SGLT2 Inhibitors: Unlocking Renal Protection in Type 2 Diabetes

Introduction Emerging evidence suggests that there is a strong interplay among type 2 diabetes mellitus (T2D), cardiovascular disease (CVD) and chronic kidney disease (CKD), such that the likelihood of having a second condition will greatly increase if a patient has one of these conditions.1–4 The cardiovascular-kidney-metabolic (CKM) syndrome, as defined by the American Heart Association (AHA), is a systemic health disorder arising from the interplay of obesity, T2D, CKD, and CVD, including heart failure, atrial fibrillation, coronary heart disease, stroke, and peripheral artery disease. It encompasses individuals at risk for CVD as well as those with established CVD.5 The AHA defined CKM syndrome stages as a continuum, starting from no CKM risk factors (stage 0), progressing to excess or dysfunctional adiposity (Stage 1), metabolic risk factors or moderate-to-high-risk CKD (Stage 2), subclinical CVD in CKM syndrome or risk equivalents (Stage 3), and finally clinical CVD in CKM syndrome (Stage 4). Each stage reflects an increasing severity of cardiovascular, kidney, and metabolic dysfunction. It is recognized that CKM diseases are emerging as a major healthcare challenge worldwide, which not only affects the health of individual patients but also has a profound impact on public health systems. Globally, it is estimated that there are 589 million,6 64.3 million,7 and 697.5 million8 people with diabetes, heart failure (HF), and CKD, respectively. According to the National Health and Nutrition Examination Survey (NHANS) between 2011 and 2018, 14.9% of US adults had diabetes, 38.2% had metabolic syndrome, 12.8% were at risk of CKD, and 9.0% reported CVD.9 In China, the number of prevalent cases is 115.8 million for T2D,10 8.9 million for HF,11 and 82 million for CKD.12 CVD (47.1%) and diabetes (2.5%) were among the top four causes of mortality in the Chinese population in 2019.10 Beyond mortality, each CKM condition contributes substantially to the disease burden of Chinese patients. For instance, T2D accounted for over 11.5 million disability-adjusted life years.13 The average annual treatment cost per HF patient was approximately 28,974 renminbi (RMB), with the majority of expenditure spent on inpatient care and only 8.2% spent on HF medication.14 A study by Yang et al15 explored the evolving CKD spectrum and its implications for public health. It was estimated that approximately 1.06 million Chinese patients had end-stage kidney disease due to diabetes, resulting in an annual dialysis cost of 1.06 billion RMB.15 Epidemiological data have highlighted the prevalence of AHA-defined CKM syndrome stages (Stage 0 to Stage 4) across different populations. Analysis of NHANS data from 2011 to 2020 revealed that nearly 90% of US adults met the criteria for CKM syndrome, with 15% classified in advanced stages. The age-adjusted prevalence of CKM syndrome stages 0 to 4 were 10.6%, 25.9%, 49.0%, 5.4%, and 9.2%, respectively. A similar trend was observed in a prospective UK cohort study, where the distribution of CKM stages was reported as 9%, 6%, 71%, 1%, and 13%.16,17 In China, the majority of patients with CKM syndrome were found to be in the early stages, with stage 1 and stage 2 accounting for 25.4% and 53.6% of cases, respectively.18 Since a more advanced stage of the syndrome was significantly associated with an increased risk of all-cause mortality, these findings underscore the need for comprehensive management and early interventions to improve patient outcomes and reduce the medical burden. Over the past few decades, the development and implementation of clinical practice guidelines have also gradually evolved from focusing on a single disease to a more comprehensive, patient-centered approach.5,19–21 This approach not only concentrates on treating the disease itself, but also prioritizes the overall health status and quality of life of the patient. The integrated management of CKM diseases exemplifies this patient-centered treatment strategy. A holistic treatment method for these diseases can yield multiple clinical benefits, greatly simplify the treatment plan, and provide a more efficient disease management strategy for patients. