GLP-1 medicines provide substantial cardio-renal benefits for type 2 diabetes (T2D) and are increasingly used for weight loss. Most high-income countries subsidize access for T2D with restrictions; use outside of these restrictions occurs through private prescriptions. Despite strong consumer demand, the extent of private access to GLP-1 medicines remains poorly quantified. We used national pharmaceutical sales data to quantify population use of GLP-1 medicines listed for T2D in Australia, May 2020-April 2025. We used Pharmaceutical Benefits Scheme (PBS) dispensing claims to measure subsidized access; we estimated private access as the difference between sales and PBS dispensings. We measured GLP-1 medicine use as number of units sold/dispensed and defined daily dose (DDD)/1000 population/day. Since May 2020, total sales of GLP-1 medicines indicated for T2D increased almost 10-fold. Most growth was in private access, driven by semaglutide and rapid uptake of tirzepatide. Supply dropped by 79% during periods of global shortage and primarily accessed through subsidized care. In the year May 2024-April 2025, the majority of GLP-1 medicines used were semaglutide (63.3%) and tirzepatide (30.7%). Half (47.8%) were accessed privately (26.9% of semaglutide; all tirzepatide). In this year, we estimate approximately 483 000-502 000 people accessed GLP-1 medicines each month, with 180 000-240 000 people accessing privately. Use of GLP-1 medicines indicated for T2D has increased dramatically, accessed by approximately half a million Australians each month, almost half of which is private. Our findings highlight demands outside of subsided care, equity concerns for access and pressures for health systems in meeting this demand.
Insulin resistance (IR) is an underrecognized feature of type 1 diabetes (T1D), present even in lean individuals. Rising obesity rates have further amplified this burden, creating a mixed metabolic phenotype that accelerates cardiorenal disease. Paradoxically, despite fewer traditional cardiovascular risk factors, individuals with T1D experience higher rates of cardiorenal complications than those with type 2 diabetes, a gap not fully explained by glycemic control. This article examines the epidemiologic, pathophysiologic, and mechanistic underpinnings of this hidden cardiorenal risk, including key drivers of end-organ damage. Broader therapeutic interventions targeting IR in T1D are essential to prevent future cardiorenal disease.
Cardiorenal syndrome (CRS) describes the bidirectional deterioration of cardiac and renal function, in which dysfunction of one organ induces or perpetuates dysfunction of the other. Since Robert Bright's 1836 observations and the formal five-subtype classification proposed by Ronco and colleagues in 2008, understanding of CRS has evolved from organ-sequential taxonomy toward a mechanism-driven, phenotype-based framework. This narrative review synthesizes contemporary evidence across the molecular, diagnostic, and therapeutic dimensions of CRS. We examine the convergent pathophysiological pathways underlying the syndrome - hemodynamic derangement, renin-angiotensin-aldosterone and sympathetic nervous system activation, systemic inflammation, oxidative stress, mitochondrial and endothelial dysfunction, and the recently characterized gut-heart-kidney axis - with particular emphasis on venous congestion as a unifying mechanistic driver. We review the global epidemiological burden of cardiorenal overlap, now estimated to affect over half of hospitalized heart failure patients, and appraise the diagnostic evolution from creatinine-dependent assessment toward multi-marker biomarker panels and point-of-care venous congestion ultrasonography (VExUS). On the therapeutic front, we highlight the shift toward combination pharmacotherapy - particularly finerenone-SGLT2 inhibitor co-administration - alongside device-based decongestive strategies and early applications of artificial intelligence in cardiorenal phenotyping. We argue that the traditional five-subtype classification, while pedagogically useful, insufficiently captures the overlapping, transitional phenotypes seen in clinical practice, and that congestion-quantified, mechanism-specific management increasingly supersedes rigid subtype-based decision-making. This review concludes by identifying priority areas for future investigation, including randomized congestion-guided decongestion trials and prospective validation of artificial intelligence-derived cardiorenal phenotypes, positioning CRS within the broader emerging construct of cardiovascular-kidney-metabolic syndrome.
