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The purpose of the review is to summarize the current pharmacological management of chronic kidney disease (CKD) in pediatric patients and critically present emerging evidence for the use of mineralocorticoid receptor antagonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Globally, CKD is the 19th leading cause of years of life lost and the current total number of children and adolescents affected with CKD Stages II-V is predicted to exceed 2 million in a global population of 2 billion children. The severity of kidney disease is strongly correlated with the extent of proteinuria. Agents that target the renin-angiotensin-aldosterone-system reduce proteinuria in mild to moderate CKD, slowing disease progression. Recent clinical trials evaluating mineralocorticoid receptor antagonists, such as finerenone and SGLT2 inhibitors, demonstrate similar results. However, additional pediatric clinical trials are necessary to determine their complete therapeutic potential. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) is one of the main public health care problems worldwide. It is associated with a marked increased risk of developing atherosclerotic vascular disease, heart failure, chronic kidney disease and death. It is essential to act during the early phases of the disease, through the intensification of lifestyle changes and the prescription of those drugs that have been shown to reduce these complications, with the aim not only of achieving an adequate metabolic control, but also a comprehensive vascular risk control. In this consensus document, developed by the different specialists that treat these patients (endocrinologists, primary care physicians, internists, nephrologists and cardiologists), a more appropriate approach in the management of patients with T2DM or its complications is provided. A particular focus is given to the global control of cardiovascular risk factors, the inclusion of weight within the therapeutic objectives, the education of patients, the deprescription of those drugs without cardiovascular benefit, and the inclusion of GLP-1 receptor agonists and SGLT2 inhibitors as cardiovascular protective drugs, at the same level as statins, acetylsalicylic acid, or renin angiotensin system inhibitors. [ABSTRACT FROM AUTHOR]

The purpose of this manuscript is to review the effects of sodium-glucose cotransport protein 2 inhibitors (SGLT2is) in patients with chronic kidney disease according to basic mechanisms, current recommendations, and future perspectives. Based on growing evidence from randomized, controlled trials, SGLT2is have proven their benefit on cardiac and renal adverse complications, and their indications expanded into the following five categories: glycemic control, reduction in atherosclerotic cardiovascular disease (ASCVD), heart failure, diabetic kidney disease, and nondiabetic kidney disease. Although kidney disease accelerates the progression of atherosclerosis, myocardial disease, and heart failure, so far, no specific drugs were available to protect renal function. Recently, two randomized trials, the DAPA-CKD and EMPA-Kidney, demonstrated the clinical benefit of the SGLT2is dapagliflozin and empagliflozin in improving the outcome in patients with chronic kidney disease. For the consistently positive results in cardiorenal protection, the SGLT2i represents an effective treatment to reduce the progression of kidney disease or death from cardiovascular causes in patients with and without diabetes mellitus. [ABSTRACT FROM AUTHOR]

Aims: No studies have comprehensively compared the efficacy of sodium‐glucose cotransporter‐2 (SGLT2) inhibitors, renin–angiotensin system (RAS) inhibitors, and angiotensin receptor neprilysin (ARN) inhibitors based on different type of heart failure, including heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The aim of this network meta‐analysis was to evaluate the relative efficacy of SGLT2 inhibitor (SGLT2i), RAS inhibitor (RASi) and ARN inhibitor (ARNI) in different types of heart failure. Methods: A systemic literature search was performed from inception to 19 November 2022 for randomized control trials assessing the risk of cardiovascular (CV) death or hospitalization for heart failure (HHF) of these drugs in HF. A network meta‐analysis was performed. Risk ratio (RR) with 95% confidence intervals (CI) were synthesized. Results: Seventeen studies were selected with a total of 61 489 patients. In patients with HFrEF, ARNI led to a reduced risk of a composite outcome of CV death or HHF when compared with placebo (RR = 0.83, 95% CI 0.77–0.89). Similar trends were observed when focusing on the outcome of CV death or HHF alone. In patients with HFpEF, SGLT2i showed the beneficial effects on the CV death or HHF events when compared with placebo and RASi (RR = 0.82, 95% CI 0.74–0.92; RR = 1.16, 95% CI 1.02–1.31). For CV death, all these three drugs could not show beneficial effects in HFpEF. For the incidence of HHF in HFpEF, both SGLT2i and ARNI demonstrated the beneficial effects but SGLT2i was superior to ARNI. There were no differences in the events of discontinuation under these drugs when compared with placebo or each other in either HFrEF or HFpEF patients. SGLT2i showed the least renal injury among these interventions in HFrEF and there were no differences in the incidence of renal injury of these interventions in HFpEF. Conclusions: Among these drugs, ARNI showed the greatest ability to lower the incidence of CV death or HHF and SGLT2i exerted the least renal injury in patients with HFrEF. In patients with HFpEF, SGLT2i was associated with a reduction in the risk of CV death or HHF. There were no differences in the incidence of renal injury of these interventions in HFpEF. The intolerance of these drugs were comparable in both HFrEF and HFpEF. [ABSTRACT FROM AUTHOR]

