Cardiovascular-Kidney-Metabolic Syndrome: A New Look for an Old Syndrome

From the Chair

The concept of cardiovascular-kidney-metabolic (CMK) syndrome published recently by Ndumele and colleagues in Circulation¹ as a presidential advisory reflects an axis that has long been recognized.² However, while this review is a masterpiece of pulling together an enormous amount of information and organizing it into practical approaches to managing CKM syndrome, it has several limitations that need to be highlighted.

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Ndumele et al define CKM syndrome as a “systemic disorder with connections among heart disease, kidney disease, diabetes, and obesity.” Heart disease encompasses heart failure (HF), atrial fibrillation, coronary heart disease, stroke, and peripheral artery disease. The Ndumele review emphasizes the importance of an integrated approach among the specialties that are involved in managing CKM syndrome. It also emphasizes the role of adverse social determinants of health in determining CKM outcomes.

The growing number of therapeutic options for CKM syndrome and its components necessitates a detailed understanding of CKM syndrome-related therapies. The intricacies of using multiple agents in guideline-directed medical therapy (GDMT) for HF, GDMT for chronic kidney disease (CKD) with type 2 diabetes, and an emerging multitude of therapies for adiposity are not for the faint of heart.

An easy-to-remember staging of CKM syndrome is provided in the review:

• Stage 0, no CKM risk factors
• Stage 1, excess or dysfunctional adiposity
• Stage 2, metabolic risk factors (hypertriglyceridemia, hypertension, diabetes, metabolic syndrome) or moderate- to high-risk CKD
• Stage 3, subclinical cardiovascular disease (CVD) in CKM syndrome or risk equivalents (high predicted CVD risk or very high-risk CKD)
• Stage 4, clinical CVD in CKM syndrome; in addition, risk-enhancing factors influence the likelihood of progression along CKM stages

Ndumele and colleagues propose that patients with CKD and albuminuria should receive an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB); they recommend sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with or without diabetes, and for patients with residual albuminuria on ACEi or ARB they recommend finerenone that “can be used on background SGLT2i.”

In the paper, Ndumele and colleagues leave the clinician wondering about whether SGLT2i should be used concurrently with ACEi or ARB. The answer is yes, because three landmark trials have demonstrated this approach (CREDENCE, EMPA Kidney, and DAPA-CKD).^3-5 SGLT2i therapy showed benefit in the background of ACEi and/or ARB. The same is also true, incidentally, for the use of the nonsteroidal mineralocorticoid receptor antagonist finererone, which demonstrated efficacy when used in the context of background renin-angiotensin-aldosterone system (RAAS) inhibition. The pyramid approach advocated by Kidney Disease: Improving Global Outcomes and the American Diabetes Association guidelines, and the pillars of care approach advocated by others, emphasizes the importance of layering therapies on top of each other.

We must get this approach right because there is already profound underutilization of SGLT2i (and nonsteroidal mineralocorticoid receptor antagonists [nsMRAs]) therapy in patients with CKM syndrome. Adding ambiguity isn’t going to help. The underutilization of SGLT2i therapy is emphasized in two separate analyses. Among individuals with type 2 diabetes mellitus (T2DM) and an estimated glomerular filtration rate of >30 ml/min/1.73m², only 14% of individuals were being treated with an SGLT2i.⁶ In a second study among 105,799 patients with atherosclerotic cardiovascular disease, HF, and T2DM across 130 Veterans Administration facilities, 14.6% received an SGLT2i.⁷ Underutilization is even worse for nsMRA therapy.

Ndumele et al recommend SGLT2i therapy in all CKD patients with or without diabetes, but this statement isn’t supported by evidence. It is hard to justify using SGLT2is in kidney transplant patients because these patients were excluded from the pivotal SGLT2i trials.⁸ Likewise, evidence about whether patients with genetic kidney disease, including autosomal dominant polycystic kidney disease, benefit from SGLT2is is also lacking.⁹ The evidence is strongest for CKD patients with albuminuria, particularly those with T2DM.

One important caveat not mentioned by the authors is that SGLT2i therapy is contraindicated in patients with type 1 diabetes mellitus (T1DM) who have CKD. While it is true that T2DM is much more common than T1DM, the risk of inducing euglycemic ketoacidosis (commonly defined as ketoacidosis with a blood sugar <250 mg/dL) in T1DM patients treated with SGLT2is isn’t trivial. In the inTANDEM trial in T1DM using the SGLTi sotagliflozin, and in the DEPICT-2 trial using dapagliflozin, a three- to five-fold higher rate of diabetic ketoacidosis was observed.^10,11 Therefore, a more nuanced statement by Ndumele and colleagues cautioning against the use of SGLTi in T1DM would have been worthwhile.

