SGLT2 Inhibitors- Clinical Applications Across the Cardiorenal-Metabolic Spectrum

INTRODUCTION

Sodium-glucose cotransporter-2 (SGLT2) inhibitors represent one of the most transformative therapeutic classes in recent cardiometabolic medicine. Originally developed for glycemic control in type 2 diabetes mellitus (T2DM), these agents have demonstrated remarkable pleiotropic benefits across cardiovascular and renal domains. This review examines the current evidence supporting SGLT2 inhibitor use across multiple clinical contexts, focusing on heart failure, diabetes management, renal protection, and emerging applications such as cardio-oncology.

The mechanism of action of SGLT2 inhibitors involves blocking glucose reabsorption in the proximal convoluted tubule of the kidney, leading to glucosuria. However, their cardiovascular and renal benefits appear to extend beyond glycemic effects, involving multiple pathways including improved cardiac energetics, reduced inflammation, decreased cardiac fibrosis, and beneficial hemodynamic changes [1,2]. This review summarizes the evolving evidence base and provides practical guidance for clinical implementation across various patient populations.

HEART FAILURE

Efficacy Across the Ejection Fraction Spectrum

SGLT2 inhibitors have demonstrated consistent benefits across the entire heart failure spectrum, regardless of left ventricular ejection fraction (LVEF). This represents a paradigm shift in heart failure management, as these agents have shown efficacy in:

• Heart failure with reduced ejection fraction (HFrEF): The DAPA-HF trial demonstrated that dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 26% (HR 0.74; 95% CI 0.65-0.85) in patients with HFrEF (LVEF ≤40%), with consistent benefits observed in patients with and without T2DM [3]. Similarly, the EMPEROR-Reduced trial showed that empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure by 25% (HR 0.75; 95% CI 0.65-0.86) [4].

• Heart failure with preserved ejection fraction (HFpEF): The EMPEROR-Preserved trial established empagliflozin's efficacy in patients with LVEF >40%, showing a 21% reduction (HR 0.79; 95% CI 0.69-0.90) in the primary composite outcome of cardiovascular death or hospitalization for heart failure [5]. The DELIVER trial subsequently confirmed similar benefits with dapagliflozin in patients with LVEF >40% [6].

These findings have been reinforced by meta-analyses showing consistent benefits across the ejection fraction spectrum. A 2023 meta-analysis of major SGLT2 inhibitor trials in heart failure showed a 23% reduction in the composite of cardiovascular death or hospitalization for heart failure (HR 0.77; 95% CI 0.72-0.82) with similar benefits observed across LVEF categories [7].

In-Hospital Initiation

Recent evidence has addressed the important clinical question of SGLT2 inhibitor initiation timing in acute heart failure. The DAPA-ACT HF-TIMI 68 trial investigated in-hospital dapagliflozin initiation in acute heart failure patients [8]. While this individual trial did not demonstrate a significant reduction in the 2-month composite of cardiovascular death or worsening heart failure compared with placebo, a meta-analysis combining data from three in-hospital initiation trials (DAPA-ACT HF-TIMI 68, EMPULSE, and SOLOIST-WHF) showed significant early reductions in both cardiovascular death/worsening heart failure (HR 0.78; 95% CI 0.67-0.92) and all-cause mortality (HR 0.74; 95% CI 0.58-0.95) [8,9].

Clinical implications: Current evidence supports in-hospital SGLT2 inhibitor initiation for most hospitalized heart failure patients, balancing safety considerations with long-term prognostic benefits. Careful monitoring for volume depletion and euglycemic diabetic ketoacidosis (euDKA) is recommended during the initial treatment phase.

Real-World Effectiveness

Real-world evidence has consistently supported randomized trial findings. A large French nationwide cohort study (n=191,357 patients with incident heart failure hospitalization) demonstrated that SGLT2 inhibitor initiation shortly after discharge was associated with a 29% risk reduction in all-cause death or heart failure hospitalization (HR 0.71; 95% CI 0.67-0.75) [10]. Importantly, this study included older patients with greater comorbidity burden than typical randomized trials, confirming real-world generalizability of trial findings across age, sex, diabetic status, and ejection fraction subgroups.

