Cardiorenal protection in focus - using modern therapy options

Type 2 diabetics can lead a relatively normal life if they adhere to therapy guidelines and maintain _HbA1c levels for as many years as possible.
are in the target area. Conversely, derailed glycemic control over time increases the risk of microvascular and macrovascular complications. In the pathogenesis of diabetic nephropathy are included
In addition to metabolic, hemodynamic and inflammatory factors are also involved. In addition to SGLT-2-i and GLP-1-RA, finerenone may also slow the progression of chronic kidney disease and reduce the risk of cardiovascular events.

Diabetes mellitus type 2 usually begins insidiously. Prolonged disturbances in insulin and blood glucose levels lead over time to macro- and microangiopathy and ultimately to further cell and tissue damage, explained Prof. Roger Lehmann, MD, Chief Physician, Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich [1,5]. _HbA1c levels have been shown to be correlated with the risk of diabetes complications [2,3]. In this context, one also speaks of a “metabolic memory” or “_HbA1c years”. One possible explanation for this phenomenon is that sustained hyperglycemia leads to the formation of persistent epigenetic changes such as DNA, histone methylation, and acetylation, which persist after cessation of hyperglycemia [4]. Microvascular complications of type 2 diabetes (T2D) include diabetic nephropathy.

Diabetic nephropathy is associated with cardiovascular risks

Currently, about 60% of all elderly patients with T2D have diabetic nephropathy (CKD, chronic kidney disease). It is less well known that around half of type 2 diabetics already have renal sequelae at the time of diagnosis, for example in the form of microalbuminuria or even macroalbuminuria. Diabetes and hypertension are the leading causes of CKD. Failure to diagnose early asymptomatic CKD increases the risk for later dialysis dependence. Currently, about half of dialysis patients are type 2 diabetics, the speaker pointed out, adding that 70% of these patients do not die from nephropathy but due to cardiovascular damage [5]. This is because diabetic nephropathy is associated with a massively increased cardiovascular risk. The lower the eGFR, the higher the risk for CVD events and mortality; the extent of albuminuria is positively correlated with the occurrence of cardiovascular events, Prof. Lehmann elaborated [5].

“Albuminuria increases before eGFR decreases, so it is an early prognostic marker”
Prof. Dr. med. Roger Lehmann, University Hospital Zurich [5].

Diabetes surveillance: determine not only eGFR but also albuminuria

Diabetes and hypertension are the most important risk factors for CKD, but there are others such as glomerulonephritis or hypercholesterolemia. In addition to regular monitoring of _HbA1c and blood pressure, serum creatinine/microalbuminuria and LDL levels are recommended once a year in T2D patients [6]. In addition, an ophthalmologic examination should be performed every year [6].

Not only nephropathy but also retinopathy is a microangiopathic complication. In patients with microalbuminuria and concomitant retinopathy, it is almost certain that it is diabetic nephropathy and not CKD of another cause, Prof. Lehmann elaborated. Microalbuminuria is an expression of generalized vascular endothelial dysfunction in type 2 diabetes. In contrast to macroalbuminuria, microalbuminuria is no longer reversible; it is only possible to slow down the progression of CKD.

according to [5]

Nowadays, the albumin-creatinine quotient is usually determined in spontaneous urine rather than in collected urine, Prof. Lehmann reported. “Albuminuria increases before eGFR decreases, so it is an early prognostic marker,” the speaker explained [5]. The criteria for the diagnosis of chronic kidney disease are a decrease in glomerular filtration rate (eGFR <60 ml/min/1.73^m2) lasting more than three months and/or micro- or macroalbuminuria (<3 mg/mmol = normal albuminuria; 3-30 mg/mmol = microalbuminuria; >30 mg/mmol = macroalbuminuria).

Therapy: besides SGLT-2-i or GLP-1-RA also finerenone available

Figure 2 shows the algorithm proposed by KDIGO (Kidney Disease: Improving Global Outcomes) for drug treatment of CKD in T2D [11]. SGLT-2 inhibitors (SGLT-2-i) block sodium-glucose co-transporter 2 in the proximal tubule of the kidneys, resulting in more glucose and more sodium being excreted. Increased sodium at the macula densa of the distal tubule results in constriction of the afferent arteriole and a reduction in glomerular filtration pressure. The hyperfiltration decreases and there is a reduction in perfusion, which ultimately protects the kidney, explained Prof. Lehmann [5].

Empagliflozin is an active substance from the SGLT-2-i group which reduced the combined renal endpoint (macroalbuminuria, doubling of serum creatinine, dialysis or death due to renal disease) by 44% in the EMPA-REG cardiovascular endpoint study [7]. GLP-1 receptor agonists are somewhat inferior to SGLT-2-i in terms of nephroprotection, but they act natriuretically and therefore also have some effect on the kidney. A relatively new therapeutic option for CKD is finerenone. This non-steroidal selective antagonist of the mineralocorticoid receptor mainly targets the factors of inflammation and fibrosis and can also slow down the progression of diabetic kidney disease.

The current therapeutic options for chronic CKD are mainly based on metabolic, hemodynamic and inflammatory factors (Fig. 1) . In recent years, SGLT-2 inhibitors and GLP-1-RA have become available, which not only support good glycemic control but also have additional cardiorenal benefits. Also, finerenone, a nonsteroidal selective antagonist of the mineralocorticoid receptor has not only been shown to be nephroprotective but also had a beneficial effect in cardiovascular endpoints. In addition to these treatment options, the treatment of hypertension and hypercholesterolemia is also an important aspect in patients with CKD, and with regard to factor nutrition, it is advisable to reduce salt consumption, said Prof. Lehmann.

according to [5]

In the FIDELIO-DKD study. (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease). significantly decreased the incidence of the composite renal endpoint (renal failure, sustained decrease in eGFR by ≥40%, or death due to renal disease) and the composite cardiovascular outcome (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) with finerenone [8]. In the FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trial, finerenone also significantly reduced the combined cardiovascular endpoint [9]. FIDELITY confirmed the placebo superiority of finerenone regarding overall cardiovascular outcomes (HR: 0.86; 95% CI: 0.78-0.95) [10]. Moreover, with finerenone, there was less frequent decrease in eGFR by more than 57% and less frequent renal failure (dialysis or renal transplantation) or renal death.

Congress: ZAIM Medidays

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