In the last years, major progress occurred in heart failure (HF) management. Quadruple therapy is now mandatory for all the patients with HF with reduced ejection fraction. Whilst verciguat is becoming available across several countries, omecamtiv mecarbil is waiting to be released for clinical use. Concurrent use of potassium‐lowering agents may counteract hyperkalaemia and facilitate renin–angiotensin–aldosterone system inhibitor implementations. The results of the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR‐Preserved) trial were confirmed by the Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction (DELIVER) trial, and we now have, for the first time, evidence for treatment of also patients with HF with preserved ejection fraction. In a pre‐specified meta‐analysis of major randomized controlled trials, sodium–glucose co‐transporter‐2 inhibitors reduced all‐cause mortality, cardiovascular (CV) mortality, and HF hospitalization in the patients with HF regardless of left ventricular ejection fraction. Other steps forward have occurred in the treatment of decompensated HF. Acetazolamide in Acute Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that the addition of intravenous acetazolamide to loop diuretics leads to greater decongestion vs. placebo. The addition of hydrochlorothiazide to loop diuretics was evaluated in the CLOROTIC trial. Torasemide did not change outcomes, compared with furosemide, in TRANSFORM‐HF. Ferric derisomaltose had an effect on the primary outcome of CV mortality or HF rehospitalizations in IRONMAN (rate ratio 0.82; 95% confidence interval 0.66–1.02; P = 0.070). Further options for the treatment of HF, including device therapies, cardiac contractility modulation, and percutaneous treatment of valvulopathies, are summarized in this article. [ABSTRACT FROM AUTHOR]

