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Erin Michos @ErinMichos

Erin Michos is an Associate Professor in the Division of Cardiology at Johns Hopkins University School of Medicine, with a joint appointment in the Department of Epidemiology at the Johns Hopkins Bloomberg School of Public Health. She is the Associate Director for Preventive Cardiology at Johns Hopkins, and she is the co-Editor-in-Chief for the American Journal of Preventive Cardiology (AJPC). Her research focuses on women’s cardiovascular health, preventive cardiology, and cardiometabolic diseases. She was a co-author of the 2020 KDIGO Guideline for Diabetes Management in CKD.

Competitors for the Cardiorenal Region

Diuretic Resistance Mechanisms vs Diuretic Resistance Treatments

Cardiac Biomarkers in CKD vs Kidney Biomarkers in CHF

Copyright: Sri J / Shutterstock

­As a cardiologist, I am very excited to join the NephMadness challenge this year. Despite historical “wars” between our two specialties over loop diuretic titration (“too wet” vs “too dry”), cardiology and nephology now have many “friends” in common that confer BOTH cardiovascular and kidney outcome benefits. Notably, these includes sodium-glucose co-transporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoid antagonist (MRA) finerenone, and glucagon-like peptide-1 receptor agonists (GLP1-RA).

Entering the NephMadness tournament is the CardioRenal region, so you know which region I am rooting for!

But before I talk about the specific competitors in this region, I want to remind my fellow cardiologists that cardiovascular disease (CVD) is the leading cause of death among persons living with chronic kidney disease (CKD), which is why preventive efforts towards mitigating both disease processes is so very important. Furthermore, both a reduction in estimated glomerular filtration rate (eGFR) and the presence of albuminuria are independently associated with an increased risk for CVD and mortality in a graded fashion. However, the measurement of both kidney markers is sub-optimally done in cardiology clinical practice.

Unfortunately, many patients with CKD, who are at elevated cardiovascular risk, go unrecognized without an intentional assessment for albuminuria. CKD can contribute to CVD through several mechanisms such as progression of atherosclerotic disease, valvular calcification, and myocardial fibrosis. As such, CKD is considered a cardiovascular risk enhancing factor in the American College of Cardiology (ACC)/American Heart Association (AHA) prevention guidelines.

OK, now on to our competitors for the Cardiorenal Region. Congrats to all the teams for playing the game so well. I learned so much from reading these 4 well-written sections, all of which are very relevant to my clinical practice. Do I have to pick a team?

Well, as a cardiologist who manages a lot of patients with heart failure (HF) or at risk for HF, I am cheering for the “Diuretic Resistance Treatment” team because this team also discusses the cardiologists’ friends the SGLT2i and MRAs. Despite their well-established benefits, SGLT2i and MRAs remain underutilized in heart failure. Not only to facilitate diuresis of course, but to prevent incident heart failure hospitalization (HHF) and cardiovascular (CV) death.

Copyright: Alohaflaminggo / Shutterstock

SGLT2i

In two randomized clinical trials enrolling exclusively a CKD population (i.e. CREDENCE and DAPA-CKD), SGLT2i reduced the risk for both the primary adverse kidney outcomes but also the secondary cardiovascular outcomes among patients with CKD. The CREDENCE trial enrolled patients with albuminuric diabetic kidney disease with eGFR ≥30 mL/min/1.73 m² and showed that the canagliflozin-treated patients had a 39% lower risk of HHF (HR 0.61; 0.47-0.90), compared to placebo. In the DAPA-CKD trial which enrolled CKD patients with or without diabetes with eGFR ≥25 mL/min/1.73 m², dapagliflozin conferred a 29% reduction in HHF and CV death (HR 0.71; 0.55-0.92); with similar benefit regardless of diabetes status. The SCORED trial, which also enrolled an exclusive CKD population, demonstrated CV risk reduction with sotagliflozin. There is still an ongoing trial with a combined cardio-renal primary outcome evaluating empagliflozin which enrolled patients with CKD with and without diabetes, and with and without albuminuria (EMPA-KIDNEY), which should be informative about the benefits of SGLT2i among a broader CKD population.

