Metformin, widely used for type 2 diabetes, raises concerns about its use in chronic kidney disease (CKD) due to risks like lactic acidosis and renal function impact. This study uses Mendelian randomization (MR) and summary data-based MR (SMR) to explore metformin's potential causal relationship with CKD and associated genes.

We employed MR methods (MR-Egger, weighted median, IVW) and sensitivity analyses to explore the causal relationship between metformin and CKD. SMR was used to analyze eQTL and CKD data from the UK Biobank and FinnGen, intersecting these with metformin drug targets to identify genes associated with CKD.

MR analysis indicated that metformin may increase CKD risk (IVW model: OR = 144.67, p < 0.01). However, given the high OR value, additional studies are warranted to validate this finding. SMR identified genes ANPEP, STK11, ACACB, and RPS6KB as significantly associated with CKD risk.

The study suggests metformin could elevate CKD risk and identifies relevant genes. Clinicians should exercise caution when prescribing metformin, particularly for patients with renal issues. Further research is needed to confirm these findings and guide clinical practices.

The global increase in the prevalence of type 2 diabetes has led to the development and implementation of new classes of antidiabetic medications, introducing advanced therapeutic options for the management of the disease. These new medications, though primarily designed to regulate blood glucose levels, also have applications in weight management, potentially transforming the current approaches to diabetes treatment. Newer medications, however, have ophthalmic side effects with controversies in trials and real-life data. We comprehensively assessed the ocular benefits and adverse effects of traditional and newer-generation anti-diabetic drugs. Our primary focus is on how these newer medications affect the stage of diabetic retinopathy. Additionally, we explore the associations between these medications and other ocular conditions, including age-related macular degeneration, glaucoma, orbital conditions, and diseases impacting the ocular surface. Furthermore, we provide contextual background by discussing the ocular effects of traditional anti-diabetic drugs.

This study designed to evaluate the reno-protective effects of Empagliflozin (EMPA), a sodium-glucose co-transporter 2 (SGLT2) inhibitor, against carbon tetrachloride (CCl4)-induced nephrotoxicity in mice targeting JNK/MKK4/NRF2/NF-KB pathway.

Male albino mice were given EMPA (10 mg/kg, orally) for 4 weeks prior to a single i.p. injection of 10 % CCl4 (20 ml/kg). Mice were sacrificed 48 h post CCl4 injection.

EMPA attenuated CCl4-induced renal injury, as reflected by a decrease in serum urea and creatinine levels, also preserved the histological integrity of kidney tissue. Theses reno-protective effects of EMPA can be mainly due to its 1. Antioxidant, (↑CAT, ↑SOD, ↑Nrf-2 and ↑ARE), 2. Anti-inflammatory (↓NF-κB and ↓TNF-α) and 3. Anti-apoptotic (↓Caspase-3) proprieties. EMPA also inhibited JNK/MKK4 signaling pathway, which plays a critical role in kidney damage.

These finding confirm the reno-protective effect of EMPA with a modulatory impact on JNK/MKK4/Nrf2/NF-κB signaling network; suggesting its therapeutic utility to minimize acute kidney injury (AKI) in clinical setting in the future.

Glycaemic therapy in type 1 diabetes (T1D) is focused on insulin, with the majority of studies investigating different insulin preparations, delivery devices and dosing accuracy methods. While insulin deficiency is the key mechanism for hyperglycaemia in T1D, individuals with this condition can also develop insulin resistance (IR), making optimisation of glycaemia more challenging. Importantly, IR in T1D increases the risk of both microvascular and macrovascular complications; yet, it is rarely targeted in routine clinical care. In this narrative review, we briefly discuss the mechanistic pathways for diabetes complications in individuals with T1D, emphasising the adverse role of IR. We subsequently cover the use of adjunctive glycaemic therapies for improving the metabolic profile in T1D, focusing on therapies that have possible or definite cardiovascular or renal protective properties in individuals with type 2 diabetes. These include metformin and agents in the thiazolidinedione, Sodium-Glucose Cotransporter-2 inhibitor (SGLT2i) and Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) groups. In addition to reviewing the role of these agents in improving metabolic parameters, we address their potential vascular and renal protective effects in individuals with T1D. We suggest a pragmatic approach for using these agents in T1D, based on current knowledge of their benefits and risks, while also highlighting gaps in knowledge and areas that require further research. It is hoped that the review raises awareness of the role of adjunctive therapies in T1D and offers healthcare professionals simple guidance on using such agents for the management of high-risk individuals with T1D.

To evaluate the efficacy and safety of empagliflozin in patients with type 2 diabetes mellitus (T2DM) undergoing elective on-pump coronary artery bypass grafting (CABG).

Investigator-initiated, pragmatic, single-center, randomized, open-label trial with blinded outcome adjudication conducted in Brazil. A total of 145 patients with T2DM scheduled for elective on-pump CABG were randomized to receive empagliflozin 25 mg daily plus standard care (n = 71) for at least 3 months, which was discontinued 72 h before surgery, or to received standard care alone (n = 74). The primary outcome was postoperative acute kidney injury (AKI) within 7 days of surgery, defined by creatinine-based criteria (namely, Acute Kidney Injury Network; Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease; or Kidney Disease: Improving Global Outcomes). Secondary outcomes included 30-day postoperative atrial fibrillation and type 5 myocardial infarction (MI). Safety outcomes were ketoacidosis, urinary tract infection, hospital-acquired pneumonia, and wound infection within 30 days after CABG.