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors, initially developed as glucose-lowering agents, are characterized by a unique mechanism of action for glycemic control. Over the past decade, accumulating evidence has demonstrated that SGLT-2 inhibitors not only confer cardiorenal protection independent of their glucose-lowering effects, but also slow kidney disease progression in individuals with CKD, regardless of underlying etiology or T2D status. Additionally, SGLT-2 inhibitors improve clinical outcomes in HF patients, irrespective of the ejection fraction level, while maintaining a generally favorable safety profile. In this regard, the expanding clinical applications of SGLT-2 inhibitors in the treatment of T2D, HF and CKD diseases have opened up new possibilities for the integrated management of CKM syndrome and have become an important component of the integrated management plan. In this narrative review, we aim to summarize the current understanding of the mechanism of action of SGLT-2 inhibitors in CKM syndrome. We also aim to highlight their growing role in the treatment paradigm and provide a reference for nephrologists, endocrinologists, cardiologists, primary care physicians, and other medical specialists to formulate effective clinical management strategies. To ensure the current literature was available for the review, we searched PubMed, EMBASE, the Cochrane Library, UpToDate, Wanfang Medical Database, China National Knowledge Infrastructure (CNKI), and Baidu Scholar for literature published up to October 2025 on the clinical diagnosis and management of CKM syndrome and the clinical application of SGLT-2 inhibitors. The search was limited to large randomized controlled trials (RCTs), large prospective/retrospective data analyses, systematic reviews, meta-analyses, and clinical management consensuses or guidelines. Duplicate publications, small-sample clinical reports, commentaries, editorials, letters, news reports, narrative reviews, and conference abstracts that were not published in peer-reviewed journals were excluded. The Interconnection Among Cardiovascular-Kidney-Metabolic Diseases It is now recognized that CKM diseases often begin subtly early in life and are closely linked through overlapping risk factors, including hypertension, diabetes, dyslipidemia, obesity, and chronic inflammation. These risk factors share similar pathological mechanisms with CKM diseases, contributing to the activation of inflammatory pathways, oxidative stress, insulin resistance, renin-angiotensin-aldosterone system (RAAS) dysregulation, endothelial dysfunction, and a tendency for thrombosis. These conditions often coexist and exacerbate one another, forming a complex network for disease progression. Disorders like T2D and obesity contribute to systemic inflammation, insulin resistance, and dyslipidemia, which increase the risk of endothelial dysfunction, a precursor to cardiovascular diseases and microvascular kidney damage. Metabolic dysfunction and hypertension drive cardiovascular diseases like atherosclerotic cardiovascular disease (ASCVD), with atherosclerosis impairing blood flow to vital organs, including the kidneys, and leading to CKD. In turn, CKD worsens cardiovascular and metabolic diseases by causing fluid retention, hypertension, electrolyte imbalances, and impairments in glucose and lipid metabolism.22 Atherosclerosis plays a central role in the development and progression of CKM diseases, serving as a key etiological factor directly linked to CKM syndrome. Population-based retrospective studies demonstrate that subclinical atherosclerosis, as assessed by the coronary artery calcium (CAC) score, is independently associated with an increased risk of adverse cardiovascular outcomes and all-cause mortality in patients with CKM risk factors, including CKD, diabetes, and metabolic syndrome.23–25 Extensive epidemiological and clinical research showing that conditions like T2D, CVD and CKD often coexist and share common pathological mechanisms has shaped the concept of CKM syndrome.1 In the past 5 years, several Chinese and International Societies have released guidelines or scientific statements that focus on the early prevention and risk factor screening, as well as interdisciplinary care models to effectively manage these interconnected diseases.26–37 In 2023, the American Heart Association (AHA) convened a multidisciplinary group of experts and issued a presidential advisory for CKM,5 concluding that CKM syndrome represents a multidirectional pathophysiology leading to increased morbidity and mortality, exceeding the mere aggregate of its components. Chinese researchers have proposed a sixth innovative cardiorenal syndrome (CRS) subtype, based on the concept of “chronic co-impairment” of the heart and kidneys. This subtype is characterized by the onset of chronic systemic conditions such as diabetes, hypertension, amyloidosis, and systemic lupus, followed by a gradually progressive decompensation and decline in cardiac and renal function, ultimately leading to cardiac and renal failure.38 This novel type 6 CRS definition closely aligns with the concept of CKM disease. Kidney Sits at the Intersection of Cardiovascular-Kidney-Metabolic Diseases Kidney disease often arises as a secondary condition to cardiovascular (CV) or endocrine disorders. T2D is a major driver of CKD, with approximately 40% of T2D patients also having a diagnosis of CKD.3 Persistent hyperglycemia and insulin resistance in T2D trigger harmful