Activity Transcript

Chapter 1

Tina Vilsbøll, MD, DMSc: Hello. My name is Tina Vilsbøll. I am a doctor and a professor working at Steno Diabetes Center in Copenhagen, Denmark, affiliated to the University of Copenhagen. I'm here to share with you my thoughts about whether strengthened glycemic control correlates to cardiovascular risk management in patients with type 2 diabetes.

Many, many things have happened in recent years, and we have learned a lot. We do, unfortunately, now know that patients with type 2 diabetes are so much more likely to suffer from cardiovascular disease and related death. Nearly 87% of patients with type 2 diabetes, they actually have increased risk of cardiovascular disease. We also know that 3 out of 4, or 75%, of our patients with type 2 diabetes, they actually die due to cardiovascular disease, numbers that are much higher compared to patients without diabetes. And finally, we know that cardiovascular mortality is almost 200% higher among patients with type 2 diabetes when we compare them to individuals without diabetes.

One of the things we discuss a lot is when does it start, and is it a continuous thing? It is so that type 2 diabetes progress. And unfortunately, both micro- and macrovascular complications, they do in some patients start even before they're diagnosed. Inflammation is a continuous process, different speed in different patients, but ending towards the right towards atherothrombosis, plaque instability, and an increase enough of patients to get cardiovascular disease events with thrombosis and so on.

Macrovascular complications affect multiple organs, and it can actually occur since its start. The development even before they're diagnosed, it can occur early in diabetes. Coronary artery disease, more than 25% of our patients who are actually asymptomatic. They actually have findings which show that they have coronary alterations if we screen them. They have an increased risk of heart failure. Also, peripheral arterial disease, and also a devastating condition as stroke is a 2-fold increase within is 5 years after the diagnosis of type 2 diabetes. So they are, indeed, our individuals were type 2 diabetes, are indeed high-risk individuals.

What do we do about this? Well, it's not simple. For decades, we have as diabetologists focus very much on decreasing glucose. Cardiologists focus on their part. But what we know today is that multifactorial intervention is important. We have to control glycemia. Oh yes, indeed. And indeed, with specific drugs. We also had to look towards lifestyle modification, lowering blood pressure, and control dyslipidemia.

That was done very beautifully by the Steno-2 study published years ago. We now have a 21-year follow-up of the Steno-2, beautiful effect on mortality rate, microvascular complications. And actually, the individuals in the multifactoral intervention which was conducted in high-risk individuals in the Steno-2, they experienced 8.1 years more until the first cardiovascular event. And they lived longer, indeed.

The Steno-2 was a beautiful trial, but the patients did still have a higher risk compared to other trials. And I could spend hours talking about the beautiful trials, the UKPDS, the ENCORE, the ADVANCE, the VADT study demonstrating effect on microvascular complications. But until recently, until we had these new classes of glucose-lowering drugs, SGLT-2 and GLPq1s, we were actually not able to change the destiny, you could say, of cardiovascular disease.

But we still have room for improvement. We have talked a long time about patients being dysregulated. What we know of today looking at these days published in 2021, in blue, illustrated HbA1c below 7[%], but in red, patients with HbA1c below 8[%]. The number of patients who are not in a good glycemic control are still far too high in our patients out there. Uncontrolled glucose levels are associated with a substantial mortality and an increased cardiovascular risk numbers with respect to microvascular complications. But with respect to cardiovascular disease, 8% in stroke and myocardial infarction, and with respect to cardiovascular disease, an increase of 15%.

The consequences of clinical inertia in type 2 diabetes matters. It's summarized here. Increased healthcare system and public health costs, it's just more expensive not to be aggressive in the treatment. We know that the slower you are, the more clinical inertia we have in the clinic, there is a reduced likelihood for the patient to actually achieve target. We know that there is increase of a cardiovascular event and also the microvascular complication. So therapeutic inertia is an important contributor to the excess cardiovascular event in patients with type 2 diabetes. We have done a lot recent years, but there's so much more to do for us right now and in the future.