AKI occurred in 22.5% of the empagliflozin group vs. 39.1% in the control group (relative risk [RR] 0.57 [95% CI 0.34-0.96]; P = 0.03). Rates of atrial fibrillation (15.4% vs. 13.5%; RR 1.15 [95% CI 0.52-2.53]; P = 0.73) and type 5 MI (1.4% vs. 4.1%; RR 0.35 [95% CI 0.04-3.26]; P = 0.62) were similar between groups. No statistically significant differences between groups were observed for safety events. Three deaths occurred, all in the control group.

Empagliflozin use before on-pump CABG in patients with T2DM was associated with a reduced incidence of postoperative AKI without an increase in safety events. These findings warrant confirmation in larger clinical trials.

Recent research has established a strong link between metabolic abnormalities and an increased risk of dementia. In parallel, there is growing epidemiological evidence supporting the neuroprotective effects of antidiabetic medications against cognitive impairments. Among these, sodium-glucose co-transporter (SGLT2) inhibitors have emerged as pharmacological candidates with promising potential in alleviating the burden of age-related diseases, particularly neurodegenerative diseases (NDD). SGLT2 inhibitor therapies are FDA-approved medications routinely prescribed to manage diabetes. This novel class was initially developed to address cardiovascular disorders and to reduce the risk of hypoglycemia associated with insulin-secretagogue agents. It subsequently attracted growing interest for its beneficial effects on central nervous system (CNS) disorders. However, the molecular mechanisms through which these glucose-lowering therapies mitigate cognitive decline and limit the progression of certain brain degenerative diseases remain largely unexplored. Consequently, the neuroscientific community needs further studies that gather, analyze, and critically discuss the available mechanistic evidence regarding the neuroprotective effects of SGLT2 inhibitors. This review aims to critically examine the most relevant published findings, both in vitro and in vivo, as well as human studies evaluating the impact of SGLT2 inhibitors exposure on Alzheimer's disease (AD). It seeks to integrate the current understanding of their beneficial effects at the molecular level and their role in addressing the pathophysiology and neuropathology of AD. These insights will help extend our knowledge of how SGLT2 inhibitor therapies are associated with reduced risk of dementia and thus shed light on the link between diabetes and AD.

Acute kidney injury (AKI) following transcatheter aortic valve implantation (TAVI) is associated with significantly worse outcomes, leading to increased short- and long-term mortality. We sought to evaluate the impact of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the risk of AKI in patients with type 2 diabetes mellitus (T2DM) and severe aortic stenosis (AS) undergoing TAVI.

Multicenter international registry of consecutive T2DM patients with severe AS undergoing TAVI between 2021 and 2024. The study population was stratified by the presence of chronic kidney disease (CKD), defined according to the KDIGO guideline, and anti-diabetic therapy at hospital admission (SGLT2i versus no-SGLT2i users). AKI was defined according to the Valve Academy Research Consortium 3 (VARC-3) criteria.

The study population consisted of 514 patients stratified into those without CKD (n = 226, 44%), of whom 43 (19%) were treated with SGLT2i, and 288 (56%) with CKD, of whom 71 (24.7%) were on SGLT2i treatment. The median age was 81 [77-84] years, and 60.1% were males. SGLT2i use did not impact renal function in patients without CKD, with AKI occurring in 7.1% of the cases, regardless of SGLT2i use. Among CKD patients, AKI occurred more frequently in no-SGLT2i users compared to those receiving SGLT2i (19.8% versus 8.5%, p = 0.027), with a significant increase in post-TAVI and discharge serum creatinine values for no-SGLT2i users (p = 0.001 after TAVI and p < 0.001 at hospital discharge). Only in the CKD group, the use of SGLT2i was identified as an independent predictor of a lower rate of AKI (OR 0.70, 95%CI 0.42-0.91, p = 0.014). Patients who developed AKI had a higher incidence of major adverse cardiovascular events during follow-up, regardless of CKD (p < 0.025 for both groups).

In diabetic patients with CKD undergoing TAVI, SGLT2i therapy was associated with a lower occurrence of AKI compared to those not treated with SGLT2i, suggesting a potential nephroprotective effect in this high-risk population.

Individuals with both obesity and type 2 diabetes mellitus (T2DM) are at heightened risk for developing cardiovascular and kidney-related complications. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown promising effects on heart health and renal function. This study aims to evaluate the influence of empagliflozin on these outcomes among Chinese patients suffering from obesity and T2DM.

This study included 500 adults with obesity and T2DM who were treated with empagliflozin for at least 6 months. Demographic information, clinical data, and treatment records were collected. Primary outcomes included changes in cardiovascular parameters and renal function measured at 1 week and 1, 3, and 6 months after treatment initiation. Secondary outcomes included heart failure hospitalization, mortality, and safety events.

Both systolic blood pressure (SBP) and diastolic blood pressure (DBP) showed significant reductions after 6 months of empagliflozin therapy (p < 0.001). Renal function improved significantly, with a rise in estimated glomerular filtration rate (eGFR) and a decline in serum creatinine levels (p < 0.01). Glycated hemoglobin (HbA1c) levels initially increased after 1 week but continued to decrease thereafter (p < 0.001). Albuminuria modestly reduced over time, with significant decreases from baseline to 3 months (p < 0.01). Body weight was also significantly reduced after 6 months (p < 0.001). Major adverse cardiovascular events (MACE) occurred in 8.4% of patients, and 1.0% progressed to end-stage renal disease. Multivariate analysis identified higher HbA1c levels and lower DBP as significant predictors of MACE, while reduced eGFR and elevated albuminuria were significant predictors of chronic kidney disease (p < 0.05).

