What is the role of SGLT2 (sodium-glucose cotransporter 2) inhibitors in managing patients with heart failure and chronic kidney disease (CKD) stage III?

SGLT2 Inhibitors for Heart Failure and CKD Stage III

SGLT2 inhibitors are strongly recommended as first-line therapy for patients with heart failure and CKD stage III (eGFR 30-59 mL/min/1.73 m²), regardless of diabetes status, as they reduce cardiovascular death, heart failure hospitalizations, and kidney disease progression. 1

Initiation Criteria

Start SGLT2 inhibitors in all patients with CKD stage III and heart failure who have eGFR ≥20 mL/min/1.73 m². 1, 2

• The strongest evidence supports use in patients with:

  • eGFR 20-59 mL/min/1.73 m² AND urine albumin-to-creatinine ratio (ACR) ≥200 mg/g (≥20 mg/mmol) - Class 1A recommendation 1
  • Concomitant heart failure (any ejection fraction) - Class 1 recommendation for HFrEF, Class 2a for HFpEF 1, 2, 3

• For patients with eGFR 30-44 mL/min/1.73 m² and ACR <200 mg/g, SGLT2 inhibitors are still recommended (Class 2B) based on consistent eGFR slope benefits across all trials 1

Specific Benefits in CKD Stage III

Cardiovascular Protection

• Reduces heart failure hospitalizations by 32-36% in CKD patients (HR 0.68,95% CI 0.63-0.73) 4
• The benefit is more pronounced in patients with eGFR <60 mL/min/1.73 m² (HR 0.68) compared to eGFR ≥60 (HR 0.76) 4
• Decreases cardiovascular death by 10 fewer deaths per 1000 patients in very high-risk CKD 3
• Reduces composite cardiovascular death or heart failure hospitalization by 21-35% 1

Kidney Protection

• Reduces composite kidney outcome (≥50% eGFR decline, ESKD, or renal death) by 44% (HR 0.56) 2
• Prevents kidney failure by 58 fewer events per 1000 patients in very high-risk CKD 3
• Slows eGFR decline rate significantly compared to standard care 5

Agent Selection and Dosing in CKD Stage III

Preferred Agents with Proven Kidney and CV Benefits

Dapagliflozin:

• Dose: 10 mg once daily - no adjustment needed for eGFR 30-59 1
• Can initiate down to eGFR 25 mL/min/1.73 m²; continue if eGFR falls below 25 1

Empagliflozin:

• Dose: 10 mg once daily for eGFR 30-44 1
• FDA labeling states "use not recommended" for eGFR <45, but KDIGO/ADA consensus supports continuation for kidney/CV benefit 1

Canagliflozin:

• Dose: Maximum 100 mg daily for eGFR 30-44 1
• May continue 100 mg daily if tolerated for kidney and CV benefit until dialysis 1

Continuation Strategy

Once initiated, continue SGLT2 inhibitors even if eGFR falls below 20 mL/min/1.73 m², unless kidney replacement therapy is initiated. 1, 2, 3

• The CREDENCE and DAPA-CKD trial protocols specifically continued study drug when eGFR fell below initiation thresholds 1
• Cardiovascular and renal benefits persist at low eGFR independent of glucose-lowering effects 2

Managing the Initial eGFR Dip

Expect a reversible eGFR decline of 3-5 mL/min/1.73 m² within the first 4 weeks - this is hemodynamic and does NOT require discontinuation. 1

• Following this initial dip, GFR typically stabilizes during ongoing therapy 1
• This acute decline reflects reduced intraglomerular pressure (a beneficial mechanism) rather than kidney injury 2, 6
• Do not stop the medication based on this expected initial decline 1

Safety Considerations and Risk Mitigation

Volume Status

• Reduce diuretic dose in patients at risk for hypovolemia before initiating SGLT2 inhibitors 1
• Monitor volume status at follow-up, but routine diuretic adjustment is generally not required 1

Genital Mycotic Infections

• Occurs in 6% vs 1% with placebo - higher risk in women 1, 2
• Counsel patients on daily genital hygiene to keep area clean and dry 1
• Most infections are easily treated; severe Fournier gangrene is rare 1

Euglycemic Ketoacidosis

• Hold SGLT2 inhibitors during acute illness (nausea, vomiting, diarrhea) - implement "sick day protocol" 1
• Maintain at least low-dose insulin in insulin-requiring patients 1
• Educate patients on "STOP DKA" protocol: Stop SGLT2 inhibitor, Test for ketones, maintain fluid and carbohydrate intake 1

Hypoglycemia

• Reduce insulin or sulfonylurea doses if used concomitantly to avoid hypoglycemia 1, 2
• SGLT2 inhibitors alone reduce severe hypoglycemia risk (RR 0.85) 1

Combination with Other Cardioprotective Agents

SGLT2 inhibitors should be used concomitantly with:

• RAS inhibitors (ACE inhibitors or ARBs) - all major kidney trials tested SGLT2 inhibitors on top of background RAS blockade 1
• Nonsteroidal mineralocorticoid receptor antagonists (finerenone) - cardiovascular effects of finerenone are at least as beneficial when combined with SGLT2 inhibitors 2
• Beta-blockers and other guideline-directed HF therapies - SGLT2 inhibitors facilitate persistent use of these agents by reducing hyperkalemia risk 1

Common Pitfalls to Avoid

1. Do not discontinue SGLT2 inhibitors based on the initial eGFR dip - this is expected and beneficial 1
2. Do not wait for "optimal" glycemic control - benefits are independent of HbA1c and glucose-lowering effects 2
3. Do not restrict use to diabetic patients - benefits extend to non-diabetic CKD and heart failure 1, 3
4. Do not stop when eGFR falls below initiation threshold - continue until dialysis is started 1, 3
5. Do not use ertugliflozin - it lacks proven kidney and cardiovascular outcome data; prioritize agents with established benefits 1

Contraindications

Absolute contraindications:

• eGFR <20 mL/min/1.73 m² for initiation (but continue if already on therapy) 1, 2
• Active dialysis or ESKD 2
• History of serious hypersensitivity reaction 2