What are the indications and uses of dapagliflozin (SGLT2 inhibitor) in patients with type 2 diabetes?

Dapagliflozin Indications and Uses in Type 2 Diabetes

Primary Indication: Glycemic Control

Dapagliflozin is FDA-approved 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 mellitus. 1

• Mechanism of action: Dapagliflozin selectively inhibits SGLT2 in the proximal renal tubule, blocking approximately 90% of glucose reabsorption and increasing urinary glucose excretion by 30-80 grams daily in a dose-dependent, insulin-independent manner 2, 3, 4

• Glycemic efficacy: Produces HbA1c reductions of 0.5-0.9% when used as monotherapy or add-on therapy, with effects maintained up to 1-4 years 2, 5, 6

• Dosing for glycemic control: Start 5 mg once daily, may increase to 10 mg once daily if additional glycemic control is needed and eGFR ≥45 mL/min/1.73 m² 7, 1

Critical Renal Limitation for Glycemic Control

Do not initiate dapagliflozin for glycemic control if eGFR <45 mL/min/1.73 m²—the drug becomes ineffective due to insufficient filtered glucose reaching the proximal tubule. 2, 7

Cardiovascular Indications (Independent of Diabetes Status)

Heart Failure with Reduced Ejection Fraction (HFrEF)

Dapagliflozin 10 mg once daily reduces cardiovascular death and hospitalization for heart failure by 26% in patients with HFrEF (LVEF ≤40%), regardless of diabetes status. 7, 5

• Initiate if eGFR ≥25 mL/min/1.73 m² 7
• Fixed dose of 10 mg daily—no titration required 7

Heart Failure with Preserved Ejection Fraction (HFpEF)

Dapagliflozin 10 mg once daily reduces cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in patients with LVEF >40%. 7, 1

• 76% of patients in the DELIVER trial were >65 years old 1

Type 2 Diabetes with Established ASCVD or Multiple CV Risk Factors

Dapagliflozin reduces hospitalization for heart failure in patients with type 2 diabetes and established atherosclerotic cardiovascular disease or multiple cardiovascular risk factors. 5, 1

• The DECLARE-TIMI 58 trial demonstrated significant reduction in major adverse cardiovascular events and heart failure hospitalizations 2

Chronic Kidney Disease Indication

Dapagliflozin 10 mg once daily reduces the risk of sustained eGFR decline ≥50%, end-stage kidney disease, and renal or cardiovascular death by 39% in patients with CKD (eGFR 25-75 mL/min/1.73 m²), regardless of diabetes status. 2, 7

Patient Selection Criteria

• eGFR 25-75 mL/min/1.73 m² (can initiate down to eGFR ≥20 mL/min/1.73 m² per some guidelines) 2, 7
• UACR ≥200 mg/g (some guidelines recommend ≥30 mg/g) 2, 7
• Benefits demonstrated in both diabetic (67.5%) and non-diabetic (32.5%) patients 7

Renal-Specific Benefits

• Reduces kidney-specific composite outcome (≥50% sustained eGFR decline, ESKD, or renal death) by 44% 7
• Slows rate of eGFR decline by approximately 1 mL/min/1.73 m²/year 7
• Reduces cardiovascular death or heart failure hospitalization by 29% in CKD patients 7

Combination Therapy Strategies

With Metformin

Dapagliflozin as add-on to metformin provides complementary mechanisms—metformin reduces hepatic glucose production while dapagliflozin increases urinary glucose excretion. 1, 6

• No dose adjustment needed for either drug if eGFR ≥60 mL/min/1.73 m² 7
• Low hypoglycemia risk with this combination 7

With DPP-4 Inhibitors (e.g., Sitagliptin)

Adding dapagliflozin 10 mg to sitagliptin ± metformin reduces HbA1c by an additional 0.48% compared to placebo, with 2 kg greater weight loss. 1

• Continue sitagliptin without adjustment if eGFR ≥45 mL/min/1.73 m² 7

With Insulin

Dapagliflozin 5-10 mg added to insulin ± up to 2 oral agents reduces HbA1c by 0.5-0.6% and body weight by 1.0-1.7 kg compared to placebo. 1

• Critical safety consideration: Maintain at least low-dose insulin even during sick days when dapagliflozin is held to prevent diabetic ketoacidosis 7

With GLP-1 Receptor Agonists

Dapagliflozin 10 mg combined with exenatide extended-release 2 mg weekly provides superior glycemic control (HbA1c reduction -1.77%) compared to either agent alone. 1

• Complementary cardiovascular and renal benefits when used together 5

Place in Treatment Algorithm

For patients with type 2 diabetes and established heart failure, CKD, or ASCVD, initiate dapagliflozin independent of HbA1c levels and metformin use—these are organ protection indications, not purely glycemic indications. 2, 5

Early vs. Late Therapy

• Early initiation recommended: Start dapagliflozin as part of foundational therapy within 3-6 months of heart failure diagnosis alongside ACE inhibitors/ARNIs, beta-blockers, and MRAs 7
• Can be used as monotherapy in metformin-intolerant patients 3
• Preferred over sulfonylureas when weight loss is desired 6, 8

Additional Metabolic Benefits Beyond Glycemic Control

Dapagliflozin provides pleiotropic effects that extend beyond glucose lowering, making it particularly valuable in patients with metabolic syndrome. 9, 8

• Weight loss: 1.6-2.1 kg reduction compared to placebo 1, 6
• Blood pressure reduction: Modest decrease (2-5 mmHg systolic) through osmotic diuresis and natriuresis 3, 9, 8
• Lipid profile improvement: Favorable effects on triglycerides and HDL 8
• Uric acid reduction: Decreases serum uric acid levels 8
• Anti-inflammatory effects: Reduces high-sensitivity C-reactive protein 8

Safety Considerations and Contraindications

Absolute Contraindications

• Do not initiate if eGFR <25 mL/min/1.73 m² (though may continue if already on therapy until dialysis) 7, 1
• Withhold at least 3 days before major surgery or prolonged fasting to prevent euglycemic diabetic ketoacidosis 7, 5

Common Adverse Effects

• Genital mycotic infections: Occur in ~6% vs. 1% with placebo—counsel on hygiene measures 7, 5
• Urinary tract infections: More frequent than placebo 2, 5
• Volume depletion: Higher risk in elderly, those on diuretics, or with low baseline blood pressure 5, 1

Rare but Serious Risks

• Euglycemic diabetic ketoacidosis: Can occur with normal blood glucose levels—educate patients to check ketones if experiencing malaise, nausea, or vomiting 7, 5
• Fournier gangrene: Necrotizing fasciitis of the perineum—requires immediate treatment if suspected 5

Sick Day Management Protocol

Instruct patients to stop dapagliflozin immediately during any acute illness with reduced oral intake, fever, vomiting, or diarrhea. 7

• Check blood or urine ketones if malaise, nausea, or vomiting develops 7
• Resume only after recovery and normal oral intake is re-established 7
• Do not reduce insulin doses excessively when holding dapagliflozin 7

Monitoring Requirements

Initial Assessment

• Check eGFR and volume status before initiation 7
• Correct volume depletion if present before starting 7

Ongoing Monitoring

• Recheck eGFR within 1-2 weeks after initiation (expect transient 3-5 mL/min/1.73 m² dip) 7
• Monitor eGFR every 3-6 months if eGFR 45-59 mL/min/1.73 m², or annually if ≥60 mL/min/1.73 m² 7
• Assess for genital/urinary infections at each visit 7

Critical Pitfall 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. 2, 7