Type 2 diabetes mellitus (T2DM) is a multifactorial disease associated with complications that significantly affect both survival and quality of life, including cardiovascular, renal, cognitive, sexual, and reproductive dysfunctions. Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2is) have emerged as a transformative class of drugs, demonstrating benefits that extend beyond glycemic control. Large clinical trials have shown that SGLT2is reduce hospitalization for heart failure by 25-35% and slow progression of chronic kidney disease by 30-45%, with variation based on the specific agent, dose, and patient population. This narrative review examines not only these well-established benefits but also emerging evidence regarding their effects in less-explored domains. SGLT2is have been associated with improved cognitive performance, potentially through reductions in neuroinflammation and oxidative stress. In the sexual and reproductive domains, studies in men with diabetes mellitus suggest potential benefits of SGLT2is in improving erectile function, sperm motility, and testosterone levels, likely mediated by antioxidant and anti-inflammatory mechanisms. By integrating current evidence across multiple systems, this review emphasizes the role of SGLT2is in a holistic, multidisciplinary approach to the management of patients with T2DM.

Chronic kidney disease (CKD) increases the risk for cardiovascular morbidity and mortality and it's prevalence continues to rise throughout the world. Newer, more efficacious therapies, slow progression of CKD, decrease long-term sequela like end-stage kidney disease (ESKD) and cardiovascular events, improving survival. Postmarketing cardiovascular outcome trials (CVOT) have demonstrated improved cardiovascular outcomes with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) like canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin in patients with type 2 diabetes mellitus (T2DM), Similarly, secondary analysis of CVOT and renal outcome trials with the use of SGLT2i in patients without T2DM showed improved renal function and albuminuria. In these studies, nondiabetic CKD was defined as an estimated glomerular filtration rate (eGFR) of 20-75 mL/min/1.73 m2 with albuminuria ranging from 200 to 5,000 mg/g in the absence of diabetes. As a class effect, in addition to modulation of hemodynamic and metabolic activities, SGLT2i exert renal protection by suppressing inflammation and fibrosis. We conducted an extensive search in the PubMed database for original papers published from 2009 through 2024 using keywords such as nondiabetic kidney disease, diabetic kidney disease, SGLT2i, and kidney outcomes. Based on our research of published literature, we present a review and propose, consideration of SGLT2i in nondiabetic kidney disease for long-term cardiovascular and renal benefit (Dharia A, Khan A, Sridhar VS, Cherney DZI. Annu Rev Med 74: 369-384, 2023). We will highlight relevant translational studies to propose a possible cell-based mechanism for cardiovascular benefits noted secondary to use of SGLT2i.

Several previous studies have identified a potential risk of acute kidney injury (AKI) associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors, based on adverse event reports. However, recent European observational studies have shown conflicting results.

To evaluate the risk of AKI in patients with type 2 diabetes (T2DM) who were treated with dapagliflozin compared with sitagliptin.

We conducted a retrospective cohort study on patients with T2DM who were newly prescribed dapagliflozin or sitagliptin between September 1, 2014, and June 30, 2021, using the nationwide National Health Insurance Review and Assessment (HIRA) Service database in Korea. Propensity scores were estimated using a multivariable logistic regression model, and matching was performed at a 1:1 ratio to balance the dapagliflozin and sitagliptin groups. The outcome of interest was the occurrence of AKI hospitalization 90 days post-exposure, captured by a validated algorithm based on the International Classification of Diseases 10th Revision (ICD-10) code: N17. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using a Cox proportional hazards model.

Among 94,977 dapagliflozin users matched to sitagliptin users, AKI events occurred in 132 dapagliflozin users versus 198 sitagliptin users, with incidence rates of 2.92 and 8.93 per 1000 person-years, respectively. The risk of AKI events was 34% lower in dapagliflozin users (HR: 0.66, 95% CI: 0.53-0.83) compared with sitagliptin users. This protective effect remained consistent in sensitivity analyses.

Contrary to the United States Food and Drug Administration's safety warning, our findings suggest that dapagliflozin may have a protective effect against AKI in patients with T2DM. This is consistent with recent findings from European post-marketing safety studies and may serve as supportive evidence.

Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease and significantly increases cardiovascular risk and mortality. Despite conventional therapies, including renin-angiotensin-aldosterone system inhibitors, substantial residual risk remains. The emergence of sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists has reshaped DKD management. Beyond glycemic control, these agents provide distinct and complementary cardiorenal benefits through mechanisms such as hemodynamic modulation, anti-inflammatory effects, and metabolic adaptations. Landmark trials, including CREDENCE, DAPA-CKD, EMPA-KIDNEY, and FLOW, have demonstrated their efficacy in preserving kidney function and reducing adverse outcomes. SGLT2 inhibitors appear more effective in mitigating glomerular hyperfiltration and lowering heart failure risk, whereas GLP-1 receptor agonists are particularly beneficial in reducing albuminuria and atherosclerotic cardiovascular events. Although indirect comparisons suggest that SGLT2 inhibitors may offer greater protection against kidney function decline, direct head-to-head trials are lacking. Combination therapy holds promise, however further studies are needed to define optimal treatment strategies. This review synthesizes current evidence, evaluates comparative effectiveness, and outlines future directions in DKD management, emphasizing precision medicine approaches to enhance clinical outcomes. The integration of these therapies represents a paradigm shift in diabetes care, expanding treatment options for people with diabetes mellitus at risk of kidney failure.

The four-drug regimen for heart failure with reduced ejection fraction (HFrEF) significantly reduces the risks of hospitalization and mortality. To identify key adverse drug events (ADEs) warranting attention with this regimen, we conducted a real-world pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS) events.

We collected ADE reports of the four-drug regimen from FAERS that matched this regimen over a 10-year period. Disproportionality analysis and subgroup analysis were performed using four algorithms. Time-to-onset (TTO) analysis was used to assess the temporal risk patterns of ADE occurrence. Lastly, logistic regression was applied to investigate the relationship-value between patient characteristics and ADEs.

A total of 1,237 cases with 6,580 ADE reports were collected. Disproportionality analysis identified the most frequent ADEs as hypotension, acute kidney injury (AKI), and hyperkalemia. TTO analysis revealed a median TTO of 39 days for all important medical events, and the median TTO for AKI was 28 days, both fitting an early failure curve.

