Sodium–glucose cotransporter 2 inhibitors (SGLT2i) were originally developed as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus (T2DM) by inhibiting renal glucose reabsorption in the proximal tubule and promoting glucosuria [1]. Their insulin-independent mechanism and favorable safety profile initially positioned them as adjunctive glucose-lowering therapies in combination with other antidiabetic agents. However, findings from large cardiovascular (CV) outcome trials have fundamentally reshaped this therapeutic paradigm. Beyond glycemic control, SGLT2i have demonstrated consistent reductions in heart failure (HF) hospitalization, attenuation of chronic kidney disease (CKD) progression, and improvement in major adverse CV outcomes across diverse patient populations [1, 2]. These findings have shifted the perception of SGLT2i from conventional metabolic therapies toward multisystem disease-modifying agents with broad cardiometabolic effects.

The emerging concept of the cardiovascular–renal–metabolic (CRM) continuum reflects the complex and bidirectional interactions linking metabolic dysfunction, CV disease, and kidney injury, where conditions such as T2DM, HF, and CKD share common upstream drivers including insulin resistance, ectopic lipid accumulation, mitochondrial dysfunction, oxidative stress, chronic low-grade inflammation, and maladaptive neurohormonal activation [3, 4]. These interconnected processes promote progressive multi-organ injury through coordinated metabolic, endothelial, and hemodynamic disturbances, explaining the frequent coexistence and mutually reinforcing progression of cardiac and renal dysfunction in metabolic disease [2, 4]. The CRM framework therefore emphasizes the need for therapeutic strategies that target shared pathophysiological pathways rather than isolated disease manifestations [5, 6]. While prior reviews have mostly adopted disease-specific or organ-centered perspectives, often focusing on glycemic control or discrete cardiorenal outcomes, this review advances a unifying conceptual framework in which SGLT2 inhibition is understood as systemic metabolic stress modulation, integrating hemodynamic, energetic, inflammatory, and fibrotic pathways into a coordinated pathophysiological axis rather than parallel mechanisms [5, 7]. This approach positions metabolic stress as a central driver of CRM disease progression and extends beyond traditional models by linking mechanistic pathways with clinical phenotypes, candidate biomarkers, and therapeutic strategies, thereby providing a more integrated and translational framework for cross-disciplinary implementation of SGLT2i [1–3, 8].

The global burden of CRM disease continues to rise, driven by the close interplay between metabolic dysfunction, HF, and CKD. Approximately half of individuals with T2DM develop CKD during their lifetime, while HF and CKD frequently coexist due to shared hemodynamic, metabolic, and inflammatory mechanisms. These conditions disproportionately affect elderly individuals, populations with obesity or metabolic syndrome, and patients in low- and middle-income countries where diabetes prevalence is rapidly increasing. Improvements in survival among patients with T2DM have paradoxically prolonged exposure to CV and renal complications, amplifying the clinical and economic burden of these interconnected disorders [2, 4]. Despite this growing epidemiological convergence, much of the existing literature evaluates SGLT2i within traditional disease-specific frameworks, with reviews often focusing separately on diabetes, HF, or CKD. Such siloed approaches may overlook the broader biological mechanisms through which SGLT2 inhibition confers systemic cardiorenal protection and rarely integrate mechanistic insights with phenotype-independent therapeutic effects or multidisciplinary clinical implementation across cardiology, nephrology, and endocrinology [5–7]. In this context, the present review synthesizes mechanistic, clinical, and translational evidence to position SGLT2i as multisystem disease-modifying therapies across the CRM continuum, providing a unified framework that links metabolic, CV, and renal pathophysiology while highlighting opportunities for earlier and more coordinated clinical integration.

