Cardio-renal-metabolic syndrome in context

Epidemiology of CRMS

Meta-analysis of studies reveals a certain link between the development of cardiovascular, renal, and metabolic diseases. Patients with T2DM have a 2× higher risk of developing CVD, and the prevalence of T2DM is significantly higher among patients with heart failure. Evidence that heart failure directly initiates the development of T2DM is still lacking, but it is certain that the coexistence of T2DM and heart failure worsens the overall prognosis of patients. Diabetes significantly increases the occurrence of CKD, which develops in half of patients with T2DM and one-third of type 1 diabetics. Similarly, there is a higher proportion of diabetics in the CKD cohort than in the general population. CKD is also considered a significant risk factor for the development of CVD, and mortality increases with declining glomerular filtration rate. Furthermore, the presence of heart failure increases the risk of developing CKD by approximately 2×.

Pathophysiological Mechanisms

Hyperglycemia associated with diabetes leads to increased mitochondrial superoxide production and exacerbation of oxidative stress. Reactive oxygen species damage the body through several mechanisms. They form advanced glycation end products (AGEs) that react with specific receptors and can modify biological structures. This leads to the activation of inflammatory pathways, vascular endothelial damage, and the development of diabetes complications (diabetic cardiomyopathy, CKD, and atherosclerosis). Hyperglycemia further activates the RAAS, significantly affects fundamental metabolic pathways, and impairs tissue healing.

Atherosclerosis potentiated by T2DM manifests as coronary artery disease (CAD), stroke, or peripheral arterial disease (PAD). The basic underlying cause is endothelial damage. T2DM is associated with dyslipidemia, which further contributes to the formation of atherosclerotic plaques. Predominant vasoconstriction leads to hypertension. Advanced cardiovascular system damage can lead to the development of heart failure due to diabetic cardiomyopathy. Key roles in its pathogenesis are played by hyperglycemia, hyperinsulinemia, lipotoxicity, and coronary artery endothelial dysfunction. Another significant complication of diabetes is diabetic kidney disease (defined as any renal function abnormality related to diabetes). Initially, hyperfiltration dominates, gradually leading to nephron damage and a decrease in estimated glomerular filtration rate (eGFR) to the level of renal failure. The relationship between cardiac and renal impairment can be summarized under the term cardio-renal syndrome. In heart failure, cardiac output decreases, and an excess of vasoconstrictive agents leads to chronic reduction in renal perfusion, decreased eGFR, and CKD progression.

Dysfunction of the cardiovascular system also significantly affects metabolic pathways, thereby contributing to the development of T2DM. The main mechanisms include endothelial dysfunction, insulin resistance associated with increased sympathetic activity (acting on α-adrenergic receptors), and RAAS in heart failure. Angiotensin II directly affects insulin signaling pathways and pancreatic beta-cell function. Other neurohumoral factors include natriuretic peptides and pro-inflammatory cytokines. CKD also has some influence on metabolism − and therefore the development of T2DM −, but the exact pathophysiological mechanism is not yet known. Insulin resistance and disruption of insulin signaling regulation most likely play a role here as well. CKD is also associated with a chronic inflammatory state and increased oxidative stress. Insulin sensitivity and glucose homeostasis are affected by metabolic acidosis and vitamin D deficiency, which are often present in CKD.

Management of CRMS

Given the proven connection between individual clinical conditions (T2DM, CVD, and CKD), addressing the cardio-renal-metabolic syndrome as a whole is expected to bring clear benefits to patients. Clinical study results highlight the positive effect of sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA). These agents have shown a positive effect on glycemic control and cardiovascular prognosis in patients with T2DM. SGLT2i act based on natriuretic and osmotic effects, while GLP-1RA have anti-atherogenic and immunomodulatory effects. Cardio-renal protective effects in diabetics have also been observed with the mineralocorticoid receptor antagonist (MRA) finerenone. Individual medications can be chosen or combined based on the needs and therapeutic goals of the particular patient.

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Source: Marassi M., Fadini G. P. The cardio-renal-metabolic connection: a review of the evidence. Cardiovasc Diabetol 2023 Jul 31; 22 (1): 195, doi: 10.1186/s12933-023-01937-x.