Empagliflozin significantly improved cardiovascular and renal outcomes in Chinese populations with obesity and T2DM, with sustained benefits observed over 6 months. Elevated HbA1c, lower DBP, increased albuminuria, and reduced eGFR were associated with higher risks of adverse events during treatment period, highlighting the necessity of careful monitoring in high-risk patients.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed nonalcoholic fatty liver disease (NAFLD), has become a great public healthcare burden and is closely associated with type 2 diabetes (T2D) and insulin resistance. However, there is no specific treatment for MASLD. Recent clinical findings have indicated a possible beneficial effect of sodium-glucose cotransporter 2 (SGLT2) on MASLD. This study aimed to investigate the effects of dapagliflozin (Dapa) on MASLD in T2D mice.

Four-week-old ob/ob mice were fed with a high-fat diet (HFD) for 8 weeks and then randomly divided into two groups supplemented with Dapa or vehicle for another 12 weeks. C57BL/6J mice fed with a standard chow diet (CD) were used as the control group. Metabolic outcomes, liver pathology, lipidomics and insulin signaling were assessed.

We showed that Dapa reduced body weight and ameliorated hyperglycemia and fatty liver in obese diabetic ob/ob mice. Compared with vehicle, dapa improved the NAFLD activity score mainly by attenuating fat deposition. Importantly, Dapa decreased the expression levels of mRNAs and proteins related to fatty acid synthesis and increased the expression levels of β-oxidation-related factors. We also found that Dapa treatment improved insulin signaling by increasing PI3K and Akt phosphorylation.

Dapa protects mice from diet-induced weight gain and improves hepatic lipotoxicity and insulin resistance in diabetic MASLD mice. Our results revealed that Dapa has a therapeutic effect on MASLD and could be a potential drug candidate for the treatment of MASLD.

Cotadutide is a dual glucagon-like peptide-1/glucagon receptor agonist. The objective of the analysis was to develop a pharmacokinetic-pharmacodynamic (PK/PD) model to describe the relationship between cotadutide exposure and response on urine albumin-to-creatinine ratio (UACR), urinary albumin (UALB), and body weight in participants with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM) using data from a Phase2b study (NCT04515849).

A total of 247 participants with CKD and T2DM were randomized and titrated to either 100, 300 or 600 μg cotadutide, 1 mg semaglutide or placebo. UACR was measured biweekly from either morning void (Weeks 14 and 26) or spot urine (other visits). The analysis was implemented using a longitudinal non-linear mixed-effect model. The potential impact of covariates on efficacy in participants was quantified.

PK/PD models were developed, and a significant relationship was identified between cotadutide exposure and PD biomarkers of UACR, UALB and body weight. The models described the data adequately; greater changes in PD responses were observed with higher cotadutide doses. Baseline mean blood pressure and baseline UALB were found to affect the reductions in UACR and UALB, respectively. Model-predicted relative change from placebo in UACR, UALB and body weight after 26 weeks of 600 μg cotadutide treatment were -45.6% (-52.4%, -38.7%), -47.2% (-56.0%, -39.9%) and -5.3% (-7.6%, -4.1%), respectively.

This modelling assessment was successfully applied for cotadutide to understand the relationship between cotadutide dosing regimen and the response in UACR, UALB and body weight. These models have general application in analysing and interpreting data from CKD/diabetic kidney disease (DKD) studies.

To verify the influence of glucagon-like peptide-1 receptor agonists (GLP-1 RA) on renal function parameters in type 2 diabetes based on well-known randomized controlled trials (RCTs).

PubMed, Cochrane, Web of Science, Embase, and grey literature were searched for RCTs published until December 24, 2024. The quality of the RCTs was assessed using the Cochrane risk-of-bias tool. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated for continuous variables using meta-analysis. The primary outcomes were composite renal function parameters, including serum creatinine (Cr) levels, estimated glomerular filtration rate (eGFR), urinary albumin excretion (UAE), and urinary albumin-to-creatinine ratio (UACR).

Pooled data from 24 studies revealed that GLP-1 RA positively influenced renal outcomes in the type 2 diabetes group to some extent compared with that in the control group. GLP- 1 RA decreased serum creatinine levels (WMD=-0.10, 95%CI -0.19 to -0.01, I2 = 33%, P < 0.05), eGFR(WMD = 0.54, 95% CI 0.19 to 0.90, I2 = 27%, P < 0.05), UAE (WMD=-11.92, 95% CI - 23.50 to - 0.33, I2 = 0%, P < 0.05) and UACR (WMD: -1.01 mg/g, 95% CI:-1.68, -0.34, I2 = 15%, P < 0.05) in the type 2 diabetes group.

GLP-1 RA treatment significantly elevated eGFR, decreased the UACR, and positively influenced renal function outcomes in the type 2 diabetes group.

Not applicable.

Youth under the age of 18 years represent a distinct subset of the population living with chronic kidney disease (CKD). The etiology of CKD differs greatly between children and adults, and young people with CKD face an extended lifetime living with their disease. Few rigorous randomized controlled trials in CKD have included people under the age of 18 years. As such, the recent success of CKD trials with sodium glucose co-transporter 2 inhibitors, mineralocorticoid antagonists, dual endothelin agonists, and hypoxia-induced factor prolyl hydroxylase inhibitors have largely not extended to children and adolescents. There are many reasons to believe these medications could prove as transformative in youth as they have in older adults, but trial data are missing. Innovative strategies are required to ensure that trials of recent, and future, agents in youth with CKD are successful.

