What are the indications, adverse effects, precautions, and contraindications of Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, specifically dapagliflozin (Farxiga)?

Dapagliflozin (Farxiga): Indications, Adverse Effects, Precautions, and Contraindications

Indications

Dapagliflozin is FDA-approved for four distinct indications, each with specific dosing requirements based on renal function. 1

Chronic Kidney Disease

• Reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression 1
• Dose: 10 mg orally once daily 1
• Can be initiated if eGFR ≥25 mL/min/1.73 m² 1
• Not recommended for polycystic kidney disease or patients requiring immunosuppressive therapy for kidney disease 1

Heart Failure

• Reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure (regardless of ejection fraction) 1
• Dose: 10 mg orally once daily 1
• Can be initiated if eGFR ≥25 mL/min/1.73 m² 1

Type 2 Diabetes with Cardiovascular Risk

• Reduce the risk of hospitalization for heart failure in adults with type 2 diabetes and either established cardiovascular disease or multiple cardiovascular risk factors 1
• Dose: 10 mg orally once daily 1
• Can be initiated if eGFR ≥25 mL/min/1.73 m² 1

Glycemic Control

• As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes 1
• Starting dose: 5 mg orally once daily 1
• Can increase to 10 mg once daily for additional glycemic control 1
• Critical limitation: Not recommended for glycemic control if eGFR <45 mL/min/1.73 m² as it is likely ineffective based on mechanism of action 1
• Not recommended for type 1 diabetes 1

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Dosing Algorithm by Renal Function

For Glycemic Control (Type 2 Diabetes)

• eGFR ≥45 mL/min/1.73 m²: Start 5 mg daily, may increase to 10 mg daily 1
• eGFR <45 mL/min/1.73 m²: Do not use for glycemic control (ineffective) 1

For Cardiovascular/Renal Protection (CKD, Heart Failure, CV Risk Reduction)

• eGFR ≥25 mL/min/1.73 m²: 10 mg once daily 1
• eGFR <25 mL/min/1.73 m²: Do not initiate 1
• If eGFR falls below 25 mL/min/1.73 m² during treatment: May continue 10 mg daily until dialysis 1

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Contraindications

Dapagliflozin has only one absolute contraindication per FDA labeling. 1

• History of serious hypersensitivity reaction to dapagliflozin or any excipients, including anaphylaxis and angioedema 1

Additional contraindications from clinical guidelines:

• Pregnancy or breastfeeding 2
• On dialysis 2
• End-stage renal disease (ESRD) 2

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Precautions and Cautions

Critical Surgical Precaution

• Withhold dapagliflozin at least 3 days before major surgery or procedures with prolonged fasting to prevent postoperative ketoacidosis 2, 1
• Resume only when patient is clinically stable and has resumed oral intake 1

Diabetic Ketoacidosis (Most Serious Risk)

• Euglycemic diabetic ketoacidosis can occur even with normal blood glucose levels (<250 mg/dL) 2, 1
• Risk factors: Type 1 diabetes (contraindicated), type 2 diabetes, pancreatic disorders, under-insulinization, acute illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, alcohol abuse 1
• Withhold during acute illness, particularly with fever, vomiting, diarrhea, or reduced oral intake 3
• Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held 3
• Assess for ketoacidosis in any patient presenting with nausea, vomiting, abdominal pain, malaise, or shortness of breath regardless of glucose level 1

Volume Depletion and Hypotension

• May cause intravascular volume contraction, particularly in patients with renal impairment, low systolic blood pressure, elderly patients, or those on diuretics 2
• Consider stopping or reducing diuretic dose when initiating dapagliflozin 2
• Assess volume status before starting and correct volume depletion if present 3

Hypoglycemia Risk with Concomitant Medications

• If HbA1c well-controlled at baseline or history of frequent hypoglycemia, wean or stop sulfonylurea/glinide and consider reducing total daily insulin dose by ~20% when starting dapagliflozin 2
• Low intrinsic hypoglycemia risk when used alone 4

Amputation and Peripheral Vascular Disease

• Use with caution in patients with prior amputation, severe peripheral neuropathy, severe peripheral vascular disease, or active diabetic foot ulcers or soft tissue infections 2
• Note: Increased amputation risk has been seen with canagliflozin but not with dapagliflozin to date 2

Bone Fracture Risk

• Possible increased risk of bone fractures with canagliflozin (not specifically noted for dapagliflozin) 2

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Adverse Effects to Monitor

Common Adverse Effects

Genital Mycotic Infections (Most Common)

• Occur in approximately 6% of patients on SGLT2 inhibitors versus 1% on placebo 3
• More frequent in dapagliflozin-treated patients than placebo 5, 4
• Daily hygienic measures may reduce risk 3

Urinary Tract Infections

• More frequent with dapagliflozin than placebo 2, 5, 4

Lower Limb Ulcerations and Soft Tissue Infections

• Monitor in high-risk patients 2

Serious Adverse Effects

Euglycemic Diabetic Ketoacidosis

• Life-threatening event that can occur with normal glucose levels 2, 1
• Educate all patients on signs/symptoms and instruct to discontinue immediately if they occur 1

Necrotizing Fasciitis of the Perineum (Fournier Gangrene)

• Rare but serious; requires prompt treatment if suspected 3

Laboratory Changes

• Increased hematocrit 6
• Increased serum parathyroid hormone levels 6
• Decreased serum uric acid 6
• Initial reversible eGFR dip of 3-5 mL/min/1.73 m² within first 1-4 weeks (transient and expected) 3

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Key Monitoring Parameters

• Renal function: Check eGFR before initiation, within 1-2 weeks after starting, then every 3-6 months if eGFR 45-59 mL/min/1.73 m², or annually if eGFR ≥60 mL/min/1.73 m² 3
• Volume status: Assess before starting and monitor for signs of dehydration 3
• Ketones: Consider monitoring in high-risk patients (type 1 diabetes, acute illness, reduced intake) 1
• Signs of genital/urinary infections: Educate patients on recognition and prevention 3

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Common Pitfalls to Avoid

• Do not discontinue dapagliflozin solely because eGFR falls below 45 mL/min/1.73 m² — cardiovascular and renal protective benefits persist even when glycemic efficacy is lost 3
• Do not use for glycemic control if eGFR <45 mL/min/1.73 m² — it is ineffective for this indication 1
• Do not forget to withhold during acute illness — this is critical to prevent ketoacidosis 3
• Do not reduce insulin excessively when holding dapagliflozin during illness — complete insulin cessation increases DKA risk 3