In adult patients with type 2 diabetes, what are the indications, recommended dosing, contraindications, and monitoring parameters for sodium‑glucose cotransporter‑2 (SGLT2) inhibitors?

SGLT2 Inhibitors: Comprehensive Clinical Guide

Primary Indications

SGLT2 inhibitors are now mandatory therapy for three major indications regardless of diabetes status or glycemic control: type 2 diabetes with cardiovascular disease or CKD, heart failure (both reduced and preserved ejection fraction), and chronic kidney disease with albuminuria. 1

Type 2 Diabetes Mellitus

• Glycemic control: Adjunct to diet and exercise in adults with type 2 diabetes 2
• Cardiovascular protection: Reduce risk of cardiovascular death in patients with established cardiovascular disease 3
• Priority use: Patients with HbA1c ≥7% on metformin who have established CVD, heart failure, or CKD (eGFR 20-60 mL/min/1.73 m² and/or albuminuria ≥200 mg/g) 1

Chronic Kidney Disease (with or without diabetes)

• Strong recommendation for high-risk patients: eGFR 30-44 mL/min/1.73 m² with albuminuria ≥200 mg/g 1
• Strong recommendation for very high-risk patients: eGFR <30 mL/min/1.73 m² with albuminuria ≥200 mg/g 1
• Weak recommendation for moderate-risk patients: eGFR 45-59 mL/min/1.73 m² with albuminuria 30-200 mg/g 1
• In very high-risk patients, treatment prevents 48 fewer deaths and 58 fewer kidney-failure events per 1,000 patients over 5 years 1

Heart Failure

• Mandatory therapy for all adults with heart failure (HFrEF and HFpEF), regardless of diabetes status 1
• Reduces cardiovascular death or heart failure hospitalization by 26-29% 1

Additional Considerations

• Consider in patients with metabolic-dysfunction-associated steatotic liver disease (MASLD) and overweight/obesity 1

---

Recommended Dosing

Available Agents and Standard Doses

Empagliflozin 3, 2:

• Initial: 10 mg orally once daily (morning, with or without food)
• May increase to 25 mg daily if needed for glycemic control
• For cardiovascular/renal protection: 10 mg daily is the recommended dose 1

Canagliflozin 3:

• Initial: 100 mg orally once daily before first meal
• May increase to 300 mg daily if eGFR ≥60 mL/min/1.73 m² and additional glycemic control needed

Dapagliflozin 3, 1:

• Initial: 5 mg orally once daily
• May increase to 10 mg daily if needed
• For cardiovascular/renal protection: 10 mg daily for all indications except solely glycemic control 1

---

eGFR-Based Dosing Modifications

Critical Distinction: Glycemic Control vs. Cardiorenal Protection

The cardiovascular and kidney benefits of SGLT2 inhibitors persist even when glucose-lowering efficacy is lost, and these benefits are out of proportion to glycemic effects. 4

For Glycemic Control

Empagliflozin 3, 2:

• eGFR ≥45 mL/min/1.73 m²: No adjustment required
• eGFR <45 mL/min/1.73 m²: Do not initiate; discontinue if eGFR persistently <45 mL/min/1.73 m²

Canagliflozin 3:

• eGFR ≥60 mL/min/1.73 m²: No adjustment
• eGFR 45-59 mL/min/1.73 m²: Maximum 100 mg daily
• eGFR <45 mL/min/1.73 m²: Not recommended for glucose lowering

Dapagliflozin 3:

• eGFR ≥45 mL/min/1.73 m²: No adjustment
• eGFR <45 mL/min/1.73 m²: Not recommended for glucose lowering

For Cardiovascular/Renal Protection

Initiation threshold: May initiate when eGFR ≥20 mL/min/1.73 m² (some guidelines accept ≥25 mL/min/1.73 m²) 1, 5

Continuation during treatment: Continue even if eGFR falls below 20 mL/min/1.73 m² unless not tolerated or kidney replacement therapy is initiated 1, 5

Canagliflozin-specific for CKD indication 3:

• eGFR ≥60 mL/min/1.73 m²: No adjustment
• eGFR 30-59 mL/min/1.73 m²: 100 mg daily
• eGFR <30 mL/min/1.73 m² with albuminuria >300 mg/day: 100 mg daily
• eGFR <30 mL/min/1.73 m² without albuminuria: Initiation not recommended

Mechanism of eGFR-Based Dosing

SGLT2 inhibitors lose glucose-lowering efficacy as eGFR declines because glucosuria diminishes when filtered glucose load decreases, but cardiorenal benefits persist through hemodynamic effects including osmotic diuresis and natriuresis. 4, 6

• eGFR 45-60 mL/min/1.73 m²: Reduced but present glucose-lowering efficacy 4
• eGFR 30-45 mL/min/1.73 m²: Substantially reduced glucose-lowering efficacy 4
• eGFR <30 mL/min/1.73 m²: Minimal to no glucose-lowering effect 4
• Benefits extend down to eGFR 20 mL/min/1.73 m² for cardiorenal protection 4, 1

---

Contraindications

Absolute Contraindications

Empagliflozin 2:

• History of serious hypersensitivity reaction to empagliflozin or excipients
• Severe renal impairment, end-stage renal disease, or dialysis

All SGLT2 inhibitors 5:

• Active dialysis or kidney replacement therapy
• Severe renal impairment (eGFR <20 mL/min/1.73 m² for initiation) 5