To examine whether a transparent, rule-based cardiorenal-metabolic classification distinguished mortality and cardiovascular outcome patterns among adults with type 2 diabetes (T2D). This retrospective cohort included 61,250 adults with T2D from Hong Kong DM2016. Three phenotypes were defined from baseline cardiorenal burden and hypertension: lower-risk metabolic, hypertensive metabolic, and cardiorenal disease. Outcomes were all-cause and cardiovascular mortality, myocardial infarction, stroke, heart failure, and atrial fibrillation. Because individual follow-up times were unavailable in the public dataset, cardiovascular event outcomes were evaluated in outcome-specific at-risk cohorts. Modified Poisson regression estimated risk ratios (RRs). The phenotypes comprised 29.4%, 20.9%, and 49.8% of participants, respectively. Compared with the lower-risk metabolic phenotype, the cardiorenal disease phenotype was associated with higher risks of all six outcomes; adjusted RRs ranged from 2.59 (95% CI, 2.36-2.84) for all-cause mortality to 9.17 (95% CI, 6.50-12.94) for myocardial infarction. The hypertensive metabolic phenotype was associated with myocardial infarction (RR, 1.56; 95% CI, 1.02-2.39), stroke (RR, 7.63; 95% CI, 5.27-11.06), and atrial fibrillation (RR, 1.76; 95% CI, 1.30-2.38), but not heart failure. This transparent, rule-based classification summarized differences in recorded mortality and cardiovascular outcomes in T2D but should be interpreted as a descriptive framework rather than a validated prediction tool.
The heart and kidneys are connected in both health and disease. Coordinated dysfunction of these organ systems is a result of complex interactions related to vascular and biochemical maladaptations. The historical perspective that kidney dysfunction in heart failure is overwhelmingly a product of reduced cardiac forward flow and arterial underfilling has been challenged by mounting evidence. Efforts in 2004 to introduce the term cardiorenal syndrome were based on observations that increased circulatory volume, specifically venous congestion, play a key role in kidney dysfunction. Contemporary studies done after 2004, as well as revisiting historical renal physiology experiments in a new light, have illuminated some of the pathophysiology of how venous congestion in decompensated heart failure causes the "congested kidney." Cardiorenal syndrome, specifically type 1 occurring in the setting of acute heart failure, in part is defined by the fact that renal venous hypertension drives kidney dysfunction. To illuminate this point further, we compare and contrast the importance of arterial underfilling in cardiogenic shock vs cardiorenal syndrome.
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated efficacy in glycaemic control and cardiorenal protection across multiple meta-analyses. However, their applicability to the Indonesian population remains uncertain due to demographic, lifestyle, and healthcare disparities. This study aims to evaluate the effectiveness of SGLT2is in managing metabolic control, cardiorenal risk factors, and their safety relative to non-SGLT2is in the T2DM population in Indonesian real clinical settings. This study applied a multicenter retrospective cohort design, enrolling adult Indonesian T2DM patients who had received treatment for at least 12 months. Intragroup paired analysis and intergroup comparative studies were performed regarding metabolic control, cardiorenal, and safety parameters. A total of 638 patients were included, with 319 patients contributing to paired analyses. In paired data analysis, SGLT2is significantly improved HbA1c, fasting plasma glucose (FPG), body weight, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), lipid profile, and atherosclerotic cardiovascular disease (ASCVD) risk (p < 0.05). Compared to non-SGLT2is, SGLT2is are associated with greater reductions in HbA1c, FPG, body weight, BMI, and SBP. Although no intergroup differences were observed in other parameters, adjusted analyses revealed additional benefits of SGLT2is in lowering low-density lipoprotein (LDL) cholesterol and maintaining estimated Glomerular Filtration Rate (eGFR), though SBP effects became nonsignificant. No major safety signals were observed. These findings support the use of SGLT2is as effective agents for improving glycaemic control, body weight, blood pressure, lipid profile, and ASCVD risk in Indonesian patients with T2DM. Further studies are warranted to clarify their safety, long-term renal effects, and to explore the comparative effects of individual SGLT2is and dosing strategies.