processes such as glomerular hyperfiltration, oxidative stress, and inflammation, leading to progressive kidney damage characterized by glomerular injury, albuminuria, and declining renal function. Conversely, CKD can lead to metabolic dysregulation, worsening insulin resistance, and contributing to the onset or progression of T2D. The incidence of T2D is significantly higher in patients with CKD compared with the general population.39,40 Although the underlying mechanism remains unclear, contributing factors may include insulin resistance, metabolic acidosis, vitamin D deficiency, or toxin accumulation due to impaired kidney function.22 A similar observation has also been reported in patients with HF, where half of them also experience CKD.4 Conversely, kidney disease can also lead to multiple complications including an increase in the risk of CV events.22 CKD patients often have elevated blood pressure, lipid metabolism disorders, anemia, etc. Together, these factors increase the workload on the heart and the risk of myocardial infarction and heart failure. The CKM AHA Presidential Advisory advocates measurement of the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) in patients with CKD, diabetes, hypertension or metabolic syndrome. This underscores the increasingly pivotal role of kidney function in CKM diseases.5 In line with this, kidney protection and delaying CKD progression are crucial components of the comprehensive CKM care model structure.5 From a clinical perspective, kidney function can also pose a barrier to the treatment of CV or endocrine disorders. Renal insufficiency can reduce drug clearance and increase the risk of drug accumulation and adverse reactions,41 thereby impacting the number of drug classes and standard doses that patients can tolerate. Severely reduced renal function will also restrict the application of guideline-recommended medical therapy (GDMT) in managing these diseases. Mechanism of Action and Clinical Evidence of the Beneficial Effects of SGLT-2 Inhibitors for Renal Protection in the Context of CKM Disease Mechanism of Action The primary mechanism of action of SGLT-2 inhibitors involves inhibition of the coupled reabsorption of sodium and glucose from the glomerular filtrate in the proximal renal tubule, leading to increased excretion of sodium and glucose in the urine.42 Additionally, SGLT-2 inhibitors exhibit a multifaceted mechanism of action that benefits cardiovascular, renal, and metabolic health (Figure 1). SGLT-2 inhibitors can exert a variety of nephroprotective effects by direct effects on kidney function. They can increase distal sodium delivery, restore tubule-glomerular feedback, and decrease intraglomerular pressure, which subsequently reduces albuminuria. By reducing the solute transport load in proximal tubules, SGLT-2 inhibitors can potentially alleviate their energy burden. SGLT-2 inhibitors may also boost oxygen supply via increased ketone production and erythropoietin secretion, further reducing the risk of hypoxia. Lastly, SGLT-2 inhibitors can prevent inflammation and fibrosis, and ameliorate kidney mitochondrial metabolism to protect renal function.43,44 SGLT-2 inhibitors also demonstrate beneficial effects beyond the kidney. Firstly, they improve metabolism by reducing glucotoxicity, which helps decrease HbA1c levels by 0.7%.45,46 Additionally, they are also capable of lowering uric acid levels. Furthermore, SGLT-2 inhibitors can reduce afterload through arterial vasodilation and diminish preload via natriuresis and diuresis, leading to a decrease in effective circulating volume and blood pressure. They can also prevent cardiac remodeling, enhance cardiac function, and improve cardiac efficiency.47,48 SGLT-2 Inhibitors Can Improve a Range of Metabolic and Cardiovascular Risk Factors Associated with CKD As medications primarily used to manage T2D, SGLT-2 inhibitors not only improve glycemic control, but also positively impact body weight, uric acid levels, and lipid profiles, and provide CV benefits, all of which are risk factors for CKD development. The CV benefits of SGLT-2 inhibitors, including a reduction in major adverse CV events such as heart failure, myocardial infarction, and stroke, have been substantiated by a series of Phase 3 RCTs (Table 1). 