Relative Contraindications and Special Populations

• Polycystic kidney disease: Not recommended 1
• Immunosuppressive therapy for kidney disease: Not recommended 1
• Kidney transplant recipients: Not recommended due to limited data and potential infection risk 1
• Type 1 diabetes or diabetic ketoacidosis: Not indicated 2

Clinical Situations Requiring Caution

• Volume depletion risk: Elderly (≥75 years), patients on diuretics, low systolic blood pressure 2
• Ketoacidosis risk factors: Consider carefully before initiating 2
• History of lower-extremity amputation (canagliflozin): Use with caution 7
• History of bone fracture (canagliflozin): Use with caution 7

---

Monitoring Parameters

Pre-Initiation Assessment

Before starting SGLT2 inhibitors, assess: 1, 2

• Renal function: eGFR and urine albumin-to-creatinine ratio 1
• Volume status: Correct volume depletion, especially in elderly, those on diuretics, or with low systolic blood pressure 1, 2

During Treatment

Renal function monitoring 1:

• If baseline eGFR <60 mL/min/1.73 m²: Monitor every 3-6 months
• If baseline eGFR ≥60 mL/min/1.73 m²: Monitor annually
• Expect initial reversible eGFR decline of 3-5 mL/min/1.73 m²—this should NOT prompt discontinuation 1

Infection monitoring 1, 7:

• Genital mycotic infections: Occur in ~6% of treated patients vs. ~1% with placebo 1
• Urinary tract infections: Monitor and treat promptly 2
• Urosepsis and pyelonephritis: Evaluate for signs/symptoms and treat promptly 2

Metabolic monitoring 2:

• Ketoacidosis: Assess patients with signs/symptoms of metabolic acidosis regardless of blood glucose level 2
• Hypoglycemia: Monitor when combined with insulin or insulin secretagogues 2
• LDL-C: Monitor and treat as appropriate 2

Volume status 1, 2:

• Monitor for signs/symptoms of hypotension and volume depletion 2
• Consider reducing concurrent diuretic doses 5

Temporary Discontinuation Situations

Withhold SGLT2 inhibitors during: 5, 2

• Prolonged fasting
• Surgery
• Critical medical illness
• Settings of reduced oral intake or significant fluid losses 2

---

Common Pitfalls and How to Avoid Them

Pitfall 1: Discontinuing Due to eGFR Decline for Glycemic Control

Do not discontinue SGLT2 inhibitors solely because glucose-lowering efficacy has declined. 4 The cardiorenal protective benefits persist independent of glycemic effects down to eGFR 20 mL/min/1.73 m² 4, 1.

Pitfall 2: Stopping Due to Initial eGFR Dip

Do not mistake the initial reversible eGFR dip (3-5 mL/min/1.73 m²) as a reason to discontinue therapy. 4, 1 This hemodynamic effect is expected and not harmful 5.

Pitfall 3: Inadequate Volume Assessment

Always assess and correct volume status before initiation, particularly in elderly patients (≥75 years), those on diuretics, or with low systolic blood pressure. 1, 2 Failure to do so increases risk of hypotension and acute kidney injury 2.

Pitfall 4: Missing Ketoacidosis Risk

Monitor for ketoacidosis even with normal blood glucose levels (euglycemic DKA). 2, 7 Withhold during prolonged fasting, surgery, or critical illness 5, 2.

Pitfall 5: Using Wrong Indication for eGFR Threshold

Distinguish between glycemic control (discontinue at eGFR <45 mL/min/1.73 m²) and cardiorenal protection (continue down to eGFR 20 mL/min/1.73 m²). 1 Patients with compelling cardiovascular or renal indications should continue therapy despite low eGFR 1.

---

Combination Therapy

Synergistic Agents

Renin-angiotensin system inhibitors (ACEi or ARB): Can be used together with SGLT2 inhibitors for additive kidney protection 1

Non-steroidal mineralocorticoid receptor antagonists: May be added when albuminuria persists despite optimal SGLT2 inhibitor and RASi therapy 1

GLP-1 receptor agonists: Alternative for CKD patients with eGFR 20-60 mL/min/1.73 m² and/or albuminuria, especially when additional weight loss or cardiovascular benefit is desired 1

Metformin: Remains first-line oral agent for type 2 diabetes; SGLT2 inhibitors are added when glycemic targets are not met 1

Hypoglycemia Risk Management

Consider lowering the dose of insulin secretagogue or insulin when initiating SGLT2 inhibitors to reduce hypoglycemia risk. 2 SGLT2 inhibitors have low intrinsic hypoglycemia risk when used alone or with metformin 4.

---

Mechanism of Action and Clinical Implications

Primary Mechanism

SGLT2 inhibitors block renal glucose reabsorption in the S1 and S2 segments of the proximal convoluted tubule, increasing urinary glucose excretion (glucosuria) and lowering blood glucose independently of insulin. 4, 8

Pleiotropic Effects Beyond Glucose Lowering

Hemodynamic effects 8, 6:

• Osmotic diuresis and natriuresis
• Reduced sodium reabsorption with increased sodium delivery to distal tubule
• Activation of tubuloglomerular feedback to correct glomerular hyperfiltration
• Reduced blood pressure

Metabolic effects 4:

• Reduced proximal tubular oxygen consumption and ATP demand
• Mitigation of renal cortical hypoxia
• Insulin-sparing effect improving β-cell function over time
• Enhanced peripheral insulin sensitivity

These pleiotropic mechanisms explain why cardiovascular and renal benefits persist even when glucose-lowering efficacy is minimal at low eGFR levels. 4, 6