When do you use a SGLT2 (sodium-glucose linked transporter 2) inhibitor, such as a Flozin (e.g. canagliflozin, dapagliflozin, empagliflozin), in the treatment of type 2 diabetes?

When to Use SGLT2 Inhibitors (Flozins) in Type 2 Diabetes

SGLT2 inhibitors should be added to metformin in patients with type 2 diabetes who have established atherosclerotic cardiovascular disease (ASCVD), heart failure, or chronic kidney disease (eGFR 25-75 mL/min/1.73 m² with albuminuria ≥200 mg/g), regardless of baseline HbA1c or glycemic control needs. 1

Primary Indications for SGLT2 Inhibitor Therapy

Cardiovascular Disease Protection (First Priority)

• Initiate an SGLT2 inhibitor (empagliflozin, canagliflozin, or dapagliflozin) in all patients with type 2 diabetes and established ASCVD, even if HbA1c is at goal on metformin alone. 1
• These agents reduce the composite endpoint of cardiovascular death, non-fatal MI, and non-fatal stroke by 14% (canagliflozin HR 0.86, empagliflozin HR 0.86). 1
• Cardiovascular death is reduced by 38% with empagliflozin (HR 0.62) and all-cause mortality by 32% (HR 0.68). 1
• Hospitalization for heart failure is reduced by 33-35% across trials (HR 0.65-0.67). 1

Heart Failure Indication

• Use dapagliflozin 10 mg daily or empagliflozin in patients with heart failure (reduced or preserved ejection fraction), regardless of diabetes status. 2, 3
• This indication exists independently of glycemic control and applies even to non-diabetic patients with heart failure. 4, 3

Chronic Kidney Disease Protection (Second Priority)

• Initiate an SGLT2 inhibitor when eGFR is 25-75 mL/min/1.73 m² with albuminuria (UACR ≥200 mg/g) to prevent kidney disease progression. 1, 2
• Dapagliflozin reduces the composite renal outcome (≥50% sustained eGFR decline, ESKD, or renal/CV death) by 39% (HR 0.61). 2
• Renal and cardiovascular benefits persist down to eGFR of 30 mL/min/1.73 m², even though glucose-lowering efficacy is minimal at this level. 1, 2

Glycemic Control (When Other Indications Absent)

• Add an SGLT2 inhibitor when HbA1c remains ≥7% on metformin monotherapy and the patient does not have contraindications. 1
• SGLT2 inhibitors reduce HbA1c by 0.5-0.8% when added to metformin, similar to sulfonylureas or DPP-4 inhibitors. 1, 5, 6
• The advantage over other agents is the additional benefit of weight loss (1.5-2.5 kg) and blood pressure reduction (3-5 mmHg systolic) without hypoglycemia risk. 1, 6

Dosing Based on Renal Function

Initiation Thresholds

• For glycemic control: Do not initiate if eGFR <45 mL/min/1.73 m² (dapagliflozin, empagliflozin) or <60 mL/min/1.73 m² (canagliflozin 300 mg). 1, 2
• For cardiovascular/renal protection: Can initiate down to eGFR ≥25 mL/min/1.73 m². 1, 2

Continuation During Declining Renal Function

• Continue SGLT2 inhibitors even if eGFR falls below initiation threshold during treatment, as cardiovascular and renal benefits persist. 1, 2
• Dapagliflozin can be continued at 10 mg daily if eGFR falls below 25 mL/min/1.73 m² after initiation. 2
• Canagliflozin should be limited to 100 mg daily if eGFR is 45-59 mL/min/1.73 m². 1

Expected eGFR Changes

• Anticipate a transient eGFR decline of 3-5 mL/min/1.73 m² within the first 1-4 weeks, which is hemodynamic and reversible. 2
• Check eGFR 1-2 weeks after initiation; if decline >30% with signs of volume depletion, reduce diuretics first before stopping the SGLT2 inhibitor. 2

Clinical Algorithm for Selection

Step 1: Assess for High-Risk Conditions

• Does the patient have established ASCVD (prior MI, stroke, PAD)? → Yes: Start SGLT2 inhibitor immediately. 1
• Does the patient have heart failure? → Yes: Start dapagliflozin 10 mg or empagliflozin. 2, 3
• Does the patient have CKD with eGFR 25-75 and UACR ≥200 mg/g? → Yes: Start SGLT2 inhibitor. 1, 2

