Cardiovascular-kidney-metabolic (CKM) syndrome

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Hi, and welcome to this Australian Prescriber Podcast. I'm Dr Justin Coleman, a GP in Inala in Brisbane working in Aboriginal health. And with me today, I have Professor Karen Dwyer, who's Director of Nephrology and Kidney Care Services at the Royal Melbourne Hospital. Welcome to our humble little podcast, Karen.

Thanks very much, Justin. I'm really pleased to be here.

We're talking today about a syndrome you may or may not have heard of, CKM syndrome and that's cardiovascular-kidney-metabolic syndrome. I guess in summary, Karen, it's what we've been vaguely talking about for 20 years, which is that people with a metabolic syndrome seem to have multiple organs affected and there seems increasing utility to focus on the whole lot rather than one organ at a time. Is that the philosophy behind this?

Yeah, 100%. I think this recognition is really important. We practise in a lot of silos. An individual in front of us might have diabetes, might have kidney disease, might have cardiovascular disease. And I think the beauty of thinking of this as a syndrome is that it's understanding then that all these conditions are interconnected. And really, they're manifestations of the same process at play and they manifest in different ways, but it's the same underlying pathophysiology.

And in addition to heart, kidney and metabolic, I would add liver disease. So fatty liver is a really core component of that as well. It simplifies for the clinician and for the patient that we have an underlying pathophysiology and manifestations. And what we're now seeing in terms of guideline-directed medical therapy is there's lots of overlap between the different guidelines, again, suggesting a lot of intersection between all those conditions.

Not surprisingly, they're driven by environmental and behaviour factors, lifestyle factors, which of course are heavily influenced in turn by social determinants and our modern environment. With the epidemiology of this, we've divided CKM into 4 different stages. How important is it that we distinguish between the stages? Or do you see it as sort of a general progression from mild to severe?

Thinking of it in stages is actually really helpful. And whilst it is a continuum and as you progress, it really highlights more progressive or advanced disease, it gives us a framework to look at early intervention and management, and I would then suggest remission.

So stage one of CKM is really the presence of that central adiposity. So, the visceral fat where we get inflammation, oxidative stress, insulin resistance is the main driver for CKM. We know central adiposity, that visceral fat, is highly prevalent. And understanding and being on the lookout for that is really, really helpful, because intervention here, we can reduce that visceral fat, that central adiposity, we can get CKM remission.

As we move into CKM stage 2, we're starting to see the emergence of some biomarkers that are becoming abnormal. So, the presence of metabolic syndrome, which I think has kind of been forgotten in our medical toolkit, and I think this is a really important area to target as well. So, starting to get some high sugars, we might have someone that's entering prediabetes. Recognising that prediabetes is not benign. It doesn't mean that you don't have diabetes yet You're already starting to get complications of hyperglycaemia. And we know with lifestyle intervention, you can get remission of prediabetes and that's something that we should be striving for.

And this is where we might start to see the presence of early CKD, the presence of proteinuria. And proteinuria, I think, is a really important biomarker to be looking for. It tells us that there's a lot of endothelial activation of the blood vessels within the kidney. And if that's happening in the kidney, it's happening in the heart, it's happening elsewhere. So, looking for those biomarkers where early intervention and management can lead to remission is really critical.

As you move into stage 3, that's when we're starting to get more advanced disease. You might be starting to see subclinical heart failure, for example, before stage 4, which is more severe heart failure and more advanced kidney disease. And I think in those later stages, it's just perhaps a little bit more difficult to get remission, but this is where we can slow progression. This is where we can really improve the health and well-being of a person and ensure that they don't go down to that next stage of more advanced kidney disease, which, as we know, is associated with premature mortality. And if someone needs dialysis, that's a really huge impost on someone's quality of life, let alone quantity of life.

You mentioned the biomarker of albuminuria, which is important. Interested readers, I suggest you go to the article in Australian Prescriber, other screening bloods include fasting glucose, HbA1C, eGFR, liver function test, uric acid and a lipid panel. We're talking about both prevention and management. And it does seem to me, in terms of lifestyle modification, the 2 are very much intertwined and overlap in the sense that particularly as you say for the early stages, if you prevent going to the next stage, it's also possible with significant weight loss to head backwards and go to a lesser stage and potentially even remission.

And I think that's what we need to be thinking about with CKM. This is an opportunity for remission and I'd love to have the narrative changed in terms of how we talk about these diseases, chronic kidney disease. It says it in the name. This is a progressive, inevitable kind of progression. I think we need to change our language in this space, because we know that we can achieve remission and, with remission, we can reduce or have albuminuria disappear. We can see that cardiac function can improve. Our organs can remodel and improve their function.