In the comprehensive management of HFrEF with the four-drug regimen, in addition to routine monitoring of ADEs such as hypotension and hyperalemia, early-onset AKI should be a particular focus.

Chronic kidney disease (CKD) has become highly prevalent worldwide, with major implications for public health, including increased risk of progression to kidney failure, cardiovascular events, and mortality. Up to a decade ago, renin-angiotensin system inhibitors, that is angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, were the only available pharmacological interventions to slow kidney function loss and limit the associated cardiovascular morbidity and mortality in this context. More recently, landmark trials have demonstrated the ability of novel therapeutics to significantly ameliorate kidney and cardiovascular outcomes in patients with CKD, when added on top of optimized renin-angiotensin system blockade. These include sodium-glucose cotransporter-2 inhibitors in patients with diabetic and nondiabetic kidney disease, as well as the nonsteroidal mineralcorticoid receptor antagonist finerenone and the glucagon-like peptide-1 receptor agonist semaglutide in patients with diabetic kidney disease. We herein review the evolving scenario and the latest evidence for the treatment of CKD, mainly focusing on proteinuric CKD. We started with a presentation of established and more recently approved classes of kidney protective drugs, followed by a discussion of therapeutic interventions under clinical investigation to slow CKD progression. Finally, we underscore the added value of personalized and multidrug interventions, which are becoming increasingly more feasible with the availability of a growing number of kidney protective agents, and are likely to stand as the most powerful tools to safely slow, or even prevent, the progression of proteinuric CKD. SIGNIFICANCE STATEMENT: Chronic kidney disease (CKD) is highly prevalent globally, and is associated with substantial morbidity and mortality. This review provides a comprehensive overview of the currently approved and emerging therapeutic options for the treatment of proteinuric CKD. As novel kidney protective agents have recently become available, the outcomes of patients with CKD could hopefully improve over the few decades ahead.

Few studies have discussed the effects and mechanism of dapagliflozin on diabetic kidney disease (DKD) with different glomerular filtration rate (GFR) and systolic blood pressure (SBP). This study aimed to investigate the variation in the eGFR and proteinuria after dapagliflozin treatment in DKD patients with different filtration status and SBP levels.

First, we conducted a cross-sectional study to determined hyperfiltration threshold for the DKD trial. Then, we enrolled 259 DKD patients with an eGFR greater than 70 mL/min/1.73m2 and an albumin-to-creatinine ratio (ACR) between 30 and 200 mg/g to receive treatment with dapagliflozin. Hyperfiltration was defined as the 95th percentile of eGFR above the age- and gender- specific in healthy subjects, DKD patients were divided into hyperfiltration and non-hyperfiltration groups, and SBP > 120 mmHg and ≤ 120 mmHg groups. The eGFR, ACR, and blood and urine electrolytes were measured before and after treatment.

The mean eGFR change at 2 weeks in the hyperfiltration with SBP > 120 mmHg group was greater than in the non-hyperfiltration with SBP ≤ 120 mmHg group (P = 0.048). The mean ACR reduction values were greater in the non-hyperfiltration with SBP ≤ 120 mmHg group than in the hyperfiltration with SBP > 120 mmHg group at 12 weeks (P = 0.042). There was no difference in other blood or urine electrolytes before and after treatment, except for the fractional excretion of sodium (FENa), which significantly increased after 2 weeks (P < 0.001) and recovered after 8 weeks (P = 0.305).

DKD with non-hyperfiltration with SBP ≤ 120 mmHg had a lower mean eGFR decline and greater decrease in the ACR after treatment. The initial increase in FENa and subsequent decrease after dapagliflozin treatment may be the main mechanism behind the eGFR variation.

Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially developed as antihyperglycemic agents, have revolutionized heart failure (HF) management, offering substantial benefits across all stages and phenotypes of the disease. Regardless of left ventricular ejection fraction (LVEF), these agents have proven efficacy in both chronic and acute HF presentations. This review explores SGLT2i applications spanning the HF continuum, from early stages (Stage A) in at-risk individuals to the mitigation of progression in advanced HF (Stage D). Evidence from numerous trials has shown that SGLT2i significantly lower rates of HF hospitalization, improve renal function, and decreases cardiovascular mortality, highlighting their multifaced mechanisms of action in HF care. This review also highlights the potential mechanisms by which SGLT2i exert their beneficial effects on the cardiovascular and renal systems, each contributing to early and sustained clinical improvements. However, the integration of SGLT2i into guideline-directed medical therapy poses practical challenges, including initiation timing, dosing, and monitoring, which are addressed to support effective treatment adaptation across patient populations. Ultimately, this review provides a comprehensive assessment of SGLT2i as a foundational therapy in HF, emphasizing their role as an intervention across multiple stages aimed at improving outcomes across the entire HF spectrum.

Use of sodium-glucose cotransporter 2 inhibitors (SGLT-2 inhibitors) falls short of their cardiorenal protective benefits. Patient and provider-level barriers hinder the adoption of these life-saving medications. Innovative practices to provide primary care providers (PCPs) with added clinical-decision support via a dedicated remote interdisciplinary diabetes rounds (IDRs) team could promote SGLT-2 inhibitor selection.

To evaluate the impact of the IDR's proactive provider outreach on the prescribing rate of SGLT-2 inhibitors and assess the application of an SGLT-2 inhibitor case-finding algorithm to allow targeted intervention in a population-health-based setting.

This is a quality improvement prospective cohort observational study from October 2021 to May 2022. Patients who met the prespecified criteria for SGLT-2 eligibility were reviewed via IDR with recommendations sent to the PCP via the electronic health record. The primary analysis employed a multivariate logistic regression to assess the difference in SGLT-2 inhibitor prescription rates between reviewed and not reviewed patients, adjusting for variables affecting SGLT-2 inhibitor prescribing. The secondary analysis measured the algorithm's accuracy in identifying patients with compelling indications.

The IDR team reviewed a total of 206 patients (mean age, 63 years; 53.9% women; 42.7% Black; mean A1c 8.3%) with a successful PCP appointment. Patients reviewed by the IDR team had an increased prescribing rate within 90 days of the visit (adjusted odds ratio 5.1, 95% CI 3.06-8.47). The algorithm identified 1084 SGLT-2 inhibitor-eligible patients with a sensitivity of 90.4% (95% CI, 86.4%, 94.4%) and specificity of 85.1% (95% CI, 79.9%, 90.4%).