49–62 A recent meta-analysis involving 90,943 patients demonstrated that, compared with standard of care, SGLT-2 inhibitors resulted in a 14% reduction in CV mortality, a 12% reduction in all-cause mortality, an 11% reduction in major adverse CV events, a 30% reduction in HF hospitalizations, and a 23% reduction in the combined outcome of CV death or HF hospitalization.63 A retrospective study further indicated that the use of SGLT-2 inhibitors in patients with T2D and CKD was associated with a 20% reduction in the risk of new-onset stroke compared with non-users.64 Cardiovascular outcome trials (CVOTs) of SGLT-2 inhibitors have enrolled varying proportions of patients with ASCVD. While these trials did not specifically target atherosclerosis-related endpoints, the observed improvements in CV outcome indirectly suggest a potential benefit of SGLT-2 inhibitors in mitigating atherosclerosis. A meta-analysis involving 23,987 patients without established ASCVD demonstrated that, among those with coexisting CKD and T2D, SGLT-2 inhibitors resulted in a 26% reduction in atherosclerotic major adverse CV events.69 SGLT-2 inhibitors may potentially slow the progression of atherosclerosis and reduce the risk of related cardiovascular events through mechanisms such as improving vascular function, exerting anti-inflammatory and antioxidant effects, and regulating metabolism. However, direct evidence of plaque regression remains limited and requires further investigation. Some animal studies and clinical observations have suggested that SGLT-2 inhibitors may reduce the size of early atherosclerotic lesions or stabilize them,69,70 as well as improve atherosclerosis-related markers.71 Analysis of a large real-world dataset from Israel revealed that in patients with T2D and established ASCVD, compared with no use of SGLT-2 inhibitors or GLP-1RAs, SGLT-2 inhibitor monotherapy, GLP-1RA monotherapy, and their combination reduced the risk of all-cause mortality by 72% (HR 0.28; 95% CI 0.27–0.29), 61% (HR 0.39; 95% CI 0.37–0.40), and 83% (HR 0.17; 95% CI 0.16–0.18), respectively.72 The relevant clinical outcomes of SGLT-2 inhibitors in ASCVD populations from RCTs are summarized in Table 2. SGLT-2 inhibitors may confer arterial protection via multiple mechanisms, including improved glycemic control, body weight reduction, antihypertensive effects, and antifibrotic actions. They also modulate inflammatory pathways, enhance vascular function, and attenuate oxidative stress.73 Findings from observational studies and RCTs further demonstrate that SGLT-2 inhibitors favorably influence various markers of subclinical atherosclerosis, such as intima-media thickness (IMT), epicardial adipose tissue (EAT), endothelial function, and arterial stiffness.74 Furthermore, the CREDENCE trial showed that patients with T2D and CKD can benefit from canagliflozin therapy in lowering systolic blood pressure. This benefit was observed across all patient subgroups based on blood pressure, and patients on canagliflozin treatment required fewer interventions for blood pressure control.76 Real-world evidence also supports the utility of SGLT-2 inhibitors. A retrospective multi-ethnic cohort study reported that SGLT-2 inhibitors were associated with a 12% reduction in all-cause hospitalizations and a 34% reduction in all-cause mortality compared with DPP-4 inhibitors.77 Another large international study of T2D patients from the Asia Pacific region, the Middle East, and North America showed that SGLT-2 inhibitors were associated with lower risks of death (HR 0.51; P < 0.001), hospitalization for HF (HR 0.64; P = 0.001), death or hospitalization for HF (HR 0.60; P < 0.001), myocardial infarction (HR 0.81; P < 0.001), and stroke (HR 0.68; P < 0.001).67 Early Use of SGLT-2 Inhibitors to Reduce the Risk of CKD Development The AHA Presidential Advisory pointed out that SGLT-2 inhibitors can consistently benefit the reduction of CKD progression, the need for kidney replacement therapies, and incident CVD.19 The following text summarizes the accumulating evidence from randomized clinical trials suggesting that early use of SGLT-2 inhibitors may have the potential to prevent the onset of CKD, ultimately improving overall patient outcomes (Table 1). The EMPA-REG OUTCOME study was the first CV outcomes trial that demonstrated the benefit of SGLT-2 inhibitors on CV mortality, all-cause mortality, and hospital admission for heart failure,49 as well as an association with slower progression of kidney disease and lower rates of clinically relevant renal events.50 The empagliflozin group had a decrease in the prespecified renal composite outcome of incident or worsening nephropathy compared with the placebo group (hazard ratio [HR] 0.61; 95% CI 0.53 to 0.70, P < 0.0001).50 For patients with a baseline eGFR ≥60 mL/min/1.73 m2, the eGFR remained stable in the empagliflozin groups while it declined steadily in the placebo group during long-term follow-up50 (Table 1). Subsequently, the CANVAS51 and DECLARE-TIMI 5852 studies have reported similar outcomes. In the CANVAS study, 79.9% of the enrolled patients did not have CKD at baseline.78 In those with a baseline eGFR≥60 mL/min/1.73 m2, canagliflozin reduced the risk of the composite renal outcome (a 40% decrease in eGFR, end-stage kidney disease, or renal death) by 47% (95% CI 0.39 to 0.73). Canagliflozin also helped preserve renal function in these patients, as evidenced by the annual change in eGFR.78 Dapagliflozin also appeared