Cardiorenal syndrome (CRS) is a pathological condition characterized by the synergistic deterioration of cardiac and renal function. This review attempts to systematically elucidate the pathophysiological mechanisms of CRS from the perspective of intercellular communication between cardiac and renal cells. We first analyze the characteristics of communication between the heart and kidneys under physiological conditions and then describe the pathological communication pathways mediated by intercellular communication (such as soluble factors and extracellular vesicles) in cardiorenal syndrome. We then provide a detailed analysis of the unique communication features observed in different subtypes of CRS. Based on this, we reinterpret the role of existing therapies in regulating cardio-renal cell communication and propose potential targeted strategies, including extracellular vesicle therapy and microRNA (miRNA)-targeted delivery systems. Finally, we discuss the challenges facing this field and future research directions, with the aim of providing new insights into the mechanisms and treatment of CRS.
Patients with T2D exhibit substantial heterogeneity across the BMI spectrum. We aimed to characterize cardiometabolic profiles, treatment patterns, and complication burden and to assess the association between BMI categories and major cardiorenal complications. We conducted a cross-sectional analysis of 519,005 adults with T2D attending 296 Italian diabetes centers in 2023. Clinical characteristics, comorbidities, and treatment patterns were compared across standard WHO BMI cut-offs. Associations between BMI category and coronary artery disease, heart failure (HF), cerebrovascular disease, peripheral artery disease, and chronic kidney disease (CKD) were evaluated using multivariable models. Obesity was present in 35.4% of the patients and overweight in 39.1%. Despite similar HbA1c levels, cardiometabolic risk factors progressively worsened across BMI categories. Patients with obesity were younger, with shorter diabetes duration and lower crude rates of most cardiovascular complications. After adjustment, obesity was associated with CKD (PR 1.13, p < 0.001) and HF (PR 1.41, p < 0.001), whereas associations with atherosclerotic outcomes were weaker. In this large real-world T2D cohort, the lower crude prevalence of cardiovascular complications in patients with obesity was partly explained by confounding factors. Obesity was associated with a higher prevalence of CKD and HF, highlighting the importance of weight-centred approaches and comprehensive cardiorenal risk assessment in T2D.
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and progressive β-cell dysfunction, resulting in persistent hyperglycemia and long-term vascular complications. The global prevalence of T2DM continues to rise and is strongly associated with cardiovascular disease, chronic kidney disease, and the broader cardiovascular-kidney-metabolic (CKM) syndrome. This review summarizes the pathophysiology of T2DM, with emphasis on insulin resistance, endothelial dysfunction, oxidative stress, and activation of the renin-angiotensin-aldosterone system, all of which contribute to progressive end-organ damage. Chronic hyperglycemia further promotes inflammatory and fibrotic pathways that accelerate diabetic kidney disease and atherosclerotic cardiovascular disease. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has emerged as a therapeutic option for patients with T2DM and chronic kidney disease. Clinical trial data demonstrate that finerenone reduces albuminuria and provides cardiovascular and renal protection by reducing inflammation and fibrosis. Its use is associated with a generally acceptable safety profile, although hyperkalemia remains an important adverse effect requiring routine monitoring. Overall, T2DM is a multifactorial disease that requires comprehensive management targeting metabolic dysregulation as well as inflammatory and hormonal pathways. Finerenone represents an important advancement in cardiorenal protection. Understanding the interconnected mechanisms underlying CKM syndrome is essential for improving long-term outcomes in individuals with T2DM.