IDR team's review of eligible patients with recommendations to PCPs was associated with significantly increased SGLT-2 inhibitor prescription rates. Development of an algorithm with high sensitivity and specificity for targeted intervention may provide a pathway for channeling therapy and decreasing clinical inertia in population health management efforts.

While the kidney-protective effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors have attracted much attention, there are limited real-world clinical data examining the effects of SGLT2 inhibitors on kidney function in older individuals. We aimed to compare the kidney outcomes between SGLT2 inhibitor and dipeptidyl peptidase 4 (DPP4) inhibitor use in older adults with diabetes.

Using a nationwide claims database, we studied 6354 older adults (≥60 years of age) who had diabetes and were newly initiated on SGLT2 inhibitors or DPP4 inhibitors. A 1:4 propensity score matching algorithm was used to compare changes in estimated glomerular filtration rate (eGFR) between SGLT2 inhibitor and DPP4 inhibitor users. The primary outcome was a decrease in the rate of eGFR, which was obtained using a linear mixed-effects model with an unstructured covariance.

Following propensity score matching, 6354 individuals including 1271 SGLT2 inhibitor users and 5083 DPP4 inhibitor users {median age 68 years [interquartile range (IQR) 65-70], male 60.4%, median eGFR 69.0 ml/min/1.73 m2 [IQR 59.1-79.0], median haemoglobin A1c [HbA1c] 6.9% [IQR 6.5-7.4]} were analysed. SGLT2 inhibitor users had a slower eGFR decline than did DPP4 inhibitor users [-0.97 ml/min/1.73 m2/year (95% CI -1.24 to -0.70) versus -1.83 ml/min/1.73 m2/year (95% CI -1.97 to -1.69); P for interaction <.001]. This finding remained consistent across subgroups based on age, sex, body mass index, HbA1c level, renin-angiotensin system inhibitor use and baseline eGFR. Additionally, the risk of a ≥20%, ≥30% and ≥40% decrease in eGFR from baseline was significantly lower in SGLT2 inhibitor users than in DPP4 inhibitor users.

Our analysis, utilizing a nationwide epidemiological dataset, demonstrated that the decrease in eGFR was slower in individuals ≥60 years of age with diabetes who were prescribed SGLT2 inhibitors compared with those prescribed DPP4 inhibitors, suggesting a potential advantage of SGLT2 inhibitors for kidney outcomes even in older individuals with diabetes.

Aims/Background Dapagliflozin is a sodium-glucose cotransporter inhibitor that functions to lower blood sugar by promoting glucose excretion. We conducted a meta-analysis to assess the therapeutic efficacy of dapagliflozin in patients with type 2 diabetes mellitus complicated by coronary heart disease. The objective of this analysis is to provide additional clarity on dapagliflozin's effectiveness in this specific patient population. Methods A systematic review of the literature was performed by searching China National Knowledge Infrastructure (CNKI), Wanfang, Wip Chinese Science, Technology Journals, China Biomedicine, Pubmed, Web of Science, and Cochrane Library. Related literature regarding the effectiveness of dapagliflozin, published since the inception of databases until October 2023, was searched and selected. Subsequent to the screening process, the Jadad scale was used to assess the quality of the gathered literature. The NoteExpress3.2 software (Beijing Aegean Music Technology Co., Ltd., Beijing, China) was utilized to manage the literature. Statistical analysis was conducted using RevMan5.4.1 software (The Cochrane Collaboration, London, UK). The p-value of the Q test determined the heterogeneity of the studies, guiding the choice between fixed or random effect models for establishing the combined effect. Forest plots were used to visualize dapagliflozin's efficacy in treating patients with type 2 diabetes mellitus and coronary heart disease. A funnel plot was plotted to assess potential publication bias. Results Twenty-three studies were eligible for inclusion in this meta-analysis. The results revealed that dapagliflozin has better clinical efficacy (odds ratio [OR] = 3.88, 95% confidence interval [CI] 2.59 to 5.82), left ventricular ejection fraction (LVEF) (OR = 5.43, 95% CI 4.02 to 6.84). The values of left ventricular end-diastolic diameter (LVEDD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were lower in the experimental group (OR: -4.03 and -84.65, 95% CI -5.08 to -2.98 and -127.05 to -42.25, respectively). In addition, further analysis showed that the experimental group experienced a lower incidence of adverse reactions (OR = 0.30, 95% CI 0.16 to 0.57). Conclusion Dapagliflozin is more effective in controlling type 2 diabetes mellitus complicated by coronary heart disease.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors (such as dapagliflozin, empagliflozin, and canagliflozin) are essential for the treatment of type 2 diabetes because they improve the urine excretion of glucose. Although there are advantages, including weight loss and enhanced heart health, caution is necessary because of possible negative effects, such as higher urine output and euglycemic diabetic ketoacidosis. They may slow chronic kidney disease progression, therefore, renal function must be monitored. This study aims to determine the efficacy of SGLT2 inhibitors in the prevention of renal deterioration in terms of reduction of estimated glomerular filtration rate (eGFR) in patients with compromised renal functions.

This study aimed to document the long-term effects of SGLT2 inhibitors on kidney function. PubMed and Google Scholar were the key sources of scholarly publications, and Boolean operators were used to perform exact searches. Nine articles were considered relevant out of a total of 244, following extensive screening of titles, abstracts, and full texts according to PRISMA recommendations.

This study included randomized, double-blind, placebo-controlled trials evaluating the long-term effects of SGLT2 inhibitors on renal function across patient demographics and locations. Clinical investigations showed different effects on eGFR across control and study groups, suggesting renal protection. A meta-analysis showed that SGLT2 inhibitors enhanced kidney function more than the controls.

This meta-analysis concluded that SGLT2 inhibitors have the potential to prevent eGFR reduction and improve renal function in patients with compromised renal function and underlying conditions such as chronic kidney disease or type 1 and 2 diabetes. However, this meta-analysis showed beneficial results in the prevention of renal deterioration within several follow-up periods, with an average of 11 to 12 months.

