Dear colleagues, It's a great pleasure to welcome you to this online case discussion. My name is Niko Marx. I'm a cardiologist from the University of Aachen in Germany and I'd like to introduce my colleague professor Lehrke also from the Cardiology Department here, in Aachen and Michael, you're going to present us a case on CV risk in diabetes.

Yes, Niko. Well, let's start with my disclosures. So I brought a case, an everyday case, this patient, which came to our department with acute myocardial infarction, who is directly brought to the cath lab, where closure of the LAD was found and PCI was performed. The history of this patient is a patient who had coronary artery disease diagnosed before and he had PCI of the RCA done eight years ago and PCI of the RCX done four years ago. So he's got three vessel disease and obviously the disease hasn't come to stop. So we've seen progression over time, it's not been the only vascular bed where we see atherosclerotic disease. But there's also peripheral artery disease IIb and if we look at his risk factors this patient was diagnosed with diabetes when coronary artery disease was diagnosed first, eight years ago. So he's already got indication of macrovascular disease, he's got diabetic retinopathy and he's also got chronic kidney disease, which most likely is also attributed to his diabetes. In addition, he's got dyslipidemia, he's got hypertension and he's got obesity.

And with all these diagnoses, he already was treated with different medications. So what we found when this patient came to the hospital was he was treated with metformin. With two grams a day. He did receive sitagliptin, he did receive ramipril and amlodipine to treat his hypertension. And for LDL-cholesterol, he was treated with atorvastatin with 20 milligrams, a day. So what was reached with these drugs?

As we said, he has got not really obesity, he is more overweight. He's got a BMI of 29 kg per square meter. He does still have arterial hypertension, although already being treated with two antihypertensive drugs. His diabetes is not well controlled. His HbA1c is 8.2.His eGFR was 78 milliliters per minute, indicating CKD II. His LDL-cholesterol we see, 20 milligrams atorvastatin, is lowered below 100, but not below 55 which it should be. So he's got 84 milligrams per deciliter LDL-cholesterol. His triglycerides are elevated, consistent with this increased HbA1c, is 265 milligrams per deciliter. HDL-cholesterol is lower as indication of metabolic syndrome and also as a parameter which is a little bit interesting CRP, non HDL-cholesterol is 122 milligrams per deciliter. There's also some indication of inflammation with an elevated hs-CRP of 10 milligrams per liter, which is novel. And we're thinking about inflammation, more and more these days. Also, in cardiology and happily enough, we found that also after acute myocardial infarction, because he came early, he still had normal left ventricular function, with a left ventricle EF of 56%.

Well, Michael, this is full program, there's room for improvement. There's a couple of things we should address and I totally agree with you. And so it's not only one risk factor, which is relevant for patients with diabetes. I think we all agree. The patient with diabetes is at cardiovascular risk. How do you say? I'm not saying catastrophe, but very often there's a couple of different factors which we can improve.

So what is our possibility? Let's look at possibilities we have. This patient came in with acute myocardial infarction. We did perform PCI and obviously, because we did perform PCI did implant the stent, we need aspirin and we need a second P2Y12 inhibitor. So we used or use as a standard prasugrel in this patient, which should be given to him for 12 months in a combined drug therapy. Michael can I step in here? This patient had myocardial infarction already and you presented the medication when he came to the hospital, there was no aspirin. What happened here? That's difficult to say and is something which should be worked up and obviously this patient had an indication for aspirin and should have had aspirin from the beginning and then after the stent a second drug should be introduced for 12 months. Yeah. So, but that's life. - Okay.

Let's have a look at the blood pressure. Where do we want to go with the blood pressure? Well, I think the target should be less than 130 over 80 in patients with diabetes, there's good evidence, but not below 120 systolic, because there's an increase in events again and if I see a blood pressure of 145 over 85 with ramipril and amlodipin, there's again room for improvement and you adjust the therapy in your patient. And I totally agree and I think after myocardial infarction, we have a good reason to start the beta blocker, because this is going to help to reduce pro-atherogenic problems. Although we know beta blockers are not the first choice for blood pressure lowering and I think because there's quite a gap between 145 and 130, we decided to add a second drug. We also introduced a diuretic, but this is obviously something we have to follow up on and make sure that this combination is going to work. So this is something for the next visit, which is very important.

