This is my Conflict of Interest slide. I have interaction with various companies but do not take any personal honorarium. The cardiology challenge to manage diabetes in cardiovascular risk reduction over the next 10 to 15 minutes I would like to discuss four points with you, starting with cardiovascular risk in patients with diabetes. If you look at death from cardiovascular disease, over the last years from 1998 to 2013, you can see that there is a clear decline in events based on the introduction of various therapeutic approaches such as ACE inhibitors, statins or interventional strategies in cardiology but if you compare CV death in cardiovascular-CV death in patients with type 2 diabetes to non-diabetic subjects, you can see even today there's a two-fold increase in risk in patients with type 2 diabetes and broken down to a man of 60 years of age today, this is his life expectance and if, if he has diabetes, he loses six years and if he has diabetes and has suffered from a myocardial infarction, even loses 12 years, suggesting that there's a tremendous need to reduce cardiovascular risk in patients with diabetes. Over the last years, we have seen large cardiovascular outcome trials in patients with diabetes with glucose lowering agents that I'd like to share with you the evidence here. A total of 16 cardiovascular outcome trials have been published between 2013 and 2019, with novel agents and two classes of agents are in particular importance here when talking about risk reduction and these are GLP-1 receptor agonists and SGLT-2 inhibitors. SGLT-2 inhibitors block in the proximal tubule of the kidney the reabsorption of glucose, thus leading to an increased urinary glucose excretion and since this is a co-receptor for sodium, there is also an increase in sodium excretion. Several large cardiovascular outcomes trials, placebo-controlled, have assessed the effect of these agents on cardiovascular events here and three of the trials showed a significant reduction of the combined 3-P MACE endpoint of CV death, myocardial infarction and stroke. In EMPA-REG Outcome, you have Empagliflozin, in the CANVAS program Canagliflozin, and in the dedicated CKD diabetes population, Canagliflozin showed a significant reduction of 3-P MACE. In DECLARE, Dapagliflozin showed a trend towards a reduction but this was a lower risk population with only 40-percent of the patients having cardiovascular disease and the result here was non-significant. In addition, in the recently presented VERTIS CV Trial, Ertuglifozin did not have a significant effect on 3-P MACE. In addition, the combined end point of heart failure hospitalization or cardiovascular death was significantly reduced in these three trials here, Empagliflozin, Canagliflozin, and Dapagliflozin, they all versus placebo reduced the combined end point of heart failure hospitalization or CV death. In contrast, the recently presented VERTIS Trial showed a trend but the effect was not significant for Ertugliflozin on this end point. However, in the VERTIS Trial, like in the other trials, Ertugliflozin also led to a significant reduction of heart failure hospitalization alone, an effect that started like in the other trials very early in the beginning of the trial. In addition, in one of the trials, the empiric outcome trial, Empagliflozin significantly reduced all-cause mortality. You can estimate here 32-percent significant risk reduction in patients treated with Empagliflozin compared to placebo. The second important class when talking about CV risk reduction are GLP-1 receptor agonists and these agents activate the GLP-1 receptor, thus mimicking the activity of the incretin hormone GLP-1 and thus leading very-by various mechanisms to reduction in blood glucose. Four large cardiovascular outcome trials with subcutaneous applicable GLP-1 receptor agonists showed a reduction in 3-P MACE. The Liraglutide in LEADER, SUSTAIN-6 showed this for Sernaglutide, Albiglutide in HARMONY and Dulaglutide in REWIND. They all showed versus placebo reduction, significant reduction of the 3-P MACE endpoint. In addition, in one of the trials, LEADER Trial, the Liraglutide significantly reduced all-cause mortality versus placebo so there is overwhelming evidence in the high risk group of patients with type-2 diabetes that one of these agents can reduce cardiovascular risk and this had important impact on most recent guideline recommendations and have led to a shift in paradigm focusing on CV risk reduction rather than on glucose lowering alone, and so the first guideline I'd like to talk to you is the ESC guidelines that we published last year and here, there was a shift in paradigm because the first step irrespective of HbA1c is the assessment of the CV risk category. There are three categories. Patients at very high risk are those with diabetes and established cardiovascular disease or end organ damage such as kidney, chronic kidney disease or left ventricular hypertrophy or a patient with three or more additional risk factors. High risk patients are those with a long duration of diabetes but no end organ damage but other risk factors and this is the definition here of moderate risk. So this is the first step, and once patients are categorized it is important to initiate treatment here and I show you one example, so if a patient has cardiovascular disease or is it high, very high risk? Such a patient should receive an SGLT-2 inhibitor or a GLP-1 receptor agonist based on the overwhelming evidence coming from the large cardiovascular outcome trials with SGLT-2 inhibitors or GLP-1 receptor agonists. If the patient is at moderate risk, Metformin monotherapy is recommended as a Class 2A recommendation. Let's look at the tables and clear recommendations that are given in these guidelines, empagliflozin, canagliflozin, or dapagliflozin are recommended in patients with type 2 diabetes and cardiovascular disease or at very high, slash, high risk to reduce cardiovascular events, a Class A recommendation, again, based on the evidence that I shared with you. In addition, with respect to GLP-1 receptor agonists, Uraglutide, sernaglutide, or Dulaglutide are recommended in these patients also to reduce cardiovascular events as a Class A recommendation so strong recommendation in Level A means there is good evidence from several trials and these are the trials that I shared with you. Moreover, Liraglutide is recommended in these patients to reduce the risk of deaths. This is a Class 1 recommendation coming from one trial, the LEADER Trial, which showed the reduction in all-cause mortality. The most recent update of the ADA EASD consensus also followed a shift in paradigm by suggesting as the EASD did that these agents, SGLT-2 inhibitors or GLP-1 receptor agonists should be prescribed, irrespective of baseline HbA1c or individualized HbA1c targets so also in these guidelines in addition to glucose lowering, see the risk reduction based on the data from the last cardiovascular outcome trials is the most important step here. The question is how in cardiology department can this be managed, can this be approached? And here, what I would like to introduce to you is our approach her in Aachen to manage patients with diabetes. In our cardiology department, which is a large interventional department, we performed diabetes screening in all patients that are hospitalized here for an intervention, for heart failure, or another kind of cardiovascular disease and so if the HbA1c measurement, which is performed in all patients shows an HbA1c of 6.5 or above and a fasting blood plasma glucose is 126 or higher, the diagnosis of diabetes is made. If the HbA1c level is in between, between 5.7 and 6.5, we recommend an OGTT, and if the diagnosis of diabetes is made in our department, we start Metformin therapy and one of these drugs, an SGLT-2 inhibitor or a GLP-1 receptor agonist. There's been a lot of discussion whether this can be done in a cardiology department but there is increasing evidence for example coming, first GLT-2 inhibitors from a trial showing that the initiation of the drug in patients re-compensated after cardiac decompensation is feasible and is safe in such a condition. So, to summarize the management of patients with diabetes and cardiovascular disease from a cardiologist's point of view, the first important step is risk stratification based on risk factors or the presence of cardiovascular disease and so patients are categorized in moderate risk, high or very high risk, and those at high or very high risk, and these are the patients that we usually see in our department, if the patients are in this category, an SGLT-2 inhibitor or a GLP-1 receptor agonist with proven cardiovascular benefit should be prescribed. Thank you for your attention.

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