We aim to explore the potential of nicotinamide n-methyltransferase (NNMT) as a sensitive marker of renal tubular injury and the possibility of an NNMT inhibitor to combine with sodium-glucose cotransporter 2 (SGLT2) inhibitor to protect proximal tubular epithelium in vivo and in vitro model of Type 2 diabetes mellitus (T2DM), respectively.

In vivo, immunohistochemical staining, Masson's trichrome staining and Sirius red staining were used to observe the changes of NNMT expression, renal tubular injury and interstitial fibrosis in renal tissue from the db/db mice. Bioinformatic analysis was also conducted to broaden the range of data validation. In vitro, Western Blot and quantitative RT-PCR were used to measure the degree of damage of HK-2 cells.

Our in vivo data showed upregulation of NNMT expression paralleled renal tubular damage and interstitial fibrosis. Our in vitro data revealed both NNMT inhibitors and SGLT2 inhibitors can protect against the injury as assessed by extracellular matrix (ECM) synthesis and profibrotic phenotype transition of HK-2 cells, and the combination of these two agents can further reduce these injuries.

The present study is the first to show that NNMT is a promising marker of renal tubular injury in diabetic nephropathy (DN) and NNMT inhibitors can synergize with SGLT2 inhibitors to protect HK-2 better. Our findings will provide the insight and pave the way of developing novel therapeutic strategies for chronic renal tubular injury associated with T2DM.

Intestinal microbiota are pathophysiologically involved in diabetic nephropathy (DN). Dapagliflozin, recognized for its blood glucose-lowering effect, has demonstrated efficacy in improving DN. However, the mechanisms beyond glycemic control that mediate the impact of dapagliflozin on DN remain unclear. Here, we investigated the effects of dapagliflozin on DN and gut microbiota, elucidating how it mitigates DN via the gut-kidney axis. Low-dose dapagliflozin markedly ameliorated renal inflammation and fibrosis and improved gut barrier function in high-fat diet (HFD)/streptozotocin (STZ)-induced DN mice and db/db mice without affecting blood glucose levels. These effects were associated with altered gut microbial composition and function. Eradication of the resident microbiota abolished the protective effects of dapagliflozin against kidney injury in DN mice. Moreover, dapagliflozin significantly altered microbial metabolites in DN mice, decreasing argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S-allylcysteine (SAC) levels. ASA and PA increased the expression of renal inflammation- and fibrosis-related markers in HK-2 cells, whereas SAC ameliorated renal damage and altered the microbial composition in a manner similar to dapagliflozin in DN mice. Notably, Muribaculaceae and Desulfovibrionaceae were correlated with the alleviation of DN-associated renal dysfunction by low- and high-dose dapagliflozin treatments in DN mice. These findings demonstrate a potential application of dapagliflozin in managing DN by targeting the gut microbiota.NEW & NOTEWORTHY We demonstrated that dapagliflozin administration alleviated renal inflammation and fibrosis in vivo and in vitro, along with reshaping the gut microbiota composition and altering levels of key microbial metabolites, including argininosuccinic acid (ASA) and palmitic acid (PA), while increasing S-allylcysteine (SAC). Importantly, the genera Muribaculaceae and Desulfovibrionaceae emerged as pivotal microbial genera mediating the protective effects of dapagliflozin against diabetic nephropathy.

Diabetic kidney disease (DKD) is the most common cause of kidney failure, characterized by chronic inflammation and fibrosis. The complement system is increasingly implicated in the development and progression of diabetic nephropathy. The important complement anaphylatoxins C3a and C5a are key mediators of the innate immune system, which regulates cellular inflammation, oxidative stress, mitochondrial homeostasis and tissue fibrosis. This review summarizes the involvement of anaphylatoxins in the pathogenesis of diabetic kidney disease, highlights their important roles in the pathophysiologic changes of glomerulopathy, tubulointerstitial damage and immune cell infiltration, and discusses the modulatory effects of new anti-diabetic drugs acting on the complement system. Based on available clinical data and findings from the preclinical studies of complement blockade, anaphylatoxin-targeted therapeutics may become a promising approach for patients with DKD in the future.

To investigate how estimated glomerular filtration rate (eGFR) decline following sodium-glucose cotransporter-2 inhibitors (SGLT2i) initiation predicts long-term cardiorenal outcomes.

From 2016 to 2020, a longitudinal cohort of 4942 diabetic patients treated with SGLT2i were enrolled and followed until December 2021. Patients were categorized into mild (≤30%), moderate (>30%∼≤40%) and severe (>40%) decline groups by the maximal eGFR change between 2 to 12 weeks after SGLT2i treatment. Cox regression was used to explore the association between eGFR decline and risks of a composite outcome of all-cause mortality, major adverse cardiovascular events (MACE), and major adverse renal events (MARE) after comprehensively adjusting for clinical and laboratory confounders.

After a median follow-up of 2.57 years, 125 deaths, 192 MACE, and 247 MARE occurred. Severe and moderate eGFR decline groups showed higher risks of composite outcome (severe adjusted hazard ratio [aHR], 4.56; 95% CI, 2.70 to 7.70; moderate aHR, 1.94; 95% CI, 1.17 to 3.24) and death (severe aHR, 3.54; 95% CI, 1.16 to 10.83; moderate aHR, 3.63; 95% CI, 1.22 to 10.77) vs mild decline group. The severe decline group also had higher MACE (aHR, 3.65; 95% CI, 1.76 to 7.59) and MARE (aHR, 4.94; 95% CI 2.71 to 9.01) risks, whereas the moderate decline group only demonstrated higher MARE risk (aHR, 2.25; 95% CI, 1.22 to 4.14). The results were consistent in restricted cubic spline and sensitivity analyses.

An excessive eGFR decline greater than 30% after SGLT2i initiation was progressively associated with higher hazards of major adverse cardiorenal events. Careful and vigilant surveillance with timely treatment in such patients are suggested.

