Chronic kidney disease (CKD) is a major contributor to long-term morbidity and mortality, particularly among patients with coexisting cardiovascular disease and type 2 diabetes mellitus (T2DM). CKD rarely exists in isolation and is strongly associated with cardiovascular disease and heart failure, creating a complex, high-risk population that requires integrated management across care settings [1–3].

Although renin-angiotensin-aldosterone system (RAAS) blockade remains the cornerstone of CKD management, landmark kidney outcome trials have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors provide additional renal and cardiovascular benefits when added to standard therapy [1–3]. These findings highlight the persistent need for therapies that further reduce the risk of kidney disease progression and cardiovascular events in patients with CKD. The complexity of managing CKD, particularly in patients with multiple comorbidities, underscores the importance of integrating evidence-based therapies into individualized patient care.

SGLT2 inhibitors have transformed the therapeutic landscape of CKD. Initially developed as glucose-lowering agents for T2DM, they were subsequently shown to reduce hospitalization for heart failure and slow CKD progression in large cardiovascular outcome trials [4–6]. Dedicated kidney outcome trials, including CREDENCE, DAPA-CKD, and EMPA-KIDNEY, further demonstrated significant renal and cardiovascular benefits in patients with CKD, including those without diabetes [1–3]. These findings have established SGLT2 inhibitors as foundational therapies across a broad spectrum of kidney function and albuminuria levels [1–3].

Despite compelling evidence, real-world uptake of SGLT2 inhibitors remains suboptimal [7, 8]. Underprescription among eligible high-risk patients has been consistently reported, reflecting gaps in implementation and barriers to adoption in routine clinical practice [7–12]. Factors such as clinician familiarity, prescribing priorities, healthcare system barriers, and care coordination continue to limit the timely initiation of SGLT2 inhibitors in eligible patients [7–12].

Primary care clinicians play a pivotal role in identifying eligible patients with CKD and implementing evidence-based SGLT2 inhibitor therapy [7–12]. This systematic review synthesizes evidence from randomized controlled trials and real-world primary studies to evaluate the renal, cardiovascular, safety, and implementation outcomes of SGLT2 inhibitors in CKD. By integrating evidence from landmark clinical trials with real-world practice, this review aims to support evidence-based prescribing and facilitate the earlier adoption of SGLT2 inhibitors in routine CKD management.

This systematic review synthesized evidence from 15 primary studies evaluating the role of SGLT2 inhibitors in CKD, encompassing randomized controlled trials, observational studies, and implementation-focused research. Collectively, the evidence demonstrates that SGLT2 inhibitors consistently reduce the risk of kidney disease progression and adverse cardiovascular outcomes while maintaining an overall favorable safety profile across diverse CKD populations [1–6]. Beyond confirming their clinical efficacy, the included real-world and primary care studies revealed a persistent gap between the growing evidence supporting SGLT2 inhibitor therapy and its adoption in routine practice, highlighting implementation rather than efficacy as one of the major remaining challenges in optimizing CKD care [7–14].

One of the most important observations from this review is the progressive evolution of evidence supporting SGLT2 inhibitors in CKD. Early cardiovascular outcome trials, including EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58, were primarily designed to evaluate cardiovascular safety in patients with type 2 diabetes but consistently demonstrated favorable renal outcomes as secondary endpoints [4–6]. These findings generated the hypothesis that SGLT2 inhibitors exert renoprotective effects beyond glucose lowering, prompting dedicated kidney outcome trials. Subsequently, CREDENCE provided the first robust evidence that SGLT2 inhibitors significantly reduced kidney disease progression in patients with diabetic CKD [3], while DAPA-CKD and EMPA-KIDNEY extended these benefits to broader CKD populations, including individuals without diabetes, thereby substantially expanding the therapeutic role of SGLT2 inhibitors in nephrology [1, 2]. Together, these landmark trials transformed SGLT2 inhibitors from glucose-lowering agents with secondary renal benefits into established cardiorenal therapies for patients with CKD.

Another notable evolution across the landmark kidney outcome trials was the gradual expansion of eligible CKD populations. CREDENCE and DAPA-CKD primarily enrolled patients with albuminuric CKD at high risk for disease progression, whereas EMPA-KIDNEY broadened eligibility to include patients with a wider spectrum of CKD, thereby extending the evidence base to more diverse clinical populations [1–3]. This progression suggests that the renoprotective effects of SGLT2 inhibitors are applicable across a broad range of CKD phenotypes, although differences in trial populations should be considered when interpreting individual study findings [1–3].

The consistent renal and cardiovascular benefits observed across the landmark trials also suggest that the therapeutic effects of SGLT2 inhibitors extend beyond glycemic control. This concept is further supported by the post hoc analysis of the CREDENCE trial, which demonstrated that the cardiorenal benefits of canagliflozin were only minimally attenuated after adjustment for achieved HbA1c, indicating that glucose lowering explained only a small proportion of the observed treatment effect [15]. These findings provide clinical evidence that the renoprotective effects of SGLT2 inhibitors cannot be attributed solely to improvements in glycemic control and instead likely reflect multiple complementary mechanisms. These findings suggest that mechanisms beyond glucose lowering contribute substantially to the observed cardiorenal benefits, although the precise biological pathways were not specifically evaluated in the studies included in this review [1–3, 15]. This observation is further reinforced by the significant renal benefits observed in non-diabetic CKD populations enrolled in DAPA-CKD and EMPA-KIDNEY, where improvements in kidney outcomes occurred despite the absence of diabetes [1, 2].