Chapter 2

Nikolaus Marx, MD: Hello. My name is Niko Marx. I'm a cardiologist at the University of Aachen in Germany, with a longstanding interest in research and treatment of patients with diabetes. Today, I'd like to discuss with you the evolution of cardiology/diabetes society guideline recommendations regarding the use of glucose-lowering drugs with proven cardiovascular benefit.

Given the fact that I'm a cardiologist, I'd like to start with the most recent 2019 European Society of Cardiology (ESC) guidelines in diabetes, prediabetes, and cardiovascular disease from the European Society of Cardiology developed in collaboration with the European Association for the Study of Diabetes. And important, it does not take into account other factors such as drug approval or cost, which is taken into consideration in other guidelines.

This guideline, as a first step in patients with diabetes recommends cardiovascular risk stratification. Patients at very high risk are those with established cardiovascular disease and diabetes, or diabetes and other organ target damage, or diabetes and 3 or more risk factors, as well as early onset of type 1 diabetes of long duration. High-risk patients are those with diabetes with the duration of 10 years or above without target organ damage, but other additional risk factors. And then, there's a group of patients at moderate risk.

And [the first question, when we are seeing a patient with diabetes, is to assess whether the patient has ASCVD, so atherosclerotic-related cardiovascular disease, or is at high, very high risk. If this is the case, there's a class 1 recommendation, which means it is recommended to treat the patient with an SGLT2 inhibitor or a GLP-1 receptor agonist, based on the overwhelming evidence that has been created over the last years in cardiovascular outcome trials. And if this is not the case, the patient's at moderate risk, the recommendation is a class 2A. Patients should receive metformin, based on the UKPDS data in the population of patients with newly diagnosed diabetes and no cardiovascular disease.

To put this together. First step is risk categorization, and then depending on the presence of risk factors or ASCVD categorization in moderate, high, or very high risk. And those at high or very high risk are recommended to be treated with an SGLT2 inhibitor or GLP-1 receptor agonist with proven cardiovascular benefit.

Then, at the same time, the American and European Diabetes Association published a consensus document here. In here, first-line therapy is always metformin. Then, again, based on cardiovascular risk, patients should receive either a GLP-1 receptor agonist or an SGLT2 inhibitor based on the presence of ASCVD or a heart failure or chronic kidney disease.

There's been a lot of discussion when the cardiology guidelines were published between cardiologists and diabetologists. And I'd like to focus on 1 aspect. The ESC guidelines recommend GLP-1 receptor agonist, or SGLT2 inhibitors as first-line therapy or a second line after metformin monotherapy, while the diabetes guidelines recommend GLP-1 receptor agonist and SGLT2 inhibitors as second line, after metformin. Slight differences. There's been a lot of discussion, but more important, and this is something that I'd really like to stress here, more important than this difference is the shift in paradigms in 2019. In both guidelines, given that GLP-1 receptor agonist and SGLT2 inhibitors should be given independent of individual HbA1c targets and baseline HbA1c. So, based on cardiovascular risk.

Interestingly, the most recent guidelines from the American Diabetes Association recommend independently of baseline HbA1c or individualized HbA1c drug or metformin, the treatment with GLP-1 receptor agonist or SGLT2 inhibitors. So, saying that it's important to give these drugs to reduce cardiovascular risk irrespective of glucose control and irrespective of baseline glucose-lowering medication.

So, clear recommendation of both cardiology and diabetology guidelines based on the evidence. But let's have a look, how often these drugs are given in clinical practice. Well, this is a study in almost 10,000 adults with patients with type 2 diabetes. And as you can see here, I only pick patients with type 2 diabetes and cardiovascular disease. So, those with a clear recommendation. And only 1 in 5 patients receives one of these drugs for which we have clear evidence that they reduce cardiovascular morbidity and mortality. And I think this is a clear call for action here. It's time to apply the evidence.

As a first step to ensure that every patient is identified, each patient with cardiovascular disease should be screened for the presence of diabetes, and patients with diabetes should be evaluated for the presence of cardiovascular disease. Because if both comorbidities come together, these patients exhibit not only an elevated risk for 3-point major adverse cardiac events (MACE), but also for heart failure mortality. And based on this, treatment should be tailored. For example, for a patient with diabetes and coronary artery disease, it is well established that this patient should receive antiplatelet therapy, low-density lipoprotein (LDL) lowering or blood pressure lowering. But now, based on the new evidence of the guideline recommendations, these patients should receive an SGLT2 inhibitor and, or a GLP-1 receptor agonist, because all of these agents improve the prognosis of this high-risk patient.

