What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in the management of patients with type 2 diabetes, especially those with cardiovascular disease or impaired renal function?

SGLT2 Inhibitors in Type 2 Diabetes Management

Primary Recommendation

SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) should be initiated in all patients with type 2 diabetes who have established cardiovascular disease, heart failure, or chronic kidney disease, independent of baseline HbA1c or need for additional glucose lowering. 1

---

Core Indications and Patient Selection

Cardiovascular Disease

• Initiate SGLT2 inhibitors with demonstrated cardiovascular benefit in all patients with type 2 diabetes and established atherosclerotic cardiovascular disease (ASCVD) to reduce major adverse cardiovascular events (MACE), cardiovascular death, and heart failure hospitalization. 1
• Empagliflozin, canagliflozin, and dapagliflozin have Class I, Level A evidence for reducing cardiovascular death by 14-38% in patients with established CVD. 1, 2
• These agents reduce heart failure hospitalization by 26-35% regardless of prior heart failure history. 1, 3

Chronic Kidney Disease

• Start SGLT2 inhibitors in patients with diabetic kidney disease when eGFR ≥25 mL/min/1.73 m² and UACR ≥200 mg/g to reduce kidney disease progression by 39-44%. 1, 4, 5
• The DAPA-CKD trial demonstrated a 44% reduction in the composite renal outcome (sustained eGFR decline ≥50%, end-stage kidney disease, or renal death; HR 0.56,95% CI 0.45-0.68). 4, 5
• Benefits persist even when eGFR falls below 45 mL/min/1.73 m², where glucose-lowering efficacy diminishes but cardiovascular and renal protection continues. 1, 4

Heart Failure

• Dapagliflozin 10 mg daily and empagliflozin are indicated for heart failure with reduced ejection fraction (HFrEF) regardless of diabetes status. 4, 3
• Dapagliflozin reduces cardiovascular death or worsening heart failure by 26% (HR 0.74,95% CI 0.65-0.85) in HFrEF patients. 4, 3

---

Dosing Algorithm by Clinical Indication

Standard Dosing

• Empagliflozin: 10 mg or 25 mg orally once daily 1, 6
• 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 (fixed dose for all indications) 4

Renal Function-Based Adjustments

For Glycemic Control:

• eGFR ≥45 mL/min/1.73 m²: No dose adjustment required 1, 4
• eGFR <45 mL/min/1.73 m²: Do not initiate for glycemic control (ineffective due to mechanism of action) 1, 4

For Cardiovascular/Renal Protection:

• eGFR ≥25 mL/min/1.73 m²: Initiate at standard dose (10 mg dapagliflozin or 10-25 mg empagliflozin) 4
• eGFR <25 mL/min/1.73 m²: Do not initiate, but may continue if already on treatment until dialysis 4
• Critical distinction: Cardiovascular and renal benefits persist at eGFR 25-44 mL/min/1.73 m² even when glucose-lowering efficacy is lost. 1, 4

---

Drug Selection Strategy

Consider SGLT2 Inhibitor First When Priorities Include:

• Reducing cardiovascular death and heart failure hospitalization 1
• Slowing kidney disease progression 1
• Once-daily oral dosing 1
• Weight loss (modest, 2-3 kg) 7

Consider GLP-1 Receptor Agonist First When Priorities Include:

• Reducing MACE and cardiovascular death as primary goal 1
• Substantial weight loss (>5 kg) 1
• eGFR consistently <25 mL/min/1.73 m² (where SGLT2i cannot be initiated) 1, 4

Combination Therapy

• Combining semaglutide and dapagliflozin provides complementary cardiovascular and renal protection through independent mechanisms without significant safety concerns. 8
• SGLT2 inhibitors address hemodynamic pathways while GLP-1 receptor agonists target metabolic/inflammatory pathways. 8

---

Initiation and Monitoring Protocol

Pre-Initiation Assessment

• Check eGFR and assess volume status 1, 4
• Evaluate for contraindications: pregnancy, breastfeeding, dialysis, history of recurrent genital infections 1, 4
• For canagliflozin specifically: avoid in patients with prior amputation, severe peripheral arterial disease, neuropathy, diabetic foot ulcers, or osteoporosis. 1

