What are the indications, recommended starting doses, contraindications, monitoring parameters, and alternative therapies for SGLT2 inhibitors in adults with type 2 diabetes?

SGLT2 Inhibitors: Comprehensive Clinical Guide

Primary Indications

SGLT2 inhibitors are indicated for three distinct purposes in adults with type 2 diabetes: glycemic control, cardiovascular protection, and renal protection—each with different eGFR thresholds and priority populations. 1

Glycemic Control

• Start SGLT2 inhibitors when HbA1c ≥7% despite metformin and lifestyle modifications 1, 2
• Recommended starting dose: 100 mg canagliflozin, 10 mg dapagliflozin, or 10 mg empagliflozin once daily before the first meal 1, 3
• Canagliflozin may be increased to 300 mg daily in patients tolerating 100 mg who have eGFR ≥60 mL/min/1.73 m² and require additional glycemic control 1, 3
• Empagliflozin may be increased to 25 mg daily for additional glycemic benefit 1

Cardiovascular Protection (Priority Indication)

• Mandatory therapy for all adults with type 2 diabetes and heart failure (either reduced or preserved ejection fraction), regardless of HbA1c level 1, 2, 4
• Reduces cardiovascular death or heart failure hospitalization by 26-29% 1, 2, 4
• Indicated for adults with type 2 diabetes and established atherosclerotic cardiovascular disease to reduce risk of major adverse cardiovascular events 1, 2
• Canagliflozin specifically reduces risk of myocardial infarction, stroke, or cardiovascular death 1, 3

Renal Protection (Priority Indication)

• Initiate in adults with type 2 diabetes and CKD (eGFR 20-60 mL/min/1.73 m² and/or albuminuria ≥200 mg/g) for minimizing CKD progression, reducing cardiovascular events, and preventing heart failure hospitalizations 1, 2, 4
• Reduces composite renal outcome (sustained eGFR decline ≥50%, end-stage kidney disease, or renal death) by 39-44% 1, 2, 5
• Canagliflozin reduces risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and heart failure hospitalization in diabetic nephropathy with albuminuria 1, 3

Additional Indications

• Consider in adults with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) with overweight/obesity for glycemic management and adjunctive weight loss 2

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Dosing by Clinical Indication

For Glycemic Control

eGFR (mL/min/1.73 m²)	Canagliflozin	Dapagliflozin	Empagliflozin
≥60	100-300 mg daily [1,3]	10 mg daily [1]	10-25 mg daily [1]
45-59	Maximum 100 mg daily [1,3]	10 mg daily [1]	10 mg daily [1]
30-44	Maximum 100 mg daily [1,3]	Not recommended for glycemic control [1]	Not recommended for glycemic control [1]
<30	Not recommended [1,3]	Contraindicated [1]	Contraindicated [1]

For Cardiovascular/Renal Protection

• Standard dose: 10 mg dapagliflozin, 10 mg empagliflozin, or 100 mg canagliflozin once daily 4
• May be initiated when eGFR ≥20-25 mL/min/1.73 m² 2, 5, 4
• Continue therapy even if eGFR falls below 45 mL/min/1.73 m² or below 20 mL/min/1.73 m² during treatment, as cardiorenal benefits persist despite reduced glycemic efficacy 2, 5, 4

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Absolute Contraindications

• History of serious hypersensitivity reaction to the specific SGLT2 inhibitor 1, 3
• End-stage renal disease or dialysis 1
• Type 1 diabetes mellitus (not recommended for glycemic control) 1, 3
• Pregnancy or breastfeeding (dapagliflozin specifically contraindicated) 1

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Critical Precautions and Monitoring

Pre-Initiation Assessment

• Measure eGFR and urine albumin-to-creatinine ratio before starting therapy 4
• Assess volume status and correct volume depletion, especially in patients ≥75 years, on loop diuretics, or with low systolic blood pressure 1, 4, 3

Perioperative Management

• Withhold SGLT2 inhibitors at least 3 days before planned surgery or procedures with prolonged fasting to prevent postoperative euglycemic diabetic ketoacidosis 1, 2
• Temporarily discontinue during acute illness with reduced oral intake, fever, vomiting, or diarrhea 2