The timely and rational institution of therapy is a key step towards reducing the global burden of chronic kidney disease (CKD). CKD is a heterogeneous entity with varied aetiologies and diverse trajectories, which include risk of kidney failure but also cardiovascular events and death. Developments in the past decade include substantial progress in CKD risk prediction, driven in part by the accumulation of electronic health records data. In addition, large randomized clinical trials have demonstrated the effectiveness of sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide 1 receptor agonists and mineralocorticoid receptor antagonists in reducing adverse events in CKD, greatly expanding the options for effective therapy. Alongside angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, these classes of medication have been proposed to be the four pillars of CKD pharmacotherapy. However, all of these drug classes are underutilized, even in individuals at high risk. Leveraging prognostic estimates to guide therapy could help clinicians to prescribe CKD-related therapies to those who are most likely to benefit from their use. Risk-based CKD management thus aligns patient risk and care, allowing the prioritization of absolute benefit in determining therapeutic selection and timing. Here, we discuss CKD prognosis tools, evidence-based management and prognosis-guided therapies.

Hypertension and chronic kidney diseases (CKDs) are known risk factors for the development or worsening of heart failure. In last years, several new therapeutic approaches for the management of people with diabetic and nondiabetic CKD and hypertension have been investigated. In this brief review, the most recent findings regarding the ability of SGLT-2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists (nsMRA) and GLP-1 receptor agonists to prevent heart failure in patients with hypertension and CKD will be discussed.

In the last 3 years, several large clinical trials involving very large numbers of CKD patients have been published showing that these new therapeutic approaches significantly reduce the risk of heart failure events and hospitalizations in patients with diabetic and nondiabetic nephropathies and hypertension as well as in patients with heart failure without nephropathy. Moreover, these drugs retard the progression of CKD towards end-stage kidney disease.

These observations already have a major impact on the management of people with hypertension and CKD. SGLT-2 inhibitors are now recommended as first-line therapy in people with diabetes, CKD and heart failure. The use of nsMRA is increasing and could replace spironolactone over time in heart failure as well as in early CKD stages.

Empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has garnered significant interest due to its potential cardiovascular benefits, particularly in patients experiencing acute myocardial infarction (AMI) who are undergoing primary percutaneous coronary intervention (PCI). This systematic review aims to evaluate the effectiveness of Empagliflozin in improving clinical outcomes in this patient population. A systematic review of randomized controlled trials (RCTs) was conducted to assess the effects of Empagliflozin on clinical outcomes in patients with AMI undergoing primary PCI. Electronic databases, including PubMed, Scopus, Web of Science, Cochrane, and the Scientific Information Database, were searched up to July 31, 2024. The risk of bias in the included studies was evaluated using the Cochrane Collaboration criteria. Data analysis was performed using Comprehensive Meta-Analysis software version 3, with outcomes expressed as risk ratios (RR) and 95% confidence intervals (CI). Seven studies were included in the meta-analysis. The results demonstrated that Empagliflozin significantly reduced the risk of heart failure hospitalization compared to placebo, with a risk ratio of 0.48 (95% CI: 0.23-0.99; P = 0.049), indicating a 52% reduction in hospitalization risk. However, secondary outcomes showed that Empagliflozin was associated with a reduction in cardiovascular mortality (RR = 0.45; 95% CI: 0.06-3.02; P = 0.415) and the need for coronary revascularization (RR = 0.75; 95% CI: 0.15-3.59; P = 0.717), although these results did not achieve statistical significance. Empagliflozin is associated with a significant reduction in heart failure hospitalizations among patients with AMI undergoing primary PCI, while its effects on cardiovascular mortality and the necessity for coronary revascularization were not statistically significant. Despite these secondary outcomes, the favorable safety profile of Empagliflozin supports its use as a treatment option for high-risk patients following acute coronary events. Further research is warranted to investigate the long-term impact of Empagliflozin on cardiovascular outcomes in this population.

The mechanisms of the renoprotective effects of sodium-glucose cotransporter 2 inhibitors are unknown. This study aimed to explore the effect and mechanism of tofogliflozin on urinary albumin by administration, withdrawal, and re-administration.

Individuals with type 2 diabetes mellitus and stage 2 or 3 diabetic nephropathy were enrolled. Tofogliflozin was administered for 24 weeks, withdrawn for 12 weeks (withdrawal period), and re-administered for 24 weeks. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR). The secondary endpoints included hemoglobin A1c (HbA1c), hepatic biomarkers, lipid profiles, physical examinations, and blood counts.

A total of 47 individuals were enrolled. UACR significantly decreased throughout the observation period. It also significantly decreased, increased, and again decreased during the period of the 1st administration, withdrawal, and re-administration, respectively. HbA1c, body weight, waist circumference, and systolic blood pressure also showed the same tendency. Aspartate aminotransferase and alanine aminotransferase significantly decreased throughout the observation period, but did not increase during the withdrawal period.

Urinary albumin improved during the administration of tofogliflozin and worsened during its withdrawal, suggesting the reversibility of its renoprotective effect. The administration of tofogliflozin should be continued to avoid the reversal of glycemic control, renoprotective effects, and other beneficial effects.

Microangiopathy is a key complication of diabetes, adversely effecting several organs including the heart, kidneys, eyes, and nerves. This review focuses on myocardial microvascular dysfunction, a condition characterized by altered vasomotion and long-term structural changes to coronary arterioles, resulting in impaired regulation of blood flow in response to varying oxygen demands of cardiomyocytes. Presence of myocardial microvascular dysfunction is associated with increased risk of cardiovascular disease, even in the absence of obstructive coronary artery disease. Several noninvasive imaging techniques to assess coronary physiology have significantly enhanced our understanding of the myocardial microcirculation. These methods allow for detailed visualization and quantification of blood flow, endothelial function, and inflammation in the microvasculature, providing critical insights into the early stages of microvascular disease in diabetes. A significant area of development is the use of advanced hybrid imaging techniques such as positron emission tomography/computed tomography (PET/CT) and positron emission tomography/magnetic resonance imaging (PET/MRI). The integration of advanced imaging technologies with artificial intelligence is also a key future direction. Overall, these advancements aim to improve the early detection and management of microvascular complications in diabetes, ultimately enhancing outcomes and quality of life. The aim of this review is to provide an overview of both established and emerging noninvasive imaging techniques for assessing myocardial microvascular dysfunction.