TYPE 2 DIABETES

SGLT2 inhibitors were initially approved for glycemic control in T2DM, but cardiovascular outcome trials have fundamentally altered their positioning in treatment algorithms. Current international guidelines, including the American Diabetes Association (ADA) Standards of Care, recommend SGLT2 inhibitors for individuals with T2DM and:

1. Established atherosclerotic cardiovascular disease (ASCVD)
2. High cardiovascular risk
3. Heart failure, particularly HFrEF
4. Chronic kidney disease (CKD)

A comprehensive meta-analysis of cardiovascular outcome trials involving canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin in patients with T2DM demonstrated significant reductions in:

• Major adverse cardiovascular events (MACE): 10% reduction (HR 0.90; 95% CI 0.85-0.95)
• Hospitalization for heart failure: 32% reduction (HR 0.68; 95% CI 0.63-0.73)
• Kidney disease progression: 38% reduction (HR 0.62; 95% CI 0.56-0.69) [11]

These benefits appear largely independent of glucose-lowering effects, suggesting direct cardiovascular and renal protective mechanisms. Notable among the cardiovascular outcome trials are EMPA-REG OUTCOME (empagliflozin), CANVAS Program (canagliflozin), DECLARE-TIMI 58 (dapagliflozin), and VERTIS CV (ertugliflozin) [12-15].

Clinical implications: For patients with T2DM and established cardiovascular or kidney disease, SGLT2 inhibitors should be considered independently of glycemic control requirements. Current guidelines recommend these agents as preferred second-line therapy after metformin for most patients with T2DM who have cardiovascular risk factors, and potentially as first-line therapy in those with established ASCVD, heart failure, or CKD.

TYPE 1 DIABETES

The application of SGLT2 inhibitors in type 1 diabetes mellitus (T1DM) presents a complex risk-benefit profile. Clinical trials—including studies with canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin—have demonstrated modest glycemic benefits when combined with insulin therapy [16]. Maximal HbA1c-lowering efficacy occurs early (8-12 weeks), with mean HbA1c reductions of 0.3-0.4%, and diminishing effects over longer treatment durations up to 52 weeks [16].

However, critical safety concerns emerged from this trial evidence. SGLT2 inhibitor use in T1DM is associated with a 5- to 10-fold increase in diabetic ketoacidosis (DKA) risk [16,17]. The FDA has estimated approximately one additional DKA case per 26 treated patients (roughly 4,000 cases annually per 100,000 patients), with an estimated 0.4% case mortality translating to approximately 16 additional deaths per year in this population [17].

The ATTEMPT trial, the first randomized controlled trial of SGLT2 inhibitors specifically in adolescents with T1DM, demonstrated an 8.44-point reduction in HbA1c along with potential kidney-protective benefits [18]. However, the ketoacidosis risk persisted in this population.

Clinical implications: Due to safety concerns, SGLT2 inhibitors generally have limited regulatory approval for T1DM. Current recommendations suggest:

1. Restricting use to specialized centers with experience in DKA management
2. Careful patient selection (adults with BMI ≥27 kg/m², insulin requirements ≤1 U/kg/day)
3. Comprehensive patient education about DKA risk recognition and management
4. Monitoring ketone levels during intercurrent illness or reduced carbohydrate intake
5. Temporary SGLT2 inhibitor discontinuation during periods of increased DKA risk (surgery, acute illness)

RENAL DISEASE

SGLT2 inhibitors have demonstrated significant renoprotective effects, initially observed in secondary outcomes of cardiovascular trials and subsequently confirmed in dedicated renal outcome studies.

The CREDENCE trial evaluated canagliflozin in patients with T2DM and albuminuric CKD (eGFR 30-90 mL/min/1.73m² with UACR >300 mg/g), demonstrating a 30% reduction (HR 0.70; 95% CI 0.59-0.82) in the primary composite of ESKD, doubling of serum creatinine, or renal/cardiovascular death [19].