New onset diabetes mellitus after organ transplantation (NODAT) is a frequent and serious complication of solid organ transplantation. It significantly impacts graft function, patient survival, and quality of life. NODAT is diagnosed based on the criteria for type 2 diabetes, with the oral glucose tolerance test (OGTT) serving as the gold standard for diagnosis. The development of NODAT is influenced by a range of risk factors, which are classified into modifiable and non-modifiable categories. Post-transplant, regular glycemic monitoring at specific intervals is essential for timely diagnosis and initiation of therapy. Early intervention can help prevent or delay the onset of diabetes-related complications. The treatment strategy for NODAT involves lifestyle modifications and pharmacological interventions. These include medications such as metformin, sulfonylureas, glinides, thiazolidinediones, DPP-4 inhibitors, GLP-1 agonists, SGLT-2 inhibitors, and insulin. Adjusting immunosuppressive therapy-either by reducing dosages or substituting drugs with lower diabetogenic potential-is a common preventative and therapeutic measure. However, this must be performed cautiously to avoid acute graft rejection, which poses a greater risk to the patient compared to NODAT itself. In addition to managing diabetes, addressing comorbidities such as hypertension and dyslipidemia is crucial, as they elevate the risk of cardiovascular events and mortality. Patients with NODAT are also prone to developing common diabetes-related complications, including diabetic nephropathy, neuropathy, retinopathy, and peripheral vascular disease. Therefore, regular follow-ups and appropriate treatment are vital to maintaining quality of life and improving long-term outcomes.

Several sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to have beneficial effects on renal function in patients with type 2 diabetes. However, the long-term effects of luseogliflozin, an SGLT2 inhibitor, remain uncertain in real-world settings. This multicenter, open-label, prospective observational study evaluated the long-term effects of luseogliflozin on renal function in Japanese patients with type 2 diabetes. Fifty-four outpatients initiated on luseogliflozin at Fukuoka University Chikushi Hospital or associated clinics were enrolled from April 2018 to December 2019, with 46 patients included in the final analysis set. The primary outcome was the change in estimated glomerular filtration rate (eGFR) from baseline to 104 weeks, and secondary outcomes included the change in eGFR at week 52 and changes in body weight and blood and urinary parameters at 52 and 104 weeks. The mean duration of diabetes was 8.1 years. Baseline eGFR was 75.8 ± 17.4 mL/min/1.73m2, and no decline in eGFR was observed from baseline to 104 weeks. Decline in eGFR was suppressed in the two groups stratified by baseline eGFR (< 60 and ≥ 60 mL/min/1.73m2). No changes were noted in urinary albumin excretion rate. Blood glucose, body weight, blood pressure, liver function, and uric acid levels showed significant improvements. There were four adverse events, but no serious adverse events closely related to luseogliflozin treatment. In type 2 diabetes patients, 2-year treatment with luseogliflozin provided beneficial metabolic effects and improved the rate of decline in eGFR, suggesting a renal protective effect.

Our meta-analysis fills gaps by assessing sodium-glucose cotransporter-2 (SGLT2) inhibitors' renal outcomes in chronic kidney disease (CKD) patients including long-term effects and the subgroup analyses of estimated glomerular filtration rate (eGFR) values and follow-up times.

The literature search of relevant randomized controlled trials (RCTs) was conducted in Medline, Embase, and the Cochrane Central from the inception to 8 June 2023 on patients with CKD treated with SGLT2 inhibitors. We selected medical subject heading (MeSH) terms and free text terms associated with gliflozin and RCT. We calculated odds ratio (OR) or harzard ratio with 95% confidence intervals (CIs) for composite outcomes and dichotomous data, and weighted mean differences (WMD) for changes in eGFR.

16 RCTs enrolling 52,306 patients were in the final population, with 26,910 being treated with SGLT2 inhibitors and 25,396 serving as controls were identified. We found that there was no decline in the rate of change in eGFR after 13 weeks and SGLT2 inhibitors treatment significantly improved the rate of change in eGFR after 64 weeks (64-104 weeks: WMD, 1.024 mL/min/1.73m2/per year, 95% CI 0.643-1.406; 104 weeks: 0.978, 0.163-1.794).SGLT2 inhibitors reduced the risk of acute kidney injury (AKI) (OR 0.836; 95% CI 0.747-0.936; I2 = 0%), mainly derived from empagliflozin (P = 0.001) and increased the incidence of volume-related adverse events (AEs) by 23%.However, no statically differences were observed in death due to kidney disease (P = 0.182) or events of eGFR < 15 mL/min/1.73 m2 (P = 0.202).

The results of our meta-analysis showed that after 64 weeks of treatment, SGLT2 inhibitors showed a significant benefit on eGFR rate with no further decline after 13 weeks and the improvement was slighter in lower eGFR values. Additionally, SGLT2 inhibitors reduce AKI when using empagliflozin, while there is an increased risk of volume-related AEs exclusively in stage 2 CKD. Trial registration CRD42023437061.

The renoprotective effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in both diabetic and nondiabetic nephropathy are widely recognized due to results from randomized controlled trials notably the DAPA-CKD and EMPA-KIDNEY trials. Research exploring the mechanisms of renoprotection indicates that SGLT2 inhibitors exert protective effects on podocytes by enhancing autophagy and stabilizing the structure of podocytes and basement membranes. Furthermore, reductions in lipotoxicity, oxidative stress, and inflammation have been confirmed with SGLT2 inhibitor treatment. Recent clinical studies have also begun to explore the effects of SGLT2 inhibitors on nondiabetic podocytopathies, such as focal segmental glomerulosclerosis. In this review, we summarize clinical and laboratory studies that focus on the podocyte-protective effects of SGLT2 inhibitors, exploring the potential for broader applications of this novel therapeutic agent in kidney disease.

VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the sodium-glucose cotransporter 2 inhibitor ertugliflozin in patients with type 2 diabetes and established atherosclerotic CV disease. The aim of the current analyses was to evaluate VERTIS CV cardiorenal outcomes according to baseline use of renin-angiotensin-aldosterone system (RAAS) inhibitors or diuretics, including mineralocorticoid receptor antagonists (MRAs).

Participants received ertugliflozin 5 mg, ertugliflozin 15 mg, or placebo once daily and were followed for a mean of 3.5 years. Prespecified CV and kidney outcomes were analyzed by Cox proportional hazard modeling in participant subgroups defined by baseline use of RAAS inhibitors (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers) or diuretics (loop diuretics, non-loop diuretics, MRAs), with interaction testing to assess for treatment effect modification.