Although randomized controlled trials established the efficacy of SGLT2 inhibitors under carefully controlled conditions, the included real-world studies suggest that these benefits are largely reproducible in routine clinical practice. Analysis of the Japan Chronic Kidney Disease Database demonstrated slower eGFR decline and a lower risk of adverse kidney outcomes among patients initiating SGLT2 inhibitors compared with other glucose-lowering therapies, supporting the external validity of the landmark clinical trials [13]. Similarly, the multinational new-user cohort study reported favorable kidney and cardiovascular outcomes across diverse healthcare settings, indicating that the cardiorenal benefits of SGLT2 inhibitors extend beyond highly selected trial populations [14]. Together, these findings strengthen the generalizability of the randomized trial evidence and support the effectiveness of SGLT2 inhibitors in routine clinical care, despite the greater clinical heterogeneity and treatment variability encountered in real-world practice.

Despite compelling evidence supporting the cardiorenal benefits of SGLT2 inhibitors, implementation studies consistently demonstrated substantial underutilization across diverse healthcare systems [7–12]. Importantly, the barriers to implementation extended beyond simple physician awareness. Cross-sectional studies from Canada, Portugal, and Denmark documented low prescribing rates even among patients with clear cardiorenal indications, suggesting that evidence alone has not been sufficient to change prescribing behavior [7–10]. Qualitative data from Hong Kong (China) further highlighted that physicians’ uncertainty about glucose-independent benefits, concerns about adverse effects, prior prescribing habits, and healthcare system constraints all contributed to therapeutic inertia [11]. Similarly, a large real-world analysis from Italy demonstrated that prescribing decisions were frequently influenced by patient characteristics such as age and body mass index rather than by cardiorenal risk, indicating that clinical decision-making does not always align with contemporary evidence [12]. Collectively, these findings suggest that improving implementation will require multifaceted interventions that address clinician education, healthcare system barriers, and prescribing behavior, rather than relying solely on publishing additional clinical trial evidence.

The safety findings should be interpreted in the context of implementation, because perceived adverse effects remain an important barrier to prescribing. Across the landmark trials, SGLT2 inhibitors were generally well tolerated, but clinically relevant safety signals varied by study, including increased genital infections in EMPA-REG OUTCOME and DECLARE-TIMI 58, rare cases of diabetic ketoacidosis in DECLARE-TIMI 58, and the amputation signal observed in the CANVAS Program [4–6]. Importantly, later CKD-focused trials provided additional reassurance, with CREDENCE reporting no significant differences in amputation or fracture rates, DAPA-CKD confirming the known safety profile of dapagliflozin, and EMPA-KIDNEY showing similar rates of serious adverse events between treatment groups [1–3]. These findings suggest that safety concerns should prompt careful patient selection, counseling, and monitoring rather than broad avoidance of SGLT2 inhibitors in eligible CKD patients.

The findings of this review have important implications for the management of CKD in both primary and specialty care. As evidence supporting SGLT2 inhibitors has expanded from patients with diabetic CKD to broader CKD populations, timely identification of eligible patients and initiation of therapy have become increasingly important [1–3]. However, implementation studies consistently demonstrate that strong clinical evidence alone has not translated into widespread adoption in routine practice [7–12]. Across diverse healthcare settings, persistent barriers—including knowledge gaps regarding cardiorenal benefits, concerns about adverse effects, prescribing habits, and healthcare system constraints—continue to limit the use of SGLT2 inhibitors among eligible patients [7–12]. These findings underscore the need for implementation strategies that address the barriers identified in the included studies to help bridge the gap between evidence and routine clinical practice.

This systematic review has several strengths. First, it synthesized evidence from multiple study designs, including randomized controlled trials, observational studies, and qualitative implementation research, providing a comprehensive overview of both the efficacy and real-world application of SGLT2 inhibitors in CKD. Second, by integrating evidence from landmark clinical trials with studies evaluating prescribing patterns and implementation barriers, this review extends beyond demonstrating clinical efficacy to examining factors that influence the translation of evidence into routine practice. Finally, the inclusion of recent studies reflecting contemporary guideline-directed use of SGLT2 inhibitors enhances the clinical relevance of the findings and provides an up-to-date perspective on their evolving role in CKD management.

Several limitations should be considered when interpreting the findings of this review. First, the included studies were heterogeneous in study design, patient populations, interventions, and outcome measures, precluding quantitative synthesis via meta-analysis. Second, the evidence base comprised randomized controlled trials, observational studies, and qualitative research, each with inherent methodological strengths and limitations that should be considered when interpreting the overall findings. Third, most implementation studies were conducted in high-income countries with differing healthcare systems, which may limit the generalizability of implementation barriers and prescribing patterns to other healthcare settings. Finally, only English-language studies published during the predefined search period were included, potentially excluding relevant evidence published in other languages or outside the search window. This systematic review was not prospectively registered in PROSPERO or another international registry. In addition, methodological quality assessment using tools such as RoB 2 or ROBINS-I was not performed. Nevertheless, the consistency of findings across diverse study designs and healthcare settings strengthens the overall conclusions of this review.

Future research should focus on strategies to improve the implementation of SGLT2 inhibitors in routine clinical practice. While substantial evidence now supports their cardiorenal benefits, comparatively few studies have evaluated interventions to overcome prescribing barriers and optimize uptake among eligible patients. Future implementation research should assess educational interventions for healthcare providers, health system–level strategies to reduce therapeutic inertia, and approaches to improve patient awareness and acceptance of SGLT2 inhibitor therapy. In addition, studies evaluating long-term effectiveness across broader, more diverse CKD populations, including different healthcare systems and resource settings, would further strengthen the evidence base and facilitate the equitable translation of guideline-directed therapy into clinical practice.