Background/Objectives: Esaxerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA) with potent cardiorenal protective effects. However, the clinical effects of switching from eplerenone to esaxerenone in patients with chronic heart failure complicated by hypertension remain unclear. This study investigated the effects of switching from eplerenone to esaxerenone on blood pressure, heart failure biomarkers, renal function, and the renin-angiotensin-aldosterone system (RAAS). Methods: A total of 156 patients with chronic heart failure and hypertension who had been receiving eplerenone for more than one year were prospectively enrolled. Eplerenone was switched to esaxerenone, and the patients were followed for 6 months. Blood pressure, heart rate, brain natriuretic peptide (BNP), renal function, urinary albumin-to-creatinine ratio (UACR), plasma renin activity (PRA), plasma aldosterone concentration (PAC), and urinary osmolality (U-OSM) were evaluated. Results: Following the switch to esaxerenone, systolic and diastolic blood pressure significantly decreased (both p < 0.001), whereas heart rate remained unchanged. BNP levels significantly decreased at 3 and 6 months (p = 0.008 and p = 0.002, respectively). Serum creatinine decreased (p = 0.017), estimated glomerular filtration rate increased (p = 0.028), and UACR significantly decreased at both time points (both p < 0.001). PRA and PAC significantly increased after switching (both p < 0.05), whereas angiotensin II levels remained unchanged. U-OSM significantly decreased (p = 0.01 and p = 0.002 at 3 and 6 months, respectively). No major cardiovascular events or severe adverse events were observed. Conclusions: In patients with chronic heart failure and hypertension, switching from eplerenone to esaxerenone was associated with reductions in blood pressure, BNP, UACR, and urinary osmolality, together with improvements in renal function. These findings suggest favorable physiological changes following the switch from a steroidal to a non-steroidal mineralocorticoid receptor antagonist, although confirmation in randomized controlled studies with clinical outcome measures is warranted.
Background/Objectives: Cisplatin (CP) is a widely used chemotherapeutic agent; however, its dose-dependent effects on different tissues are not fully understood. This study aimed to investigate the early dose-related cardiorenal toxicity of CP at biochemical, molecular, and histopathological levels. Methods: Male Wistar albino rats were divided into four groups: Control, 5 mg/kg CP, 7.5 mg/kg CP, and 12 mg/kg CP. Cardiac and renal tissues were collected three days after administration. Oxidative stress and inflammatory parameters were analyzed using ELISA. Histopathological evaluation and semi-quantitative scoring were performed on tissue sections. Apoptosis-related proteins were assessed using Western blotting and immunohistochemistry. Results: In both renal and cardiac tissues, LPO, MDA, and SOD levels showed significant dose-dependent changes, whereas inflammatory parameters did not differ significantly among the groups. Although Bax and Bcl-2 proteins displayed significant dose-dependent variations in both tissues at the protein level, immunohistochemical analyses showed no notable differences in cardiac tissue. Conclusions: Acute cisplatin exposure produced dose-related biochemical, molecular, and histopathological alterations in both cardiac and renal tissues. Oxidative stress-related changes were more prominent than cytokine-mediated inflammatory responses during the acute experimental period. Within the conditions of this acute model, lower cisplatin doses were associated with less pronounced tissue alterations.
Sodium-glucose cotransporter inhibitors, glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor blockers have revolutionized type 2 diabetes and by providing substantial cardiovascular and renal protection in this. This article summarizes the data for these newer agents in type 1 diabetes (T1D). Here we also emphasize the need for more long-term studies of these agents in T1D to assess their impact on cardiovascular risk.
This article highlights the increased risk of cardiovascular and renal disease in individuals with type 1 diabetes (T1D). In recent years, the treatment landscape of type 2 diabetes has been revolutionized beyond strictly glycemic and metabolic effects by drugs, which have been shown to have additional benefits, including substantial cardiovascular and renal protection. However, until very recently, individuals with T1D were excluded from most trials that evaluated cardiovascular disease (CVD) and chronic kidney disease (CKD) risk with these agents. Here we discuss the data highlighting the high CVD, heart failure (HF), and CKD risk in T1D.
