The Synergistic Treatment of Heart and Kidney Disease

Background: The incidence and prevalence of both cardiac and renal disease in Germany are steadily rising. Heart disease is the most common cause of death, especially among people with chronic kidney disease. Impaired kidney function increases the risk of cardiovascular events, and vice versa.

Methods: This narrative review is based on pertinent publications retrieved by a literature search up to the year 2025, with particular attention to the guidelines of the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF) and the European Society of Cardiology (ESC). Supplementary searches were conducted on individual aspects of the epidemiology, diagnosis, and treatment of heart and kidney disease.

Results: The heart and the kidneys are closely pathophysiologically linked. Both can be damaged by shared vascular risk factors, including diabetes mellitus, arterial hypertension, and chronic inflammation. These shared mechanisms give rise to a continuum of diseases. Multiple RCTs have shown in recent years that the morbidity and mortality of patients with heart and kidney diseases can be significantly lowered by treatment not only with ACE inhibitors, but also with sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 receptor agonists (GLP1-RA), and nonsteroidal mineralocorticoid receptor antagonists (nsMRA). Absolute risk reductions in the range of 1.8% to 6.7% have been found to be achievable for most of the combined endpoints studied, depending on the particular active substance used.

Conclusion: Heart and kidney diseases often arise together and can be treated with new pharmacotherapeutic strategies. Open questions remain concerning the potential synergistic effects of the drugs mentioned above, the suitable management of polypharmacy, and the enabling of cost-effective care.

Cite this as: Mahfoud F, Götzinger F, Kramann R, Marx N, Schwenger V: The synergistic treatment of heart and kidney disease. Dtsch Arztebl Int 2026; 123: 19–26. DOI: 10.3238/arztebl.m2025.0131

The heart and kidneys are closely linked through neurohumoral mechanisms that play a central role in regulating fluid balance and blood pressure (e1). Increased wall tension in the left ventricle leads to increased natriuresis in the kidneys via the release of natriuretic peptides. The kidneys can activate the renin-angiotensin-aldosterone system (RAAS) by releasing renin, which raises the blood pressure and cardiac preload and afterload by inducing vasoconstriction and sodium retention. Common risk factors such as arterial hypertension, diabetes mellitus (DM), smoking, and obesity cause chronic damage mechanisms in both organs. These processes are characterized by neurohumoral hyperactivity leading to increased RAAS activity, with elevated aldosterone levels and activation of the autonomic nervous system (e2). Persistent dysregulation of these types can lead to the development of chronic renal and cardiovascular disease.

Learning objectives

This article is intended to enable readers to:

• diagnose chronic kidney disease with the knowledge that it is often associated with diabetes and cardiovascular disease;
• understand the prognostic significance of chronic kidney disease, especially for patients who also have cardiovascular disease;
• be aware of new cardiometabolic therapies and their indications.

Chronic kidney disease in the
cardiovascular context

Cardiovascular diseases are rising in both incidence and prevalence and remain the leading cause of death in Germany and around the world (e3, e4, e5, e6, e7, e8, e9, e10). Cardiometabolic risk factors such as arterial hypertension, type 2 diabetes mellitus (T2DM), obesity, smoking, and dyslipidemia contribute to approximately 20% of all deaths worldwide (1). Heart failure (HF) (also called congestive heart failure), a clinical syndrome characterized by hypervolemia-associated signs and classic symptoms such as dyspnea, is the most common cause of hospitalization in Germany and the Western world (e6, e11, e12). Chronic kidney disease (CKD) is one of the more common comorbidities of cardiovascular disease (e13, e14, e15, e16). Nearly 50% of patients with HF have CKD (2). Cardiovascular disease is the most common cause of death in patients with CKD (2). CKD is defined by (3, e17):

• persistent structural changes in the kidneys, and/or
• an estimated glomerular filtration rate (eGFR) lower than 60 mL/min/1.73 m² body surface area, and/or
• albuminuria, as indicated by a urine albumin-to-creatinine ratio (UACR) of 30 mg/g or 3 mg/mmoL or above in spontaneous urine over a period of at least 3 months.

