My name is John Deanfield, and I am Professor of Cardiology at University College in London. It’s my pleasure to be here today to talk to you about GLP-1 receptor agonists and their role in treatment of patients with cardiovascular disease. These are my disclosures. You can see that I am on the Steering Committee for the SOUL and SELECT Studies, but there are no conflicts of interest for this presentation. Now, if we think about the threats to our future cardiovascular health, the big change in the last 20 or so years has been the emergence of diabetes for cardiovascular disease risk. This epidemic of diabetes that we’re seeing in the population is largely driven by a change in weight with an increase in obesity levels around the world. Look at the consequences of diabetes for future cardiovascular risk. If you’re unfortunate enough to develop diabetes, on average you’re scheduled [ph 00:01:06] to die about six years earlier than if you did not have diabetes. And these deaths occur in young people between 40 and 60 both for men and women. If you have diabetes and receive effective cardiovascular treatment, diabetes doubles the risk of cardiovascular events. Now, why is it that there is an epidemic of diabetes in the population? Well, it’s almost entirely driven by a change in body mass index in the population around the world. You can see here that over the last 30 years a huge increase in body mass index in both men and women. And this is not confined to one part of the world. It is occurring all over the world. There are now 650 million adults living with obesity in the world and this number is increasing rapidly. This is not a benign situation. You can see the impact of obesity and increasing BMI on life expectancy. If you have a normal BMI, you’ve got an 80 percent chance of reaching the age of 70. However, as your BMI increases that risk goes up, so that if your BMI is 40 or greater you have only a 50 percent chance of reaching the age of 70. And much of that increase in risk is driven by an increased development of cardiovascular disease and its complications. Now, very exciting over the last few years, we now have therapies that can target cardiovascular risk in our patients with diabetes. And one of the main classes of drugs that have demonstrated this are the GLP-1 receptor agonists. You see here two big trials that showed cardiovascular benefit with the use of these drugs in patients with diabetes. On the left is the LEADER Trial using liraglutide, and on the right the SUSTAIN 6 Trial with semaglutide. Both of these showed a highly significant increase in cardiovascular benefit over the five or so years of the study-in the LEADER Trial and even quicker in the patients who received semaglutide in SUSTAIN 6. So, how is it that GLP-1 receptor agonists are reducing atherosclerotic burden? Well, there are direct effects by activating GLP-1 receptors in the gut, reducing permeability, triglycerides, inflammation, and lipid deposition. But there are also direct effects on the arterial wall with an anti-atherogenic impact. You can see here how plaque lesions are reduced, inflammatory status in the vessel wall is reduced, and this produces a benefit in terms of atherosclerosis progression, and in some studies, risk of atherosclerotic event occurring. This has been translated into clinical studies, and one of the main mechanisms for that may be the impressive reduction in weight that can be achieved with these drugs. You see here the results of a recent study, the STEP 4 Study, which took people with a elevated BMI-the average BMI an entrance of the study was 38, and the average age of entry was just 46-and treated them for 20 weeks with subcutaneous semaglutide. You can see that over that 20 weeks they lost about 10 percent of their body weight. Very impressive change. And they were then randomized to either placebo or continuation of semaglutide. The individuals who got the continued semaglutide continued to lose weight so that by six to eight weeks they lost a highly impressive 18.2 percent of their body weight. Recently, other drugs in combination can be given which produce an even more impressive weight loss. You see here the AM8 [ph 00:04:51] agonists and semaglutide together in a Phase I trial showing that in just 20 weeks you can lose 17 percent of your body weight. These are huge effects on body weight which may have not just a beneficial effect from weight loss but also a direct effect on future cardiovascular risk. And with that in mind, we can ask a different question. We can ask the question of whether or not we should be intervening early to prevent both diabetes and future cardiovascular risk. And this is now a key issue in medical practice. We know that we ought to be doing this from very large clinical trials like the Nurses’ Health Study that was published many years ago. This took more than 100,000 nurses who were followed for 20 years in terms of their risk of developing diabetes and cardiovascular events. You can see that some of these nurses remain nondiabetic throughout the study, whereas others were diabetic at baseline. Not surprisingly, the nurses who had diabetes had a much greater cardiovascular risk in the follow-up period. But look at the two columns in the middle. You can see that after the diagnosis of diabetes in the course of the follow-up there was an increase in risk, but the risk of a cardiovascular event was even apparent before