A total of 8,246 patients were randomized in VERTIS CV. At baseline, 6,686 (81%) participants were being treated with RAAS inhibitors, 3,542 (43%) with diuretics, 1,252 (15%) with loop diuretics, and 674 (8%) with MRAs. No significant interactions were observed for cardiorenal outcomes by baseline use of RAAS inhibitors or MRAs (p interaction > 0.05 for all). Statistically significant interactions for a first event of hospitalization for heart failure (HHF) or CV death, and of HHF (alone), were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin treatment versus placebo.

In VERTIS CV, baseline use of diuretics, particularly loop diuretics, identified a subgroup that demonstrated greater benefit with ertugliflozin on first HHF/CV death and HHF outcomes, with no modification of treatment effect observed with baseline use of RAAS inhibitors or MRAs. There was no evidence of treatment effect on the kidney composite outcomes by baseline use of RAAS inhibitors, diuretics, loop diuretics, or MRAs.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1a), and non-steroidal mineralocorticoid receptor antagonists (ns-MRA) are promising treatments for chronic kidney disease. This umbrella review of network meta-analyses evaluated their effects on cardiovascular outcomes, kidney disease progression, and adverse events, using the TOPSIS method to identify the optimal intervention based on P-scores. A total of 19 network meta-analyses and 44 randomized controlled trials involving 86,150 chronic kidney disease patients were included. Compared to placebo, SGLT2i were associated with reduced risks of cardiovascular events [Hazard ratio (HR): 0.776, 95% confidence intervals (CI): 0.727-0.998], kidney disease progression (HR: 0.679, 95% CI: 0.629-0.733), acute kidney injury (HR: 0.873, 95% CI: 0.773-0.907), and serious adverse events (HR: 0.881, 95% CI: 0.847-0.916). GLP1a and ns-MRA were also associated with significant reductions in cardiovascular and kidney-specific composite outcomes. Indirect evidence showed that SGLT2i demonstrated a lower risk of kidney disease progression compared to GLP1a (HR: 0.826, 95% CI: 0.716-0.952) and ns-MRA (HR: 0.818, 95% CI: 0.673-0.995), representing the best intervention across all endpoints. In conclusion, while SGLT2i, GLP1a, and ns-MRA all reduce cardiovascular and kidney disease risks in chronic kidney disease, SGLT2i appears to provide the most favorable balance of efficacy and safety.

Coronary heart disease and type 2 diabetes mellitus (T2DM) often co-occur, presenting substantial health risks, particularly following acute myocardial infarction (AMI). While percutaneous coronary intervention (PCI) is a prevalent treatment, complications such as microvascular dysfunction may lead to heart failure, necessitating additional therapies. This editorial examines the emerging roles of sacubitril/valsartan and sodium-glucose co-transporter 2 inhibitors in managing post-PCI. Recent research investigates the combined effects of dapagliflozin and telmisartan on myocardial microperfusion in post-AMI heart failure patients with T2DM. The findings suggest that this combination enhances myocardial microcirculation, improves cardiac function, and achieves better glycemic control, with a reduced incidence of major adverse cardiovascular events. Despite ongoing challenges, the integration of dapagliflozin and sacubitril/valsartan represents a significant advancement in post-AMI care. Further investigation in larger cohorts and more diverse patient populations is required to confirm its long-term clinical outcomes.

Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.

Sexual dimorphism plays an important role in the pathogenesis and progression of CKD. Men with CKD often exhibit faster kidney function decline, leading to higher rates of kidney failure and mortality compared with women. Studies suggest that sex hormones may influence this apparent dimorphism, although the mechanisms underlying these influences remain poorly understood. In this review, we first summarize recent findings on sex differences in the prevalence and progression of CKD. Subsequently, we will focus on ( 1 ) the role of sex hormones in these sex differences, ( 2 ) kidney structural and hemodynamic differences between men and women, ( 3 ) the influence of sex hormones on pathophysiological processes leading to kidney disease, including glomerular hyperfiltration and key pathways involved in kidney inflammation and fibrosis, and finally, focus on the consequences of the underrepresentation of women in clinical trials. Understanding these sex differences is critical for advancing precision medicine and improving outcomes for both men and women with CKD.

This study aimed to investigate the association between the utilization of Sodium-dependent glucose cotransporters inhibitors (SGLT2i) in real-world settings and kidney outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) in mainland China.

In a retrospective analysis of electronic medical records from West China Hospital of Sichuan University, patients with T2D and CKD were included. Patients were divided into two groups, those initiating treatment with SGLT2i and those receiving other glucose-lowering drugs (oGLDs). The primary focus lies in examining the impact of SGLT2i on the decline slope of eGFR and major kidney events in these patients.

We enrolled 944 patients diagnosed with both T2D and CKD. Out of these, 605 patients were prescribed SGLT2i, while the remaining 339 patients received oGLDs. The median follow-up duration were 16.8 months and 20.6 months, respectively. Throughout the follow-up period, we observed a significant decrease in the rate of eGFR decline in patients using SGLT2i (4.94 mL/min/1.73 m2 per year reduction compared to oGLDs, 95% CI: 4.73-5.15). A total of 101 kidney composite endpoint events occurred, with 31 events in the SGLT2i group and 70 events in the oGLDs group. The use of SGLT2i was associated with a 65% decrease in the risk of kidney composite endpoint events (hazard ratio 0.35, 95% CI 0.19-0.63).

In clinical practice, SGLT2i have shown favorable effects on kidney prognosis in patients with T2D and CKD in mainland China. These effects remain consistent across patients with varying risks of CKD progression.

ChiCTR2300068497.

Both chronic kidney disease (CKD) and type 2 diabetes (T2D) are modern epidemics worldwide and have become a severe public health problem. Chronic kidney disease progression in T2D patients is linked to the need for dialysis or kidney transplantation and represents the risk factor predisposing to serious cardiovascular complications. In recent years, important progress has occurred in nephroprotective pharmacotherapy in CKD patients with T2D. In the current position paper, we described a nephroprotective approach in CKD patients with T2D based on the five following pillars: effective antihyperglycemic treatment, SGLT2 inhibitor or semaglutide, antihypertensive therapy, use of RASi (ARB or ACEi), and in selected patients, finerenone, as well as sodium bicarbonate in patients with metabolic acidosis. We thought that the current statement is comprehensive and up-to-date and addresses multiple pathways of nephroprotection in patients with CKD and T2D.