As the diagnosis of CKD may have therapeutic implications and a persistent increase in UACR suffices for diagnosis of CKD, determining the UACR in spontaneous urine is essential, especially in patients with cardiovascular disease. In a meta-analysis, UACR was found to be 87% sensitive and 88% specific for the detection of CKD (e18). The combined determination of eGFR and UACR enables more accurate prognostication in CKD (4). In patients with CKD, the more severe the albuminuria and the lower the eGFR, the higher the mortality and risk of cardiovascular events (e17, e19). Albuminuria is a risk marker for mortality and hospitalizations due to HF (HHF). The hazard ratio [HR] for microalbuminuria is 1.43 (95% confidence interval: [1.21; 1.69]; p<0.0001); for macroalbuminuria, 1.75 [1.39; 2.20]; p<0.0001) (e13, e20, e21). It should be noted that UACR may be falsely elevated in the setting of a urinary tract infections or hematuria.

Methods of determining the estimated glomerular
filtration rate

The eGFR is a key parameter for diagnosing assessment of CKD progression, as well as for determining the appropriate dosage of renally metabolized drugs. As the direct measurement of GFR is complex and costly, GFR is usually estimated with one of several formulae that have been developed for this purpose. In Germany, the eGFR is most commonly calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) formula, as recommended by the national guidelines (e17, e22). Creatinine values are the most common basis for calculating eGFR (e23); some formulae, however, also include cystatin C, which is less influenced by age, sex, diet, and muscle mass (e23). One disadvantage of cystatin C is that its concentration is affected by thyroid disorders (higher in hyperthyroidism, lower in hypothyroidism) and by certain drugs (e.g., glucocorticosteroids elevate the cystatin C concentration in kidney transplant patients) (e24, e25, e26). Cystatin C-based renal function testing is more expensive and should therefore be restricted to selected patients, e.g., those with a low or very high muscle mass.

Cardiorenal syndrome

Cardiorenal syndrome (CRS) is an umbrella term for five different entities of combined disease in these two organs (e1) in which acute or chronic damage to the heart causes acute or chronic kidney disease, or vice versa (e1). Distinguishing among CRS subtypes on clinical grounds is often difficult and not always of direct therapeutic relevance. For example, acute HF can cause temporary hypoperfusion of the kidney via reduced stroke volume, leading in turn to hypoxic tubular damage or a loss of filtration pressure (e27). On the other hand, acute kidney injury can cause heart damage via volume retention and uremic toxins (e.g., indoxyl sulfate, phosphate, urea) (e28). In chronic HF and concomitant CKD, impaired renal function poses a special challenge for drug management. Many cardiovascular drugs are not approved for patients with markedly reduced eGFR (in particular, eGFR < 30 mL/min/ 1.73 m²) or have not been adequately studied in such patients. This is particularly relevant for patients with HF, as some of the drugs that are used to improve the clinical outcome (e.g., SGLT2 inhibitors and RAAS inhibitors) may further lower the eGFR via pharmacological mechanisms such as vasoconstriction of the glomerular afferent arteriole or vasodilation of the efferent arteriole (e29, e30). Nonetheless, a reduced eGFR after the treatment is started does not necessarily imply that the anti-heart-failure drug should be paused or discontinued. Table 1 contains an overview of the main drugs against HF and whether and how they may be used in patients with CKD.

Table 1

The main drugs used to treat heart failure and their applicability in patients with chronic kidney disease

The cardiovascular kidney metabolic syndrome

The so-called cardiovascular kidney metabolic syndrome (CKM) is a constellation of metabolic risk factors that promote CKD and cardiovascular disease via chronic organ damage and vascular dysfunction. The American Heart Association first defined the CKM syndrome in 2023 (5), emphasizing the importance of structured staging to enable its early detection as well as targeted risk stratification and treatment (Table 4). The presence of fatty tissue deposits on the heart or liver and their endocrine activity imply that chronic inflammation, insulin resistance, and ensuing vascular dysfunction play a pathophysiological role (e31, e32, 6). The presence of fatty tissue in the liver, pericardium, and epicardium and around blood vessels is associated with a higher frequency of cardiovascular events (e32). Hyperactivity of the sympathetic nervous system plays an important role as well (e33). These processes increase the risk of developing HF, coronary heart disease, stroke, and peripheral arterial disease. The targeted secondary prevention of CKM diseases through the control of blood pressure and blood sugar level is important (5, e34). The prevalence of CKM syndrome in patients with HF and preserved ejection fraction (HFpEF) and its relevance to clinical outcomes in this population was investigated in an analysis of 4 HF studies (7, 8, 9, 10, 11, 12). CKM disease was defined as the presence of T2DM, CKD, or atherosclerotic disease (a prior heart attack, stroke, coronary intervention, or bypass procedure) (8). Over two decades, the prevalence of CKM rose from 72.7% to 83.4%. Patients with HF without CKM disease had the lowest rates of primary clinical events (3.6–6.5 events per 100 patient-years), while the event rate among patients with three CKD diseases was more than twice as high (HR 2.16–2.56) (8). This analysis underscores the growing prognostic significance of CKD syndrome, especially in patients with HFpEF.