to prevent and reduce the progression of kidney disease compared with placebo in patients enrolled in the DECLARE-TIMI study, most of whom had preserved renal function.53 For patients with a baseline eGFR ≥90 mL/min/1.73 m2 or 60 to <90 mL/min/1.73 m2, dapagliflozin reduced the risk of the composite renal-specific outcome (a sustained decrease in eGFR by at least 40% to less than 60 mL/min/1.73 m², end-stage renal disease, or renal death) by 50% (95% CI 0.34 to 0.73) and 46% (95% CI 0.40 to 0.73), respectively. The change in mean eGFR was also less in the dapagliflozin groups after 2 years of treatment in patients with an eGFR≥60 mL/min/1.73 m2.53 From a series of studies conducted in patients with HF, including EMPEROR-Reduced,65 EMPEROR-Preserved,66 DAPA-HF,54 and DELIVER,55 it has been shown that SGLT-2 inhibitors can provide kidney protection in patients with HF across all ranges of ejection fraction, including those without CKD. The EMPEROR-Reduced study enrolled 3730 HF patients, including 1978 (53%) with concomitant CKD and 1752 (47%) without. Subgroup analysis showed that the risk of a prespecified composite kidney outcome (sustained profound decline in eGFR, chronic dialysis, or transplantation) was reduced in the empagliflozin group with an HR of 0.46 (95% CI 0.22 to 0.99). Additionally, empagliflozin slowed the decline of eGFR, one of the key secondary outcomes, by 2.41 mL/min/1.73 m2/year (95% CI 1.49 to 3.32) in patients without CKD.56 The pre-specified analysis of the EMPEROR-Preserved trial also demonstrated that empagliflozin effectively slowed the decline in eGFR and reduced the risk of composite kidney outcomes across the entire spectrum of baseline kidney function, including patients without prevalent CKD.79 Dapagliflozin has shown similar benefits in slowing the rate of eGFR decline in HF patients without CKD, as observed in the DAPA-HF and DELIVER trials.57,80 The unexpected and remarkable renal-protective effects of SGLT-2 inhibitors in patients with no evidence of CKD at baseline suggested that the early use of these drugs may bring benefit in reducing the risk of developing CKD. SGLT-2 Inhibitors Address the Two Key Treatment Goals in CKD The Improving Global Outcomes (KDIGO) clinical management guidelines for CKD highlight slowing CKD progression and controlling CV risk as two primary treatment goals for CKD patients.20 In recent years, SGLT-2 inhibitors have been demonstrated to be a key therapeutic option that addresses both of these goals. The CREDENCE study (n = 4401) was the first confirmatory trial to explore the effect of SGLT-2 inhibitors on slowing CKD progression in patients with T2D and CKD.60 The enrolled patients had an eGFR of 30 to <90 mL/min/1.73 m2 and UACR of >300 to 5000 mg/g. After a median follow-up of 2.62 years, there was a significant reduction in the risk of the composite primary endpoint, which included end-stage kidney disease, a doubling of the serum creatinine level, or death from renal or CV causes, in comparison with placebo (HR 0.70; 95% CI 0.59 to 0.82, P = 0.00001).60 The DAPA-CKD study, which included 4304 CKD patients with or without T2D, enrolled those with an eGFR of 25 to 75 mL/min/1.73 m2 and a UACR of 200 to 5000 mg/g.59 Patients were randomized to receive either dapagliflozin or placebo. After a median follow-up of 2.4 years, the dapagliflozin group experienced a 39% risk reduction in the composite endpoint of a sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal or vascular causes (HR 0.61; 95% CI 0.51 to 0.72, P < 0.001).59 The HR for the renal-specific composite outcome (a sustained decline in eGFR of at least 50%, end-stage kidney disease, or death from renal causes) was 0.56 (95% CI 0.45 to 0.68, P < 0.001).59 The EMPA-KIDNEY study, which is presently the largest confirmatory study with 6609 participants, investigated the effects of empagliflozin in CKD patients with different primary diseases and albuminuria statuses.58 The study found that progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to less than 10 mL/min/1.73 m2, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) and death from CV causes, occurred less frequently in the empagliflozin group compared with the placebo group, with an HR of 0.72 (95% CI 0.64 to 0.82). Additionally, the HR for progression of kidney disease alone also favored the empagliflozin group (HR 0.71; 95% CI 0.62 to 0.81).58 Prespecified exploratory analyses showed that the rate of decline in eGFR, after an initial decrease, was slower in the empagliflozin group across all key subgroups, including those with a low UACR. In patients with CKD and albuminuria, the empagliflozin group exhibited a reduced annual eGFR decline of 2 to 2.5 mL/min/1.73 m², while in those with normal albumin levels, the annual eGFR decline was lowered to 0.1 mL/min/1.73 m², well below the aging-related GFR loss.81 A hypothetical