What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in treating type 2 diabetes and heart failure?

SGLT2 Inhibitors: Role in Type 2 Diabetes and Heart Failure

Primary Recommendation

SGLT2 inhibitors are first-line therapy for patients with type 2 diabetes who have established cardiovascular disease, heart failure (regardless of ejection fraction), or chronic kidney disease, and should be prescribed independently of baseline HbA1c levels or glycemic targets. 1

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Indications by Clinical Scenario

Type 2 Diabetes with Established Cardiovascular Disease

• Prescribe SGLT2 inhibitors (empagliflozin, canagliflozin, or dapagliflozin) to reduce major adverse cardiovascular events (MACE), hospitalization for heart failure, and cardiovascular death. 1
• Empagliflozin specifically reduced cardiovascular death by 38% and heart failure hospitalization by 35% in the EMPA-REG OUTCOME trial. 2, 3
• The decision to initiate SGLT2 inhibitors should be made independently of current HbA1c or glycemic targets—cardiovascular protection is the primary goal, not glucose lowering. 1

Heart Failure (With or Without Diabetes)

• All patients with symptomatic heart failure (NYHA class II-IV) should receive SGLT2 inhibitors regardless of diabetes status or ejection fraction. 4
• For heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%): Dapagliflozin 10 mg daily or empagliflozin 10 mg daily reduces the composite of worsening heart failure or cardiovascular death by 25-26%. 4
• For heart failure with preserved ejection fraction (HFpEF, LVEF >40%): Empagliflozin reduced cardiovascular death or heart failure hospitalization by 21% in EMPEROR-Preserved; dapagliflozin reduced this composite by 18% in DELIVER. 1, 4
• Initiate SGLT2 inhibitors during heart failure hospitalization in stabilized patients—deferring initiation results in many eligible patients never receiving the medication within one year. 4
• SGLT2 inhibitors reduce first heart failure hospitalizations by 27-39% across multiple trials, with benefits appearing within weeks of initiation. 4

Chronic Kidney Disease (With or Without Diabetes)

• For patients with eGFR 20-75 mL/min/1.73 m² and UACR ≥200 mg/g, prescribe dapagliflozin 10 mg daily to prevent CKD progression, end-stage kidney disease, cardiovascular death, and heart failure hospitalization. 1, 4, 5
• The threshold for initiation has been lowered to eGFR >20 mL/min/1.73 m² based on subgroup analyses from DAPA-CKD and EMPEROR trials showing safety and efficacy at these lower levels. 1
• In the DAPA-CKD trial, dapagliflozin reduced the primary renal outcome (sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death) by 39%. 4
• Do not initiate SGLT2 inhibitors if eGFR <20 mL/min/1.73 m² as they are unlikely to be effective. 4, 5

Type 2 Diabetes Without Established CVD/HF/CKD

• For glycemic control alone, start with dapagliflozin 5 mg daily, which can be increased to 10 mg daily for additional glucose lowering. 5
• SGLT2 inhibitors are not recommended for glycemic control when eGFR <45 mL/min/1.73 m² as they are ineffective for glucose lowering at this level (though cardiovascular and renal benefits persist down to eGFR 20). 5

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Agent Selection

Choosing Between SGLT2 Inhibitors

• For heart failure: Use dapagliflozin 10 mg daily or empagliflozin 10 mg daily—both have Class I evidence from dedicated heart failure trials (DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, DELIVER). 4, 2
• Avoid ertugliflozin for heart failure—it lacks dedicated cardiovascular outcome trials and has no evidence base for heart failure treatment. 4
• For type 2 diabetes with established CVD: Empagliflozin, canagliflozin, or dapagliflozin are all acceptable as they have proven cardiovascular benefits. 1, 2
• The American Diabetes Association and American College of Cardiology do not preferentially recommend one SGLT2 inhibitor over another for cardiovascular disease. 2

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Contraindications and Precautions