To support this framework, a structured narrative review was conducted using PubMed/MEDLINE, Embase, and Google Scholar to identify relevant studies published between January 2016 and November 2025. Search terms included combinations of “SGLT2 inhibitors,” “cardiorenal outcomes,” “heart failure,” “chronic kidney disease,” “metabolic syndrome,” and “cardiovascular–renal–metabolic continuum.” Priority was given to randomized controlled trials, meta-analyses, large observational studies, guideline statements, and translational mechanistic investigations. Additional references were identified through manual screening of key trial bibliographies and consensus guidelines. Adult population studies and clinically relevant therapeutic outcomes were prioritized, while preclinical data were included selectively to support mechanistic interpretation. Given the narrative design of this review, no preregistered protocol or formal risk-of-bias assessment was performed, and study selection was guided by relevance to key mechanistic and clinical themes rather than predefined inclusion criteria.

Under physiological conditions, approximately 90% of filtered glucose is reabsorbed in the proximal renal tubule via SGLT2, which couples glucose transport with sodium reabsorption to maintain metabolic homeostasis. In diabetes mellitus, chronic hyperglycemia upregulates SGLT2 expression, increasing tubular glucose and sodium reabsorption and contributing to persistent hyperglycemia and maladaptive renal hemodynamics. SGLT2i were therefore initially introduced as adjunct glucose-lowering therapies for T2DM alongside lifestyle modification and other antihyperglycemic agents. By inhibiting proximal tubular glucose reabsorption, these agents promote glucosuria and natriuresis, leading to modest reductions in glycated hemoglobin (HbA1c) levels. However, clinical trials have demonstrated that their CV and renal benefits extend beyond glycemic control and are observed even in individuals without diabetes [8].

Beyond glucose lowering, SGLT2 inhibition induces osmotic diuresis and natriuresis, resulting in modest reductions in plasma volume, blood pressure (BP), and cardiac preload. These hemodynamic effects contribute to improved ventricular loading conditions and reduced stress. Concurrent urinary caloric loss also promotes modest weight reduction and decreases ectopic fat deposition, including hepatic and myocardial fat, which may further improve cardiometabolic risk profiles, although the precise mechanisms underlying these effects remain incompletely understood [8, 9].

SGLT2i influence both cardiac metabolism and renal hemodynamics. By promoting a shift in myocardial substrate utilization toward ketone bodies, particularly β-hydroxybutyrate, these agents improve myocardial energetic efficiency and may contribute to the rapid clinical benefits observed in HF trials, supporting their use in patients with symptomatic heart failure with reduced ejection fraction (HFrEF) regardless of diabetes status [9]. At the renal level, inhibition of proximal tubular glucose and sodium reabsorption increases distal sodium delivery, restoring tubuloglomerular feedback and promoting afferent arteriolar vasoconstriction, thereby reducing intraglomerular pressure, decreasing albuminuria, and slowing CKD progression [8, 9].

In addition to these hemodynamic effects, SGLT2i exert anti-inflammatory and anti-fibrotic actions. Treatment has been associated with reductions in pro-inflammatory cytokines, chemokines, and circulating uric acid levels. Furthermore, decreased proximal tubular sodium and glucose reabsorption reduces renal oxygen demand, improving tissue oxygenation and mitochondrial metabolic efficiency in renal cells [8, 9].

SGLT2 inhibition also induces a cellular “fasting-like” metabolic state characterized by activation of adaptive pathways that promote autophagy and improve mitochondrial function. These processes enhance cellular energy homeostasis while reducing oxidative stress and inflammatory signaling. Collectively, these mechanisms suggest that the cardiorenal benefits of SGLT2i are largely glucose-independent, instead of reflecting broader metabolic and hemodynamic effects across multiple organ systems [8].

Although SGLT2i were initially developed to improve glycemic control by increasing urinary glucose excretion, accumulating evidence indicates that their metabolic effects extend well beyond glucose lowering. These agents influence multiple cardiometabolic pathways, including adipose tissue distribution, vascular function, uric acid metabolism, and hepatic lipid handling, thereby contributing to broader CRM protection [33].

One of the most consistently observed extra-glycemic effects is modest weight reduction accompanied by improvements in body composition. Meta-analyses of randomized controlled trials demonstrate that SGLT2i therapy is associated with reductions in visceral adipose tissue (VAT), subcutaneous fat, body weight, waist circumference, and body mass index. These changes likely result from chronic urinary caloric loss and may contribute to improved insulin sensitivity and reduction of cardiometabolic risk [34].