Table 4

The stages of cardiovascular kidney metabolic syndrome as defined by the American Heart Association

The prevention of heart and kidney disease

Arterial hypertension and T2DM are among the main risk factors for heart and kidney disease (1). The German national care guideline therefore recommends blood pressure control (target < 140/90 mm Hg, individually adjustable) and glycemic control with an HbA1c target range of 6.5–8.5% in patients with cardiovascular and renal diseases (3, e17, 13, 14, 15, 16). As advanced kidney disease (>G3aA3) is associated with a high to very high risk of cardiovascular events, low-density lipoprotein cholesterol (LDL-C) should also be monitored in accordance with the guidelines. The target values for lowering cardiovascular morbidity and mortality, as recommended by the ESC, are <70 mg/dL (1.8 mmol/L) for patients at high risk and <55 mg/dL (<1.4 mmol/L) for patients at very high cardiovascular risk (e17, e35, e36, e37). The German national care guideline for diabetes recommends the same target values (13). The German national care guideline for CKD also recommends lipid-lowering therapy for patients under age 75 who suffer from CKD and have an elevated cardiovascular risk (14) (Case Illustration).

Sodium-glucose cotransporter 2 inhibitors

Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower glucose and sodium reabsorption in the proximal renal tubule. This contributes to improved glycemic control in patients with T2DM (e29). Meta-analyses of randomized controlled trials have shown that SGLT2 inhibitors reduce cardiovascular events in patients with T2DM and atherosclerotic cardiovascular disease (relative risk reduction [RRR] 11%; HR 0.89 [0.83; 0.96], p = 0.0014) and slow the progression of CKD (RRR 45%; HR 0.55 [0.48; 0.64]; p<0.0001) (17). Moreover, in patients with HFrEF SGLT2 inhibitors lower the frequency of cardiovascular mortality, HHF (RRR 26%; HR 0.74 [0.68; 0.82]; p<0.0001) and renal endpoints (RRR 38%; HR 0.62 [0.43; 0.90]; p = 0.013) (19, 20, 21, 22, 23, 24). In patients with HFpEF, they significantly reduce HHF (RRR 23%; HR 0.77 [0.67; 0.89]) and also seem to lower cardiovascular mortality, although this finding fails to reach statistical significance (RRR 12%; HR 0.88 [0.74; 1.05]) (14, 25). In patients with CKD, SGLT2 inhibitors reduce cardiovascular deaths (RRR 13%; HR 0.87 [0.79; 0.95]; p = 0.003) and renal endpoints (RRR 23%, HR 0.77 [0.68; 0.88]; p<0.001) (18, 26, 27, 28, 29, e38, e39) independent of etiology of CKD. On the basis of this evidence, the ESC, in its current guidelines, recommends SGTL2 inhibitors for all patients with T2DM and atherosclerotic cardiovascular disease, with a class IA recommendation (Table 2) (19). The same recommendation applies to patients with HF, regardless of ejection fraction (30). Moreover, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend SGLT2 inhibitors alongside standard treatment with RAAS inhibitors and statins in patients with T2DM and CKD whose eGFR is 20 mL/min/1.73 m² or higher, regardless of the presence or absence of albuminuria (IA) (3, e17). The KDIGO guidelines also recommend SGLT2 inhibitors for patients with CKD without T2DM who have an eGFR ≥ 20 mL/min/1.73 m² and a UACR ≥ 200 mg/g (22.6 mg/mmoL) (IA), or else an eGFR of 20–45 mL/min/1.73 m² regardless of the UACR (2B) (3, e17). Long-term data from the EMPA-Kidney trial also showed that the protective effect of empagliflozin on eGFR loss persists for up to 1 year after the end of treatment (28). The German national care guideline-DM recommends the use of SGLT2 inhibitors in addition to metformin in patients with T2DM and clinically relevant cardiovascular disease with an HbA1c >7% (no recommendation grade) (13). The German national care guideline-CKD recommends their use in patients with an eGFR<45 mL/min/1.73 m² or a UACR ≥ 300 mg/g (33.9 mg/mmoL) (14).