Now, the next point is obviously the lipids, so I already pointed out. LDL-cholesterol of 84 is not optimal. We want to go below 55 milligrams per deciliter. What is your suggestion? What I do? - The patient is on atorva 20 already, so you need to increase the dose, you can do 40 and then 80 but doubling the dose only lowers to a certain extent. So my suggestion would be to increase atorvastatin, then add ezetimibe as a second drug with the different mechanism because this patient is a really high risk patient, now, after myocardial infarction with diabetes. So we really want to make sure that his LDL is less than 55 milligrams per deciliter. And I totally agree and I think with the LDL-cholesterol we really have a good target to be sure that we improve the prognosis of the patient, and that's what we exactly did. We increased atorvastatin and we added ezetimibe and we are hoping to lower LDL-cholesterol below 55 milligrams per deciliter. The triglycerides, also non-HDL-cholesterol are secondary therapy goals. So we first want to make sure that we reach LDL-cholesterol because the evidence that we improved cardiovascular risk by also addressing triglycerides is less good, is something we should consider, but it's not our primary target, which is LDL-cholesterol. Michael, let me jump in here for a second. So for the triglycerides, I think you are right, it's not primary target. In addition his HbA1c is above target. So once we lower blood glucose, the triglycerides may go down further.

One quick point, you mentioned the CRP and the increasing or emerging role of inflammation in cardiovascular disease. Still, this hs-CRP is taken after myocardial infarction. So I think if you would want to address that, it's probably worth doing a control after a few weeks. I totally agree. So this is too early to make conclusions.

Okay, so this is easy for cardiologists, because we know blood pressure, lipids and all that. But let's come to diabetes. His HbA1c is 8.2 and there's again room for improvement. So what is the evidence that the reduction of blood glucose reduces macrovascular events? Just guide us through that. I think it's very important that we understand that patients with diabetes have strongly increased risk of cardiovascular disease and future events. But it's very difficult to address this disease. Although HbA1c is associated with worse prognosis. If we lower HbA1c this wasn't very successful for macrovascular disease. And we have a couple of different trials, because nobody was willing to believe that this is not gonna work, but it's just different in comparison to LDL-cholesterol or hypertension lowering HbA1c doesn't necessarily improve prognosis with macrovascular disease and this is shown here. This is the evidence: ACCORD, ADVANCE, VADT. So that was a bit of a frustration.

At the same time, and that's the good thing, the scene has moved on and we've learned that if we use specific drugs, we find specific drug classes which are very well able to improve prognosis in patients with diabetes. This whole thing started with DPP-4 inhibitors. So these were the drugs, which first were needed to prove evidence. These are cardiovascular safe, but they don't improve prognosis. But then, nicely, we must say we did find out that we have SGLT2 inhibitors and also GLP-1 receptor agonists and these drugs have much better evidence, and we now know that if we use these drugs, we finally are able to improve prognosis in patients with diabetes.

So this is the evidence for the GLP-1 receptor agonist and the important thing is that we by now have different substances and they all show the same results. So it's easy again for us because we have good evidence and the results are complementary. We can now basically bring them together and really be sure that we do something good for the patient. So we do have a guideline from 2019 which will be renewed very soon, I think next year actually, but because of this evidence we now have a class I indication to use GLP-1 receptor agonists in patients with high cardiovascular risk.

So can I ask you Niko, how would you approach this patient and what is the evidence? How can you basically bring this all together? Well, in the guidelines the first step is not to look at HbA1c, but look at cardiovascular risk first. And this patient, and that is shown here, he has ASCVD, so he's a very high-risk patient. And for this particular patient population, and maybe you can show the trials, we have evidence for both SGLT2 inhibitors and GLP-1 receptor agonists, and you showed the data for the GLP-1 receptor agonists, that they work independent of HbA1c lowering and reduce cardiovascular risk. And only if a patient doesn't have ASCVD or is at low or moderate risk, based on UKPDS, we would recommend metformin as first-line therapy. Important here is that patients with ASCVD receive one of these drug classes for which we have seen a reduction in cardiovascular morbidity and mortality, but the question is, which of the drug classes would you choose?