Chapter 3

Tina Vilsbøll, MD, DMSc: Hello. My name is Tina Vilsboll. I am a professor at the University of Copenhagen, Denmark, and I'm a consultant at Steno Diabetes Center, also in Copenhagen, Denmark. I have the honor today to share with you my thoughts about the rational for the multifactorial benefits about GLP-1, glucagon-like peptide-1, or the great little peptide being used in the clinic as GLP-1 receptor agonists. Right now, we actually have many different kinds of drug classes in our toolbox for treating type 2 diabetes. We have learned a lot of things recent years. We know that it is very complicated to treat type 2 diabetes because the phenotype of type 2 diabetes is not only something about insulin secretion, it is so much more than that. We know that the incretin hormones, a decreased incretin effect is important.

But with GLP-1 receptor agonists, it works widely in the phenotype of type 2 diabetes. And so does actually the dipeptidyl peptidase 4 (DPP-4) inhibitors, but the effect is not the same as with the GLP-1 receptor agonists. And then, of course, we have the SGLT2 inhibitors that we'll also talk a little bit about later. So treating type 2 diabetes is not just something about having glucose go down. We have a lot of risk factors that we are now here in this program talking very much about the correlation between type 2 diabetes, obesity, and cardiovascular disease. And there are, indeed, risk factors for arteriosclerotic cardiovascular disease in type 2 diabetes. There are some that you can't do anything about. Age, it happens for us all. We become older and older. Gender, you can do something about it, but it doesn't work in respect to the risk of atherosclerosis, arteriosclerotic cardiovascular disease.

And then genetics, but when we sit in front of our patient in the everyday clinic, there are several things that we can actually work on with respect to risk factors. That is hyperglycemia, large story itself, but is also hypertension, dyslipidemia, obesity, information, smoking, lifestyle, and then all these biomarkers working with respect to the heart and epicardial fat among that. It's actually treating the whole patient and treating all these risk factors that we see unfortunately in many our patients with type 2 diabetes. And the really interesting part about GLP-1 is that we have GLP-1 receptors widely spread throughout the body. We know that it is, indeed, in the pancreas, where it works by stimulated insulin secretion when glucose is on board, doesn't induce hypoglycemia. But we also have GLP-1 receptors in the heart. We know that the endothelial function is really interesting and interaction with GLP-1 receptor agonists in this aspect. We also know that the bone, we know that that's actually a story that we talk about with respect to GLP-1, but very much indeed these days also will dual action with GIP.

Then the gastrointestinal tract. Yes, that's actually where we see the side effects with the GLP-1 receptor agonists, but there are changes at least in the acute setting with short-acting GLP-1s with respect to gastrointestinal motility. With respect to the kidneys, it has been given quite a lot of attention, especially nowadays where we have the SGLT2 inhibitors, which clearly works in the kidneys, but GLP-1 actually also has some really interesting effects in the kidneys. We know that they do actually induce diuresis. They increase natriuresis, which is actually central in the very immediate effect that we see with respect to the blood pressure when we use GLP-1 receptor agonists.

Well, then these areas which are central in the brain for appetite, they are actually reached by the peripheral injection. It changes satiety, it changes appetite, and that it changed rewarding. And those of you who have tried to use GLP-1 receptors agonists have also had patients come back and said, "Well, doctor, you completely changed my cravings for the unhealthy stuff." Then we have some discussions on muscles and glucose uptake peripherally.

Most studies show that there are some effects, but that are probably indirect effects that you see after a body weight decrease. And then the liver. Lot of discussion going on there. Today, the overall take-home is that there are no GLP-1 receptors in the liver, but secondary effects due to all the great effects that we see from the pancreas and body weight and so on. We have had GLP-1 for the treatment now for more than 15 years in type 2 diabetes, it's still, to my opinion, not used in enough patients and things are changing right now. We are definitely seeing a drift towards also in the type 2 diabetes guidelines towards more attention towards obesity. Is that an issue? Yes, it is, indeed.

