Dear colleagues, it’s a great pleasure for me to welcome you to this case discussion about diabetes.

My name is Nikolaus Marx. I'm a cardiologist from Aachen in Germany. And with me is Professor Adie Viljoen from Cambridge. We will discuss this case together. Adie, good to have you here. I will hand the conversation over to you.

Niko, it is great to be here with you. Thank you very much. These are my disclosures. I'm involved in a lot of clinical trials in diabetes, obesity, and cardiovascular disease.

I want to introduce this patient to you, Jonathan, he's a lawyer as you can see. He's 58 years old, he has type 2 diabetes, which he has had for approximately three years, but obviously, we don't really know. He may have had hyperglycemia for longer and when we did a blood test we discovered that he may have had diabetes. You will see that he has a strong family history of diabetes. He has a sedentary lifestyle. He is very stressed, he smokes a lot, which is an additional risk factor. And you can see his blood pressure there. But again at the bottom you can see that weight is a real issue for him. He has a high BMI.

So, why did he end up seeing me in clinic? Well, he was referred to me because of the fact that the primary care physician mentioned that he couldn't take any statins. That they give him muscle aches and pains. You can see clearly that his lipids are not well controlled. Obviously, diabetic dyslipidemia features quite strongly and he has high triglyceride levels. And then you can see his HbA1c levels. Many clinicians may believe that 7.6% is not that bad. But we certainly see a lot of risk factors,

Niko. Maybe you want to comment on this type of patient? Absolutely. So, this gentleman is a high cardiovascular risk patient. He has not only diabetes but he also has hypertension. His blood pressure is too high for someone with diabetes. So here we would aim to lower the blood pressure to less than 130 over 80. Not too low: not lower than 120, systolic. In addition to that, his lipids are too high. We need to actually treat this. Obviously, he had statin but it is a very common situation where people say, we have muscle pain. I think it's worth further evaluating that and trying to get back on statins. The HbA1c is not too bad actually and it depends on his medication, whether we can improve something.

Thank you very much for that and, as you say, this is a multifactorial risk factor intervention and we in the diabetes world have been often blamed to be very glucose centric. And often we would look at this HbA1c of 7.6% and say, well that's actually reasonably good, but of course, there are so many issues to deal with this patient, Jonathan. We have to think of his lipids, as you say, what about his blood pressure, which you've already alluded to. And I think the lifestyle is a real issue. He is overweight, he smokes, he's stressed. This certainly adds to both these micro- and macrovascular risks, which he is probably going to develop or may have developed already. We have to tackle so many things in this consultation, and we also have limited time in a consultation to talk about all these things with one patient. Smoking cessation, of course, is really important, and it is difficult for patients to stop smoking. So a lot to address with this patient.

Multifactorial risk factor intervention is important for patients with type 2 diabetes. But let's take a look at his medication. And there, you can see, he's on metformin, he's on ramipril five milligrams, he's on omeprazole and I wonder why, perhaps, it's because he's overweight. He may have some dyspepsia, he smokes. So lifestyle could potentially add to get rid of omeprazole.

Niko, maybe you can comment on the ramipril 5 milligrams and that blood pressure. Yes. Well first of all, it's good that he has an ACE inhibitor, because we've known for years that RAAS inhibition is good for the kidney and good for the prognosis. Still, ramipril has a half-life of about 13 hours so usually, we would give that twice daily and seeing his blood pressure I think it would be good to up titrate to twice 5 mg. Yes, indeed and you'd say, obviously the one medication that's lacking is a statin. So I think the key here is, as you say, a lot of patients claim on statins intolerance, musculoskeletal symptoms and we know some patients do have that, but a careful history and examination could reveal more, as it did in this case. So I asked him a few more questions and he actually doesn't have musculoskeletal symptoms, but these are precipitated when he actually walks. And that has led me to investigate this further with ABPI, ankle brachial pressure index, which can be quite easily done within the clinical setting. And you see these are diminished especially on the left for him. So this tells us that he has insufficient circulation because of atherosclerotic disease, most likely. And that's certainly a huge risk factor.

