My name is Professor John Deanfield from the University College in London and it's a pleasure to be part of this symposium, looking at diabetes and heart disease, and new approaches, not just to its treatment, but also potentially for prevention as well. These are my disclosures. None of them are relevant through the content of this presentation. Now, we're in the middle of a COVID pandemic but actually behind all of this another epidemic is going on and that is the worldwide epidemic of type 2 diabetes. As you can see from this slide, the incidence of diabetes is going up enormously around the world so that by 2025, it is estimated that there will be more than 430 million people with diabetes in the world. If you put all those diabetics together, diabetes is now the third most populous country in the world after China and India. Not only are there millions of people with diabetes, but the impact it's having on health care costs is also enormous. Diabetes expenditure was around $727 billion in 2017 and it's also going up by 2045 when it will reach $776 billion. Now if you get diabetes, the cardiovascular consequences are profound. On the left, you see the impact of diabetes in men, looking at the effect on overall death and years of life lost, but also importantly in blue on the cardiovascular deaths and you can see from the age of 40 onwards numerous deaths in diabetes are caused by cardiovascular disease so a 50 year old with type 2 diabetes with no cardiovascular disease is around six years older than an individual who has cardiovascular disease and diabetes at the time of death. Not only does diabetes shorten life expectancy significantly from cardiovascular disease, but if you have the disease, the impact in clinical trials is also enormous. In the recent Fourier Trial, looking at cholesterol lowering with PCSK9 inhibitors diabetes doubled the risk of cardiovascular events in the clinical trial. Now, the risk for cardiovascular disease and mortality from diabetes doesn't begin at the point of diagnosis but actually begins much earlier. These are old data from the Nurses' Health Study which looked at the cohort of almost 120,000 women, followed for 20 years. You can see that in that 20-year follow-up, a number of nurses had diabetes at baseline on the right-hand column and you can see not surprisingly that their risk of dying of a cardiovascular event was substantially higher. On the second right-hand column, you can see that a number of nurses developed diabetes during the 20-year follow-up and again not surprisingly after the diagnosis of diabetes, their risk was also substantially higher. But look at the second column. This was the risk of a cardiovascular event prior to the diagnosis of diabetes, almost three times higher than the risk of those nurses who remained non-diabetic throughout the study. So, there is a ticking clock in terms of cardiovascular risk that is developing cardiovascular risk long before the presence of dysglycemia even and the level of type 2 diabetes. Now, what is it that is driving this epidemic of diabetes and heart disease as a consequence in the world? The answer is it is largely driven by the worldwide epidemic of obesity. Obesity with an increase in adipose tissue doesn't just increase your body weight, but changes dramatically the inflammatory status in the body. As adipose sites develop, they secrete important inflammatory cytokines, promotes systemic inflammation, with damaging effects on the vascular wall, on the liver, on muscles and on the pancreas, promoting not just diabetes but also in parallel that same inflammation driving cardiovascular events. Now, excitingly, we now have evidence that weight loss can reverse type 2 diabetes and actually also reduce the associated risk of cardiovascular disease. These are really important data that appeared from a primary care study in the United Kingdom, the DIRECT Trial. This took individuals with recently diagnosed type 2 diabetes and they undertook a structured weight loss program aiming to reduce their weight by around 15-percent. You can see the individuals who got that structured weight loss program had almost a 50-percent remission in the diagnosis of type 2 diabetes in the first year of the treatment. Even by the second year, the remission rate for diabetes was around 35-percent, without change in drugs but just by reducing their body weight. We also have evidence that bariatric surgery can reduce cardiovascular mortality. These are recent data from Israel, more than 8,000 people, 65-percent women, who's BMI at the start was 40 and who's median age was 46, and you can see that both different types of bariatric surgery examined were associated with substantial reduction in overall mortality and cardiovascular events. Now, what is really exciting is in the last few years, we have evidence that we have medical therapies now that can also achieve substantial weight loss when given to patients. These are recent data for the GLP-1 receptor agonist semaglutide in the STEP 4 Trial. Patients in STEP 4 were randomized to semaglutide and placebo after initial period of all of them receiving semaglutide. In the first 20 weeks of the trial, when all the patients received semaglutide, there was around a 10-percent weight loss, impressive enough, but over the next year the individuals who were then randomized to semaglutide had a further almost 10-percent weight loss, resulting in a total weight loss of almost 19-percent. On the right-hand panel, you can see the GOP1 receptor agonist can be combined with other novel therapies achieving weight loss, to get even more impressive effects on body weight in an even shorter period of time. These sort of weight losses that are seen with these combinations of therapy and with semaglutide alone are almost the equivalent of the sort of weight losses we see with bariatric surgery. Now, this raises the opportunity that we might be able to alter the