Current guidelines recommend good glycemic control in patients with type 2 diabetes (T2D) to limit the progression of associated complications with combination therapies. This study aimed to compare the rate of chronic kidney disease (CKD) progression between patients who did or did not receive sodium-glucose cotransporter-2 inhibitors (SGLT2i) using a multistate model with two intermediate states (i.e., CKD stage 4 (CKD4) and 5 (CKD5)) and one absorbing state (i.e., death).

Data from patients with T2D and CKD stage 3 (CKD3) were retrieved for analysis. Patients treated with SGLT2i were matched 1:2 by prescription date with non-SGLT2i patients. The multistate model was constructed from Cox survival regression models specific to each transition stage. Cumulative failure and transition probabilities were estimated from bootstrapping.

Data from 6582 patients (2194 and 4388 patients in the SGLT2i and non-SGLT2i groups, respectively) were analyzed. At 10-year follow-up, patients in the SGLT2i group were more likely to remain at CKD3 compared to the non-SGLT2i group: 82.3% (95% CI 79.9%, 84.6%) vs 60.4% (57.6%, 63.4%). Transition probabilities to CKD4, CKD5, and death were lower in the SGLT2i group than non-SGLT2i group: 11.3% (9.5%, 13.3%) vs 19.8% (17.4%, 22.2%), 2.4% (1.5%, 3.4%) vs 7.4% (5.8%, 9.0%), and 4.1% (2.9%, 5.3%) vs 12.4% (10.3%, 14.6%), respectively.

SGLT2i may delay the decline in renal function and slow CKD progression compared to standard care without SGLT2i.

This meta-analysis was designed to investigate cardio-renal outcomes and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) as a therapeutic option among chronic kidney disease(CKD) patients with GFR < 60 mL/min/1.73 m2, regardless of their diabetic status.

We conducted a full-scale search from MEDLINE, EMBASE and the Cochrane Library database to identify eligible studies up to Jun 2024. All randomized controlled trials (RCTs) comparing cardio-renal outcomes and/or safety of SGLT2i in CKD patients with eGFR < 60 mL/min/1.73 m2 were involved. The relative risk (RR) and 95% confidence interval (CI) for primary outcomes and adverse events were computed by random-effects mode. We used I2 statistic to analyze heterogeneity. Publication bias was assessed by Egger's test.

Our study incorporated 17 RCTS, including 27,928 patients. In CKD patients with eGFR < 60 mL/min/1.73 m2, SGLT2i decreased risks of cardiovascular events (seven studies, 17,355 participants, RR 0.77, 95% CI 0.70-0.84), hospitalization for heart failure (HHF) (seven studies, 17,869 participants, RR 0.73, 95% CI 0.65-0.82), cardiovascular death (eight studies, 23,079 participants, RR 0.81, 95% CI 0.74 to 0.88) and renal composite outcomes (eight studies, 22,525 participants, RR 0.70, 95% CI 0.61-0.80) with lower risks of any serious adverse effects(fourteen studies, 19,654 participants, RR 0.91, 95% CI 0.87-0.95), hypoglycemia (nine studies, 16,412 participants, RR 0.91, 95% CI 0.84-0.98), hyperkalemia (four studies, 2693 participants, RR 0.68, 95% CI 0.51-0.93) and acute renal injury (five studies, 5424 participants, RR 0.79, 95% CI 0.65-0.95) compared to placebo. SGLT2i also slowed eGFR decline (total slopes: five studies, 10,370 participants, mean difference 1.17, 95%CI 0.86-1.49; chronic slopes: four studies, 8459 participants, mean difference 2.12, 95%CI 1.64-2.61). Further subgroup analyses revealed that SGLT2i decreased relative risks of cardiovascular outcomes(three studies, 1075 participants, RR 0.76, 95% CI 0.54-0.82), HHF(four studies, 1280 participants, RR 0.74, 95% CI 0.55-1.00) and renal composite outcomes (six studies,4375 participants, RR 0.78, 95% CI 0.68-0.88) with no increased adverse events in the CKD 4 patients.

SGLT2i significantly improved cardio-renal outcomes and were generally safe in CKD patients with eGFR < 60 mL/min/1.73 m2 and with eGFR < 30 mL/min/1.73 m2. Future large-scale RCTs are needed to confirm the robustness of these results.

The global prevalence of chronic kidney disease (CKD) is approximately 9%. CKD is predicted to become the fifth largest global cause of death by 2040. Moreover, CKD causes disability, diminished quality of life and poses a high cost to healthcare systems. Delaying the development and progression of CKD is therefore of the utmost importance. Several kidney-specific outcome trials on sodium-glucose co-transporter-2 inhibitors (SGLT-2s) have recently provided a paradigm shift in the treatment of people with CKD, with or without diabetes, as these agents have been shown to reduce the progression of CKD on top of maximally tolerated renin-angiotensin-aldosterone system (RAAS) blockade. The relative benefit and safety of SGLT-2is seems to be consistent across ethnicities, ages and frailty categories; however, this needs to be tested in dedicated clinical trials. Guidelines make clear recommendations for the prescription of SGLT-2is and RAAS inhibitors as standard of care for people with CKD. Their combination with other newer antidiabetic agents may provide further benefits by targeting different components of CKD mechanisms. Dedicated randomized controlled trials are needed to test whether combination with other agents could extend the use of SGLT2is and identify people in whom a combination of drugs may be most effective. Increased efforts to implement the guidelines on treatment with SGLT-2is for people with CKD are needed, particularly in those at the highest risk of adverse outcomes and without type 2 diabetes. Moreover, strategies to target the equitable use of SGLT-2is are needed.

We compared the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) on renal outcomes in individuals with type 2 diabetes, focusing on the changes in eGFR and albuminuria.

This was a multicentre retrospective observational study on new users of diabetes medications. Participant characteristics were assessed before and after propensity score matching. The primary endpoint, change in eGFR, was analysed using mixed-effects models. Secondary endpoints included categorical eGFR-based outcomes and changes in albuminuria. Subgroup and sensitivity analyses were performed to assess robustness of the findings.