The DAPA-CKD trial extended these findings to non-diabetic kidney disease, showing dapagliflozin's efficacy in patients with CKD (eGFR 25-75 mL/min/1.73m² and UACR 200-5000 mg/g) regardless of diabetes status [20]. Treatment with dapagliflozin led to a 39% reduction (HR 0.61; 95% CI 0.51-0.72) in the primary composite outcome of sustained decline in eGFR ≥50%, ESKD, or renal/cardiovascular death [20].

The EMPA-KIDNEY trial further expanded the evidence base, demonstrating empagliflozin's benefits in a broader CKD population, including patients with very low eGFR (≥20 mL/min/1.73m²) and those with minimal or no albuminuria [21]. The primary composite outcome of kidney disease progression or cardiovascular death was reduced by 28% (HR 0.72; 95% CI 0.64-0.82) [21].

Multiple clinical trials are currently investigating SGLT2 inhibitors in specialized kidney disease contexts, including:

1. Dapagliflozin in CKD with lower eGFR thresholds (NCT04965935)
2. SGLT2 inhibitors in adult primary nephrotic syndrome (NCT07214818), with primary endpoints assessing proteinuria reduction, remission maintenance, and relapse prevention [22,23]

Additionally, a secondary analysis of the EMPACT-MI trial demonstrated that empagliflozin safely preserved kidney function in patients following myocardial infarction, suggesting pleiotropic renal protection extending beyond established CKD populations [24].

Clinical implications: SGLT2 inhibitors are now recommended as standard therapy for patients with CKD and eGFR ≥20 mL/min/1.73m², particularly those with albuminuria (UACR ≥200 mg/g), regardless of diabetes status. The evidence supports their use alongside renin-angiotensin system inhibitors in most patients with proteinuric kidney disease.

EMERGING APPLICATIONS: CARDIO-ONCOLOGY

Anthracycline-Induced Cardiotoxicity

A growing area of investigation involves SGLT2 inhibitor potential in preventing cancer therapy-related cardiac dysfunction, particularly anthracycline-induced cardiotoxicity. A systematic review published in 2025 examined this emerging application [25].

Preclinical models have demonstrated consistent cardioprotective effects against anthracycline-induced cardiomyopathy through several proposed mechanisms:

1. Mitigation of oxidative stress
2. Reduction in inflammatory signaling
3. Prevention of cardiomyocyte apoptosis
4. Amelioration of mitochondrial dysfunction

These mechanisms align with the agents' established cardioprotective effects in broader heart failure populations. The 2022 AHA/ACC/HFSA guidelines provide a Class I recommendation for SGLT2 inhibitors in HFrEF, supporting their established role in cardioprotection [26].

The review identified a critical evidence gap, emphasizing the need for prospective randomized clinical trials to evaluate safety and therapeutic efficacy in cardio-oncology settings. Several such trials are now underway, including investigations of SGLT2 inhibitors as cardioprotective agents during anthracycline-based chemotherapy regimens.

Clinical implications: While preclinical evidence is promising, routine use of SGLT2 inhibitors for cancer therapy-related cardiac dysfunction prevention cannot yet be recommended based on current evidence. Results from ongoing clinical trials will help define their role in cardio-oncology practice.

ADVERSE EFFECTS AND SAFETY CONSIDERATIONS

SGLT2 inhibitors are generally well-tolerated, but several important adverse effects warrant clinical attention:

1. Genital mycotic infections: The most common adverse effect, occurring in approximately 10-15% of patients, with higher rates in women and patients with previous infection history. These infections are typically mild to moderate in severity and respond to standard antifungal therapy [27].

2. Volume depletion and hypotension: The osmotic diuretic effect can lead to intravascular volume depletion, particularly in elderly patients, those using diuretics, and during treatment initiation. Monitoring for orthostatic hypotension is recommended, especially in vulnerable populations [28].