Aims: To describe healthcare resource utilization (HCRU) of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain.  METHODS: Adults with ≥ 1 HF diagnosis and ≥ 1 year of continuous enrolment before the corresponding index date (1/January/2016) were identified through the BIG-PAC database. Rate per 100 person-years of all-cause and HF-related HCRU during the year after the index date were estimated using bootstrapping with replacement.Results: Twenty-one thousand two hundred ninety-seven patients were included, of whom 48.5% had HFrEF, 38.6% HFpEF and 4.2% HFmrEF, with the rest being of unknown EF. Mean age was 78.8 ± 11.8 years, 53.0% were men and 83.0% were in NYHA functional class II/III. At index, 67.3% of patients were taking renin angiotensin system inhibitors, 61.2% beta blockers, 23.4% aldosterone antagonists and 5.2% SGLT2 inhibitors. Rates of HF-related outpatient visits and hospitalization were 968.8 and 51.6 per 100 person-years, respectively. Overall, 31.23% of patients were hospitalized, mainly because of HF (87.88% of total hospitalizations); HF hospitalization length 21.06 ± 17.49 days (median 16; 25th, 75th percentile 9-27). HF hospitalizations were the main cost component: inpatient 73.64%, pharmacy 9.67%, outpatient 9.43%, and indirect cost 7.25%. Rates of all-cause and HF-related HCRU and healthcare cost were substantial across all HF subgroups, being higher among HFrEF compared to HFmrEF and HFpEF patients.Conclusions: HCRU and cost associated with HF are high in Spain, HF hospitalizations being the main determinant. Medication cost represented only a small proportion of total costs, suggesting that an optimization of HF therapy may reduce HF burden. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is one of the most common causes of end-stage renal disease worldwide. The treatment of DKD is strongly associated with clinical outcomes in patients with diabetes mellitus. Traditional therapeutic strategies focus on the control of major risk factors, such as blood glucose, blood lipids, and blood pressure. Renin–angiotensin–aldosterone system inhibitors have been the main therapeutic measures in the past, but the emergence of sodium–glucose cotransporter 2 inhibitors, incretin mimetics, and endothelin-1 receptor antagonists has provided more options for the management of DKD. Simultaneously, with advances in research on the pathogenesis of DKD, some new therapies targeting renal inflammation, fibrosis, and oxidative stress have gradually entered clinical application. In addition, some recently discovered therapeutic targets and signaling pathways, mainly in preclinical and early clinical trial stages, are expected to provide benefits for patients with DKD in the future. This review summarizes the traditional treatments and emerging management options for DKD, demonstrating recent advances in the therapeutic strategies for DKD. [ABSTRACT FROM AUTHOR]

Objective: To estimate the prevalence, incidence, and describe the characteristics and management of patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF) in Spain. Methods: Adults with ≥1 inpatient or outpatient HF diagnosis between 1 January 2013 and 30 September 2019 were identified through the BIG-PAC database. Annual incidence and prevalence by EF phenotype were estimated. Characteristics by EF phenotype were described in the 2016 and 2019 HF prevalent cohorts and outcomes in the 2016 HF prevalent cohort. Results: Overall, HF incidence and prevalence were 0.32/100 person-years and 2.34%, respectively, but increased every year. In 2019, 49.3% had HFrEF, 38.1% had HFpEF, and 4.3% had HFmrEF (in 8.3%, EF was not available). Compared with HFrEF, patients with HFpEF were largely female, older, and had more atrial fibrillation but less atherosclerotic cardiovascular disease. Among patients with HFrEF, 76.3% were taking renin-angiotensin system inhibitors, 69.5% beta-blockers, 36.8% aldosterone antagonists, 12.5% sacubitril/valsartan and 6.7% SGLT2 inhibitors. Patients with HFpEF and HFmrEF took fewer HF drugs compared to HFrEF. Overall, the event rates of HF hospitalization were 231.6/1000 person-years, which is more common in HFrEF patients. No clinically relevant differences were found in patients with HFpEF, regardless EF (50- < 60% vs. ≥60%). Conclusions: >2% of patients have HF, of which around 50% have HFrEF and 40% have HFpEF. The prevalence of HF is increasing over time. Clinical characteristics by EF phenotype are consistent with previous studies. The risk of outcomes, particularly HF hospitalization, remains high, likely related to insufficient HF treatment. [ABSTRACT FROM AUTHOR]