The Ndumele review recommends “for patients with residual albuminuria on ACE or ARB, finerenone, which can be used on background SGLT2i.” The evidentiary basis for this approach is lacking. In the pivotal FIGARO¹² and FIDELIO¹³ trials (and the prespecified FIDELITY pooled analysis¹⁴), the question of whether finerenone is effective in patients with residual albuminuria wasn’t examined. Rather, patients were recruited and then placed on maximal doses of ACEi or ARB. Despite maximal use of RAAS blockade, additional kidney and cardiac protection was observed with finerernone. The use of finerenone in T2DM patients with CKM stage 2-3 who have a potassium level <5.0 mEq/L would have been a more supportable statement.

In summary, there are many strengths and some weaknesses in the American Heart Association’s presidential statement by Ndumele and colleagues. The most important take-home messages for me are that while gaps remain, there is now a large amount of data that has deepened our understanding of CKM syndrome, its interconnections, and how it should be managed. The emergence of several new classes of medications provides exciting opportunities to reduce morbidity and mortality from CKM syndrome.

References

1. Ndumele CE, Rangaswami J, Chow SL, et al; American Heart Association. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation. 2023. doi:10.1161/CIR.0000000000001184
2. Whaley-Connell A, Sowers JR. Basic science: pathophysiology: the cardiorenal metabolic syndrome. J Am Soc Hypertens. 2014;8(8):604-606. doi:10.1016/j.jash.2014.07.003
3. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295-2306. doi:10.1056/nejmoa1811744
4. Herrington WG, Staplin N, Wanner C, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388:117-127. doi:10.1056/NEJMoa2204233
5. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020;383(15):1436-1446. doi:10.1056/NEJMoa2024816
6. Mahtta D, Ramsey DJ, Lee MT, et al. Utilization rates of SGLT2 inhibitors and GLP-1 receptor agonists and their facility-level variation among patients with atherosclerotic cardiovascular disease and type 2 diabetes: insights from the Department of Veterans Affairs. Diabetes Care. 2022;45(2):372-380. doi:10.2337/dc21-1815
7. Hussain A, Ramsey D, Mahtta D, et al. Utilization rates of SGLT2 inhibitors and their facility-level variation among patients with type 2 diabetes (T2DM), heart failure (HF), and atherosclerotic cardiovascular disease (ASCVD): insights from the Department of Veterans Affairs (VA). J Am Coll Cardiol. 2023;81(8_Supplement):1645. doi:10.1016/S0735-1097(23)02089-2
8. Ujjawal A, Schreiber B, Verma A. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) in kidney transplant recipients: what is the evidence? Ther Adv Endocrinol Metab. 2022. doi:10.1177/2042018822109
9. Afsar B, Afsar RE, Demiray, et al. Sodium-glucose cotransporter inhibition in polycystic kidney disease: fact or fiction. Clin Kidney J. 2022;15(7):1275-1283. doi:10.1093/ckj/sfac029
10. Buse JB, Garg SK, Rosenstock J, et al. Sotagliflozin in combination with optimized insulin therapy in adults with type 1 diabetes: the North American inTandem1 study. Diabetes Care. 2018;41(9):1970-1980. doi:10.2337/dc18-0343
11. Mathieu C, Rudofsky G, Phillip M, et al. Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (the DEPICT-2 study): 52-week results from a randomized controlled trial. Diabetes Obes Metab. 2020;22(9):1516-1526. doi:10.1111/dom.14060
12. Pitt B, Filippatos G, Agarwal R, et al. Cardiovascular events with finerenone in kidney disease and type 2 diabetes. N Engl J Med. 2021;385:2252-2263. doi:10.1056/NEJMoa2110956
13. Bakris GL, Agarwal R, Anker SD, et al; FIDELIO-DKD Investigators. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N Engl J Med. 2020;383(23):2219-2229. doi:10.1056/NEJMoa2025845
14. Agarwal R, Filippatos G, Pitt B, et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: the FIDELITY pooled analysis. Eur Heart J. 2022;43:474-484. doi:10.1093/eurheartj/ehab777