To investigate the efficacy of SGLT2 inhibitors on multiple cardiorenal outcomes across different racial/ethnic groups and regions.

We searched PubMed, Cochrane Library, Web of Science, and Embase databases in April 2024 for a systematic review and meta-analysis. Owing to inconsistencies in the reporting of the racial/ethnic and regional demographics, participants were grouped into three racial groups (Asian, Black, and White) and four regional (Asia, Central/South America, Europe, North America) groups. We compared the efficacy of SGLT2 inhibitors among these racial/ethnic and regional groups by calculating the ratio of hazard ratios (RHR). We evaluated the composite of cardiovascular death or hospitalization for heart failure (HHF), cardiovascular death, HHF, all-cause death, major adverse cardiac events, and cardiorenal composite outcomes.

We included 14 randomized placebo-controlled trials with 94,445 participants. Across the three racial/ethnic groups, SGLT2 inhibitors showed comparable efficacy. Compared with White patients, the efficacy of SGLT2 inhibitors on HHF was more pronounced in Black patients (RHR, 0.64; 95 % confidence interval [CI], 0.44-0.94), and a numerically lower risk was associated with Asian patients (RHR, 0.62; 95 % CI, 0.38-1.01). A consistent reduction in cardiovascular events with SGLT2 inhibitors was observed across all regions, while the efficacy of SGLT2 inhibitors on HHF was more pronounced in Asia than in other regions (RHR, 0.52; 95 % CI, 0.33-0.81).

SGLT2 inhibitors showed generally consistent efficacy across various racial/ethnic and regional groups, with some differences noted in specific populations. Ensuring adequate representation of diverse populations in clinical trials would be key to addressing healthcare disparities.

The impact of individual biological/targeted synthetic DMARD (b/tsDMARD) on kidney function in patients with RA remains unclear. This study aimed to determine the comparative effects of b/tsDMARDs on chronic kidney disease (CKD) incidence in patients with RA.

This multicentre cohort study included patients with RA who had baseline estimated glomerular filtration rate (eGFR) of ≥60 ml/min/1.73 m2 and started a TNF inhibitor (TNFi), cytotoxic T-lymphocyte-associated antigen-4-Ig (CTLA4-Ig), interleukin-6 receptor inhibitor, or Janus kinase inhibitor (JAKi) in Japan. Multiple propensity score-based inverse probability weighting (IPW) was used to adjust confounders. The incidence of CKD was compared among b/tsDMARDs using IPW mixed-effect Cox proportional hazards models and linear mixed-effect models with IPW-examined trajectories of eGFR.

Among 2187 patients with 3068 treatment courses and up to 11 years of follow-up, CKD occurred in 275 cases. Compared with the CTLA4-Ig group, the TNFi group had a significantly lower CKD incidence [hazard ratio (HR) 0.67, 95% CI 0.46-0.97, P = 0.04], whereas the JAKi group had a significantly higher incidence (HR 2.16, 95% CI 1.23-3.79, P = 0.01). The trajectory of eGFR was significantly greater in the JAKi group than in the CTLA4-Ig group (CTLA4-Ig: -1.28 ml/min/1.73 m2/year, JAKi: -2.29 ml/min/1.73 m2/year, P < 0.001).

TNFi use was associated with reduced CKD incidence, whereas JAKi showed a less protective association for kidney function in patients with RA.

This review article series on water and electrolyte disorders is based on the 'Electrolyte Winter Seminar' held annually for young nephrologists in Japan. This is the third article in this series that focuses on water and electrolyte disturbances caused by novel pharmacological agents for kidney disease and cancer. The advent of novel pharmacological agents in cardiorenal medicine and oncology has introduced both therapeutic benefits and challenges in managing medication-induced water and electrolyte disturbances. These medications, including sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (ns-MRAs), and immune checkpoint inhibitors (ICIs), significantly impact water and electrolyte homeostasis. SGLT2 inhibitors used widely in diabetes mellitus, heart failure, and chronic kidney disease mitigate hyperkalemia and hypomagnesemia but increase the risk of hypernatremia in patients on fluid restriction. Conversely, they are beneficial for managing hyponatremia in the syndrome of inappropriate antidiuresis (SIAD). ns-MRAs, prescribed for diabetic kidney disease, exhibit a high risk of hyperkalemia, particularly when combined with renin-angiotensin system inhibitors. ICIs, a breakthrough in oncology, frequently induce hyponatremia through immune-related adverse events, such as hypophysitis and non-immune-related adverse events like SIAD. Understanding the pathophysiology of these disturbances and implementing timely interventions, including hormone replacement and water and electrolyte management, is critical for optimizing treatment outcomes.