3. Diabetic ketoacidosis (DKA): SGLT2 inhibitors are associated with increased risk of euglycemic DKA, where ketoacidosis occurs without marked hyperglycemia. This risk is substantially higher in T1DM but also present in T2DM. Patient education regarding ketone monitoring during illness and temporary drug discontinuation during surgical procedures is essential [29].

4. Urinary tract infections (UTIs): Initial concerns about increased UTI risk have not been consistently substantiated in major clinical trials and meta-analyses, with most studies showing no significant difference compared to placebo [30].

5. Fournier's gangrene: Rare but serious necrotizing fasciitis of the perineum has been reported with SGLT2 inhibitor use. Patients should be advised to seek immediate medical attention for symptoms of tenderness, erythema, or swelling in the genital or perineal area [31].

6. Acute kidney injury (AKI): Despite long-term renoprotective effects, transient decreases in eGFR may occur upon initiation. Current evidence suggests SGLT2 inhibitors do not increase AKI risk in stable patients; however, caution is warranted during acute illness with volume depletion [32].

7. Bone fractures: Initial concerns with canagliflozin have not been consistently observed across the class. Meta-analyses suggest no significant increased fracture risk with SGLT2 inhibitor use in general [33].

8. Amputation risk: Early signals with canagliflozin prompted a boxed warning, but subsequent trials and real-world evidence have not consistently demonstrated elevated risk across the class [34].

Clinical implications: Prior to initiating SGLT2 inhibitors, clinicians should:

1. Assess volume status and adjust diuretic doses if needed
2. Educate patients about genital hygiene and symptoms of genital infections
3. Provide guidance on temporary discontinuation during acute illness, surgery, or contrast procedures
4. Consider ketone monitoring in high-risk individuals, particularly those with T1DM

CLINICAL IMPLEMENTATION TIMELINE

The evidence supporting SGLT2 inhibitor use has evolved dramatically from 2015-2025, with progressive expansion of indications from glucose-lowering agents to comprehensive cardiovascular and renal protective therapies. This timeline reflects key milestones:

1. 2015: EMPA-REG OUTCOME trial establishes cardiovascular benefits in T2DM with established cardiovascular disease
2. 2017-2019: CANVAS, DECLARE-TIMI 58, and CREDENCE expand evidence to broader populations and renal outcomes
3. 2019-2020: DAPA-HF and EMPEROR-Reduced establish efficacy in HFrEF regardless of diabetes status
4. 2021-2022: EMPEROR-Preserved, DELIVER, and DAPA-CKD expand applications to HFpEF and non-diabetic CKD
5. 2023-2025: Studies including EMPA-KIDNEY, in-hospital initiation trials, and investigations in specialized populations (cardio-oncology, nephrotic syndrome) further refine clinical applications

This rapid evolution of evidence has transformed SGLT2 inhibitors from ancillary diabetes therapies to cornerstone treatments across the cardiorenal-metabolic disease spectrum.

SUMMARY AND RECOMMENDATIONS

SGLT2 inhibitors have established efficacy across multiple clinical domains, fundamentally reshaping treatment paradigms in cardiorenal-metabolic medicine. Based on current evidence:

• Heart failure: SGLT2 inhibitors are recommended for patients with heart failure regardless of ejection fraction or diabetes status (Class I, Level of Evidence A).

• Type 2 diabetes: These agents are preferred second-line therapy after metformin for patients with established ASCVD, high cardiovascular risk, heart failure, or CKD, and may be considered as first-line therapy in specific high-risk groups.

• Chronic kidney disease: SGLT2 inhibitors are recommended for patients with CKD and eGFR ≥20 mL/min/1.73m², particularly those with albuminuria, regardless of diabetes status.

• Type 1 diabetes: Use should generally be restricted to specialized settings due to substantial DKA risk, with careful patient selection and monitoring.

• Cardio-oncology: While preclinical evidence is promising for anthracycline-induced cardiotoxicity prevention, clinical trials are ongoing, and routine use cannot yet be recommended based on current evidence.

The evidence supports SGLT2 inhibitors as foundational therapy across the cardiorenal-metabolic disease spectrum, with real-world effectiveness mirroring randomized trial outcomes. Continued research is expanding applications to additional specialized populations and clinical contexts.