Elderly critically ill ICU patients with CKD face high mortality. The independent and combined prognostic roles of glycemic variability (Glucose CV) and calcium-phosphate metabolic disorders in this population remain unconfirmed. This retrospective study contained three cohorts: MIMIC-IV (n = 1,319, development), multicenter eICU (n = 996, validation), and Chinese hospital cohort (n = 1,069, clinical validation). Multivariable Cox regression and meta-analysis were applied. Elevated Glucose CV independently predicted 28- and 90-day mortality with predominant early risk. Concurrent hypocalcemia and hyperphosphatemia indicated the poorest prognosis, and high GV produced synergistic harmful effects in this subgroup. All results were verified by external cohorts. Targeted glycemic variability management and calcium-phosphate homeostasis correction may effectively improve survival of elderly critically ill CKD patients.
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Chronic kidney disease, acute kidney injury and cardiorenal syndrome are major determinants of cardiovascular morbidity and mortality, yet conventional renal assessment based on serum creatinine, estimated glomerular filtration rate and urine output often fails to detect early structural injury or pathway-specific cardiorenal risk. This narrative review synthesized recent evidence on emerging renal and cardiorenal biomarkers with potential value for cardiovascular risk stratification beyond creatinine. Literature published between 2015 and April 2026 was reviewed, focusing on biomarkers of tubular injury, functional renal impairment, fibrosis/remodeling and mineral metabolism. NGAL and KIM-1 may detect tubular stress and proximal tubular injury before overt functional decline and have shown relevance in heart failure, acute coronary syndromes and post-cardiac surgery settings. Cystatin C and pro-enkephalin refine functional renal assessment and may improve prognostic classification when creatinine is confounded by frailty, muscle mass or acute hemodynamic changes. Soluble ST2 and galectin-3 reflect inflammation, fibrosis and cardiorenal remodeling, while FGF-23 links kidney dysfunction to cardiovascular risk through phosphate imbalance, vascular calcification and myocardial hypertrophy. Multi-biomarker panels may help identify dominant cardiorenal phenotypes and personalize monitoring intensity. However, routine implementation requires standardized assays, validated thresholds, cost-effectiveness data and prospective evidence that biomarker-guided management improves clinical outcomes.
Serum bicarbonate concentrations vary over time in chronic kidney disease (CKD), but most studies have focused on baseline values rather than longitudinal trajectories. We aimed to determine the association between long-term patterns of serum total carbon dioxide (tCO2) and adverse renal and cardiovascular outcomes. Longitudinal cohort study. Patients with CKD enrolled in a prospective cohort with repeated tCO2 measurements. tCO2 trajectories identified using group-based trajectory modeling: Low, Intermediate, High, and Improving. Renal composite outcome and major cardiovascular events. Cox proportional hazards models adjusted for demographic, clinical, and laboratory covariates. Compared with the Intermediate group, the Low trajectory group had higher risk of renal events (HR, 2.08; 95% CI, 1.25-3.46). The High trajectory group showed a trend toward lower renal risk (HR, 0.57; 95% CI, 0.31-1.03), with time-dependent protective effects during prolonged follow-up. The Improving group showed no significant differences in renal or cardiovascular risk but demonstrated a numerically lower incidence of the renal endpoint. Cardiovascular outcomes did not differ across trajectories. Observational design and potential residual confounding. Persistent low tCO2 was associated with increased renal risk, whereas high levels conferred delayed protection. The Improving group showed intermediate risk. Longitudinal monitoring of tCO2 may help guide individualized bicarbonate therapy in CKD. The kidneys help maintain the body’s acid–base balance. As kidney function declines, blood total carbon dioxide (tCO2), a surrogate for bicarbonate, may decrease and contribute to kidney damage. In this study, we followed people with chronic kidney disease over time and examined longitudinal patterns of blood tCO2 rather than relying on a single measurement. We found that patients with persistently low tCO2 levels had a higher risk of chronic kidney disease progression, whereas those with consistently higher levels had better outcomes. Importantly, patients whose tCO2 levels improved during follow-up showed intermediate risk, suggesting that recovery of acid–base status may be clinically meaningful. Monitoring changes in tCO2 over time may help identify patients at higher risk and guide kidney-protective care.