SGLT2i have also been shown to have benefit in patients with HF both with reduced ejection fraction (EMPEROR-REDUCED & DAPA-HF), and with preserved ejection fraction (EMPEROR-PRESERVED). Furthermore, the SOLOIST-WHF demonstrated that the initiation of SGLT2i in patients with diabetes with acute HF prior to discharge or shortly thereafter is safe and effective. These benefits were also consistent in those with HF with reduced but also preserved EF.

SGLT2i can confer natriuresis. They have a diuretic effect, as the induced glycosuria leads to osmotic diuresis and increased urine output. SGLT2i also appear to alter fuel metabolism, shifting away from carbohydrate utilization to ketogenesis. SGLT2i need to be reframed as “kidney and cardiovascular prevention drugs” rather than “diabetes drugs’ given their well-established benefits in persons with HF and persons with CKD, with or without diabetes.

One notable point that I would like more clinicians to be aware of is that a reversible decrease in eGFR with the initiation of SGLT2i treatment frequently occurs and is generally not an indication to discontinue therapy. This is discussed further by the “Kidney Biomarkers in Patients with Cardiac Disease” team. Clinical trials have demonstrated a reversible decrease in eGFR among persons treated with an SGLT2i, but importantly SGLT2i are associated with overall kidney protection with improved albuminuria, decreased progression to severely increased albuminuria, and reduction of risk from worsening kidney impairment, kidney replacement therapy, or renal death.  This is “the tortoise vs the hare” race in eGFR decline. So a modest initial drop in eGFR (i.e. decrease of ≤30%) should not necessitate stopping the SGLT2i. I want all cardiologist and primary care clinicians to know this issue.

Visual abstract by @hellokidneyMD on Meraz-Munoz et al.

Thus, one should tolerate an acute eGFR decrease of ≤30% with initiation of therapy and not discontinue therapy prematurely. If there is a >30% decline in eGFR, ensure that the patient is not hypovolemic (for which you would adjust the diuretic dose), discontinue any other nephrotoxic agents, and evaluate for other possible etiologies for kidney injury.

MRAs

Now, the MRAs are also good friends to cardiologists in the management of resistant hypertension and in the management of HF, both with reduced (HFrEF) and preserved (HFpEF) ejection fraction. MRAs blunt sodium avidity, lower blood pressure, reduce the risk of volume overload – translating to reduced risk of HHF and CV events. Even more recently, the non-steroidal MRA drug, finerenone, has also been shown to confer both cardiovascular and kidney protection in patients with type 2 diabetes and CKD in both a dedicated kidney outcome trial and a dedicated CV outcome trial. This was on the back-drop of ACEi/ARB therapy. The benefit of finerenone appears incremental to SGLT2i, although there were relatively few individuals taking SGLT2i in the FIDELIO-DKD and FIGARO-DKD trials. Patients with HFrEF were excluded from these trials, but there is an on-going trial evaluating finereone in HFpEF (FINEARTS-HF).

GLP1-RA

Another friend of both the heart and the kidney is the GLP1-RA. The long-acting injectable GLP1-RA have been shown to reduce atherosclerotic CVD events in patients with type 2 diabetes, with similar benefit for patients with and without CKD. GLP1-RA have also been shown to reduce kidney outcomes, primarily driven by a reduction in albuminuria. A dedicated kidney outcome trial for a GLP1-RA (the FLOW trial, NCT03819153) is ongoing.

Final Word

Well, I will end my NephMadness commentary by saying I don’t want to pick a team and I am rooting for the entire Cardiorenal region. Great job to all the competitors! I learned a lot from all four teams, and it is patients who win when there are therapies that help both the heart and the kidney.

– Guest Post written by Erin Michos @ErinMichos

As with all content on the AJKD Blog, the opinions expressed are those of the author of each post, and are not necessarily shared or endorsed by the AJKD Blog, AJKD, the National Kidney Foundation, Elsevier, or any other entity unless explicitly stated.

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