Combination therapy is a cornerstone of modern type 2 diabetes management, extending beyond traditional goals of glucose, blood pressure, and lipid control to focus on therapies protecting the heart and kidneys. The introduction of sodium-glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide receptor agonists (GLP-1RAs), and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) has reshaped clinical guidelines in recent decades. However, the effects of combining these drug classes remain uncertain. This review evaluates the current evidence on combination therapies involving SGLT2is, GLP-1RAs, and nsMRAs in type 1 and type 2 diabetes, thereby focusing on treatments that in type 2 diabetes have shown cardio-renal protection, while exploring future research directions. In type 2 diabetes, much of the evidence comes from post hoc analyses of trials that primarily examine the effects of single drugs compared with placebo. This limits the ability to draw definitive conclusions about the efficacy and safety of combination therapy. Nonetheless, observational studies indicate that combining SGLT2is and GLP-1RAs may offer superior cardiovascular and mortality benefits compared with monotherapy. Data on kidney outcomes remain limited, but SGLT2is appear particularly effective when kidney protection is the primary goal, regardless of concurrent treatment. The use of nsMRAs is still emerging, and studies investigating their combination with SGLT2is and GLP-1RAs are scarce. In type 1 diabetes, combination therapies have primarily focused on glucose control and safety, with several randomized controlled trials investigating the effects of combining treatments such as SGLT2is and GLP-1RAs with insulin. No current studies have estimated the effects on heart and kidneys. Ongoing and planned studies aim to fill critical gaps in our understanding of combination therapy for type 1 diabetes. These studies hold the promise of determining whether similar risk reductions, as observed in type 2 diabetes, can be achieved, offering hope for improved outcomes in this high-risk population. Currently, in type 2 diabetes, only one ongoing study is testing combination with an SGLT2i and a nsMRA.

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.

The efficacy and safety of finerenone (a nonsteroidal mineralocorticoid receptor antagonist) versus placebo were assessed according to different changes in estimated glomerular filtration rate (eGFR) using data from FIDELITY, a pooled individual-level analysis of two clinical trials.

Patients had chronic kidney disease (eGFR of 25 ml/min/1.73 m2 or greater) and type 2 diabetes with optimized renin-angiotensin system blockade. Risk of composite cardiovascular and composite kidney outcomes was analyzed by baseline eGFR change at month one in the total population and by treatment group.

Of 12,798 patients, 25.1% had a >10% eGFR decline, 31.2% had a >0-10% decline, 26.8% had a 0-10% increase, and 16.8% had a >10% increase after one month of treatment. Factors associated with acute eGFR decline included higher baseline urine albumin-to-creatinine ratio, eGFR, systolic blood pressure, diuretic or beta-blocker use, and finerenone use. Finerenone significantly reduced composite cardiovascular and kidney outcomes overall and had similar beneficial effect across eGFR subgroups of >10% decline, >0-10% decline, 0-10% increase, and >10% increase for composite cardiovascular (hazard ratio [95% Confidence Interval] of 0.74 [0.61-0.90], 0.87 [0.73-1.04], 1.06 [0.87-1.28], and 0.78 [0.61-0.99], respectively) and kidney outcomes (0.67 [0.53-0.85], 0.78 [0.61-1.01], 0.56 [0.40-0.77], and 0.75 [0.50-1.14], respectively) (P interaction 0.048 and 0.23, respectively). When modeled as a continuous variable, finerenone reduced the risk of cardiovascular and kidney outcomes, irrespective of acute eGFR change (P interaction 0.58 and 0.36, respectively).

The cardiovascular and kidney benefits of finerenone were not modified by an acute eGFR change after drug initiation.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to prevent the progression of diabetic kidney disease (DKD). However, their impact on renal fibrosis remains largely uninvestigated. This study aimed to explore the effect of SGLT2 inhibitor empagliflozin on renal fibrosis in DKD patients and DKD models, and the molecular mechanisms involved.

Kidney samples of DKD patients and DKD models were used in this study. DKD mouse models included STZ-treated CD-1 mice and HFD-fed C57BL/6 mice were all treated with empagliflozin for 6 to 12 weeks. Kidney pathological changes were analysed and fibrotic factors were detected. HK-2 cells were treated with normal glucose (NG), high glucose (HG), or HG with empagliflozin. RNA sequencing was employed to identify the differentially expressed genes. Epithelial-mesenchymal transition (EMT) markers were detected. Binding of transcription factor and target gene was determined using a dual-luciferase reporter assay.

Empagliflozin significantly ameliorated kidney fibrosis in DKD patients and DKD models. This was evidenced by tubulointerstitial fibrosis reduction observed through PAS and Masson staining, along with fibrotic factors downregulation. RNA sequencing and the subsequent in vitro and in vivo validation identified PKM2 as the most significantly upregulated glycolytic enzyme in DKD patients and models. Empagliflozin downregulated PKM2 and alleviated EMT and renal fibrosis. Importantly, empagliflozin improves fibrosis by downregulating PKM2. The downregulation of PKM2 by empagliflozin was achieved by inhibiting the binding of estrogen-related receptor α at the promoter.

Empagliflozin ameliorates kidney fibrosis via downregulating PKM2 in DKD.

Diabetes mellitus (DM) has emerged as the most common cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) globally in recent years. Diabetic nephropathy (DN), or diabetic kidney disease (DKD) that occurs as a direct consequence of DM, has complex pathophysiological mechanisms, such as various inflammatory processes and genetic and epigenetic factors, often accentuated by comorbid illnesses like hypertension and dyslipidemia. Therefore, management of DKD involves targeting these etio-pathological processes. Various medications with remarkable disease modifying properties have been introduced for treatment of DN in recent years. We update the current and future diagnostic and therapeutic landscapes against DKD in this article.

Cardio-kidney metabolic (CKM) syndrome represents a complex and circular interplay of cardiovascular, renal, and metabolic dysfunctions, significantly contributing to global morbidity and mortality. This expert opinion synthesizes insights from a panel of Italian specialists in cardiology, nephrology, and diabetology, advocating for a holistic and integrated framework for CKM management. The recommendations underline the critical need for early identification and stratification of CKM stages, fostering an interdisciplinary approach that bridges specialties and ensures comprehensive care. Emphasizing innovative pathways for collaboration, including dynamic referral protocols, telemedicine, and shared decision-making, the proposed strategies aim to overcome structural and organizational barriers in healthcare. By promoting a unified approach, the framework seeks to streamline CKM care, enhance communication among specialists, and improve the coordination of services. This holistic strategy represents a pivotal step toward mitigating disease progression, improving clinical outcomes, and enhancing the quality of life for patients with CKM syndrome.