Diabetic kidney disease (DKD) is a major contributor to chronic kidney disease (CKD) and end-stage kidney disease worldwide, and is strongly associated with increased cardiovascular morbidity and mortality. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed for glycemic control, are now established as key therapies for DKD patients. Large, randomized clinical trials, including CREDENCE, DAPA-CKD, and EMPA-KIDNEY, have consistently shown that SGLT2 inhibitors reduce the risk of kidney disease progression, cardiovascular events, and hospitalization for heart failure in patients with and without diabetes. These benefits extend beyond lowering glucose and are attributed to multiple complementary mechanisms, including restoration of tubuloglomerular feedback, reduction of intraglomerular pressure, natriuresis, and pleiotropic effects, such as improved metabolic efficiency, attenuation of inflammation and fibrosis, and enhanced renal oxygenation. The management of DKD is increasingly shifting toward a combination-based strategy targeting diverse pathogenic pathways. Emerging data suggest that combining SGLT2 inhibitors with other cardiorenal protective agents, such as renin-angiotensin system inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide 1 receptor agonists, may provide additional benefits. Recent guidelines emphasize the use of SGLT2 inhibitors primarily for cardiorenal protection independent of glycemic control. Despite these advances, important gaps remain in underrepresented populations, including the elderly, non-albuminuric DKD, advanced CKD, kidney transplant recipients, and patients with type 1 diabetes. This review provides an overview of the key mechanisms and clinical evidence supporting the use of SGLT2 inhibitors in DKD, along with emerging insights into combination strategies and their clinical implications.
Patients with primary aldosteronism (PA) are at increased risk of cardiovascular and kidney complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have demonstrated protective effects in individuals at high risk for cardiorenal events. This study investigates whether adding SGLT2 inhibitors to mineralocorticoid receptor antagonists (MRA) associates with better outcomes in patients with PA. We retrospectively analyzed TriNetX data (Feb 1, 2014-Feb 1, 2025) using an incident cohort design in adults with PA treated with MRAs within three months before or after PA diagnosis, excluding those who underwent adrenalectomy. Patients were divided into two cohorts based on initiation of an SGLT2 inhibitor within three months of the PA diagnosis. The primary outcome was three-year all-cause mortality; secondary outcomes included major adverse cardiovascular events (MACE) and major adverse kidney events (MAKE). We performed 1:1 propensity score matching (PSM) and estimated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) using Cox proportional hazards models. A total of 24,074 patients with PA were included; 34% had comorbid diabetes, 26% had heart failure, and 2,524 (11%) received SGLT2 inhibitors. After a well-balanced PSM, 2,507 SGLT2 inhibitor users were compared with 2,507 non-users. In the matched cohort, the incidence of all-cause mortality was 12% in SGLT2i users and 18% in non-users. The combination of SGLT2 inhibitor with MRA was associated with a lower risk of all-cause mortality (aHR, 0.59; 95% CI, 0.51-0.68; absolute risk reduction [ARR], 7%), MACE (aHR, 0.81; 95% CI, 0.69-0.94; ARR, 3%), and MAKE (aHR, 0.58; 95% CI, 0.52-0.65; ARR, 10%). Kaplan-Meier survival curves for all outcomes demonstrated early divergence and remained distinct through the three-year follow-up period. In patients with PA, adding SGLT2 inhibitors to MRAs is associated with lower mortality and cardiorenal complications. These associations offer a rationale for evaluation of this combined strategy to improve long-term outcomes in this high-risk population.