Let's look at the evidence, Michael. I think, and this is very important, I think we learned that the way SGLT2 inhibitors and GLP-1 receptor agonists work are very different. While SGLT2 inhibitors mostly reduce the risk for heart failure and improve kidney function and then by these mechanisms also improve general outcome, GLP-1 receptor agonists work differently and we also have the similar evidence that we have in the meta-analysis of all these trials, which I just presented to you, they have reduced all-cause and cardiovascular mortality, which is I think the most important endpoint to look at. But then if we look at the individual outcomes, we see that especially cardiovascular events get reduced, which is myocardial infarction and stroke, so it looks more like GLP-1 receptor agonists work in the vessel and improve atherosclerotic cardiovascular disease, which also is supported by the way the curves separate under the CRP. Importantly, if we look in patients with diabetes, which in these trials, mostly didn't have heart failure, they also work in reducing heart failure as a prevention but obviously SGLT2 inhibitors are more efficient for heart failures as we've learned. And the same is true with renal outcomes, still GLP-1 receptor agonists also for renal outcome show improved prognosis.

So if I get you right, in this particular patient with vascular disease in at least two beds, you want to reduce the atherosclerosis-related events but you showed us there are many different agents, which one would you pick? I think it's important, and that's what I say, it's very good if we see similar results with drugs being structured a little bit differently but still showing similar evidence. And this is just the landscape of GLP-1 receptor agonists. We have short-acting drugs and the field has moved to long-acting drugs, meaning that we only have an injection performed once a week or by now, there's also an oral semaglutide available. So this again is a moving target that we don't have to inject these drugs potentially anymore. And again, showing the cardiovascular evidence. We either have cardiovascular safety for some and more, where we have cardiovascular superiority. And this slide is not showing all the different substances which have shown cardiovascular superiority by now.

So, just to give one example on how these drugs are modified, this is GLP-1 with its peptide structure, and GLP-1 is cleaved very easily by DPP-4 so that's why at position number two, there's a modification of the peptide performed in the example of semaglutide, so it can't be cleaved by DPP-4 anymore. And then there's other modifications where we have attachment of a fatty acid, and this allows this peptide now to attach to albumin, so we have a strongly increased half life, which means we only have to inject it once a week.

And importantly, now we do not only have effects on blood glucose which obviously is a main indication for using these drugs. But the same time, there's no strong evidence that the lowering of the blood glucose is actually then improving prognosis. And the question remains at the moment. What is the real mechanism? And to be honest, we don't know, but there's pleiotropic effects. If I can use this word, we have a strong effect on body weight, which definitely is beneficial in patients with type 2 diabetes, because they're mostly obese. We have a nice effect on blood pressure, which helps. Both of them probably also do not explain why we have the reduced cardiovascular risk. Most likely, there's also direct effect in the vessel and we come back to inflammation. It looks like the GLP-1 has immunomodulatory actions, which I personally believe is a strong driver for the beneficial cardiovascular effect of this drug class.

So let's come back to our patient. We already had metformin in there, there was sitagliptin, if we now did use a GLP-1 receptor agonist, we'll take out sitagliptin, because this doesn't make sense to combine those two drugs. So that's what we did. We took out sitagliptin and we introduced semaglutide in a low dose of 0.25 milligrams, which is low, but it's important to start with a low dosing, because there's a certain risk for side effects, which means there's gastro-intestinal effects. If you start slowly and you slowly increase in a four week interval, most of the patients will very well tolerate introduction of the drug. It's important to talk with the patient about this point, because this could otherwise create confusion or frustration, but it's also important to make him aware. This is going to help him to lose some weight, which is a secondary therapy goal. I think something that helps to make sure that adherence works is we simply explain to the patient: small meals and not too spicy in the beginning, that may also help to reduce GI side effects, indeed.

So we are both cardiologists and in our department indeed, we implemented a system to start therapy but with respect to diabetes, this patient has retinopathy. There's some more things to do. So how do you in a practical way interact with our colleagues from the diabetes field? Because I think this patient needs a complementary approach. And this is very important and that's another point which we can address. Because if you have retinopathy in a proliferative way, you want to make sure you don't lower HbA-1c too drastically and too fast. So it's important to include all your colleagues, and in this case, especially, also the eye doctors, because you want to have a slow decrease of blood glucose in this patient, because otherwise you have some danger for the eye, which you definitely want to avoid and otherwise, it's always good to have conversations with your colleagues and also obviously with the endocrinologist to make sure we all pull on the same string to make sure we reach what we want, which is reduction of cardiovascular risk.

Michael thanks a lot for presenting the case and for the discussion. I'd like to thank you for your interest in this online format. Thank you very much. Thank you very much, it was my pleasure.

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