Objectives To assess mortality and cardiovascular and renal outcomes among patients with chronic kidney disease (CKD) (primary objective), with a particular focus on heart failure (HF) risk following diagnosis of CKD (secondary objective) in Spain. Methods We conducted an observational study comprising cross-sectional and longitudinal retrospective analyses using secondary data from electronic health records. For the primary objective, adults with prevalent CKD [estimated glomerular filtration rate (eGFR) <60 or ≥60 mL/min/1.73 m2 with a urine albumin:creatinine ratio (UACR) ≥30 mg/g at the index date (1 January 2017)] were included. For the secondary objective, adults with incident CKD in 2017 were enrolled. Results In the prevalent population, 46 786 patients with CKD without HF [75.8 ± 14.4 years, eGFR 51.4 ± 10.1 mL/min/1.73 m2; 75.1% on renin–angiotensin system inhibitors (RASis)] and 8391 with CKD and HF (79.4 ± 10.9 years, eGFR 46.4 ± 9.8 mL/min/1.73 m2) were included. In the prevalent population, the risk of all-cause death {hazard ratio [HR] 1.107 [95% confidence interval (CI) 1.064–1.153]}, HF hospitalization [HR 1.439 (95% CI 1.387–1.493)] and UACR progression [HR 1.323 (95% CI 1.182–1.481)] was greater in those patients with CKD and HF versus CKD only. For the incident population, 1594 patients with CKD without HF and 727 with CKD and HF were included. Within 24 months from the CKD diagnosis (with/without HF at baseline), 6.5% of patients developed their first HF hospitalization. Although 60.7% were taking RASis, only 3.4% were at maximal doses and among diabetics, 1.3% were taking sodium-glucose cotransporter-2 inhibitors. Conclusions The presence of HF among CKD patients markedly increases the risk of outcomes. CKD patients have a high risk of HF, which could be partially related to insufficient treatment. [ABSTRACT FROM AUTHOR]

Background This study was designed to evaluate the efficiency and safety of combination therapy with sodium–glucose cotransporter 2 (SGLT2) inhibitors and renin–angiotensin system blockers such as angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) in patients with type 2 diabetes mellitus (T2DM). Methods We searched the PubMed, Embase, Web of Science and Cochrane Library databases from their inception to May 2020. Two authors independently performed study selection, risk-of-bias assessment and data extraction. The quality and risk of bias were assessed by the Cochrane Risk of Bias Tool. Statistical heterogeneity was determined by the I 2 statistics. Results Seven studies including 1757 patients were analysed. Compared with ACEI/ARB alone, combination therapy with SGLT2 inhibitors and ACEIs/ARBs produced a reduction in systolic blood pressure (SBP) [weighted mean difference (WMD) −3.84 mmHg], diastolic blood pressure (DBP; WMD −1.06 mmHg), 24 h ambulatory SBP (WMD −4.59 mmHg), 24-h ambulatory DBP (WMD −2.08 mmHg), urine albumin:creatinine ratio (WMD −29.70%), evaluated glomerular filtration rate (WMD −3.46 mL/min/1.73 m2), haemoglobin A1c [standardized mean difference (SMD) −0.48], fasting plasma glucose (SMD −0.28), uric acid (SMD −0.35) and body weight (SMD −0.29). The risk of hypoglycaemia with combination therapy was higher than in the control group (risk ratio 1.37). As for the risks of total adverse events, genital infection and urinary tract infection, no significant difference was revealed. Conclusion Compared with ACEI/ARB alone, the combination therapy with SGLT2 inhibitors and ACEIs/ARBs in T2DM was effective and well-tolerated and could achieve additional effects including better control of blood pressure, improvement of renal outcomes, alleviation of long-term renal function and a decrease in blood glucose and body weight. The combination therapy showed an increased risk of hypoglycaemia. [ABSTRACT FROM AUTHOR]

When renal function declines, blood pressure rises, which in turn causes the kidneys to deteriorate. In order to stop this vicious cycle, it is necessary to lower the blood pressure to a "moderate" level in patients who have chronic kidney disease (CKD)-associated hypertension. Such optimization is problematic, since tight control of blood pressure might worsen the prognosis in elderly patients with CKD, especially those with advanced arteriosclerosis. Although renin-angiotensin system (RAS) inhibitors, angiotensinogen converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are first-line drugs for hypertensive patients with diabetes, they should be used with caution depending on the patients' conditions. Recently, there has been a focus on the preventive effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, anti-diabetic drugs that have been shown to have an impact, on heart and kidney complications. SGLT2 inhibitors increase the amount of sodium chloride delivered to the macular densa of the distal tubules and correct glomerular hyperfiltration by contraction of afferent arterioles via the tubule-glomerular feedback system. It might be one of the reasons why SGLT2 inhibitors show the renal- and cardio-protective effects; however, the mechanism behind their function remains to be elucidated. [ABSTRACT FROM AUTHOR]

