SGLT2 Inhibitors: Comprehensive Clinical Guide
Indications
SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) are strongly recommended for adults with chronic kidney disease at high or very high risk of progression, heart failure with reduced or preserved ejection fraction, and type 2 diabetes with cardiovascular disease or multiple risk factors. 1
Chronic Kidney Disease (Primary Indication)
- Strong recommendation for adults at high risk (eGFR 30-44 mL/min/1.73 m² with albuminuria ≥200 mg/g) or very high risk (eGFR <30 mL/min/1.73 m² with albuminuria ≥200 mg/g) of CKD progression, regardless of diabetes status 1
- Weak recommendation for moderate risk (eGFR 45-59 mL/min/1.73 m² with albuminuria 30-200 mg/g) and low risk patients 1
- Benefits in very high-risk patients include 48 fewer deaths per 1000 and 58 fewer kidney failure events per 1000 over 5 years (high certainty evidence) 1
- Applicable to all adults with CKD, with or without type 2 diabetes 1
Heart Failure
- Mandatory for all adults with heart failure (either reduced or preserved ejection fraction), regardless of diabetes status or current HbA1c 2, 3, 4
- Reduces cardiovascular death or heart failure hospitalization by 26-29% 2
- Benefits observed on top of optimal background heart failure therapy with no treatment interactions 4, 5
Type 2 Diabetes Mellitus
- Add to metformin when HbA1c ≥7% to reduce all-cause mortality, major adverse cardiovascular events, CKD progression, and heart failure hospitalizations 2
- Priority indication for patients with established cardiovascular disease, heart failure, or CKD (eGFR 20-60 mL/min/1.73 m² and/or albuminuria ≥200 mg/g) 2, 6
- Consider for patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and overweight/obesity 2
Contraindications to Specific Populations
- Not recommended for polycystic kidney disease or patients requiring immunosuppressive therapy for kidney disease 6, 7
- Not recommended for kidney transplant recipients due to limited data and potential increased infection risk 6
Recommended Dosing
For Glycemic Control (Type 2 Diabetes)
- Starting dose: 5 mg orally once daily 7
- Maximum dose: 10 mg orally once daily for additional glycemic control 7
- Do not initiate if eGFR <45 mL/min/1.73 m² as glucose-lowering efficacy is significantly reduced 8, 2, 7
For Cardiovascular and Renal Protection
- Recommended dose: 10 mg orally once daily for all indications except glycemic control 7
- Can be initiated if eGFR ≥20 mL/min/1.73 m² (some guidelines support ≥25 mL/min/1.73 m²) 8, 2, 6
- Continue therapy even if eGFR falls below 20 mL/min/1.73 m² during treatment, unless not tolerated or kidney replacement therapy is initiated 6
Critical GFR Thresholds
- For glucose lowering: Discontinue at eGFR <45 mL/min/1.73 m² 8, 2
- For cardiovascular/renal protection: Continue down to eGFR 20 mL/min/1.73 m² if patient has compelling cardiovascular or renal indications 8, 6
Contraindications
Absolute Contraindications
- History of serious hypersensitivity reaction to dapagliflozin or any excipients 7
Temporary Withholding Required
- At least 3 days before major surgery or procedures with prolonged fasting to prevent euglycemic diabetic ketoacidosis 2, 7
- During acute illness with reduced oral intake, fever, vomiting, or diarrhea 2
- During times of prolonged fasting or critical medical illness when patients may be at greater risk for ketosis 6
Monitoring Requirements
Before Initiation
- Assess renal function (eGFR and urine albumin-to-creatinine ratio) 6, 7
- Assess volume status and correct volume depletion, especially in elderly patients (≥75 years), those on diuretics, or with low systolic blood pressure 2, 7
During Treatment
- Monitor eGFR every 3-6 months if <60 mL/min/1.73 m², and annually if ≥60 mL/min/1.73 m² 6
- Expect initial eGFR decline of 3-5 mL/min/1.73 m² (reversible and not a reason to discontinue) 6
- Monitor for genital mycotic infections (6% incidence vs 1% placebo) and urinary tract infections 2, 9
- Consider ketone monitoring in patients with type 1 diabetes and others at risk for ketoacidosis 7
- Assess for ketoacidosis regardless of presenting blood glucose levels if suspected 7
Safety Monitoring
- Monitor for volume depletion symptoms 2, 6
- No increased risk of hypoglycemia in patients without diabetes 4, 10
- No increased risk of acute kidney injury 10
- Generally well tolerated with safety profile similar to placebo 9, 10
Alternative Therapies
For CKD Progression and Cardiovascular Protection
- Renin-angiotensin system inhibitors (ACEi or ARB): Can be used alongside SGLT2 inhibitors for enhanced kidney protection 6
- Nonsteroidal mineralocorticoid receptor antagonists (MRA): Consider adding for patients with persistent albuminuria despite SGLT2 inhibitor and RASi therapy 6
- GLP-1 receptor agonists: Alternative for CKD with eGFR 20-60 mL/min/1.73 m² and/or albuminuria 2
For Type 2 Diabetes Glycemic Control
- Metformin: First-line therapy 2
- GLP-1 receptor agonists: Alternative or addition to SGLT2 inhibitors, particularly for weight loss and cardiovascular protection 2
Common Pitfalls and Caveats
Do Not Discontinue for Initial eGFR Decline
- An initial, reversible decrease in eGFR (3-5 mL/min/1.73 m²) is expected and represents hemodynamic adaptation, not kidney injury 6
- Continue therapy unless not tolerated or kidney replacement therapy is initiated 6
Distinguish Between Glycemic and Cardio-Renal Indications
- Patients with eGFR 30-44 mL/min/1.73 m² should continue SGLT2 inhibitors for cardiovascular and renal protection even though glucose-lowering efficacy is reduced 8, 2
- Do not discontinue solely based on reduced glycemic efficacy if cardiovascular or renal indications are present 8
Avoid Therapeutic Inertia
- Most patients with heart failure should be treated with SGLT2 inhibitors regardless of LVEF, eGFR, or diabetic status 5
- Implementation in routine practice remains the most significant challenge despite strong evidence 5