trajectory, not just to diabetes but also to cardiovascular events and myocardial infarction and stroke in individuals with a high risk of cardiovascular disease who were also overweight, and this is the subject of a very large ongoing randomized clinical trial, the SELECT Trial, which is randomizing patients to a GLP-1 receptor agonist versus placebo and looking at the cardiovascular outcome over a five or seven year period. Now, so far, I have been talking about new strategies to either reverse newly onset diabetes by achieving weight loss or by using drugs to alter the trajectory of atherosclerosis to cardiovascular events, but a new thought emerges from these opportunities. We should be thinking about intervening much earlier, not just to treat the consequences of diabetes and atherosclerosis, but also to prevent both diabetes and cardiovascular disease. Now, this plays into what is emerging as a big paradigm shift in the management of cardiovascular risk. Instead of looking at short-term risk in high risk people late in the disease, as we have often done in clinical practice, we are now thinking about lifetime management of cardiovascular risk. It is important to manage cardiovascular risk factors and particularly obesity from an early age if we are going to get the best benefit in terms of lifetime impact on both diabetes and cardiovascular disease. These are alarming data from the United States looking at obesity levels in two-year-old children and their relationship to future levels of obesity in later life. Kids who are obese at the age of two years have an 80-percent or greater chance of having obesity at the age of 35. Now, that early obesity in childhood and adolescence has already been shown to have an adverse impact on future cardiovascular mortality. In this study from the New England Journal of Medicine, you can see how BMI during adolescence substantially tracks to future cardiovascular mortality, almost entirely due to an increase in blood pressure levels and the risk of diabetes. Now, this represents a big important opportunity for risk reduction. These are data from a study which we undertook in the longest single cohort in the world under current follow-up. This is the UK 1946 birth cohort in which we have measures of obesity over more than 60 years and can relate this to the development of arterial disease in the carotid artery in patients who are over 60 years of age. You can see in the top panel that exposure to adiposity over life was clearly related to accumulated burden of arterial disease in the carotid artery in over 60 year olds. But look at the lower panel. You can see that if you are able to lose weight for a period of at least 10 years, there is a substantial benefit on future development of arterial disease in the carotid artery, irrespective of when that weight loss period occurred. This suggests that it is exposure to risk factors that is driving long-term development of arterial disease and future cardiovascular risk. Now, this idea that weight loss could actually prevent the development of arterial disease and improve cardiovascular outcome was very nicely supported by a recent study from Lee and colleagues who looked at weight loss in pre-diabetic patients in relationship to cardiovascular mortality and you can see here in an interventional trial those who received multifactorial intervention had a substantially future risk of cardiovascular events, even before the development of clinical diabetes. And this changes our thinking about the way in which we manage arterial disease. Instead of managing the late clinical events that we start to see, usually from 50, 60 years and onwards, we now have to think about investing in our arteries by targeting atherosclerosis as it develops during that long pre-clinical period and reducing exposure to risk factors. This is just like our thinking for our financial planning for the future. None of us would think about starting to save for our retirement at the age of 64 and think we were going to do well financially. We would start much earlier, so the development of an appropriate financial strategy is dependent on early investment. It is just the same for managing cardiovascular risk factors and future cardiovascular disease. Now, at a recent study, we have been able to show that we can do this for diabetes but very interestingly, for diabetes there appears to be a threshold for obesity above which there is a substantial increase in risk of type 2 diabetes rather than just an accumulative effect over time. This is interesting because it means that we might be able to personalize strategies to reduce the risk of developing diabetes by understanding an individual's threshold to developing type 2 diabetes based on their weight, and then keeping their weight down, either by lifestyle or other interventions like drugs and actually getting them down to a level by-at which diabetes would not be promoted, very exciting new data that will now have to be tested in clinical trials. So, in conclusion, the paradigm for managing cardio metabolic risk for future prevention of diabetes and arterial disease is changing. Lowering the risk for cardiovascular disease in patients with type 2 diabetes or established cardiovascular disease is now possible but it's not enough. Substantial weight loss can be achieved by diet, surgery and now new drugs such as GLP-1 receptor agonists and ongoing trials are testing the impact on cardiovascular outcome in obese patients with cardiovascular risk factors and/or cardiovascular disease. Early intervention can personalize the strategies for prevention of type 2 diabetes and a lifetime reduction of cardiovascular disease. It is going to become our standard of care in our attempts to prevent the increased impact of this epidemic of obesity and diabetes on future cardiovascular events. Thank you very much for your attention.

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