scenario based on chronic eGFR decline rates across different eGFR subgroups in the EMPA-KIDNEY trial suggests that, empagliflozin could delay the progression to end-stage kidney disease by an estimated 1.9 years (when initiating treatment at an eGFR of 20 mL/min/1.73 m²) to 26.6 years (when initiating treatment at an eGFR of 85 mL/min/1.73 m²).81 In the CREDENCE, DAPA-CKD, and EMPA-KIDNEY trials, 50.4%, 37.4%, and 26.7%, respectively, of the patients presented with comorbid CVD.58–60 Overall results from these studies demonstrated that SGLT-2 inhibitors treatment reduced the risk of cardiovascular mortality by 22%, 19%, and 16%, respectively, compared with placebo.58–60 Furthermore, the EMPA-KIDNEY Post-Trial Follow-Up (PTFU) indicated that empagliflozin continued to provide additional cardiorenal benefits for up to 12 months after treatment discontinuation. A 25% reduction in cardiovascular mortality risk was observed (HR 0.75; 95% CI 0.59 to 0.95).82 It was proposed that the preservation and protective effect on renal function following empagliflozin therapy may have partially mediated the cardiovascular mortality benefit observed after the trial period.82 The Nuffield Department of Population Health Renal Studies Group conducted a comprehensive meta-analysis of SGLT-2 inhibitors, encompassing 13 randomized controlled trials (RCTs) with a total of 90,413 patients.83 The analysis found that SGLT-2 inhibitor treatment reduced the risk of kidney disease progression by 37%. This meta-analysis provides robust evidence that SGLT-2 inhibitors can modify the risk of kidney disease progression across various patient settings, irrespective of diabetes status, primary kidney disease, or renal function. In addition to RCTs, emerging data from real-world studies support the use of SGLT-2 inhibitors in patients with CKD. A group of Japanese researchers selected a more elderly diabetic kidney disease population (patient age ≥75 years), with a total of 696 patients identified from the Japan Chronic Kidney Disease Database. Compared with other glucose-lowering drug groups (top 3 classes: dipeptidyl peptidase 4 [DPP-4] inhibitors 77.9%, biguanides 34.2%, sulfonylureas 28.4%), SGLT-2 inhibitors were associated with a delayed eGFR decline (annual difference: 0.99 mL/min/1.73 m2).84 Safety of SGLT-2 Inhibitors Data from large RCTs indicate that SGLT-2 inhibitors generally exhibit a favorable safety profile. A meta-analysis of 13 large RCTs reported the following relative risks (RR) associated with SGLT-2 inhibitors: urinary tract infections (RR 1.08; 95% CI 1.02 to 1.15), serious urinary tract infections (RR 1.07; 95% CI 0.90 to 1.27), fungal genital infections (RR 3.57; 95% CI 3.14 to 4.06), fractures (RR 1.07; 95% CI 0.99 to 1.14), and severe hypoglycemia (RR 0.89; 95% CI 0.80 to 0.98).83 The overall relative risk of ketoacidosis with SGLT-2 inhibitor treatment was 2.12 (95% CI 1.49 to 3.04); however, only one ketoacidosis event occurred in non-diabetic patients during nearly 30,000 patient-years of follow-up.83 After excluding data from the CANVAS trial (which reported a two-fold increase in lower limb amputation risk with SGLT-2 inhibitor treatment and showed significant heterogeneity compared with other trials), no significant association was observed between SGLT-2 inhibitor use and the risk of lower limb amputation (RR 1.06; 95% CI 0.93 to 1.21).83 However, nationwide registry data from Denmark and Sweden (2013–2016) indicated that, compared with GLP-1 receptor agonists (GLP-1RAs), SGLT-2 inhibitor use was associated with a higher risk of lower limb amputation and diabetic ketoacidosis.85 SGLT-2 inhibitors may also increase the risk of urinary frequency and dehydration, as well as rare but serious adverse events, such as Fournier gangrene.86 A mild and reversible decline in eGFR (commonly referred to as an “eGFR dip”) is often observed within weeks after initiating SGLT-2 inhibitors. This decline occurs due to tubuloglomerular feedback and reduced intraglomerular pressure. However, this early reduction in eGFR does not increase the risk of acute kidney injury (AKI), negatively impact long-term renal outcomes, or compromise the efficacy of SGLT-2 inhibitors.87–90 A meta-analysis showed that SGLT-2 inhibitor use was associated with a 23% reduction in the risk of AKI compared with the placebo.83 Guideline Recommendations for SGLT-2 Inhibitors in CKM The AHA presidential statement introduced a new staging system for CKM syndrome: stage 0 (no CKM risk factors), stage 1 (excess or dysfunctional adiposity), stage 2 (metabolic risk factors or moderate/high-risk CKD), stage 3 (subclinical CVD in CKM), and stage 4 (clinical CVD in CKM).5 Patients in later stages (Stage 3 or 4) represent advanced disease with significant organ damage. The statement highlights the importance of initiating CKM-related screening early and maintaining