After matching, 5701 participants/group were included. Participants were predominantly male, aged 61 years, with a 10 year duration of diabetes, a baseline HbA1c of 64 mmol/mol (8.0%) and BMI of 33 kg/m2. Chronic kidney disease (CKD) was present in 23% of participants. During a median of 2.1 years, from a baseline of 87 ml/min per 1.73 m2, eGFR remained higher in the SGLT2i group compared with the GLP-1RA group throughout the observation period by 1.2 ml/min per 1.73 m2. No differences were detected in albuminuria change. The SGLT2i group exhibited lower rates of worsening CKD class and favourable changes in BP compared with the GLP-1RA group, despite lesser HbA1c decline. SGLT2i also reduced eGFR decline better than GLP-1RA in participants without baseline CKD.

In individuals with type 2 diabetes, treatment with SGLT2i was associated with better preservation of renal function compared with GLP-1RA, as evidenced by slower decline in eGFR. These findings reinforce SGLT2i as preferred agents for renal protection in this patient population.

Urolithiasis (UL) is increasingly prevalent due to rising cardiorenometabolic diseases, posing significant management challenges despite advances in urological techniques. Sodium-glucose cotransporter-2 (SGLT2) inhibitors, primarily used for type 2 diabetes mellitus, chronic kidney disease, and heart failure, have emerged as a potential novel approach for UL treatment. These inhibitors may help reduce the risk of urolithiasis, particularly in patients with diabetes, by improving glycemic control and altering urinary chemistry, which are crucial factors in stone formation. However, the changes in urinary composition induced by SGLT2 inhibitors might also increase the risk of uric acid stone formation. This review evaluates the potential of SGLT2 inhibitors in managing UL, highlighting both the benefits and the risks. While these inhibitors show promise in reducing new and recurrent urinary stones in patients with diabetes, data on their effects in patients without diabetes who form stones are limited. Current human evidence largely comes from post hoc analyses of randomized controlled trials (RCTs) and large-scale database studies, with only one study providing detailed stone composition data. Experimental studies in animal models and cell lines have focused on calcium oxalate (CaOx) stones, showing that SGLT2 inhibitors specifically target CaOx stone formation and related renal inflammation. Although primarily studied for CaOx stones, their potential impact on other calcium-containing stones, such as calcium phosphate, remains promising. Further research is needed to explore their therapeutic potential and optimize treatment strategies.

Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with renin-angiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection.

Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8 weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment.

Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice.

Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally designed to manage blood sugar levels in individuals with type 2 diabetes (T2D), have emerged as a crucial class of drugs for managing cardio-renal diseases. These drugs work by targeting the SGLT2 protein in the kidneys, promoting the excretion of glucose and influencing metabolic pathways beyond glucose control. The relationship between cardio-renal diseases and SGLT2 inhibitors has been explored through landmark trials and real-world evidence (RWE) studies, demonstrating significant reductions in cardio-renal complications. This review discusses the importance of RWE studies alongside randomized controlled trials in understanding the real-world effectiveness and safety of SGLT2 inhibitors. It outlines the advantages and disadvantages of RWE compared to RCTs, highlighting their complementary roles in providing comprehensive insights into treatment outcomes. By examining a range of RWE studies, the review underscores the cardio-renal benefits of SGLT2 inhibitors across various patient populations. Safety assessments indicate that SGLT2 inhibitors are generally well tolerated, with severe adverse events being rare. Common issues, such as genital mycotic infections and urinary tract infections, are acknowledged, alongside less frequent but significant adverse events including diabetic ketoacidosis, lower-limb amputations, and bone fractures. In summary, SGLT2 inhibitors show promising cardio-renal protective effects in real-world scenarios across diverse populations in T2D, indicating their potential as early intervention measures. Continued research is essential for gaining a thorough understanding of their long-term effects and safety profiles.

SGLT-2 inhibitors are a class of antidiabetic drugs with additional cardiovascular benefits. Though initially developed for glycemic control, subsequent studies in the heart failure (HF) population also demonstrated positive outcomes. Currently, they are approved for use in HF with both reduced and preserved ejection fraction. More recently, encouraging data have emerged on acute HF. Following an episode of acute myocardial infarction, patients are also at high risk for developing HF and experiencing recurrent events despite optimal therapy. The PARADISE MI study failed to demonstrate any benefits of ARNI in this scenario. The EMMY trial explored the role of SGLT-2i in >450 odds patients with acute MI. At 26 weeks SGLT-2i (empagliflozin) use led to a higher fall in NT-pro-BNP levels compared to standard treatment. There was additional improvement in left ventricular echocardiographic parameters with empagliflozin too. However, it was a small trial, had a short follow-up and there were no clinical endpoints. But none the least, it attested to the safety of SGLT-2i in the post-MI scenario. Because the primary care physician frequently encounters patients in the post-MI scenario, the manuscript provides insights into their practice. Based on contemporary evidence, the universal use of SGLT-2 inhibitors in patients following acute MI is not warranted. A further role of these drugs in post-MI HF will be clarified in ongoing trials.

Type 2 diabetes mellitus (T2DM) is a prevalent chronic metabolic disorder characterized by insulin resistance and progressive beta cell dysfunction, presenting substantial global health and economic challenges. This review explores recent advancements in diabetes management, emphasizing novel pharmacological therapies and their physiological mechanisms. We highlight the transformative impact of Sodium-Glucose Cotransporter 2 inhibitor (SGLT2i) and Glucagon-Like Peptide 1 Receptor Agonist (GLP-1RA), which target specific physiological pathways to enhance glucose regulation and metabolic health. A key focus of this review is tirzepatide, a dual agonist of the glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptors. Tirzepatide illustrates how integrating innovative mechanisms with established physiological pathways can significantly improve glycemic control and support weight management. Additionally, we explore emerging treatments such as glimins and glucokinase activators (GKAs), which offer novel strategies for enhancing insulin secretion and reducing glucose production. We also address future perspectives in diabetes management, including the potential of retatrutide as a triple receptor agonist and evolving guidelines advocating for a comprehensive, multifactorial approach to care. This approach integrates pharmacological advancements with essential lifestyle modifications-such as dietary changes, physical activity, and smoking cessation-to optimize patient outcomes. By focusing on the physiological mechanisms of these new therapies, this review underscores their role in enhancing T2DM management and highlights the importance of personalized care plans to address the complexities of the disease. This holistic perspective aims to improve patient quality of life and long-term health outcomes.