Table 2

Summary of the main guideline recommendations* on SGLT2 inhibitors, GLP1-RA, and nsMRA ASCVD,

Glucagon-like peptide-1 receptor agonists

Glucagon-like peptide-1 receptor agonists (GLP1-RA) increase glucose-dependent insulin secretion, inhibit gastric emptying, and increase satiety (31), leading to weight loss (32). GLP1-RA improve glycemic control in patients with T2DM and lessen cardiovascular events (absolute risk reduction [ARR] 2.3%; HR 0.74 [0.58; 0.95]; p<0.001; number needed to treat [NNT] 44) (33, 34) (Table 3a and eTable). They were, therefore, included in the 2023 ESC guidelines for all patients with T2DM and atherosclerotic cardiovascular disease, with a class IA recommendation (19). The German national care guideline-DM recommends GLP1-RA in patients with clinically relevant cardiovascular disease in combination with metformin in T2DM, provided the HbA1c is >7% (no recommendation grade) (14).

Table 3

The main randomized controlled trials on SGLT2 inhibitors, nsMRAs, and GLP1-RAs in patients with T2DM, heart disease, and kidney disease

eTable

Important randomized controlled trials on SGLT2 inhibitors, nsMRAs, and GLP1-RAs in patients with T2DM, heart disease, and kidney disease

In the FLOW study, treatment with the GLP1-RA semaglutide lowered the frequency of the combined renal endpoint in patients with CKD and T2DM (ARR 4.5%; HR 0.76 [0.66; 0.88]; p = 0.0003, NNT 22) (35). Patients with an eGFR between 50 and 75 mL/min/1.73 m² (inclusive) and a UACR from 300 to 5000 mg/g (33.9–565 mg/mmoL), or an eGFR of at least 25 and less than 50 mL/min/ 1.73 m² and a UACR from 100 to 5000 mg/g (11.3–565 mg/mmoL), were included (35). All received stable RAAS inhibitor treatment, and approximately 16% had also been treated with an SGLT2 inhibitor.

The secondary endpoints were also positively affected by semaglutide treatment. The mean annual drop in eGFR was slowed by 1.16 mL/min/1.73 m², the frequency of cardiovascular events was lowered by 18% (ARR 2.6%; HR 0.82 [0.68; 0.98] ; p = 0.029, NNT 39) and that of death from any cause was lowered by 20% (ARR 3.6%; HR 0.80 [0.67; 0.95]; p = 0.01; NNT 28). UACR was significantly lowered by 40% (vs. 12% in the placebo group). Body weight and HbA1c were also lowered to a greater extent by semaglutide than by placebo. Serious adverse events were less common with semaglutide than with placebo (49.6% vs. 53.8%), although this difference was not statistically significant. An important limitation is the fact that only 16% of patients were treated with an SGLT2 inhibitor. It is not yet clear whether there are any synergistic effects.

GLP1-RA are also beneficial in patients with HFpEF and obesity. In the STEP-HFpEF study (n = 529), the included patients had HFpEF and a median body-mass index of 37 kg/m². Treatment with semaglutide led to significant weight loss (−13.6% versus −2.6% placebo; p<0.001) and a better quality of life (Kansas City Cardiomyopathy Questionnaire [KCCQ], +16.6 versus +8.7; p<0.001) (36). The reduction in individual endpoints was correlated with weight loss even though the study was not powered for these important clinical endpoints. Moreover, the follow-up period was short, and the event rates were low in general.