So to come back to what I've done in my management plan for Jonathan, is to convince him to restart the statin. That took quite a long conversation. But, actually, I think when he saw these pressure indices being lower in his legs, he could understand that there might be something more concerning going on. We are thinking of starting platelet inhibition and to start him on clopidogrel. I referred him to vascular surgery. I think, the other main thing, Niko, here is, what do we do about his type 2 diabetes? It's not only about glucose, but about multiple risk factor intervention. Are there any anti glycemic medications, which can be used? What do the guidelines actually tell us? I think one point here is, he has type 2 diabetes, he's on metformin, but HbA1c is still high. So it's not bad but it's not at target. So, ideally, I would aim for an HbA1c less than 7. Here we need to consider therapies that do not increase weight and do not lead to hypoglycemia. And, ideally, have some cardioprotective effects. And if we think about these agents, of course, dpp-4 inhibitors are safe, don't cause hypos, but there's no weight loss. We have SGLT2 Inhibitors in patients without proven ASCVD. The evidence is not that strong. It mainly reduces heart failure. GLP1 receptor agonists is certainly something we need to consider. In particular, given that this gentleman is overweight and that weight reduction is of benefit, it makes patients happy.

And indeed as you can see here, we have the consensus statement from the EASD/ADA recommending the use of these medications and you'll see metformin right at the top. But when we consider patients with atherosclerotic cardiovascular disease, these are the medication, the drug classes that should be used in preference. So the GLP-1RA preferably and also highlighting to you, that these are medications, the ones with proven cardiovascular benefit, which we should use. And as you say Niko, there are additional benefits as we go across. Then if patients have weight issues or weight concern, especially in this patient Jonathan, we have to consider again as you can see the GLP-1RA and SGLT-2i class really feature here.

So how did the consensus statement come up? There are these kind of guidelines. Are they evidence-based? And the answer is yes, in the affirmative. And here, I'll show you a meta-analysis from eight GLP-1 trials that have reported now. And you see huge numbers of patients that were involved in these studies. And overall we see great benefit for this GLP-1 class. I've highlighted one specific box, the oral semaglutide for you. And the reason because of these eight trials, we've got two with this semaglutide molecule and they are all injectable medications, apart from semaglutide which is also available in the oral form. So, we have this evidence base and we should really be using these medications as recommended by the guidelines culminated with this meta-analysis which we can see with all the data we now have at our disposal. So really ...May I jump in here? - Yes. This is the three-point MACE, which is CV death, MI and stroke, the combination. But if we do a deep dive in these data and look at MI and stroke. Can you tell us something about this data based on the meta-analysis, which I think is very important in this context. So, indeed, I think when we look at the data, obviously, this is a three-point MACE, There are individual benefits. A lot of the benefits that we see in the GLP-1, if we look at the kaplan-meier curves, we see that the benefit is actually related a lot to potentially interacting in atherosclerotic cardiovascular disease. So earlier on in treatment, they may influence the development of atherosclerosis. And therefore we want to use these agents earlier.

So once we've decided to start our patients on these medications, what can we expect in terms of side effects? So generally these medications are very well tolerated. The only main side effect that we have to talk to patients about is, that patients can develop nausea, less so vomiting but patients can develop nausea and therefore we titrate the dose and we warn them not to have big meals, but we can titrate the dose, so we start on lower doses and we go up. And if we do that, these side effects dissipate over time. And here, I've listed for you all the GLP-1 and as you can see nausea being fairly common and that is the main thing that we have to address with patience. That we have to overcome this nausea and patients do overcome that, if we are able to titrate the dose over time and this dissipates and also think of larger meals, etc.

So, these medications also have a lot of other cardiovascular metabolic benefits. Of course Niko, you obviously know much about this, the reductions in blood pressure, reductions in urine albumin. Well, these agents lead to a robust reduction in blood pressure, which I think is very important, and coming back to our patient this may really be of help. The weight reduction important, but then also the effect on the kidney here with these agents. We see a reduction in UACR. So, this is also a benefit and this in combination with the potential what we call pleiotropic effects, meaning direct effect in the vessel wall, anti-inflammatory, anti-atherogenic properties.