Because when you compare patients with type 2 diabetes who are obese and nonobese, you can see that the obese individuals they have a markedly increased risk of stroke, coronary artery disease, and all-cause mortality. So GLP-1 receptor agonists have multiple effects, really interesting effects. And it is so much more than just the glucose-lowering drug.

Chapter 4

Nikolaus Marx, MD: My name is Niko Marx. I'm a cardiologist at the University of Aachen in Germany. And today I discuss with my colleague Tina Vilsboll, professor at the Steno Diabetes Center in Copenhagen: which type of patients with type 2 diabetes at high cardiovascular risk should preferably be treated with long-acting GLP-1 receptor agonist versus SGLT2 inhibitors according to guidelines. And what I'd first like to do is to summarize the evidence. Six large cardiovascular outcome trials in patients with type 2 diabetes have been conducted, and these trials showed a clear benefit demonstrating that GLP-1 receptor agonists reduced cardiovascular endpoints in patients with diabetes and high cardiovascular risk. And a recent meta-analysis looked at this a little bit more in detail, just summarizing, first of all, here, the time to first MACE, the combination of cardiovascular death, nonfatal myocardial infarction (MI) and nonfatal stroke, and you can see a clear 14% significant reduction of 3-point MACE here.

And if one looks at single components, then I just focus here on stroke. For example, there's a clear significant 17% relative risk reduction in patients treated with a GLP-1 receptor agonist, and the same holds true if we look at the end point for nonfatal MI in these patients. So, these data suggests that GLP-1 receptor agonists reduce cardiovascular endpoints in patients with diabetes and high cardiovascular risk most likely through a reduction of arteriosclerosis-related events. And if one looks at another meta-analysis, this translates into a reduction in all-cause mortality in treated patients, and Tina, this is the data that we have. How do you choose patients for a GLP-1 receptor agonist versus an SGLT2 inhibitor?

Tina Vilsbøll, MD, DMSc: Well, that is an excellent question, and it is actually it . . . to some extent it's difficult for me. First of all, I think the most important thing is that if we have a patient who has atherosclerotic cardiovascular disease, chronic kidney disease, or heart failure. It is important for us to pile in a GLP-1 receptor agonist or an SGLT2. If you don't do that, you're not a good doctor. When you look at the numbers needed to treat compared to when we learn how to use angiotensin-converting enzyme (ACE) inhibitors and statins, the numbers needed to treat from the trials you just showed are actually beautiful. And to some extent lower than when we learned how to use statins and ACE inhibitors. But when do I give a GLP-1 receptor agonist and when do I give an SGLT2 inhibitor? I would say in short, patients who are very obese or rather obese, or if they're very far from target, I do in general go to GLP-1 receptor agonist compared with the SGLT2 inhibitor.

If the patient had a clear-cut heart failure or clear-cut chronic kidney disease with predominance, then I go for the SGLT2 inhibitor. And also, the thing about obesity with the GLP-1 receptor agonists. Now we have some tools in the toolbox and for treating type 2 diabetes and obesity, but in the future, we will use even higher doses for treating patients with type 2 diabetes with GLP-1. So, we will have the opportunity to see even further effect on body weight. So, high body weight and far from target are my preferences to want the GLP-1 receptor agonist.

Dr Marx: Yeah, thanks Tina. Maybe 1 aspect to add. We don't have much data, but in some patients, even the combination of the 2 may be helpful. There's some data from the AMPLITUDE-O trial that those who have an SGLT2 inhibitor baseline still benefited from the GLP-1 receptor agonist. So, this is for some patients also potentially a very promising option.

Dr Vilsbøll: Yeah. We actually have trials with what is more than 200,000 patients who have been in cardiovascular outcome trials for actually long periods, but in the cardiovascular outcomes trials (CVOTs) we have today, it is either GLP-1 or SGLT2. So, we actually don't have a CVOT with the combination, but there are many trials looking into body weight, HbA1c, what the combination is used. And I must say that I use it very often and the modern triple therapy as I call it: metformin, GLP-1 and SGLT2, because if you look at the pathophysiology of type 2 diabetes, it makes a lot of sense. And when you then eventually in some patients end up by having the next tool insulin in your toolbox, when you have these 3 drugs, drug classes on board, you can give them basal insulin and a lot less insulin than old-fashioned doctors used to do, and then we'll have less hypoglycemia. So, yes, the combination is really good.