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have clearly demonstrated their beneficial effect in diabetic kidney disease (DKD) on top of the standard of care [blood glucose control, renin–angiotensin system blockade, smoking cessation and blood pressure (BP) control], even in patients with overt DKD. However, the indication of this drug class is still blood glucose lowering in type 2 diabetic patients with estimated glomerular filtration rate >45 mL/min/1.73 m2. Based on the new evidence, several scientific societies have emphasized the preferential prescription of SGLT2i for patients at risk of heart failure or kidney disease, but still within the limits set by health authorities. A rapid positioning of both the European Medicines Agency and the US Food and Drug Administration will allow patients with overt DKD to benefit from SGLT2i. Clinical experience suggests that SGLT2i safety management may in part mirror renin–angiotensin blockade safety management in patients with overt DKD. This review focuses on the rationale for an indication of SGTL2i in DKD. We further propose clinical steps for maximizing the safety of SGLT2i in DKD patients on other antidiabetic, BP or diuretic medication. [ABSTRACT FROM AUTHOR]

Drugs that inhibit the sodium-glucose co-transporter 2 (SGLT2) have been shown to reduce the risk of hospitalizations for heart failure in patients with type 2 diabetes. In populations that largely did not have heart failure at the time of enrolment, empagliflozin, canagliflozin and dapagliflozin decreased the risk of serious new-onset heart failure events by ≈30%. In addition, in the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of both pump failure and sudden deaths, the two most common modes of death among patients with heart failure. In none of the three trials could the benefits of SGLT2 inhibitors on heart failure be explained by the actions of these drugs as diuretics or anti-hyperglycaemic agents. These observations raise the possibility that SGLT2 inhibitors could reduce morbidity and mortality in patients with established heart failure, including those without diabetes. The EMPEROR-Reduced trial is enrolling ≈3600 patients with heart failure and a reduced left ventricular ejection fraction (≤ 40%), half of whom are expected not to have diabetes. Patients are being randomized to placebo or empagliflozin 10 mg daily, which is added to all appropriate treatment with inhibitors of the renin-angiotensin system and neprilysin, beta-blockers and mineralocorticoid receptor antagonists. The primary endpoint is the time-to-first event analysis of the combined risk of cardiovascular death and hospitalization for heart failure, but the trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all-cause mortality, and recurrent hospitalization events. By adjusting eligibility based on natriuretic peptide levels to the baseline ejection fraction, the trial will preferentially enrol high-risk patients. A large proportion of the participants is expected to have an ejection fraction < 30%, and the estimated annual event rate is expected to be at least 15%. The EMPEROR-Reduced trial is well-positioned to determine if the addition of empagliflozin can add meaningfully to current approaches that have established benefits in the treatment of chronic heart failure with left ventricular systolic dysfunction. [ABSTRACT FROM AUTHOR]

The recent discoveries in the fields of pathogenesis and management of diabetic nephropathy have revolutionized the knowledge about this disease. Little was added to the management of diabetic nephropathy after the introduction of renin angiotensin system blockers. The ineffective role of the renin- angiotensin system blockers in primary prevention of diabetic nephropathy in type 1 diabetes mellitus necessitated the search for other early therapeutic interventions that target alternative pathogenic mechanisms. Among the different classes of oral hypoglycemic agents, recent studies highlighted the distinguished mechanisms of sodium glucose transporter 2 blockers and dipeptidyl peptidase-4 inhibitors that settle their renoprotective actions beyond the hypoglycemic effects. The introduction of antioxidant and anti-inflammatory agents to this field had also added wealth of knowledge. However, many of these agents are still waiting well-designed clinical studies in order to prove their beneficial therapeutic role. The aim of this review of literature is to highlight the recent advances in understanding the pathogenesis, diagnosis, the established and the potential renoprotective therapeutic agents that would prevent the development or the progression of diabetic nephropathy. [ABSTRACT FROM AUTHOR]