I think calling it a syndrome really provides a framework that now looks at a constellation of conditions that are not necessarily chronic and progressive. We have opportunities here and this really speaks to identifying early and for me, that's the key. We need to identify the people that potentially have CKM syndrome, because with support we can get remission.

Yes. I think it's a wonderful area for the primary care team really, not just the GP, but also of course exercise phys and dietitians. Rather than talk in detail about lifestyle today, although I don't want to diminish its importance, it's vital in this condition. Perhaps we will move on to the role of pharmacotherapy and there are some medications that seem almost universally useful starting with blood pressure control. Can you take us through the medications which are particularly relevant here?

If we don't get that foundational component right, if we don't address that lifestyle, the medications may initially work, but then they stop working. So, these things can't be considered separately. It's lifestyle and it's the medication, so that we are able to use the lowest possible dose to achieve what we need to achieve, minimal side effects, et cetera.

In terms of high blood pressure or antihypertensive management, at the cornerstone of therapy has been renin-angiotensin system inhibition and we've had that for many, many years now and that remains a cornerstone. The RAS [renin-angiotensin system] blockade has renoprotective effects, cardio, cerebro-protective effects, and has a direct effect as an antiproteinuric agent. So that does remain the foundational pharmacotherapy that we would use.

If somebody has CKM syndrome and they've got presence of proteinuria, the idea is to titrate the RAS blockade to maximal doses to achieve that antiproteinuric effect. And the reason why I keep focusing on proteinuria is that it is a prognostic marker across all the organs, whether it's liver, whether it's heart, whether it's diabetes. And with kidney disease, more proteinuria is a poor prognostic marker. It heralds more progressive kidney disease, heart disease. Again, we see that in the liver field. So, it's an easily accessible biomarker, and if we can reduce that, we can reduce someone's risk of those complications.

And sticking with blood pressure for the moment, the mineralocorticoid receptor antagonist [MRA], so I'm thinking spironolactone, can also have their place a bit later on?

Yeah. So, the MRAs [mineralocorticoid receptor antagonists] are in an interesting space in CKM syndrome and it's an evolving space. There's ongoing research. In the kidney space, we now have the nonsteroidal MRAs and they have shown protection or reduced proteinuria even further. So, RAS blockade, SGLT2 [sodium-glucose co-transporter 2] inhibition, and then nonsteroidal MRAs. So that sequential introduction of agents has shown to really reduce the degree of proteinuria.

And this is where some of the challenges, and particularly I think it must be very difficult in primary care because you have all these guidelines that have some slight nuances, and MRAs are used in the setting of heart failure with reduced ejection fraction from a cardiac perspective. If we're talking just about high blood pressure though, something like spironolactone can be a very effective antihypertensive agent. So, it kind of depends on when you want to use an MRA and in what context, whether you would use something like spironolactone or something like a nonsteroidal MRA.

And you briefly alluded to the SGLT2s and certainly in the past decade, I think that's really seen a very growing place for SGLT2s when it comes to kidneys and also heart failure. Could you tell us about the role of those?

So, the SGLT2 inhibitors really changed the landscape. I suspect it's been really pivotal in leading to the characterization of CKM syndrome. These were initially marketed as a glycemic agent, so they block the SGLT2 receptor in the kidney and as a result, you get glucosuria. And once you get glucosuria, you get a reduction in insulin, and so it really addresses that pathophysiology. The drive of insulin resistance is starting to be addressed through these agents.

The early trials, as they were used for a glycemic agent, they did show a modest reduction in haemoglobin A1C, but what was noted was a more profound effect as a cardio- and a reno-protective agent. And a lot of that is mediated through reducing that degree of proteinuria. And we know that within the kidney, the podocyte, for example, has these insulin receptors on it. So, in the setting of insulin resistance, the driver of CKM syndrome, we're going to get a degree of proteinuria. If we can address that driving pathogenic process, then we start to see an improvement in proteinuria.

And the GLP-1 receptor antagonists, which these days are largely the injectables, although it's not the only way to get them in, where's their role?