Ongoing Monitoring

• Monitor eGFR every 3-6 months if baseline eGFR <60 mL/min/1.73 m², annually if ≥60 mL/min/1.73 m² 5, 4
• Expect an initial reversible eGFR decline of 3-5 mL/min/1.73 m² in the first 1-4 weeks—this is hemodynamic and should not prompt discontinuation 5, 4
• Monitor for genital mycotic infections (6% incidence vs 1% placebo) and urinary tract infections 1, 2, 4
• Assess for signs of volume depletion, especially in elderly patients 1, 4

Hypoglycemia Risk Management

• When initiating SGLT2 inhibitors with sulfonylureas or insulin, reduce sulfonylurea dose or decrease total daily insulin dose by approximately 20% to prevent hypoglycemia 1, 2
• If HbA1c is well-controlled at baseline or patient has history of frequent hypoglycemic events, wean or stop sulfonylurea when starting SGLT2 inhibitor 1

Special Safety Concerns

• Monitor for necrotizing fasciitis of the perineum (Fournier's gangrene)—assess patients with pain, tenderness, erythema, or swelling in genital/perineal area with fever or malaise and institute prompt treatment if suspected 1, 3
• Use with caution in patients with prior amputation, severe peripheral neuropathy, severe peripheral vascular disease, or active diabetic foot ulcers 1
• Monitor for lower limb ulcerations and soft tissue infections; discontinue if these occur 1, 3
• Possible increased risk of bone fractures with canagliflozin—consider fracture risk factors before initiating 1
• Evaluate and treat urinary tract infections promptly to prevent progression to urosepsis or pyelonephritis 3

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Alternative and Combination Therapies

When SGLT2 Inhibitors Alone Are Insufficient

• Add a GLP-1 receptor agonist (semaglutide, dulaglutide, liraglutide) or dual GIP/GLP-1 agonist (tirzepatide) rather than sulfonylureas 1, 2, 5
• GLP-1 receptor agonists provide cardiovascular protection, require no renal dose adjustment, and have low hypoglycemia risk 2, 5
• Tirzepatide provides greatest weight loss (6-13 kg) and HbA1c reduction (1.9-2.6%) 5

When SGLT2 Inhibitors Cannot Be Used

• In advanced CKD (eGFR <30 mL/min/1.73 m²), GLP-1 receptor agonists are preferred over insulin for glycemic management due to lower hypoglycemia risk and cardiovascular event reduction 1, 5
• DPP-4 inhibitor linagliptin requires no dose adjustment across all CKD stages but provides neutral cardiovascular effect 5
• Insulin is indicated when A1C >10% or blood glucose ≥300 mg/dL, or with evidence of ongoing catabolism 1

Combination Strategies

• Metformin plus SGLT2 inhibitor should be first-line dual therapy in patients with eGFR ≥30 mL/min/1.73 m² and cardiovascular disease, heart failure, or CKD 2, 5
• SGLT2 inhibitors can be combined with GLP-1 receptor agonists for additive cardiorenal benefits 5
• Renin-angiotensin system inhibitors (ACEi or ARB) can be used with SGLT2 inhibitors for additive kidney protection 4
• Do not combine SGLT2 inhibitors with DPP-4 inhibitors—no additional clinical advantage 5

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Common Pitfalls to Avoid

• Do not discontinue SGLT2 inhibitors when eGFR falls below 45 mL/min/1.73 m² after initiation—cardiorenal benefits persist despite reduced glucose-lowering efficacy 2, 5, 4
• Do not withhold SGLT2 inhibitors solely because eGFR is <30 mL/min/1.73 m² if already on therapy—continuation preserves cardiorenal benefits 5, 4
• Do not substitute sulfonylureas for SGLT2 inhibitors—sulfonylureas lack cardiovascular and renal benefit and increase hypoglycemia risk 2, 5
• Do not stop SGLT2 inhibitors because of the expected initial eGFR dip—this effect is hemodynamic and reversible 5, 4
• Do not continue sulfonylureas when adding SGLT2 inhibitors—this combination increases hypoglycemia risk without additional benefit 5
• Consider stopping or reducing diuretic dose when initiating SGLT2 inhibitors to prevent intravascular volume contraction 1

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Most Common Adverse Effects (≥5% Incidence)

• Female genital mycotic infections 3
• Urinary tract infections 1, 3
• Increased urination 3
• Euglycemic diabetic ketoacidosis (monitor in at-risk patients) 1, 3