it throughout life-course with monitoring protocols comprehensively, considering the common pathological mechanisms of CKM syndrome. In childhood, body weight and blood pressure should be monitored at each clinic visit starting from age 3, while lipid profile screening is recommended once at ages 9–11 and again at ages 17–21. High-risk children who are overweight or obese should also undergo testing for glucose tolerance and liver function. In adulthood, screening frequency should be based on the CKM stage: stage 0 individuals should be assessed every 3–5 years, stage 1 every 2–3 years, and stage 2 or higher, annually for metabolic syndrome components (blood pressure, lipids, blood glucose). Patients in stage 2 or higher should also undergo annual renal function assessment (eg urine albumin-to-creatinine ratio and estimated glomerular filtration rate) and targeted screening for subclinical atherosclerotic cardiovascular disease and heart failure in high-risk populations.5 With robust evidence supporting the benefits of SGLT-2 inhibitors in patients with T2D, CVD and CKD, SGLT-2 inhibitors are recommended for the holistic management of CKM disease throughout its different stages. Chinese researchers advocate that the management of patients with type 6 cardiorenal syndrome requires an integrated approach targeting both the cardiac and renal systems, with a focus on novel treatments such as SGLT-2 inhibitors.38 Several Chinese and international Societies that have developed clinical management guidelines or scientific statements for the management of CKM syndrome consistently recommend SGLT-2 inhibitors as a cornerstone therapy in this clinical setting.21,33–35,91 Table 3 summarizes the recommendations from condition-specific guidelines, as well as guidelines covering multiple CKM diseases. SGLT-2 inhibitors now serve three key roles: (1) achieving glycemic control, cardiovascular protection, and renal benefits in T2D patients, especially those with comorbidities; (2) serving as first-line therapy to slow kidney disease progression, even in non-diabetic patients; and (3) providing effective treatment for chronic HF, regardless of ejection fraction or diabetes status. Challenges in GDMT Implementation and Future Directions in China Guideline-recommended medical therapies are designed to improve clinical outcomes and streamline treatment regimens. The recently issued AHA recommendations have established a framework for various therapeutic approaches.5 In addition to SGLT-2 inhibitors which are endorsed for their ability to prevent kidney failure and provide cardioprotective effects, GLP-1RAs and RAAS inhibitors are also advocated. The recommendation is based on the observed multiple benefits on metabolic risk factors, kidney function, and the CV system. Despite the heavy burden of CKM syndrome, the implementation of these guideline-recommended therapies in real-world settings is suboptimal, leading to an adverse prognosis for patients with CKM diseases.98,99 It is important to point out that SGLT-2 inhibitors are one of the most underutilized guideline-recommended therapies globally. Only a minority of T2D patients with comorbidities (ASCVD, HF, CKD) receive an SGLT-2 inhibitor, with the proportion ranging from 6.0% to 28.0%.100 In China, a single institutional study reported similar findings: SGLT-2 inhibitors were used in only 12.3% of diabetic kidney disease patients.101 A multivariate logistic regression was also performed in the study to identify factors that are associated with the use of SGLT-2 inhibitors; they included age, body mass index (BMI), HbA1c level, eGFR, dyslipidemia, and hypertension history.101 Several other factors may also limit compliance with guideline recommendations in real-world CKM management settings. Treatment-related factors, such as adverse reactions and renal function, as well as healthcare service-related factors (including clinical inertia and insufficient interdisciplinary collaboration) may hinder the optimal selection and use of guideline-recommended therapies, such as SGLT-2 inhibitors, in China. Addressing these challenges is crucial to guiding future efforts and shaping innovative strategies that can further enhance clinical outcomes. In addition to the comprehensive benefits of SGLT-2 inhibitors in CKM syndrome mentioned above, exploring their combination with other drugs may provide additional advantages. Evidence supports the use of SGLT-2 inhibitors with other agents, such as RAAS inhibitors, GLP-1 RAs, angiotensin receptor-neprilysin inhibitors, nonsteroidal mineralocorticoid receptor antagonists (eg finerenone), and aldosterone synthase inhibitors (eg vicadrostat). These combinations, tailored to specific comorbidities, can enhance cardiorenal protection and improve glucolipid metabolism.49,51,52,58–62,65,66,68,102,103 Analyses of clinical trial data indicate that for patients