Which patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD) or high risk for cardiovascular events benefit from dapagliflozin (SGLT2 inhibitor)?

Which Patient Populations Benefit from Dapagliflozin

Dapagliflozin is recommended for adults with type 2 diabetes who have either established cardiovascular disease OR multiple cardiovascular risk factors, with particularly strong benefits for reducing heart failure hospitalization and progression of kidney disease. 1, 2

Primary Indications for Dapagliflozin

Type 2 Diabetes with Established Cardiovascular Disease

• Patients with documented atherosclerotic cardiovascular disease (prior MI, stroke, or peripheral artery disease) should receive dapagliflozin to reduce cardiovascular death and heart failure hospitalization. 1
• The DECLARE-TIMI 58 trial demonstrated a 17% reduction in the composite of cardiovascular death or heart failure hospitalization (HR 0.83,95% CI 0.73-0.95) in this population. 1, 3
• Dapagliflozin showed a 27% reduction specifically in heart failure hospitalization (HR 0.73,95% CI 0.61-0.88). 3

Type 2 Diabetes with Multiple Risk Factors (Without Established CVD)

• Patients aged ≥55 years (men) or ≥60 years (women) with at least one additional risk factor qualify as high-risk and benefit from dapagliflozin. 1
• Additional risk factors include: dyslipidemia, hypertension, current tobacco use, coronary/carotid/lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria. 1
• In the DECLARE-TIMI 58 trial, 59.4% of participants had multiple risk factors without established CVD, and dapagliflozin still reduced cardiovascular death or heart failure hospitalization. 1, 3

Heart Failure Patients (Regardless of Diabetes Status)

• Dapagliflozin is recommended for all patients with heart failure and reduced ejection fraction (HFrEF), even without diabetes, to reduce hospitalization and cardiovascular mortality. 1, 2, 4
• The DAPA-HF trial showed a 26% reduction in worsening heart failure or cardiovascular death in HFrEF patients. 4
• Benefits extend to heart failure with preserved ejection fraction (HFpEF), with an 18% reduction in the DELIVER trial. 4
• Among patients with type 2 diabetes and existing heart failure (10-15% of trial populations), dapagliflozin provides particularly robust benefits. 1

Chronic Kidney Disease Patients

• Dapagliflozin is recommended to reduce progression of diabetic kidney disease in patients with albuminuria or reduced eGFR. 1
• Benefits include reduced risk of sustained eGFR decline by 40%, progression to end-stage renal disease, or renal death. 1, 5
• The renal benefits are consistent across all baseline blood pressure categories, including normotensive patients (HR 0.39,95% CI 0.19-0.78 for renal outcomes). 5

Key Clinical Considerations

Independence from Glycemic Control

• The cardiovascular and renal benefits of dapagliflozin occur independently of baseline HbA1c levels, including patients with HbA1c <7%. 1, 6
• Treatment decisions should be made based on cardiovascular and renal risk, not glycemic targets alone. 1
• Higher baseline HbA1c is associated with greater cardiovascular risk (HR 1.12 per 1% increase for CV death/HHF), but dapagliflozin benefits are consistent across all HbA1c subgroups. 6

Blood Pressure Considerations

• Dapagliflozin provides cardiorenal benefits regardless of baseline blood pressure, including normotensive patients (SBP <120 mmHg). 5
• The drug reduces systolic blood pressure by approximately 2.4 mmHg compared to placebo, without increasing volume depletion events. 5
• No dose adjustment is needed based on blood pressure status. 5

Dosing Specifications

• A fixed dose of 10 mg orally once daily is recommended for cardiovascular and renal indications in adults. 2, 4, 3
• For pediatric patients aged 10-17 years with type 2 diabetes, doses of 5 mg or 10 mg once daily are approved for glycemic control. 3

Important Safety Caveats

Temporary Discontinuation Scenarios

• Hold dapagliflozin at least 3 days before major surgery or procedures with prolonged fasting to prevent postoperative ketoacidosis. 2, 4
• Temporarily discontinue in patients with acute illness causing inability to maintain oral intake, significant volume depletion, or severe nausea/vomiting/diarrhea. 7

Medication Interactions Requiring Dose Adjustment

• Reduce insulin dose by approximately 20% when initiating dapagliflozin to prevent hypoglycemia. 2, 7
• Consider reducing diuretic doses if patient is at risk for volume depletion. 4
• The risk of hypoglycemia is low with dapagliflozin monotherapy but increases when combined with insulin or sulfonylureas. 2

Monitoring Requirements

• Monitor for diabetic ketoacidosis (DKA), particularly in patients with type 1 diabetes or those on insulin, as this is a rare but serious adverse effect. 2, 4
• Assess volume status before initiation and correct volume depletion if present. 4
• Genital fungal infections and urinary tract infections are more common with dapagliflozin than placebo. 8, 9

Populations Where Evidence is Strongest

Established Atherosclerotic Disease

• The strongest evidence supports use in patients with documented prior cardiovascular events (40.6% of DECLARE-TIMI 58 participants). 3, 6
• This includes patients with prior ischemic stroke, who were specifically included in major trials and derive substantial cardiovascular benefits. 7

Multiple Risk Factors Without Prior Events

• Higher baseline HbA1c is associated with greater increased risk for MACE and cardiorenal outcomes in the multiple risk factors population compared to established ASCVD (P-interaction = 0.0064 and 0.0093). 6
• Despite this, dapagliflozin benefits remain consistent regardless of baseline HbA1c in both populations. 6

Renal Impairment Considerations

• Dapagliflozin can be used with eGFR ≥25 mL/min/1.73 m² for cardiovascular and renal benefits, but should not be initiated for glycemic control when eGFR <45 mL/min/1.73 m². 7
• Mean baseline eGFR in DECLARE-TIMI 58 was 85.2 mL/min/1.73 m², with 23.5% having microalbuminuria and 6.8% having macroalbuminuria. 3

Common Pitfalls to Avoid

• Do not withhold dapagliflozin from patients who achieve glycemic targets, as cardiovascular and renal benefits are independent of glucose-lowering effects. 1, 4
• Do not permanently discontinue dapagliflozin after acute events like stroke; restart once patient is clinically stable with adequate oral intake. 7
• Do not ignore the need for insulin dose reduction when initiating dapagliflozin in insulin-treated patients. 2, 7
• Do not assume normotensive patients won't benefit; cardiorenal benefits are consistent across all blood pressure categories. 5