SGLT2i also exert favorable hemodynamic and metabolic effects, including modest but consistent reductions in BP independent of glycemic control. These effects are primarily mediated through natriuresis, osmotic diuresis, and improved sodium handling, which collectively reduce vascular stiffness and hemodynamic load on the CV system [35]. In addition, SGLT2 inhibition promotes increased renal urate excretion, leading to reductions in circulating uric acid levels that may further contribute to CV and renal risk reduction [36].

Emerging evidence suggests that SGLT2i may reduce liver fat content and improve liver enzyme levels in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, much of this evidence is derived from relatively small studies using surrogate endpoints such as imaging and biochemical markers. As such, these findings should be considered preliminary, and large-scale trials incorporating histological endpoints and long-term clinical outcomes are needed to establish their role in hepatic disease [37].

Collectively, these extra-glycemic metabolic effects including improvements in adiposity, BP, uric acid metabolism, and hepatic steatosis target key drivers of cardiometabolic disease and provide a mechanistic basis for the consistent systemic benefits observed in large CV and renal outcome trials. The major metabolic effects of SGLT2i beyond glycemic control are summarized in Table 3.

Large CV and renal outcome trials consistently demonstrate that SGLT2i have a generally favorable safety profile, with most adverse effects reflecting predictable pharmacologic mechanisms rather than drug-specific toxicity. The most commonly reported events are genital mycotic infections, which occur more frequently in women and are typically mild and responsive to standard antifungal therapy, rarely requiring treatment discontinuation [22].

Volume depletion–related symptoms, including dizziness or orthostatic hypotension, may occur due to osmotic diuresis and natriuresis. These events are more likely in elderly individuals and patients receiving concomitant diuretics, emphasizing the importance of assessing baseline volume status and adjusting diuretic therapy when initiating treatment [38].

Euglycemic diabetic ketoacidosis (EDKA) represents a rare but important complication of SGLT2i therapy. It is most commonly observed in conditions associated with relative insulin deficiency, such as acute illness, prolonged fasting, or perioperative stress. Because blood glucose levels may remain near normal, clinical recognition requires awareness of this atypical presentation and appropriate patient education regarding temporary drug discontinuation during high-risk situations [39].

From a practical perspective, implementation of “sick-day rules” is essential to minimize the risk of EDKA. Temporary discontinuation of SGLT2i is recommended during acute illness, major surgery, prolonged fasting, or conditions associated with reduced oral intake or relative insulin deficiency. Perioperative management should include withholding the drug at least 3–4 days prior to major procedures and resuming only once the patient is clinically stable and able to maintain adequate oral intake [39, 40].

Early concerns regarding an increased risk of lower limb amputation were primarily observed in the cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) program involving canagliflozin. However, subsequent trials and meta-analyses have not demonstrated a consistent class-wide association. Current evidence suggests that this signal may be drug-specific or related to underlying peripheral vascular disease, although careful monitoring remains advisable in high-risk patients [40].

Initiation of SGLT2i is commonly associated with a modest and transient decline in eGFR, reflecting restoration of tubuloglomerular feedback rather than nephrotoxicity. This initial change is typically followed by long-term preservation of renal function, particularly when therapy is combined with RAAS [25]. Overall, the favorable benefit–risk profile of SGLT2i supports their use across CV and renal disease populations when appropriate patient selection and monitoring strategies are applied.

Common adverse effects, associated risk factors, and recommended monitoring strategies for SGLT2i therapy are summarized in Table 4.

Despite substantial evidence supporting the CV and renal benefits of SGLT2i, several clinically important populations remain underrepresented in randomized trials. Patients with advanced CKD, particularly those with eGFR < 15 mL/min/1.73 m² or requiring dialysis, are frequently excluded, resulting in limited evidence regarding efficacy and safety in this high-risk group [7]. Similarly, frail older adults, who often have multimorbidity, polypharmacy, and increased susceptibility to volume depletion, hypotension, and adverse drug interactions, are insufficiently represented in clinical trials, raising concerns regarding tolerability and real-world applicability. In addition, ethnic minorities and populations in low- and middle-income countries remain underrepresented despite bearing a disproportionate burden of cardiometabolic disease, with disparities in access, cost, and healthcare infrastructure further limiting implementation. Addressing these gaps will require targeted, inclusive clinical trials and real-world studies designed to capture diverse and high-risk patient populations [18].

