SGLT2 Inhibitors: Treatment Recommendations
SGLT2 inhibitors (empagliflozin, canagliflozin, or dapagliflozin) are recommended as first-line therapy for patients with type 2 diabetes and established cardiovascular disease or heart failure, and for all patients with heart failure with reduced ejection fraction (HFrEF) regardless of diabetes status, to reduce cardiovascular death and heart failure hospitalizations. 1
Indications and Patient Selection
Type 2 Diabetes with Cardiovascular Disease or High CV Risk
- Empagliflozin, canagliflozin, or dapagliflozin are recommended to reduce major adverse cardiovascular events in patients with type 2 diabetes and established CVD or very high/high cardiovascular risk 1
- Empagliflozin specifically reduces risk of cardiovascular death in this population 1
- These agents reduce heart failure hospitalizations by 27-39% across multiple trials 1
Heart Failure with Reduced Ejection Fraction (HFrEF)
- SGLT2 inhibitors are recommended for all patients with HFrEF (ejection fraction ≤40%), regardless of diabetes status 1
- Dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 26% (HR 0.74,95% CI 0.65-0.85) in the DAPA-HF trial 1
- Benefits were consistent in patients with and without type 2 diabetes 1
- The American Diabetes Association recommends SGLT2 inhibitors as first-line agents for hyperglycemia treatment in patients with diabetes who have heart failure or are at high risk 1
Diabetic Kidney Disease
- SGLT2 inhibitors are recommended to reduce progression of diabetic kidney disease 1
- Canagliflozin showed 39% reduction in heart failure hospitalization in patients with diabetic nephropathy and albuminuria (UACR 300-5,000 mg/g) 1
Dosing Regimens
Standard Doses
- Empagliflozin: 10 mg orally once daily (can increase to 25 mg if needed for glycemic control) 1
- Canagliflozin: 100 mg orally once daily (may increase to 300 mg daily if eGFR ≥60 mL/min/1.73 m²) 1
- Dapagliflozin: 10 mg orally once daily 1, 2
Renal Dose Adjustments
- Empagliflozin: Do not initiate if eGFR <45 mL/min/1.73 m²; discontinue if eGFR persistently <45 mL/min/1.73 m² (for glycemic control indication only) 1
- Canagliflozin: Maximum 100 mg daily if eGFR 30-59 mL/min/1.73 m²; not recommended if eGFR <30 mL/min/1.73 m² 1
- Dapagliflozin: Not recommended for glycemic control if eGFR <45 mL/min/1.73 m²; contraindicated if eGFR <30 mL/min/1.73 m² 1
Important caveat: These eGFR restrictions apply primarily to glycemic efficacy; cardiovascular benefits appear to extend down to eGFR of 30 mL/min/1.73 m² 1
Contraindications
Absolute Contraindications
- History of serious hypersensitivity reaction to the drug 1
- Severe renal impairment, end-stage renal disease, or dialysis (specific thresholds vary by agent) 1
- Pregnancy or breastfeeding (dapagliflozin) 1
Critical Safety Considerations
Volume Depletion
- May cause intravascular volume contraction, particularly in patients with renal impairment, low systolic blood pressure, elderly patients, or those on diuretics 1
- Consider stopping or reducing diuretic dose when initiating therapy 1
Hypoglycemia Risk
- Reduce insulin dose by approximately 20% when starting SGLT2 inhibitor therapy if HbA1c is well-controlled at baseline or history of frequent hypoglycemic events 1
- Wean or stop sulfonylurea or glinide to prevent hypoglycemia 1
Euglycemic Diabetic Ketoacidosis
- Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 1
- Monitor closely for ketoacidosis, which can occur even with normal glucose levels 1
Amputation Risk (Canagliflozin-Specific)
- Use with extreme caution in patients with prior amputation, severe peripheral neuropathy, severe peripheral vascular disease, or active diabetic foot ulcers 1
- FDA black box warning for canagliflozin regarding lower-limb amputations 1
- No increased amputation risk observed with empagliflozin or dapagliflozin to date 1
Bone Fracture Risk (Canagliflozin-Specific)
- Increased incidence of bone fractures reported with canagliflozin 1
- Use caution in patients with history of osteoporosis 1
Genitourinary Infections
- Increased risk of genital mycotic infections and urinary tract infections 1
- Patients should be monitored for severe genitourinary infections 1
Medication Interactions
Minimal Drug Interactions
- Dapagliflozin does not meaningfully affect pharmacokinetics of metformin, pioglitazone, sitagliptin, glimepiride, hydrochlorothiazide, bumetanide, valsartan, simvastatin, digoxin, or warfarin 2
- Rifampin decreases dapagliflozin AUC by 22%, but this is not considered clinically significant 2
- Mefenamic acid increases dapagliflozin AUC by 51%, but no dose adjustment recommended 2
Clinical Outcomes Evidence
Cardiovascular Death Reduction
- Empagliflozin reduced cardiovascular death by 38% (HR 0.62,95% CI 0.49-0.77) in EMPA-REG OUTCOME 1
- Empagliflozin reduced all-cause mortality by 32% (HR 0.68,95% CI 0.57-0.82) 1
Heart Failure Hospitalization Reduction
- Empagliflozin: 35% reduction (HR 0.65,95% CI 0.50-0.85) 1
- Canagliflozin: 33-39% reduction depending on population 1
- Dapagliflozin: 27% reduction in DECLARE-TIMI 58; 30% reduction in DAPA-HF 1
Renal Protection
- SGLT2 inhibitors reduce composite renal endpoints including sustained doubling of serum creatinine, 40-50% decline in eGFR, end-stage kidney disease, or renal death 1
Common Pitfalls to Avoid
Do not withhold SGLT2 inhibitors in heart failure patients without diabetes - benefits extend to non-diabetic HFrEF patients 1
Do not discontinue based solely on eGFR thresholds for heart failure indication - cardiovascular benefits persist down to eGFR 30 mL/min/1.73 m² even though glycemic efficacy diminishes 1
Do not forget to adjust concomitant glucose-lowering medications - failure to reduce insulin or sulfonylurea doses leads to hypoglycemia 1
Do not ignore volume status - assess for volume depletion risk before initiating, especially in elderly or those on loop diuretics 1
Do not continue through surgical procedures - stop 3 days before surgery to prevent ketoacidosis 1