The development of sodium-glucose co-transporter-2 (SGLT2) inhibitors represents a major turning point in the effort to preserve kidney function and prevent cardiovascular events and heart failure hospitalisations in those at high risk. These agents have now transcended their original glucose-lowering indication and provide a range of clinical benefits in people both with and without diabetes, and at varying levels of kidney function. Despite this, SGLT2 inhibitors remain underutilized by the medical community. One potential barrier to improved uptake may be concern about adverse effects. The following review summarizes the wealth of information garnered from clinical trials and real-world data in recent years to examine the safety of SGLT2 inhibitors and to provide practical advice to promote safer use of these important therapies.

Recent post hoc analyses indicate that patients with normal or low body mass index (BMI) benefit from sodium-glucose cotransporter-2 (SGLT2) inhibitor use. We aimed to evaluate the effects of SGLT2 inhibitors on renal and patient outcomes in patients with diabetes and normal or low BMI.

This single-center retrospective cohort study included 5,842 adult patients with type 2 diabetes and BMI<23 kg/m2 from 2016 to 2020. Patients were divided into control and SGLT2 inhibitor groups and matched using propensity scores. The primary outcome was the annual change in the estimated glomerular filtration rate (eGFR). Secondary outcomes included change in BMI, a composite renal outcome (eGFR decline of ≥40% from baseline or end-stage kidney disease), all-cause mortality, and cardiovascular disease (CVD).

Overall, 648 patients were selected for propensity score matching, of whom 216 (33.3%) were receiving SGLT2 inhibitors. The mean age and eGFR were 61.6 years and 84.7 mL/min/1.73 m2, respectively. The median urine albumin-to-creatinine ratio was 11.6 mg/gCr. The control group showed relatively unchanged eGFR over time, whereas the SGLT2 inhibitor group showed an increase in eGFR over time (0.0 vs +0.3 mL/min/1.73 m2/year, p=0.0398). SGLT2 inhibitor use was associated with a lower risk of mortality (HR 0.171, 95% CI 0.041 to 0.718, p=0.0159) and composite renal outcome (HR 0.223, 95% CI 0.052 to 0.952; p=0.0426), but not with the risk of CVD.

SGLT2 inhibitor use may reduce the risk of eGFR decline and all-cause mortality even in low-risk patients with diabetes and normal or low BMI.

Patients with systemic lupus erythematosus (SLE) were excluded from sodium-glucose cotransporter 2 inhibitors (SGLT2i) clinical trials. It is unknown whether the cardiorenal benefits of SGLT2i extend to patients with SLE and comorbid type 2 diabetes (T2D).

We performed an emulated clinical trial in an insurance-based cohort in the United States, evaluating SGLT2i versus dipeptidyl peptidase-4 inhibitors (DPP4i) for primary prevention of cardiovascular, renal, and other clinical outcomes among patients with both SLE and comorbid T2D. SGLT2i initiators were matched to DPP4i initiators using propensity scores (PSs) based on clinical and demographic factors. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox models.

Outcomes among 2,165 patients starting SGLT2i and 2,165 PS-matched patients starting DPP4i were compared. Over 753.1 (±479.2) mean days, SGLT2i recipients had significantly lower risks of incident acute kidney injury (HR 0.49, 95% CI 0.39-0.63), chronic kidney disease (HR 0.61, 95% CI 0.50-0.76), end-stage renal disease (HR 0.40, 95% CI 0.20-0.80), heart failure (HR 0.72, 95% CI 0.56-0.92), emergency department visits (HR 0.90, 0.82-0.99), and severe sepsis (HR 0.61, 95% CI 0.39-0.94). Risks of all-cause mortality (HR 0.89, 95% CI 0.65-1.21), lupus nephritis (HR 0.67, 95% CI 0.38-1.15), myocardial infarction (HR 0.81, 95% CI 0.54-1.23), stroke (HR 1.03, 95% CI 0.74-1.44), and hospitalizations (HR 0.76, 95% CI 0.51-1.12) did not differ. Genital infection risk (HR 1.31, 95% CI 1.07-1.61) was increased, but urinary tract infection risk (HR 0.90, 95% CI 0.79-1.03) did not differ. No significant difference was observed for diabetic ketoacidosis risk (HR 1.07, 95% CI 0.53-2.14) and fractures (HR 0.95, 95% CI 0.66-1.36).

In this emulated clinical trial, treatment with SGLT2i, compared to DPP4i therapy, was associated with significantly reduced risks of several cardiorenal complications among patients with both SLE and T2D.

Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium-glucose co-transporter 2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKDs). Whether benefits extend to children, teenagers and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2 inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years.

DOUBLE PRO-TECT Alport is a multicentre, randomized, double-blind, placebo-controlled trial. Participants (ages 10-39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (>3 months) maximum tolerated dose of a renin-angiotensin system inhibitor and have a urinary albumin:creatinine ratio (UACR) of >300 mg/g (paediatric) or >500 mg/g (adult).Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day or matched placebo. Most participants are expected to be children with a normal estimated glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to week 48) and key secondary (eGFR change from baseline to week 52) efficacy outcomes will be analysed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation.

DOUBLE PRO-TECT Alport will assess whether SGLT2 inhibitors can safely reduce the UACR change from baseline as a marker for progression of CKD in young patients living with AS.

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.

