What are the precautions and guidelines for using Dapagliflozin (Forxiga) in patients with diabetes?

Dapagliflozin: Precautions and Clinical Guidelines

Dapagliflozin is a highly effective SGLT2 inhibitor with proven cardiovascular, renal, and glycemic benefits, but requires careful attention to renal function thresholds, volume status, surgical timing, and sick day management to prevent serious complications including euglycemic ketoacidosis.

Approved Indications

Dapagliflozin is FDA-approved for multiple indications 1:

• Chronic kidney disease: Reduce risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and heart failure hospitalization in adults with CKD at risk of progression 1
• Heart failure: Reduce cardiovascular death, heart failure hospitalization, and urgent heart failure visits in adults with heart failure (regardless of ejection fraction) 1
• Type 2 diabetes with cardiovascular disease: Reduce heart failure hospitalization in patients with established CVD or multiple CV risk factors 1
• Glycemic control: Adjunct to diet and exercise in adults and pediatric patients ≥10 years with type 2 diabetes 1

The 2019 ESC guidelines strongly recommend empagliflozin, canagliflozin, or dapagliflozin in patients with type 2 diabetes and CVD or very high/high CV risk to reduce cardiovascular events 2.

Critical Renal Function Thresholds

For Glycemic Control

• eGFR ≥45 mL/min/1.73 m²: No dose adjustment required; initiate at 5 mg daily, may increase to 10 mg daily 3, 1
• eGFR <45 mL/min/1.73 m²: Not recommended for glycemic control as the drug is likely ineffective due to its mechanism of action 3, 1

For Cardiovascular and Renal Protection

• eGFR ≥25 mL/min/1.73 m²: Can initiate dapagliflozin 10 mg daily for cardio-renal protection, particularly with albuminuria (UACR 200-5000 mg/g) 3, 4
• eGFR <25 mL/min/1.73 m²: Not recommended for initiation 3
• If eGFR falls below 25 during treatment: May continue 10 mg daily until dialysis initiation 3

The DAPA-CKD trial demonstrated a 39% reduction in the composite outcome of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death in patients with eGFR 25-75 mL/min/1.73 m² 4.

Expected eGFR Changes

An initial reversible eGFR dip of 3-5 mL/min/1.73 m² typically occurs within 1-4 weeks of initiation 3. Check eGFR and creatinine within 1-2 weeks after starting dapagliflozin 3. If eGFR decreases >30% from baseline with signs of hypovolemia, reduce diuretic doses first before adjusting dapagliflozin 3.

Volume Status Assessment and Monitoring

Assess volume status before initiating dapagliflozin and correct any volume depletion 3. Use particular caution in 3:

• Elderly patients
• Patients with low systolic blood pressure
• Patients on concurrent diuretics
• Patients with renal impairment

Monitor closely for intravascular volume contraction, especially during the first weeks of therapy 3.

Surgical and Procedural Management

Withhold dapagliflozin at least 3 days (preferably 3-4 days) before major surgery or procedures requiring prolonged fasting 3, 5. This critical precaution prevents postoperative euglycemic ketoacidosis 3, 5.

A case report documented relapsing euglycemic DKA occurring 8 days after the last dose of dapagliflozin following tibial fracture surgery, with persistent glucosuria and ketonuria for 11 days after drug cessation 6. This underscores the importance of adequate preoperative discontinuation and postoperative monitoring.

Sick Day Management Rules

Temporarily discontinue dapagliflozin during any acute illness 3. Specific triggers requiring immediate discontinuation include 3:

• Fever, vomiting, or diarrhea
• Reduced food and fluid intake
• Any intercurrent illness requiring hospitalization

Patient Education Requirements

Counsel patients to 3:

• Stop dapagliflozin immediately when becoming sick and contact their healthcare provider
• Seek immediate medical attention if symptoms of ketoacidosis develop (malaise, nausea, vomiting)
• Check blood or urine ketones if feeling unwell

Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held, as complete insulin cessation increases DKA risk 3.

Resume dapagliflozin only after recovery from acute illness and re-establishment of normal oral intake 3.

Euglycemic Diabetic Ketoacidosis Risk

Although rare, euglycemic DKA is a serious complication that can occur even with normal blood glucose levels 3, 5, 6. Risk factors include 5:

• Insulin deficiency or reduced insulin doses
• Reduced caloric intake due to illness or fasting
• Acute illness or infection
• Surgical procedures
• Alcohol consumption
• Volume depletion

Monitor for DKA symptoms (malaise, nausea, vomiting) even when blood glucose is normal 3. Check ketones if these symptoms develop 3.

Hypoglycemia Risk and Insulin/Secretagogue Adjustment

Dapagliflozin has a very low intrinsic risk of hypoglycemia when used as monotherapy or with metformin, as it does not stimulate insulin secretion 7. However, risk increases when combined with insulin or sulfonylureas 7.

When initiating dapagliflozin 7:

• With insulin: Reduce insulin dose by 10-20% to prevent hypoglycemia
• With sulfonylureas: Consider reducing the secretagogue dose or switching to a DPP-4 inhibitor

Genital and Urinary Tract Infections

Genital mycotic infections and urinary tract infections are more common with dapagliflozin (2-13%) compared to placebo (0-8%) 8. Educate patients on 3:

• Symptoms of genital and urinary infections
• Prevention strategies (proper hygiene)
• When to seek medical attention

Rare but serious: Necrotizing fasciitis of the perineum (Fournier gangrene) requires prompt recognition and treatment if suspected 3.

Cardiovascular and Renal Benefits

Beyond glycemic control, dapagliflozin provides significant cardio-renal protection 9, 10, 4:

• Reduces cardiovascular death or heart failure hospitalization by 29% 4
• Reduces all-cause mortality by 31% in CKD patients 10
• Slows eGFR decline and reduces risk of ESKD 4
• Reduces blood pressure (systolic 2-5 mmHg, diastolic 1.5-3 mmHg) 8
• Promotes weight loss (~2-3 kg) 8

The ESC guidelines recommend SGLT2 inhibitors (including dapagliflozin) to lower heart failure hospitalization risk and reduce progression of diabetic kidney disease 2.

Contraindications and Special Populations

Absolute contraindications 1:

• Type 1 diabetes mellitus (not recommended for glycemic control)
• Polycystic kidney disease
• Recent or current immunosuppressive therapy for kidney disease

Use with caution in 3:

• Elderly patients (higher risk of volume depletion)
• Patients with low blood pressure
• Patients on concurrent diuretics (consider proactive dose reduction)

Monitoring Parameters

• Renal function: Assess before initiation and periodically thereafter, with specific check at 1-2 weeks post-initiation 3
• Volume status: Before starting and during therapy 3
• Ketones: If symptoms of malaise, nausea, or vomiting develop 3
• Genital/urinary symptoms: Ongoing patient education and monitoring 3