Step 2: Check Renal Function

• eGFR ≥45 mL/min/1.73 m²: Any SGLT2 inhibitor can be used for any indication. 1, 2
• eGFR 25-44 mL/min/1.73 m²: Use for cardiovascular/renal protection only, not for glycemic control. 1, 2
• eGFR <25 mL/min/1.73 m²: Do not initiate; consider GLP-1 receptor agonist instead. 2

Step 3: Assess Volume Status and Risk Factors

• Evaluate for volume depletion risk: elderly (≥65 years), on loop diuretics, low sodium diet, baseline hypotension. 1, 7
• Correct volume depletion before initiating SGLT2 inhibitor. 2, 7
• Consider lower diuretic doses when starting SGLT2 inhibitor in high-risk patients. 1, 7

Step 4: Choose Specific Agent

• Empagliflozin 10-25 mg daily: Strongest cardiovascular mortality data (38% reduction). 1
• Canagliflozin 100-300 mg daily: FDA-approved for cardiovascular risk reduction; dose-limit to 100 mg if eGFR 45-59. 1, 8
• Dapagliflozin 10 mg daily: Strongest renal outcome data and heart failure indication. 2

Critical Safety Considerations and Contraindications

Absolute Contraindications

• Do not use in type 1 diabetes for glycemic control (risk of euglycemic DKA). 7
• Allergy to the specific SGLT2 inhibitor. 7
• Dialysis or eGFR <25 mL/min/1.73 m² (for new initiations). 2

Perioperative Management

• Withhold SGLT2 inhibitors at least 3 days before major surgery or procedures requiring prolonged fasting to prevent euglycemic ketoacidosis. 2, 7
• Resume only after patient is eating and drinking normally. 7

Ketoacidosis Risk (Critical Pitfall)

• Euglycemic DKA can occur even with blood glucose <250 mg/dL. 7, 5
• High-risk situations: acute illness, reduced food intake, ketogenic diet, alcohol excess, insulin dose reduction. 7
• Educate patients to check ketones if experiencing nausea, vomiting, abdominal pain, or unusual fatigue, even with normal glucose. 7
• Stop SGLT2 inhibitor during acute illness, vomiting, or inability to eat/drink. 7

Genital Mycotic Infections

• Occur in approximately 6% of patients, more common in women. 1, 8, 7
• Provide anticipatory guidance and recommend over-the-counter antifungal treatment. 7
• Rare but serious: Fournier's gangrene (necrotizing fasciitis of perineum) requires immediate treatment. 2

Volume Depletion and Orthostatic Hypotension

• Higher risk in elderly, those on diuretics, ACE inhibitors/ARBs, or with baseline eGFR <60. 1, 7
• Monitor for dizziness, lightheadedness, syncope, especially in first weeks. 7
• Reduce diuretic dose if symptomatic hypotension occurs. 2

Urinary Tract Infections

• Not significantly increased in most trials, despite theoretical concern. 1, 5
• Monitor patients with history of recurrent UTIs. 7

Combination Therapy Considerations

With Metformin (Standard Approach)

• SGLT2 inhibitors are typically added to metformin as the foundation. 1
• Over 70% of patients in cardiovascular outcome trials were on metformin at baseline. 1

With Insulin or Sulfonylureas

• Reduce insulin or sulfonylurea dose by 10-20% when adding SGLT2 inhibitor to prevent hypoglycemia. 8, 7
• Monitor glucose closely in first 1-2 weeks. 8

With GLP-1 Receptor Agonists

• Combination therapy with both an SGLT2 inhibitor and GLP-1 RA provides complementary cardiovascular and renal benefits. 1
• Consider dual therapy in patients with multiple high-risk features (ASCVD + CKD, or ASCVD + obesity). 1

With DPP-4 Inhibitors

• Can be used together without dose adjustment (e.g., canagliflozin + sitagliptin). 8
• Provides additive glucose-lowering without increased hypoglycemia. 1

Monitoring Requirements

Baseline Assessment

• eGFR and serum creatinine. 2
• Volume status and blood pressure. 2, 7
• History of genital/urinary infections. 7

Follow-Up Monitoring

• Recheck eGFR 1-2 weeks after initiation, then periodically (every 3-6 months). 2
• Monitor for signs of volume depletion, especially in first month. 7
• Assess for genital mycotic infections at follow-up visits. 7
• Do not discontinue if eGFR declines 3-5 mL/min/1.73 m² in first month (expected hemodynamic effect). 2