In patients with pre-existing cardiovascular disease who are overweight or obese, but without DM, semaglutide lowered the incidence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke (ARR 1.5%; HR 0.80 [0.72; 0.90]; p<0.001; NNT 67) (37). Semaglutide was stopped because of side effects twice as often as placebo (16.6% versus 8.2%; p<0.001).

GLP1-RAs are an option for patients with T2DM and CKD as well as for those with HFpEF and obesity. It remains to be seen whether they are similarly effective in CKD of other origin or in HFrEF. One advantage of this class of drugs is their once-weekly subcutaneous administration, which could improve adherence. They may need to be discontinued because of side effects, mainly gastrointestinal. GLP1-RA seem to be safe in the short and medium term; long-term data on their safety, efficacy, and cost-effectiveness are not yet available.

Nonsteroidal mineralocorticoid receptor antagonists

Mineralocorticoid receptor antagonists (MRA) inhibit maladaptive, profibrotic, and inflammatory processes associated with aldosterone overactivity (e40, e41). On the basis of the findings of the RALES and EMPHASIS studies, the current guidelines contain a class IA recommendation for spironolactone and eplerenone in HFrEF in order to lower morbidity and mortality (RALES ARR 11% for cardiovascular death, HR 0.70 [0.60; 0.82] ; p<0.001, NNT 10; EMPHASIS ARR 3% for all-cause mortality, HR 0.76 [0.62; 0.93]; p = 0.008; NNT 34) (30, e42, e43, e44). The German national care guideline for chronic heart failure also recommends the use of MRA in HFrEF (38).

In addition, MRAs can contribute to a reduction in proteinuria in CKD, which is why KDIGO recommends their use (3, e17, e45). Randomized controlled trials have also shown that MRAs lower cardiovascular morbidity in patients with dialysis-dependent CKD (ARR 6.9%; HR 0.40 [0.20; 0.81]; p = 0.017; NNT 15) (e46, e47, e48).

Steroidal MRAs have low selectivity for the aldosterone receptor and can therefore antagonize androgenic and progestogenic effects, causing undesirable hormonal side effects such as erectile dysfunction, amenorrhea, and gynecomastia. Hyperkalemia and a reduction in eGFR are common as well and limit the use of steroidal MRAs in certain patient groups (e41). The nonsteroidal (ns-) MRA finerenone has a higher specificity for the aldosterone receptor. Two randomized studies have shown that finerenone significantly lowered a combined renal endpoint (renal failure, sustained eGFR loss of >40%, and death due to kidney disease) by 18% in patients with CKD and T2DM (ARR 1.8%, HR 0.82 [0.73; 0.93]; p = 0.001, NNT 56) (e49, e50, 39). In addition, finenerone significantly lowered a combined cardiovascular endpoint (cardiovascular death, non-fatal stroke or myocardial infarction, and HHF) (ARR 3.3%, HR 0.86 [0.75; 0.99]; p = 0.03; NNT 31) (e51). Finerenone was subsequently approved in Germany for the treatment of stage 3 and 4 CKD with albuminuria and T2DM.

The FINEARTS-HF trial concerned the use of finerenone in patients with HF and an LVEF ≥ 40%. Compared to placebo, finerenone therapy lowered the risk of heart failure events and improved the quality of life as measured by the KCCQ (ARR 7.0%; rate ratio 0.84 [0.74; 0.95]; p = 0.007; NNT 15), but did not prolong survival (9). It was generally well tolerated. Hyperkalemia (serum potassium ] 5.5 mmol/L) was more common with finenerone than with placebo (17.3% vs. 8.3%), and hypokalemia less common (serum potassium <3.5 mmol/L, 4.4% vs. 9.7%).

There have not yet been any comparison trials of nsMRAs versus spironolactone or eplerenone. Nor are any data available about their use in patients with HFrEF. Future studies must define the patient groups that can derive long-term benefit from nsMRAs. In view of these limitations, the Institute for Quality and Efficiency in Health Care rated the additional benefit of finerenone in patients with CKD and T2DM as low, partly because only a few patients in the FIDELIO-DKD and FIGARO-DKD studies were simultaneously treated with SGLT2 inhibitors.