Dr Marx: Thank you.

Chapter 5

Nikolaus Marx, MD: My name is Nico Marx. I'm a cardiologist at the University of Aachen in Germany, and with me is David Burnett, a nurse consultant in cardiology from the Northampton Hospital in the United Kingdom. Today, we are going to discuss the question when, how, and who, the rationale for a multidisciplinary approach. Having a large cardiology department, I'd like to share with you the concept that we implemented in our department, which we call the Aachen Cardiology approach. All patients hospitalized in the cardiology department here are screened for the presence of diabetes, and we measure HbA1c and fasting plasma glucose in all patients. If HbA1c is 6.5[%] or above and fasting plasma glucose is 126 [mg/dL] or above we, the cardiologists, can make the diagnosis of diabetes. If we newly diagnosed diabetes, we immediately start therapy with SGLT2 inhibitors and/or GLP-1 receptor agonists, the agents that have been shown to reduce cardiovascular morbidity mortality in type 2 diabetes. And given that these agents, at least now, currently are only approved with metformin, we add a small dose of metformin. To ensure that every resident fellow and consultant knows how to give these for cardiologists new agents, we created what we call the white coat card for diabetes, which contains all the necessary information on the dose, the side effects, and the uptitration. With that, David, I'd like to ask you when from your point of view, should a cardiologist start a GLP-1 receptor agonist.

David J. Burnett, RN: I think for me, it's very much about a holistic assessment of the patient. I think you need to actively, like you're saying, look for these patients, both on the wards and also when you see patients in clinic. I think firstly, I tend to look at the patient, have they got a lot of comorbidities, actually, are these drugs not indicated. But for the rest of the patients, those with cardiovascular disease and diabetes, then for me, it's looking at what medication are they on? And also how well controlled is their diabetes. It's all about selecting the right patient. For me, it's the younger patients. I think those are the patients that have got those cumulative years of hopeful risk reduction and also those patients that have got very high cardiovascular risk, the patients that have had multiple infarcts, multivessel bed, cardiovascular disease, and also as we've already heard those patients that have obesity benefit a lot from these drugs. That younger, high-risk, obese patient are definitely those patients that I would be identifying as patients that are suitable for these drugs.

In the United Kingdom, we have National Institute for Health and Care Excellence (NICE) recommendations, which govern the way we deliver care for patients with diabetes. Unfortunately, it hasn't recommended that GLP-1 receptor agonist should be the first line choice of management in patients with cardiovascular disease. This is very much driven by cost and analysis. I think still those patients that are at very high cardiovascular risk, we should be using these drugs. Now in the UK, we tend to start with metformin as a first -line drug, and then we would make our recommendation for primary care to initiate a GLP-1 antagonist or possibly, if they've got poorly control diabetes, then actually a diabetologist would be more of an appropriate person to start these drugs, I think, for those patients that have poor glycemic control.

For example, in UK, we tend to measure millimoles per mole, more than 55. Then there's a need for intensification of their medication. Again, it's a good opportunity to start one of these drugs. The patient group that I think are often overlooked to those that have good glycemic control and already on a number of different agents. Actually, there's a good opportunity to maybe switch, for example, a DPP-4, such as sitagliptin, to a GLP-1 antagonist. I think for those patients that have got complex needs, they're on high doses of insulin, they're on multiple different drugs, actually, maybe it's more appropriate for them to be referred to a diabetologist. We have the option of specialist nurses within the National Health Service (NHS) that can manage these patients from a diabetic perspective and primary care. We have nurses attached to general practitioner (GP) surgeries, again, who are very familiar with these drugs and we can recommend to start there. For the stable patient, I think it's reasonable for cardiologists with experience like yourself to start these drugs either in a clinic setting or within hospital. What's really important is for them to give a clear management plan, especially who's going to follow up these patients, who's going to monitor see how effective these drugs are and also bearing in mind, the patients will need education if you're using injectables.

