therapies, et cetera.

[05:58.6]
And furthermore females had less coexisting coronary artery disease or heart failure. So many of the so-called prototypical beliefs around PAD have been generated primarily from males, that PAD is a disease that affects mostly smokers or PAD is a disease that has a high prevalence of other polyvascular territory involvement.

[06:27.6]
In fact, we found that there were clear differences between sexes in this regard. Semaglutide was consistently efficacious in males and females, with no evidence of heterogeneity for the primary, secondary or confirmatory outcomes that I just discussed with you earlier.

[06:46.8]
Safety was also similar in males and females. So, taking a step back, what does this mean for doctors in the trenches in the field? I think, you know, it's a great advance for people with peripheral arterial disease who have really no solutions, right.

[07:06.3]
That if you have a patient living with diabetes and PAD, a GLP1 receptor agonist, if cost coverage and other issues are not an impediment, should be part and parcel of their treatment. Not simply to improve their major adverse limb events, but also to reduce their cardiovascular and cardiometabolic risk factors.

[07:27.6]
And I hope that this research at STRIDE will catalyse larger trials, looking at harder endpoints, such as major adverse limb events in people with and without diabetes to help inform us whether this can actually have even more of a dramatic effect in terms of reducing rates of amputation or other types of limb salvage, you know, procedures or interventions in the future.

[07:56.4]
So it's been really a great, you know, delight speaking with all of you here at Radcliffe. And, thank you very much for the opportunity.