The problem of polypharmacy

The potential benefits of drug treatment are offset by the problem of polypharmacy, because many patients are treated with multiple drugs at once (e52). Polypharmacy is associated with poorer adherence and a higher rate of adverse clinical events. This problem is often worse in elderly patients, as more drugs need to be taken with advancing age because of multiple comorbidities, and the probability of a drug interaction rises (e52). The benefit of fixed-dose combinations remains to be demonstrated (e53).

eBox

Explanation of the guideline recommendations

Outlook

In an analysis of 12 randomized trials of SGLT2 inhibitors, nsMRAs, and GLP1-RAs in patients with T2DM and albuminuria, the potential additive benefit of triple therapy compared to standard treatment with RAAS inhibitors and optimal risk factor control was examined. The analysis suggests a possible reduction in CKD progression (ARR 4.4%; HR 0.42 [0.31; 0.56]; NNT 23), all-cause mortality (ARR 3.1%; HR 0.67 [0.55; 0.80] ; NNT 33), cardiovascular mortality (ARR 2.4%; 0.64 [0.51; 0.80] NNT 42), major cardiovascular events (ARR 4.4%; HR 0.65 [0.55; 0.76] NNT 23), and HHF (ARR 3.4%; HR 0.45 [0.34; 0.58] NNT 30) (40). For a 50-year-old male patient with T2DM and a UACR of at least 30 mg/g (3.4 mg/mmoL), combination therapy might yield an additional 3.2 years of disease-free life (in terms of cardiovascular events) compared to standard treatment. Disease-free life until CKD progression was extended by 5.5 years, while overall survival increased by 2.4 years. Future randomized and controlled trials will address the various combinations: The CONFIRMATION-HF trial (NCT06024746) addresses the effect of combination therapy with an SGLT2 inhibitor and finerenone in patients with HF (any ejection fraction) and recent hospitalization. The possible benefit of combination therapy in CKD of other origins remains an open question. The FINALITY-HF (NCT06033950) trial will address the use of finerenone in patients with HFrEF who are intolerant to steroidal MRAs.

Conclusion

Heart and kidney diseases are closely linked. SGLT2 inhibitors, GLP1-RA, and nsMRA have been shown to reduce cardiovascular and renal events in T2DM, CKD, and HF. Combination therapy in particular could slow disease progression and prolong life expectancy through synergistic mechanisms of action. Ongoing studies will provide further important insights into the optimal combination of these substances.

Conflict of interest statement
FM has received research funding from the German Research Foundation (Deutsche Forschungsgemeinschaft, SFB TRR219, project ID 322900939) and the German Heart Foundation (Deutsche Herzstiftung). The Universität des Saarlandes has received research funding from Ablative Solutions, Medtronic, and ReCor Medical. As of May 2024, FM has received lecture fees/consulting fees from Ablative Solutions, AstraZeneca, Inari, Medtronic, Merck, Novartis, Philips, and ReCor Medical.

As of May 2024, FG has received speaker honoraria from AstraZeneca and financial support from the German Heart Foundation.

RK is a founder of Sequantrix GmbH, in which he holds shares. He serves on the advisory board of Hybridize Therapeutics and as a consultant to AMGEN, Genentech/Roche, Chugai, and Valerio Therapeutics. He has received consulting fees from Chugai, Travere, Sequantrix, Bayer, Lilly, Amgen, Novo Nordisk, Astra-Zeneca, Grünenthal, Hybridize Therapeutics, and Exigent, and honoraria for continuing medical education presentations from Astra-Zeneca, Eli Lilly, Bayer, Novo Nordisk, and Sobi. He has also received research funding from Novo Nordisk Ask Bio, Travere Therapeutics, Chugai, and Galapagos.

NM is supported by the German Research Foundation (TRR 219; Project ID 322900939 [M03, M05]). He has given lectures on behalf of Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, Lilly, and Novo Nordisk. N. Marx has conducted research projects with the financial support of Boehringer Ingelheim and has served as a consultant for Amgen, Bayer, Boehringer Ingelheim, Sanofi-Aventis, MSD, BMS, AstraZeneca, and Novo Nordisk.

VS has received lecture honoraria from Astra Zeneca and Boehringer Ingelheim.

Manuscript submitted on 17 March 2025, revised version accepted on 14 July 2025.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Felix Mahfoud, M.A.

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