Another important area of uncertainty involves the long-term durability and safety of SGLT2i therapy. Although major outcome trials demonstrate consistent cardiorenal benefits, follow-up durations are relatively limited. Long-term observational studies and pharmacovigilance data will therefore be essential to clarify the persistence of therapeutic benefit and detect rare adverse events that may emerge with prolonged exposure [44].

An important emerging area of investigation is the role of biomarker-guided precision therapy in optimizing SGLT2i use. Several candidate biomarkers have been proposed to predict treatment response across the CRM spectrum, including natriuretic peptides such as N-terminal pro-brain natriuretic peptide (NT-proBNP) for HF outcomes, urinary albumin-to-creatinine ratio (UACR) and eGFR slope for renal response, and circulating ketone levels reflecting metabolic adaptation [45, 46]. In addition, mechanistic biomarkers related to inflammation and fibrosis, including C-reactive protein (CRP), interleukin-6 (IL-6), galectin-3, and soluble suppression of tumorigenicity 2 protein (ST2), may provide insight into individual variability in therapeutic response. However, most of these biomarkers remain exploratory and are derived largely from post hoc analyses, with limited prospective validation in biomarker-enriched clinical trials. Future research should focus on integrating biomarker profiling with phenotypic stratification to enable more precise, individualized treatment strategies and improve risk–benefit assessment across diverse patient populations [47].

Expanding therapeutic applications of SGLT2i also represents an important research priority. Emerging data suggest potential benefits in additional clinical contexts, including cardio-oncology populations exposed to cardiotoxic therapies and patients with HF characterized by obesity-related metabolic dysfunction. However, robust randomized evidence in these settings remains limited, highlighting the need for targeted trials evaluating the role of SGLT2 inhibition in diverse cardiometabolic phenotypes.

Combination cardiometabolic therapy represents another promising direction. Observational studies and meta-analyses suggest that combining SGLT2i with glucagon-like peptide-1 receptor agonists (GLP-1 RA) may provide complementary metabolic and CV benefits. Nevertheless, these findings remain largely hypothesis-generating due to the absence of large outcome-driven trials specifically designed to evaluate combination strategies [45, 46].

Several key research questions remain unanswered and should guide future investigation. These include identifying which patient subgroups derive the greatest benefit from SGLT2 inhibition, particularly among non-diabetic HF and non-proteinuric CKD populations; determining whether specific biomarkers or phenotypic profiles can reliably predict therapeutic response; defining optimal sequencing and combination strategies with other cardiometabolic agents such as GLP-1 RA; and establishing the long-term safety and durability of treatment effects beyond current trial follow-up periods. Addressing these questions through adequately powered, phenotype-driven, and biomarker-enriched studies will be essential to fully realize the potential of SGLT2i within a precision medicine framework.

SGLT2i have emerged as transformative therapies across the CRM continuum. Beyond their glucose-lowering effects, these agents consistently reduce HF hospitalization, slow CKD progression, and improve CV outcomes across diverse populations, including individuals without diabetes. These benefits are largely mediated through integrated hemodynamic, metabolic, and anti-inflammatory mechanisms that target shared pathophysiological pathways linking heart, kidney, and metabolic disease.

The incorporation of SGLT2i into contemporary cardiology and nephrology guidelines reflects their role as foundational disease-modifying therapies rather than adjunct metabolic agents. Future research should focus on expanding evidence in underrepresented populations, evaluating long-term safety, and developing precision-based strategies to optimize patient selection and therapeutic combinations. Continued advances in these areas will further define the role of SGLT2 inhibition as a cornerstone of integrated cardiometabolic care.