Check out perspective from a pair of ASN Kidney Week 2023 interviews with leading trialists discussing the evolution of cardiovascular-kidney-metabolic syndrome and how pharmacotherapy has propelled the growing recognition.
The increasing prevalence of cardiometabolic health conditions, such as obesity, type 2 diabetes, cardiovascular disease, and chronic kidney disease, since the turn of the century has placed a significant strain on health systems and, as a result, has led to significant reform in the management of these diseases.
Beginning in the early 2000s, clinicians and researchers began to recognize the idea of cardiorenal syndrome but were without a well-accepted definition. In the last decade, advances in technology, pathophysiology, and pharmacotherapy, driven by the SGLT2 inhibitor class, have contributed to a near-universal recognition of the overlap in the aforementioned conditions, with this culminating in the American Heart Association’s release of a presidential advisory defines the overlap in these conditions as cardiovascular-kidney-metabolic syndrome.
“The advisory addresses the connections among these conditions with a particular focus on identifying people at early stages of CKM syndrome,” said Chiadi E. Ndumele, MD, PhD, MHS, writing committee chair and an associate professor of medicine and director of obesity and cardiometabolic research in the division of cardiology at Johns Hopkins University in Baltimore. “Screening for kidney and metabolic disease will help us start protective therapies earlier to most effectively prevent heart disease and best manage existing heart disease.”
In addition to advocating for risk calculator updates to be expanded to assess risk in people as young as age 30 years of age and to calculate both 10- and 30-year CVD risk, the AHA created a 5-stage system for identifying and managing cardiovascular-kidney-metabolic syndrome:
As part of our coverage of the American Society of Nephrology Kidney Week 2023, HCPLive Nephrology sat down with Patrick Rossignol, MD, PhD, head of medical specialties service at Princess Grace Hospital and medical director at Monaco Private Haemodialysis Centre, and Rajiv Agarwal, MD, MS, professor of medicine at the Indiana University School of Medicine and cochair of the FIDELIO-DKD and FIGARO-DKD Steering Committee, and asked for perspective on the evolving landscape through the lens of leading trialists in nephrology. Their responses are highlighted below.
HCPLive Nephrology: How have you seen the recognition of cardiovascular-kidney-metabolic syndrome evolve in recent years and how have evolutions in pharmacotherapy driven that discussion?
Rossignol: What I would say is that initially, cardiologists paid a lot of attention to cardiorenal syndromes. There was a paper from Claude Ronco and colleagues published in the Journal of the American College of Cardiology2 defining cardiorenal syndromes as five different entities depending on whether it is the heart that is the culprit or the kidney or both. This was already something really interesting because the cardiology community paid more attention to this category. That said 10 years after, with my colleagues, we revisited it in a white paper published Circulation3 because we perceived that there is a true continuum in cardiorenal disease. These are patients exposed to the same cardiovascular risk factors who may ultimately present either heart failure, CKD, or both—really emphasizing the fact that heart failure may be asymptomatic and chronic kidney disease may be mild initially, but there still evidence of heart involvement. We proposed a new concept of revisited cardiorenal syndrome, and this concept was subsequently confirmed by a positive trial with SGLT2 inhibitors.
At the end of the day, almost all patients across the cardiorenal continuum are eligible to SGLT2 inhibitors and, now, many of them will also receive this nonsteroidal mineralocorticoid receptor antagonist—finerenone—should they present with diabetic kidney disease while those with reduced ejection fraction are already receiving nonsteroidal mineralocorticoid receptor antagonists.
So, in summary, the cardiorenal patients receive the same drugs which improve the cardiorenal prognosis. There is a new concept: the fact that both cardiologists are nephrologist ultimately use the same drugs for the same patients leads us to further strengthen this concept.
Agarwal: I think we have really changed the landscape of the agents that are available to people with type two diabetes, especially with albuminuria. SGLT2 inhibitors have been incredibly successful. I chaired the adjudication committee for the CREDENCE trial, which was published in 2019. That was the landmark discovery that we made in protecting the cardiorenal health of people with type 2 diabetes.
In that trial, everybody had macroalbuminuria—everybody had to have more than 300 mg/g of albuminuria. Subsequently, we had the DAPA-CKD trial and a proportion of those patients had nondiabetic kidney disease. For the proportion with diabetic kidney disease, they dropped the UACR threshold to 200 mg/g with an upper limit was 5000 mg/g. In this trial, they also found cardiorenal protection.
The EMPA-Kidney trial was the third trial that really knocked the socks out of albuminuria. This trial told patients they do not need to have albuminuria and we will still examine the outcomes. There were 50 of these patients in that trial who did not have any exposure to ACE inhibitors or angiotensin receptor blockers. In those two groups of people— where there's no albuminuria and when there's no ACE or ARB—there is still uncertainty because the confidence intervals of protections are pretty wide in those trials. In people without albuminuria, especially zero to 30 and people who are not on ACE or ARBs, I don't think we have convincing data to show that the SGLT2 inhibitors, in people with type two diabetes who simply have impaired GFR and no other cardiovascular risk are protective, but we have ample evidence that these drugs are protective in people with any history of heart failure, including both HFrEF and HFpEF, with any preexisting atherosclerotic cardiovascular disease, or with overt albuminuria—more than 200 mg/g—is where we have most of the data.
There's a meta-analysis that's published in The Lancet, which looks at all these data and the protection for heart failure and cardiovascular outcomes is really there in people with diabetes, but there is no such protection in people without diabetes. The albuminuria information hasn't been meta-analyzed, because I don't think there is enough data and people without albuminuria.
where finerenone comes in, is that about 40% of people in the FIGARO trial, had microalbuminuria. So, that's the population which is early-stage diabetes with very little kidney disease—the mean GFR in FIGARO trial was 67 mL/min/1.73m2 and about 40% have microalbuminuria. When we look at the meta analysis of the FIGARO and FIDELIO trials together, we find that it doesn't matter the level of albuminuria. Whether it is 30 to 300 or beyond 300 mg/g, there is cardiovascular protection seen across the spectrum of albuminuria.
These findings were published in JAMA Cardiology. What we saw in this study is that kidney disease is a modifiable cardiovascular risk factor. In other words, if you have type 2 diabetes and albuminuria you need to treat much like blood pressure and cholesterol—make it a 9-1-1 call to say that you can modify cardiovascular risk in those patients.
Additionally, only 7% of the patients in the FIDELITY database have any exposure to SGLT2 inhibitors. So, these drugs are working independently of SGLT2 inhibitors and the new guidelines, don't tell you to sequence these drugs either. So, I believe these are independent pathways, the SGLT2 and the nonsteroidal MRA and I believe they're working complement early.
Now we have another pillar of care that's being constructed with the GLP-1 RA in the FLOW trial, which is being terminated early.7 I think that there will be an incredible opportunity to treat people with type two diabetes and albuminuria moving forward.