Absolute Contraindications

• History of serious hypersensitivity reaction to the specific SGLT2 inhibitor. 5, 6
• Polycystic kidney disease (SGLT2 inhibitors are not expected to be effective). 5
• Recent or current immunosuppressive therapy for kidney disease (SGLT2 inhibitors are not expected to be effective). 5

Important Safety Considerations

• Assess volume status before initiation—correct volume depletion in patients with renal impairment, elderly patients, those with low systolic blood pressure, or those on diuretics. 5, 6
• Withhold SGLT2 inhibitors at least 3 days before major surgery or procedures with prolonged fasting to reduce diabetic ketoacidosis risk. 5
• Monitor for diabetic ketoacidosis in patients with type 1 diabetes (though SGLT2 inhibitors are not indicated for type 1 diabetes) and consider ketone monitoring in high-risk type 2 diabetes patients during acute illness or surgery. 5, 6
• Reduce insulin or sulfonylurea doses by approximately 20% when initiating SGLT2 inhibitors to prevent hypoglycemia. 2

Common Adverse Effects

• Genital mycotic infections occur in 1.5-5% of patients and are generally manageable. 4, 2
• Urinary tract infections occur in 2.3-5% of patients. 4, 2
• Hypotension may occur in approximately 5.7% of patients, particularly with volume depletion. 4

Renal Function Monitoring

• A mild, transient decrease in eGFR after initiating SGLT2 inhibitors is expected and does not indicate kidney injury—do not discontinue therapy for this reason. 4
• Monitor renal function periodically during therapy as clinically indicated. 5

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Medications to Avoid in Heart Failure

Thiazolidinediones

• Avoid thiazolidinediones in patients with symptomatic heart failure—they have a strong and consistent relationship with increased heart failure risk. 1

DPP-4 Inhibitors

• The risk-benefit balance for most DPP-4 inhibitors does not justify their use in patients with established heart failure or those at high risk for heart failure. 1
• Saxagliptin increased heart failure hospitalizations in the SAVOR-TIMI 53 trial, though other DPP-4 inhibitors showed mixed results. 1

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Clinical Algorithm for SGLT2 Inhibitor Use

1. Identify eligible patients:

   • Type 2 diabetes + established CVD, heart failure, or CKD
   • Heart failure (any ejection fraction) with or without diabetes
   • CKD with eGFR 20-75 mL/min/1.73 m² and UACR ≥200 mg/g

2. Check for contraindications:

   • Serious hypersensitivity to SGLT2 inhibitors
   • Polycystic kidney disease or recent immunosuppressive therapy for kidney disease
   • eGFR <20 mL/min/1.73 m²

3. Assess volume status:

   • Correct volume depletion before initiating, especially in elderly, those with low blood pressure, or those on diuretics

4. Select agent and dose:

   • Heart failure: Dapagliflozin 10 mg daily or empagliflozin 10 mg daily
   • CKD: Dapagliflozin 10 mg daily
   • Type 2 diabetes for glycemic control: Dapagliflozin 5-10 mg daily or empagliflozin 10-25 mg daily

5. Adjust concomitant medications:

   • Reduce insulin or sulfonylurea by ~20% to prevent hypoglycemia

6. Monitor:

   • Volume status and blood pressure
   • Renal function (expect mild transient decrease)
   • Genital and urinary infections
   • Signs of ketoacidosis during acute illness or surgery

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Key Evidence Supporting SGLT2 Inhibitors

• Meta-analysis across cardiometabolic diseases (2024): SGLT2 inhibitors reduced first heart failure hospitalization by 28-32% and cardiovascular death by 11-15% across patients with heart failure, type 2 diabetes, CKD, and atherosclerotic CVD. 7
• DAPA-HF trial: Dapagliflozin reduced worsening heart failure or cardiovascular death by 26% in HFrEF patients regardless of diabetes status. 4
• EMPEROR-Reduced: Empagliflozin reduced cardiovascular death or heart failure hospitalization by 25% in HFrEF. 4
• DAPA-CKD: Dapagliflozin reduced the primary renal outcome by 39% in patients with CKD and albuminuria. 4