I think this is an evolving area. They're very commonly prescribed now. We know that they're available if someone has diabetes, but more and more are being used in the weight loss space. There is some emerging data to suggest they too have a reno and a cardioprotective effect. I suspected there is some overlap with how these agents are working similar to the SGLT2 inhibitors. We know that they work, they slow gastric emptying, you don't get that transition of food into the gut, there's less insulin produced, but these agents also have a role with glucagon. So, I think it's really changing that metabolic milieu and that has that flow on effect of the organ protection. And so, these newer agents are not only seen as therapies to reduce glucose levels, for example, they're seen as organ protective agents.

And no metabolic discussion would be complete really without talking about lipid lowering therapy, the statins and others. And presumably as one progresses through the stages and keeps an eye on cardiovascular risk, they'll enter the scene at some point.

Yeah, this is an interesting area and we're perhaps learning a lot more about what does a lipid panel mean. As we highlighted at the start, one of the earlier changes in that metabolic syndrome is the reduction in HDL cholesterol and elevated in triglycerides. And we know that that triglyceride rich environment is the thing that really makes LDL a sticky molecule. And so it's that small dense LDL that can cause that cardiac disease.

We've got things like the Australian Cardiovascular Calculator to really help us guide therapy there. Everything needs to be considered in terms of potential benefits and potential risks, so no drug is without its side effects. So, I think that's a really important discussion. But we also know that beyond our standard lipid panel, there's these newer biomarkers.

I think we're still learning how to integrate them into our assessment. So, things like ApoB, which give us a more precise indicator of cardiovascular risk is perhaps not a routine thing yet. And then there's this role of lipoprotein-a, which is another marker of lipids that's really interesting and confers some increased cardiovascular risk.

So I think in terms of lipid lowering, our standard approach is with statin therapy plus ezetimibe based on cardiovascular risk calculation, but there's a lot more to understand when interpreting lipid lowering therapy.

Professor Karen Dwyer, we've talked about 5 different medication classes and we are talking to prescribers. Could we perhaps finish with your overview as to where the lifestyle fits in versus the medication for prescribers heading forwards and backwards through the cascade?

Yeah, this is such an important question as I think polypharmacy is a real issue amongst the patients that we serve. I think if you look at all the literature with all those medications on board, there remains residual risk. So, we're clearly not able to address all the risk with the medications and that's because we're treating the organs, but we're not treating the absolute driver of this. And the driver is, as you say, very much lifestyle driven.

It's an obesogenic environment that is really promoting the development of that central adiposity, insulin resistance, oxidative stress, inflammation, that is the driver. So, anything that we can do to address that driver will provide much greater benefit than rather just addressing the medicines. And putting those 2 things together is the really powerful part, and we may be able to eliminate that residual risk.

Multiple things impact on the development of central adiposity and insulin resistance, but the major pillars are things like nutrition, because nutrition is something every day. Sleep is a really important one, physical activity, stress, social connectedness, getting out into the sun and avoiding the substances or toxins such as smoking.

The nutrition part. So here, it's really important. We really want to reduce those refined carbohydrates. They're the things that really drive up your blood glucose, so therefore drive up insulin. Avoiding sugary drinks, ultra processed food, prioritising our protein, making sure that we're getting that in.

Sleep is really important. Inadequate sleep is probably one of the most common drivers [of] chronic inflammation that always triggers an insulin resistance. And we know that there's a lot of literature. Even one night's poor sleep, we wake up with a higher blood glucose, so we're more insulin resistant. So prioritising sleep is really important.

And then, of course, physical activity. Muscle is our longevity organ. If we can use those muscles, we improve our insulin sensitivity. And then, of course, sometimes we need to add in the medicines and that's okay, because if we've got the foundations right, we're much more likely to have success and be able to then achieve remission.

I think the other part with lifestyle is people start to feel so much better, because the weight starts to move, the energy improves, the brain fog lifts, and so it's just a self-perpetuating cycle. So that to me is the real key and the medicines are the second part of that.

Professor Karen Dwyer, it's wonderful to talk to a nephrologist who has a deep understanding that the kidney is connected to the heart, is connected to the liver, is connected to the brain, is connected to a human being's sense of wellness and well-being. Thank you so much for talking to us today.

My pleasure. It's been great. Thank you very much.

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Professor Karen Dwyer is chair of the Board of Directors of the Australasian Metabolic Health Society, and a member of the Board of Directors of ePurines. She has received honoraria from AstraZeneca, Boehringer Ingelheim, Bayer and Servier for providing education to primary care professionals, and has been on the advisory boards for GlaxoSmithKline, Boehringer Ingelheim, AstraZeneca and Steering Committees for Novo Nordisk. I'm Dr Justin Coleman, thank you for listening to the Australian Prescriber podcast.

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