Dr Marx: Yeah, thanks, David. To follow up on that, I think this is critical because cardiologists are often not used to these agents. How should they, or should we initiate therapy? And what do we need to explain in particular to the patient when we give these drugs?

Mr Burnett: There are 2 routes. You can give them either as a subcutaneous injection. Those are the drugs that we're more familiar with. I think sometimes this does put off cardiologists. We're very familiar with tablets. And I think just the fact that it is injectable will actually put them off prescribing it in the first place. These drugs they're given in most cases as a weekly injection, but really important to explain to patients the rationale behind that. The fact that they will reduce glucose, better glucose control, also reduces their risk cardiovascular disease and also weight gain. I explain to my patients that essentially they're getting 3 for 1, and often it's the weight loss that is the driver. These are patients that have struggled with their weight for many years, and now there's an option of actually taking a drug that's going to help with that.

Often, that really does help with compliance. I found that it's a very useful catalyst for weight loss. I had a patient fairly recently who was always struggled with his weight. He started GLP-1 receptor agonist, lost a small amount of weight that encouraged him to lose more weight. By the time I followed him up 6 months later, he'd lost 2-and-a-half stone in weight. I think really useful message that you can get across to patients. I also explain to patients that it's a prefilled syringe, very easy to use and something that they can do within their own home. They're not going to be drawing up vials of medication, which I think is important. There is also oral semaglutide, which is a daily drug that as recently been licensed, it is another option. It's something that’s not widely used NHS. I think what has to be explained to patients, we have to start low and go slow. This then reduces the side effects that are often associated with these drugs. In most cases, you need to give it about 4 weeks before you up titrate these medications.

Dr Marx: David, I really like the slogan start low, go slow, because I think this is critical for these patients, but what are the important side effects? What does the cardiologist, but also the patient need to know about side effects?

Mr Burnett: We know with these drugs, they slow gastric emptying. Those are the main side effects associated with this. Patients can feel nauseous, they can vomit, they can have diarrhea. They normally this will settle over time. I think it's absolutely paramount to explain to patients that this is actually a normal side effect of these drugs. Quite a few patients that I've seen, haven't tolerated GLP-1 receptor in the past, haven't been given that message. So they've stopped them because they've had these side effects, so important to provide education, give dietary advice. Patients need to be advised to reduce their portion size, reduce consumption of fatty foods, stop before they feel full. If they follow that, often patients will tolerate these drugs very well. There is a small risk reports of acute pancreatitis. Patients should also be advised to seek advice if they develop severe abdominal pain, jaundice, pyrexia -- those sorts of things.

Dr Marx: Thanks, David. Last but not least, cardiologists are concerned about hypoglycemia. For example, GLP-1 receptor agonists do not cause hypoglycemia itself, but the question is, does the cardiologist need to adjust other therapies to potentially prevent side effects such as hypos?

Mr Burnett: Absolutely. I think really important to look at what other diabetic therapies the patient is on before you start a GLP-1 receptor agonist. Now I think cardiologists have become very used to prescribing SGLT2 inhibitors. But what I have experienced in my practice is sometimes that prescription has become so standard, they actually fail to look at the other drugs that the patients are on. We know that GLP-1 receptor agonists are actually, given by themselves, very low risk of causing high hypoglycemia, but you do have to anticipate drug interaction. I think patients that are on insulin, patients that are on sulfonylureas, for example, gliclazide or glipizide, we know these drugs stimulate release of insulin from a pancreatic β cells, and that causes the risk of hypoglycemia. You always need to consider maybe reducing the dose of insulin, for example, removing one of those drugs to reduce the risk of hypoglycemia. I think in time cardiologists and also other cardiology practitioners that work in the field, will see the management of diabetes as part of their routine practice, but there's still a lot learning that's needed. I think to start with, it'll be the simple patients we will be managing, but I think within time within cardiology, we will get to the point where we can actually initiate these drugs on patients that are on insulin are on sulfonylureas, but I think we're a little way off in many areas.

Dr Marx: Thank you, David.

This transcript has not been copyedited.