with CKD, a regimen comprising a RAAS inhibitor and an SGLT-2 inhibitor or finerenone may provide additive benefits by effectively slowing the rate of eGFR decline to levels comparable to or even below those with natural aging.104,105 Future research is warranted to delineate standardized protocols and precautions for the application of these SGLT-2 inhibitor combination therapies within CKM clinical practice. The therapeutic potential of SGLT-2 inhibitors beyond CKM also represents a noteworthy research direction. Recent evidence suggests a potential role for SGLT-2 inhibitors in suppressing tumor growth, indicating that they might synergize with conventional anticancer therapies to enhance efficacy and reduce toxicity.106,107 Further investigation is required to elucidate their mechanisms of action and clinical applications. Considering that CKM-related diseases are predominantly managed by specialists rather than primary care physicians in China, enhancing multidisciplinary team (MDT) collaboration may potentially ameliorate the suboptimal utilization of GDMT and overall management of CKM diseases. Given the critical role of renal protection in the pathogenesis and therapy of CKM diseases, nephrologists should serve as pivotal coordinators within the MDT. They can raise awareness of kidney diseases and their implications for CV and metabolic health, disseminate information about current evidence-based treatments, and share experiences in managing patients with renal dysfunction. Last but not least, patient and caregiver education is crucial for the success of CKM management. Promoting a healthy diet, regular physical activity, and weight management is a fundamental and an effective part of CKM treatment. Education should be prioritized for patients at higher risk of CKM, as well as for under-resourced families and communities. Enhancing physician-patient cooperation throughout the entire CKM disease journey is also essential. Limitations This narrative review synthesizes pivotal recent research to provide a comprehensive overview of the renal protective effects of SGLT-2 inhibitors in the context of CKM syndrome. The aim was to enhance understanding of their role in these connections. However, the inherent limitations of this narrative review must be acknowledged, including the lack of reproducible conclusions, potential for bias, and subjectivity stemming from a non-standardized and often non-exhaustive search approach. Additionally, the insights regarding GDMT implementation and its associated challenges are primarily based on the Chinese clinical context and may not be directly applicable to other geographic regions. Conclusions Diabetes, CVD, and kidney disease are closely interconnected disorders and are core components of CKM syndrome, making proactive early screening and intervention essential to slow their progression and improve outcomes. SGLT-2 inhibitors provide significant benefits in CKD protection, including controlling risk factors for CKD development and slowing its progression. They also contribute to improvements in CV and metabolic health. As part of a comprehensive management strategy, SGLT-2 inhibitors may help to reduce the risk of cardiovascular-renal-metabolic diseases. For patients with CKD, T2D, or heart failure (irrespective of ejection fraction), especially those with concomitant CKM risk factors such as obesity, ASCVD, or high cardiovascular risk, SGLT-2 inhibitors should be considered when selecting pharmacotherapy. Interdisciplinary approaches are critical to optimize the management of CKM diseases in China. Given that kidney function is at the core intersection of CKM diseases, nephrologists are well-positioned to spearhead the creation of an interdisciplinary team of clinicians for the co-management of patients with CKM diseases. Data Sharing Statement All data used for this publication are presented in the main article. Acknowledgments Editorial assistance was provided by Content Ed Net, Shanghai, with funding from Boehringer Ingelheim China. Funding Nan Ye was funded by Beijing Municipal Hospital Scientific Research and Cultivation Program (PX2022024), and Beijing Hospital Authority Young Talent Cultivation “Qingmiao” Program (QML20230601). Hong Cheng was funded by Special Project for Scientific Research on Health Development of the Capital (2022-2-2066). Disclosure The authors declare no conflicts of interests for this work. References 1. Maack C, Lehrke M, Backs J, et al. Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the translational research committee of the heart failure association-European society of cardiology. Eur Heart J. 2018;39:4243–4254. doi:10.1093/eurheartj/ehy596 2. Seferovic PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2018;20:853–872. doi:10.1002/ejhf.1170 3. Usman MS, Khan MS, Butler J. 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