A major public health concern gripping the nation is chronic kidney disease (CKD), and for individuals concomitantly diagnosed with type 2 diabetes mellitus (T2DM), the coexistence significantly increases the cardiovascular morbidity and mortality by two to three times higher than patients diagnosed without CKD. CKD management encompasses both non-pharmacological approaches, such as dietary sodium restriction and lifestyle modification for blood pressure control, and pharmacological approaches. Current pharmacological management focuses on four key pillars: renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and mineralocorticoid receptor antagonists (MRAs), all of which have shown renoprotective and cardiovascular benefits. An incomplete block of aldosterone activity remains a challenge and is one of the factors contributing to the progression of kidney damage. Aldosterone synthase inhibitors (ASIs), such as vicadrostat, may represent a new horizon in selectively inhibiting aldosterone synthesis while preserving cortisol production. Early-phase trials have shown reductions in albuminuria and a potential for renal protection. The question is, could ASIs emerge as a fifth pillar in CKD management and help curb the progression?

Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors, known as Gliflozins, have demonstrated efficacy in managing type 2 diabetes mellitus (T2DM) and providing cardiovascular and renal benefits. Given the prevalence of diabetes, heart failure (HF), and chronic kidney disease (CKD) in the UAE, there is a need to evaluate the prescribing patterns of Gliflozins in these population. The objective of this study was to explore the relationship between Gliflozins use for patients who were admitted to the hospital at least once from 2021 to 2023 and different clinical factors.

A retrospective medication review was conducted from 2021 to 2023 at tertiary-level care hospital in Ajman, UAE. Data were collected on prescribed Gliflozins, patient demographic information, BMI, HbA1c levels, and comorbidities (HF, CKD). Chi-square tests and binary logistic regression were used to explore associations between Gliflozin use and clinical factors.

Out of the 255 patients' data collected, Gliflozin use was significantly associated with obesity (p = 0.002), higher HbA1c levels (p < 0.001), and comorbidities, particularly HF (61.5% of HF patients) and CKD. The use of Gliflozins increased each year. Patients with HF were 8.03 times more likely to use Gliflozins, and those with diabetes were 6.86 times more likely, underscoring the multidimensional role of these medications.

Gliflozin prescribing patterns in the UAE reflect global trends, with increased use among patients with diabetes, HF, and CKD. Further research is recommended to explore factors influencing prescription practices and optimize Gliflozin therapy if gliflozins use considerably increase in new diagnosis of diabetes and CKD even in mild conditions.

People with type 2 diabetes are increasingly susceptible to complications that are not specific to diabetes. We aimed to examine the temporal trajectories of hospitalisations for traditional and non-traditional complications in people with type 2 diabetes.

We included 758,254 people with incident type 2 diabetes between 2002 and 2018 in Hong Kong, followed up until 2019. We included hospitalisations for 72 selected diseases and all-cause deaths. We derived the temporal trajectories of hospitalisations based on pairs of disease associations and identified trajectory clusters using Markov Cluster Algorithm.

During a median follow-up of 7.8 (IQR: 4-12) years, 57.6% of people experienced a hospitalisation for any of the 72 selected diseases and 22.6% of people died. Among the 5184 directional disease pairs, 95 were identified as having a significant and directional association. The three most common disease pairs were hospitalisations for urinary tract infection followed by pneumonia, ischemic heart disease followed by heart failure, and ischemic stroke followed by pneumonia. Cardiovascular and kidney diseases were predominant in the hospitalisation trajectories. However, these traditional complications had complex associations both among themselves and with various non-traditional complications across multiple systems. Three distinct trajectory clusters were identified, with heart failure/chronic kidney disease, pneumonia, and urinary tract infection as central diseases.

Cardiovascular and kidney diseases interacted with a broad set of non-traditional complications to influence the overall patterns of hospitalisation progression in people with diabetes, highlighting the need to broaden diabetes care to consider complications beyond the traditional focus.

Direct Grant for Research from The Chinese University of Hong Kong.

Renin-angiotensin system (RAS) activation plays an important role in the progression of diabetic kidney disease (DKD). However, systemic RAS blockade alone is insufficient to reverse DKD progression. We hypothesized that intrarenal renin-angiotensin system (iRAS) activation plays a crucial role in the progression of DKD. We sought to elucidate the role of the iRAS in DKD progression. Selective deletion of angiotensinogen in renal tubules ameliorated the pathological features of DKD. Our study indicates that iRAS inactivation may be a potential approach for preventing DKD disease severity and its progression.

Type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) frequently coexist, posing a significant challenge due to increased risks of cardiovascular disease and mortality. Glucagon-like peptide-1 receptor agonists, such as semaglutide, have demonstrated potential for enhancing glucose control and reducing cardiovascular and renal risks.

Randomized controlled trials (RCTs) were taken to compare semaglutide with placebo or standard care in adults with T2DM and CKD. Key outcomes assessed included cardiovascular mortality, major adverse cardiovascular events (MACE), kidney-related adverse events, all-cause mortality, and hospitalization rates.

Three RCTs involving 10 013 patients were included. Semaglutide demonstrated a 29% reduction in cardiovascular mortality (risk ratio [RR]: 0.71; 95% confidence interval [CI]: 0.52-0.97; P = 0.03; I 2 = 59%) and a 20% reduction in MACE (RR: 0.80; 95% CI: 0.71-0.91; P = 0.0007; I 2 = 0%). A significant 20% decrease in kidney-related adverse events was observed (RR: 0.80; 95% CI: 0.71-0.89; P < 0.0001; I 2 = 0%), and semaglutide also reduced the need for cardiovascular medications (RR: 0.86; 95% CI: 0.81-0.91; P < 0.00001; I 2 = 13%).

Semaglutide shows promise as a therapeutic option for T2DM patients with CKD, significantly improving cardiovascular and renal outcomes. Its integration into treatment regimens for high-risk patients may enhance clinical outcomes and reduce treatment complexity. However, more extensive and longer-term studies are needed to confirm these findings.