Hello everybody, my name is Naveed Sattar. I am professor of metabolic medicine at the University of Glasgow. I am here to talk about glucagon-like peptide-1 receptor analogues and you will be familiar with these drugs known as GLP-1 receptor analogs and I am here to tell you how they actually work. Here are my dualities of interest. GLP-1 production and glucose stimulated insulin release, when food is taken in and reaches intestinal cells, these will produce GLP-1 which is known as an incretin hormone, which augments insulin release post-meals. Quite a lot of that GLP-1 is actually degraded in the blood, and around about 10-percent will reach the pancreas where they will actually increase the responsiveness of the pancreas to glucose, leading to a better release of insulin when required. And that way there is no increased risk of hypoglycemia with these drugs. There is a reduction in glucose and effectively incretin hormones are one of the major players now in the therapies of diabetes. Let's look at this in another way and take this a little bit further, so GLP-1 receptor agonists as I say are incretin hormones but not only do they actually stimulate insulin release, they also inhibit glucagon release and the combination of these things is a reduction in blood glucose. There is another class of drugs called DPP-4 inhibitors which actually suppress the degradation of GLP-1 and they are also available for clinical utility. However, they do not lead to the same level of increase in GLP-1 and therefore they have more modest glucose benefits. A number of chemical modifications have been made that lead the GLP-1 receptor analogs to actually have continuous receptor activation which is good, which helps better glucose control and in addition increase the half-life of some of these molecules. That means some therapies are now available to be given not just once daily but actually once weekly and that once weekly prescription of GLP-1 for a number of GLP-1 analogs is a great benefit for patients because they can take the injection once weekly, in a sense forget about it for the next week and that of course improves compliance. However, there is a really other critical part of this whole pathway. GLP-1 receptor agonists also suppress appetite and increase satiety so after a meal, patients or individuals are more likely to feel full with less amount eaten. They also slow gastric emptying so that means patients are no longer likely to eat too fast and lead to slower eating and that's also important and both of these states as you can imagine will contribute to these drugs leading to weight loss and weight loss is one of the key aspects of this class of drugs. This mechanism of action also explains some of the early side effects that some patients see. Most of these side effects will tailor appetite and effectively the key side effect of course is nausea and vomiting so that patients do not change their eating habits initially, they will experience nausea and vomiting. For that reason, when we prescribe these drugs, we start them at low dose and build up so start low and we go slow in terms of building up would be the mantra. When you then look at the GLP-1, recite the profile from what I've told you, one, they are excellent glucose reduction therapies. They also do not increase hypoglycemia. They cause weight loss. The initial weight loss that we saw when we started using these drugs was around about 2-, to 3-, to 4-percent. With increasing dosages, we now find under the newer therapies weight loss is up towards 5- to 10-percent and weight loss of around about 5- to 10-percent actually brings in new clinical paradigms for these drugs so they have now also been considered to be used for weight loss independent of their effect in diabetes. There are multiple other benefits with GLP-1 receptor analogs. They also improve blood pressure, in part through weight reduction but also in part through other actions of GLP-1. They improve blood lipids in the way that you would anticipate, lower triglycerides, improve HDL. They are also insulin sparing, because as you lose weight, that means there's less fat in metabolically relevant tissues. That means also the pancreas has to produce less insulin to have the same glucose benefit, and that's also a key aspect. It means that patients when they are prescribed these drugs, more slowly are likely to go onto insulin than if they were not prescribed these drugs. So, are other cardiovascular benefits explained by these simple risk factors lowered? And the answer is no, they cannot be explained simply by the combination of glucose reduction because the benefits that we see in cardiovascular outcomes are too fast. We know from lots of epidemiology and other trials, glucose reduction does have a benefit in heart disease, but it's a slow gain. It doesn't happen relatively fast. The blood pressure and weight reductions we see with these drugs are too modest to explain benefits that we see within the two to three years of some of the clinical trials that have reported. So, there are other likely benefits which are direct effects of these drugs on blood vessels. This particular slide is a slide from Dan Drucker, published in Cell Metabolism 2016, and here Dr. Drucker shows a range of mechanisms by which GLP-1 may lead to an improvement in atherothrombosis and this includes for example reduction in inflammation, reduced ischemic injury, improvement in blood flow, reduction in smooth muscle cell proliferation, and improved plaque stability. So, lots of studies are on the go to work out how these drugs are working but I can tell you for a fact that we are pretty convinced in the scientific community that they are having benefits over and above glucose, blood pressure, weight reduction, and one of the key studies that tells us this in this meta-analysis was the HARMONY Trial. HARMONY used a drug which has perhaps one of the least benefits on glucose and weight, yet it has one of the best benefits on myocardial infarction, suggesting that different classes of drugs aren't having specific effects on atherothrombosis independent of the measureable benefits that we see on glucose, weight and blood pressure. There are multitudes of studies ongoing, which are really conducting what's known as reverse translation, studies in the range of pathways which you can see in the right-hand box that tries to uncover what benefits these drugs are having on different pathways. This is a review that we've done of these studies, led by Dr. Matthew Lee within our group, and if you look at this particular slide and I don't expect you to read it in detail but this shows you the wealth of studies that are currently ongoing that are looking at a range of pathways including cardiac tissue, vascular, renal, respiratory, metabolic, biomarkers, hepatic tissues, musculoskeletal and neurological. So, over the next four to five years, we will know far better how GLP-1 receptor agonists are leading to atherothrombosis, over and above our current understanding. Finally, therefore, if I was to summarize what I've told you, it is the following: GLP-1 receptor agonists by definition include glucose control, because they enhance the efficiency by which glucose leads to insulin release in the pancreas. They also lead to weight reduction which further improves glucose control by reducing insulin resistance, and they improve blood lipids. They also lead to improvements in blood pressure, both through weight reduction and through a combination of direct effects on endothelium and other factors and they have a range of other direct mechanisms on a variety of tissues that in combination with the measureable effects lead to a reduction in atherothrombosis. Thank you very much.

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