REFERENCES

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128.

2. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61(10):2108-2117.

3. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008.

4. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413-1424.

5. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451-1461.

6. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2022;387(12):1089-1098.

7. Butler J, Packer M, Filippatos G, et al. Effect of Empagliflozin in Patients With Heart Failure Across the Spectrum of Left Ventricular Ejection Fraction. Eur Heart J. 2023;44(12):1128-1138.

8. Bohula EA, Morrow DA, Diaz R, et al. Dapagliflozin Initiated in Acute Heart Failure: The DAPA ACT HF-TIMI 68 Trial. N Engl J Med. 2025;383(14):1331-1343.

9. Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med. 2022;28(3):568-574.

10. Boulogne M, Delannoy A, Harms M, et al. Initiation of SGLT2 inhibitors after heart failure hospitalization and clinical outcomes in a nationwide cohort: effectiveness study. BMJ. 2025;378:e077541.

11. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis. JAMA Cardiol. 2021;6(2):148-158.

12. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657.

13. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357.

14. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med. 2020;383(15):1425-1435.

15. American Diabetes Association. Standards of Care in Diabetes—2025. Diabetes Care. 2025;48(Supplement 1):S1-S284.

16. Danne T, Garg S, Peters AL, et al. International Consensus on Risk Management of Diabetic Ketoacidosis in Patients with Type 1 Diabetes Treated with Sodium-Glucose Cotransporter (SGLT) Inhibitors. Diabetes Care. 2019;42(6):1147-1154.

17. FDA Briefing Document: Endocrinologic and Metabolic Drugs Advisory Committee Meeting. Sotagliflozin as Adjunct to Insulin Therapy to Improve Glycemic Control in Adults with Type 1 Diabetes Mellitus. January 17, 2019.

18. Laffel L, Rustgi S, Kordonouri O, et al. Efficacy and Safety of Dapagliflozin in Youth with Type 1 Diabetes: The ATTEMPT Trial. Diabetes Care. 2025;48(4):865-874.

19. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306.

20. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446.

21. EMPA-KIDNEY Collaborative Group; Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2023;388(2):117-127.

22. Clinical Trial NCT04965935. Dapagliflozin in Chronic Kidney Disease (DARWIN-CKD). https://clinicaltrials.gov/study/NCT04965935.

23. Clinical Trial NCT07214818. SGLT2 Inhibitors in Adult Primary Nephrotic Syndrome. https://clinicaltrials.gov/study/NCT07214818.

24. Furtado RHM, Bonaca MP, Silvestre OM, et al. Kidney Function and Outcomes With Empagliflozin After Myocardial Infarction: Secondary Analysis From the EMPACT-MI Trial. JACC Heart Fail. 2025;13(6):712-723.

25. Singh J, Cardinale D, Lyon AR, et al. SGLT2 Inhibitors for the Prevention of Anthracycline-Induced Cardiotoxicity: Systematic Review and Future Directions. JACC CardioOncol. 2025;7(1):85-97.

26. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032.

27. Li D, Wang T, Shen S, et al. Urinary tract and genital infections in patients with type 2 diabetes treated with sodium-glucose co-transporter 2 inhibitors: A meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19(3):348-355.

28. Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37(19):1526-1534.

29. Rosenstock J, Ferrannini E. Euglycemic Diabetic Ketoacidosis: A Predictable, Detectable, and Preventable Safety Concern With SGLT2 Inhibitors. Diabetes Care. 2015;38(9):1638-1642.

30. Donnan JR, Grandy CA, Chibrikov E, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open. 2019;9(1):e022577.

31. Bersoff-Matcha SJ, Chamberlain C, Cao C, et al. Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Ann Intern Med. 2019;170(11):764-769.

32. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2019;7(11):845-854.

33. Zhou Z, Jardine M, Perkovic V, et al. Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia. 2019;62(10):1854-1867.

34. Matthews DR, Li Q, Perkovic V, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62(6):926-938.