I think this might explain why, kind of surprisingly, when we saw the first data, These agents lead to such a robust reduction in cardiovascular events and I think this is contributing to it. And when we make a choice of what treatment our patients should receive, obviously, we see this great cardiovascular benefit, we need to prescribe the medications, which have shown benefit within the trial setting, which I've just shown you. But also if we look at other parameters, which of course are important for us in the diabetes world, a lot of the trials, the primary endpoint is the HbA1c, and you'll see, this is a combination of a lot of data here. I've boxed one of the head-to-head trials, in which we've had, I co-authored this paper, which is a comparison to canagliflozin, a SGLT2 inhibitor, and you'll see canagliflozin being efficacious, but semaglutide actually being superior and we have a lot of data within the GLP-1 class, comparisons within the GLP-1 class or other comparators, as you can see, even insulin glargine which is quite an efficacious treatment, showing the superiority of semaglutide.

And then the other main thing I think for this patient Jonathan is the weight. Isn't it, Niko? I fully agree, he's overweight. And when he reduces weight, we may get the blood pressure a little down and he may be able to exercise and it makes people happy to see that they lose weight. And here, you have the data comparing these different trials and you can see there's a really robust reduction in weight with GLP-1 receptor agonists and this in particular showing here for example, the semaglutide data. Yes indeed, and I think that's one of the big challenges, of course, we all face. We tell patients about their parameters. Your lipids are better, but they don't necessarily feel better. In fact, he came and said, well, the statins give me side effects. And maybe when the HbA1c improves, but the one thing that is tangible for patients, is if the weight comes down and I think that's a fantastic tangible effect which patients experience. So patients, have all these benefits from these medications.

We think of this great cardiovascular benefit that patients are receiving, but the question is, how are we doing in terms of prescribing in the real-world setting? And I just want to briefly just show you one study called the CAPTURE study, which is recently published, recent data, 13 countries, five continents, 10,000 patients looked at prospectively. And Niko, as you can see there, if we look at the Y-axis at, these are patients receiving either a SGLT2i or a GLP-1RA. And you'll see actually a very low proportion. That's really kind of shocking data for me when I saw these, because we have good evidence and in my mind or based on the data, these agents belong to the group of platelet inhibitor, blood pressure-lowering agents and statins for which we have clear benefit that they reduce morbidity and mortality. And I think the key question is, what can we do to overcome this low prescription rate? Is it clinical inertia? Is it being afraid of injectables or something like that? I can share with you the concept we have here in our department. We have first of all a concept that every patient who is referred to Cardiology, is screened for the presence of diabetes. And then we have clear, we developed what we call white coat cards, that every resident can carry with him, we have all the instructions, how to start the treatment? What are the limitations if kidney function is reduced? And this has helped to kind of overcome that people are hesitant to prescribe these drugs. And for example, we usually give the once-weekly GLP-1 receptor agonist, start at a low dose. But what we learned and this may also be important in this context, we need to educate the patient. Small meals, no spicy food. And titration should be done over a couple of weeks and this has been successful. But in addition to that, I think we need to make sure that at least in the Cardiology world. People understand that these data, the data from these trials, show clear evidence for risk reduction. And maybe if we meet in a year or two, hopefully we'll see different data, but there is a clear need: a call for action. Indeed, and that's a fantastic example that you have. And in the UK, there are more of more of these cardiometabolic clinics happening and we are coming together as a community. And I think that's important,

it's a great to be with you today, Niko, as a cardiologist to talk about this, not only to talk about diabetes and to talk about glucose, but to talk about atherosclerotic cardiovascular disease, and what it means for our patients and the fact that we can do so much more for our patients with type 2 diabetes. We have these agents available. They are available, widely available, and we should just be using them more and then our patients can benefit and close this gap which we know exists between patients with type 2 diabetes and patients that do not have this.They have this accelerated atherosclerosis and we can actually just buy time, time for our patients. - I fully agree Adie. I couldn't agree more. It's time to apply the evidence and I think it's time to team up and make sure that we overcome the hurdles that prevent patients from receiving these drugs.

Adie, thanks for the case. Thanks for a great discussion and thanks to our colleagues for attending the session. Thank you very much. - Thank you very much.

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