What is the role of Sodium-Glucose Cotransporter 2 inhibitors (SGLT2-i) in patients with heart failure, Chronic Kidney Disease (CKD), and diabetes, including those on insulin therapy?

SGLT2 Inhibitors in Heart Failure, CKD, and Diabetes: Use Even on Insulin

SGLT2 inhibitors should be initiated and continued in all patients with type 2 diabetes, heart failure, and/or CKD (eGFR ≥20 mL/min/1.73 m²), regardless of whether they are on insulin therapy, as these agents provide cardiovascular and renal protection independent of glucose-lowering effects. 1

Primary Indication: First-Line Therapy Regardless of Glycemic Control

• SGLT2 inhibitors are recommended as first-line therapy to prevent CKD progression and cardiovascular events in patients with type 2 diabetes and CKD, independent of baseline HbA1c or current glycemic control. 1
• These agents reduce cardiovascular death, heart failure hospitalizations, and progression of kidney disease through mechanisms beyond glucose lowering, including reduction in intraglomerular pressure and improved tubuloglomerular feedback. 1
• The KDIGO 2022 guidelines position SGLT2 inhibitors as first-line drug therapy based on 11 published clinical trials demonstrating strong evidence of efficacy. 1

Specific eGFR Thresholds for Initiation and Continuation

• Initiate SGLT2 inhibitors in patients with eGFR ≥20 mL/min/1.73 m², with strongest evidence for those with concomitant albuminuria or heart failure. 1
• Eligible patients include those with eGFR ≥20 mL/min/1.73 m², with high priority for patients with ACR ≥200 mg/g (≥20 mg/mmol). 1
• Once initiated, continue SGLT2 inhibitors even if eGFR falls below 20 mL/min/1.73 m², unless kidney replacement therapy is initiated. 1, 2
• The EMPA-KIDNEY trial demonstrated efficacy at eGFR as low as 20 mL/min/1.73 m², and EMPEROR trials showed benefit in heart failure patients at these low eGFR levels. 1, 2

Specific Agents and Dosing

• Preferred SGLT2 inhibitors with proven cardiovascular and renal benefits:
  • Canagliflozin 100 mg once daily 1, 3
  • Dapagliflozin 10 mg once daily 1, 3
  • Empagliflozin 10 mg once daily 1, 3
• The lowest doses provide full cardioprotective benefit; higher doses are not necessary for cardiovascular or renal protection. 3

Managing Insulin Therapy When Initiating SGLT2 Inhibitors

Hypoglycemia Risk Assessment and Mitigation

• Reduce insulin dose by approximately 20% when initiating SGLT2 inhibitors to prevent hypoglycemia. 3
• Patients on insulin or sulfonylureas, those with history of severe hypoglycemia, or those with HbA1c at or below goal are at highest risk for hypoglycemia. 1
• Maintain at least low-dose insulin in insulin-requiring individuals to mitigate risk of euglycemic diabetic ketoacidosis. 1
• Follow-up assessment should include asking about hypoglycemia and reviewing glycemia monitoring. 1

Critical Safety Consideration: Euglycemic Ketoacidosis

• Patients with type 2 diabetes requiring insulin are at particular risk for euglycemic ketoacidosis with minimal to no elevation in blood glucose. 1
• Institute a sick day protocol: pause SGLT2 inhibitor treatment during periods of acute illness, surgery, or metabolic stress. 1, 3
• Blood or urine ketone monitoring may be used for ketosis detection. 1
• Patients with signs, symptoms, or biochemical evidence of ketoacidosis should discontinue SGLT2 inhibitor therapy and seek immediate medical attention. 1

Heart Failure Benefits Independent of Diabetes Status

• For heart failure with reduced ejection fraction (LVEF ≤40%), SGLT2 inhibitors reduce cardiovascular death and heart failure hospitalization (Class 1 recommendation). 2
• For heart failure with preserved ejection fraction (LVEF >40%), SGLT2 inhibitors decrease heart failure hospitalizations (Class 2a recommendation). 2
• The EMPEROR-Reduced and EMPEROR-Preserved trials demonstrated efficacy at eGFR levels as low as 20 mL/min/1.73 m². 2
• In very high-risk CKD patients with heart failure, SGLT2 inhibitors decrease all-cause mortality by 48 fewer deaths per 1000 patients. 2

Renal Protection: Specific Benefits

• SGLT2 inhibitors reduce the composite kidney outcome (≥50% eGFR decline, ESKD, or renal death) by 44% (HR 0.56). 1
• The DAPA-CKD trial showed a 39% risk reduction for the primary endpoint and 32% risk reduction for development of ESKD. 1
• SGLT2 inhibitors reduce kidney failure by 58 fewer events per 1000 patients in very high-risk CKD. 2
• These agents slow CKD progression independent of glycemic control through reduction in intraglomerular pressure. 2

Managing the Initial eGFR Dip

• SGLT2 inhibitor initiation is associated with a reversible decline in eGFR, but this generally does not require drug discontinuation. 1
• Anticipate an acute drop in eGFR, which is generally not a reason to stop the SGLT2 inhibitor. 1
• SGLT2 inhibitor use appears to protect patients from acute kidney injury despite the initial eGFR decline. 1
• Trial protocols (CREDENCE, DAPA-CKD) specified continuation of study drug when eGFR fell below initiation thresholds. 1

Volume Status Management

• Assess volume status before initiating SGLT2 inhibitors and consider reducing loop diuretic dose by 50% in patients on high-dose diuretics to prevent symptomatic hypotension. 3
• Patients with concurrent diuretic use, tenuous volume status, or history of AKI are at higher risk for volume depletion. 1
• Re-assess volume status and volume depletion symptoms at follow-up. 1
• Adjustment of background diuretic therapy is generally not required when initiating an SGLT2 inhibitor, but may be prudent in some patients. 1

Additional Safety Considerations

• Counsel patients about increased risk of genital yeast infections (6% vs 1% placebo) and importance of proper genital hygiene. 1, 3
• Daily hygienic measures may lessen infection risk, and most genital mycotic infections are easily treated. 1
• Severe cases of Fournier gangrene have been reported, though rare. 1
• Contraindications include severe renal impairment (eGFR <20 mL/min/1.73 m²), ESKD, dialysis, and history of serious hypersensitivity reaction. 3

Combination with Other Cardioprotective Agents

• SGLT2 inhibitors can be used concomitantly with RAS inhibitors and nonsteroidal mineralocorticoid receptor antagonists (ns-MRA) like finerenone. 1
• The cardiovascular effects of finerenone appeared at least as beneficial among people using versus not using an SGLT2 inhibitor. 1
• SGLT2 inhibitors may reduce the risk of hyperkalemia for patients treated concomitantly with RAS inhibitors and ns-MRA. 1
• The benefits of SGLT2 inhibitors and finerenone may be additive due to complementary mechanisms of action. 1

Glycemic Effects at Low eGFR

• The glucose-lowering effect of SGLT2 inhibitors is more pronounced in hyperglycemic states and diminishes as blood glucose normalizes. 4
• The glycemic benefits of SGLT2 inhibitors are reduced when eGFR is <45 mL/min/1.73 m². 4
• However, cardiovascular and renal benefits persist at low eGFR independent of glucose-lowering effects, making continuation appropriate even when glycemic benefit is minimal. 1, 2