the diagnosis of diabetes. This is the ticking clock for future cardiovascular risk with the development of prediabetes, and subsequently, diabetes. Now, what strategies do we have that might be able to prevent both type 2 diabetes and cardiovascular disease? Well, it turns out that weight management may be absolutely crucial in determining whether or not we’re likely to progress to diabetes and our opportunities to reverse diabetes should it develop. We’ve recently reported a large study that looked at the genetic inferences on risk of diabetes from Mendelian randomization studies, and also, observational data for the effect of weight on diabetes risk. We were able to show that there appears to be a threshold of weight that each of us has above which we have the risk of progressing to develop diabetes. If we could lower our weight below that personalized weight threshold, we might be able to both avoid diabetes and even reverse it were we to get it in clinical practice. So, a strategy to reduce and sustain our weight below our personal BMI threshold should be very effective at both preventing and even reversing diabetes. Where is any [ph 00:07:27] evidence that such weight loss can indeed reverse diabetes? Well, a recent clinical trial from the United Kingdom strongly supported this idea that significant weight loss could achieve reversal of diabetes. You see here the results of the DIRECT Study published a couple of years ago in The Lancet, where an average of 15 percent weight loss was achieved by diet and almost 50 percent of the people with new-onset diabetes had regression of their diabetes. At two years, a fairly impressive 35 percent were still free of diabetes. Now, could we achieve similar results with an intervention with a drug like semaglutide? Well, here is a big study that is ongoing now that is going to address this question. The SELECT Trial will recruit more than 17,000 patients, both men and women, over the age of 45, who are overweight and obese with a BMI of greater than 27. But importantly, they did not have diabetes at the point of entry into this trial. They will be randomized to semaglutide 2.4 mg once weekly against placebo, and the outcome will be a cardiovascular event, time from randomization to first occurrence of a composite cardiovascular adverse outcome. And this will be very interesting in telling us whether we can take overweight people on the trajectory to diabetes, give them a drug which will have a direct vascular benefit, and also be associated with weight loss and see what that does to future cardiovascular risk. Now, excitingly, there are other classes of drugs emerging that are going to benefit cardiovascular outcome in patients who have diabetes and even in patients who do not yet have diabetes. The SGLT2 inhibitors are exciting in terms of their potential benefit, particularly on patients who have heart failure, and it may well be that we can see in the future a combination of the use of these two classes of drugs to benefit cardiovascular outcome in a wide range of patients that we see in cardiological practice. Now, what are the barriers to the use of GLP-1 receptor agonists in our clinical practice? Well, you can see here the practice of using GLP-1 receptor agonists in a single healthcare system in Boston over the last 10 or 15 years. You can see the GLP-1 receptor agonist used by cardiologists along the bottom, that very small-that purple line showing you how little uptake there’s been for the use of these drugs by cardiologists over the last 15 or so years despite the impressive benefit that has been shown in clinical trials. And we need to ask ourselves why that is. Well, one of the important components may well be that we as cardiologists aren’t very keen on using injectable agents. A big advance that has occurred in the last couple of years is the ability to take semaglutide and give it in an oral formulation by using a carrier snack to deliver the semaglutide transgastrically. And you can see how with this particular combination of semaglutide and snack, the drug can be absorbed orally and produce its clinical benefits. This is now subject to another important clinical trial, the SOUL Study, this time in patients who have got diabetes looking at the impact of oral semaglutide administered in this way on cardiovascular outcome. So, in conclusion, we have a changing paradigm for managing cardiometabolic risk in our clinical practice, and GLP-1 receptor agonists will be an important component of our treatment strategies. They have an established role in the treatment of glucose control in type 2 diabetes, but they also benefit cardiovascular outcome in patients with diabetes by direct vascular effects and by weight loss. Ongoing trials are testing the impact of cardiovascular outcome in non-type 2 diabetic overweight and obese patients who have got cardiovascular risk factors and some of them established cardiovascular disease. And this will be very important in defining the opportunities for this group of patients in terms of cardiovascular risk reduction. Early treatment with GLP-1 receptor agonists may help with personal strategies for prevention of type 2 diabetes and lifetime reduction of cardiovascular disease risk. This is a very exciting area that is likely to change our clinical practice in the next few years. Thank you very much for your attention.

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