Medication Adjustments at Initiation

• If HbA1c well-controlled or history of frequent hypoglycemia: reduce sulfonylurea dose by 50% or basal insulin dose by 20%. 1
• Consider reducing thiazide or loop diuretic dose to avoid hypovolemia. 1, 4
• Discontinue DPP-4 inhibitors if starting combination therapy (not applicable to SGLT2i alone). 1

Monitoring Schedule

• Recheck eGFR within 1-2 weeks after initiation (expect transient 3-5 mL/min/1.73 m² dip that stabilizes). 4
• Monitor glucose closely for first 4 weeks 1
• Assess for volume depletion symptoms (lightheadedness, orthostasis, weakness) 1
• Monitor kidney function every 3-6 months if eGFR 45-59 mL/min/1.73 m², annually if eGFR ≥60 mL/min/1.73 m² 4

---

Critical Safety Considerations and Risk Mitigation

Euglycemic Diabetic Ketoacidosis (DKA)

• Withhold SGLT2 inhibitors at least 3 days before major surgery or procedures requiring prolonged fasting. 1, 4
• Hold during acute illness with reduced oral intake, fever, vomiting, or diarrhea. 4
• Educate patients that DKA can occur even with blood glucose 150-250 mg/dL. 1
• Symptoms include nausea, vomiting, weakness, malaise. 1, 4
• Maintain at least low-dose insulin in insulin-requiring patients even when SGLT2i is held. 4

Volume Depletion

• Higher risk in elderly (≥75 years), those on concurrent diuretics, or with low baseline blood pressure. 1
• Assess volume status before initiation and correct if depleted. 1, 4

Genital Mycotic Infections

• Occur in approximately 6% of patients versus 1% on placebo. 4
• Educate patients regarding symptoms and hygiene measures. 1, 4
• Not a contraindication but use caution in patients with recurrent infections. 1

Amputation Risk (Canagliflozin-Specific)

• Increased risk observed in CANVAS trial. 1
• Avoid canagliflozin in patients with history of amputation, severe peripheral arterial disease, neuropathy, or diabetic foot ulcers. 1
• Educate patients on foot care and schedule follow-up foot examinations. 1

Fournier Gangrene

• Rare but serious: necrotizing fasciitis of the perineum requires immediate treatment. 4

---

Common Pitfalls to Avoid

Do Not Discontinue Based on eGFR Alone

• Do not stop SGLT2 inhibitors solely because eGFR falls below 45 mL/min/1.73 m²—cardiovascular and renal protective benefits persist even when glycemic efficacy is lost. 1, 4
• Continue until eGFR falls below 25 mL/min/1.73 m² or dialysis is initiated. 4

Do Not Delay Initiation

• Start SGLT2 inhibitors early as foundational therapy, independent of baseline HbA1c or metformin use. 1, 4
• Benefits are independent of glucose-lowering needs. 1, 4

Do Not Combine with Thiazolidinediones

• Thiazolidinediones increase heart failure risk and should be avoided in patients with symptomatic heart failure. 1

Sick Day Management

• Patients must be counseled to stop SGLT2 inhibitors immediately during acute illness and contact their healthcare provider. 4
• Resume only after recovery and normal oral intake is re-established. 4

---

Special Populations

Elderly Patients (≥75 Years)

• No upper age limit for use. 4
• Increased vigilance for hypotension and volume depletion required. 4
• Assess volume status carefully before initiation. 4

Advanced CKD (eGFR 20-30 mL/min/1.73 m²)

• Do not use for glycemic control at eGFR <30 mL/min/1.73 m². 4
• May initiate at eGFR ≥25 mL/min/1.73 m² for cardiovascular/renal protection. 4
• Consider GLP-1 receptor agonists for glycemic control if eGFR >30 mL/min/1.73 m². 4

Patients on Insulin or Sulfonylureas

• Reduce sulfonylurea by 50% or insulin by 20% when initiating SGLT2 inhibitors to prevent hypoglycemia. 1
• Monitor glucose closely for first 4 weeks. 1