What is the cardiac advantage of dapagliflozin (SGLT2 inhibitor) in patients with type 2 diabetes and established cardiovascular disease or high risk of developing it?

Cardiac Advantages of Dapagliflozin

Dapagliflozin reduces hospitalization for heart failure by 27-36% and cardiovascular death by 18%, with consistent benefits across all patients with type 2 diabetes regardless of baseline cardiovascular disease status. 1, 2

Primary Cardiovascular Benefits

Heart Failure Outcomes

• Dapagliflozin reduces the composite outcome of cardiovascular death or hospitalization for heart failure by 17-18% compared to placebo in patients with type 2 diabetes and established cardiovascular disease or multiple risk factors 1, 3
• The benefit is primarily driven by a 27-36% reduction in hospitalization for heart failure alone, which represents the most robust cardiac advantage 1, 4
• In the DAPA-HF trial, dapagliflozin demonstrated a 26% reduction in worsening heart failure or cardiovascular death in patients with heart failure and reduced ejection fraction, with effects consistent regardless of diabetes status 1, 2
• The DELIVER trial showed an 18% reduction in the composite of worsening heart failure or cardiovascular death in patients with heart failure and preserved ejection fraction (HFpEF) 1, 2

Cardiovascular Death Reduction

• Dapagliflozin reduces cardiovascular death by 18% in patients with established heart failure 1
• In patients with prior myocardial infarction specifically, dapagliflozin reduces major adverse cardiovascular events (MACE) by 16% with an absolute risk reduction of 2.6%, whereas no effect was seen in patients without prior MI 5
• The benefit for MACE appears greatest within 2 years after an acute cardiac event 5

Mechanism-Independent Benefits

Glucose-Independent Effects

• The cardiovascular and renal benefits occur independently of baseline HbA1c levels and glucose-lowering effects, as demonstrated by comparable outcomes in patients with and without diabetes 1, 2
• Benefits are consistent in patients with HbA1c <7%, indicating that treatment decisions should be based on cardiovascular and renal risk rather than glycemic targets alone 2

Blood Pressure-Independent Benefits

• Dapagliflozin reduces hospitalization for heart failure and renal outcomes regardless of baseline systolic blood pressure, including in normotensive patients (SBP <120 mmHg) 6
• In normotensive patients, the hazard ratios were 0.66 for hospitalization for heart failure and 0.39 for renal outcomes 6
• Dapagliflozin produces a modest placebo-corrected systolic blood pressure reduction of 2.4 mmHg at 48 months 6

Additive Benefits with Standard Therapy

• Dapagliflozin provides consistent cardiovascular benefits regardless of background use of ACE inhibitors/ARBs, beta-blockers, diuretics, or mineralocorticoid receptor antagonists 7
• In patients receiving triple therapy (ACE inhibitor/ARB + beta-blocker + diuretic), dapagliflozin still reduced cardiovascular death/hospitalization for heart failure by 24% and kidney outcomes by 38% 7
• The American Diabetes Association and American College of Cardiology recommend SGLT2 inhibitors as a class for patients with type 2 diabetes and established cardiovascular disease, without preferential recommendation between dapagliflozin and empagliflozin 8, 9

Renal Protection as Cardiovascular Benefit

• Dapagliflozin reduces the risk of sustained eGFR decline by 40%, end-stage kidney disease, or renal death by approximately 47-51% 1, 4
• At 48 months, estimated glomerular filtration rate was higher with dapagliflozin versus placebo, while urinary albumin-to-creatinine ratio was lower 4
• The National Kidney Foundation recommends dapagliflozin to reduce progression of diabetic kidney disease in patients with albuminuria or reduced eGFR 2

Clinical Application Algorithm

Who Should Receive Dapagliflozin for Cardiac Protection:

1. All patients with type 2 diabetes and established atherosclerotic cardiovascular disease to reduce cardiovascular death and heart failure hospitalization 2
2. Patients with type 2 diabetes and multiple cardiovascular risk factors, defined as age ≥55 years (men) or ≥60 years (women) plus at least one additional risk factor (dyslipidemia, hypertension, tobacco use, arterial stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria) 2
3. All patients with heart failure (both HFrEF and HFpEF), regardless of diabetes status, to reduce hospitalization and cardiovascular mortality 2
4. Patients with prior myocardial infarction, who derive particularly robust benefit with 16% MACE reduction and 2.6% absolute risk reduction 5

Dosing

• Standard dose is 10 mg once daily for cardiovascular and heart failure indications 2, 3
• Discontinue at least 3 days before planned surgery to prevent postoperative ketoacidosis 2, 9

Safety Considerations

• Monitor for genital mycotic infections and urinary tract infections, which are common adverse effects 8
• Assess volume status before initiation and correct volume depletion if present; consider reducing diuretic dose in patients at risk for volume depletion 2
• Assess for euglycemic diabetic ketoacidosis risk, particularly before surgery or during acute illness 8
• Consider reducing insulin or sulfonylurea doses by approximately 20% when initiating to prevent hypoglycemia 8
• No significant treatment interactions with concomitant cardiovascular medications for adverse events of volume depletion, acute kidney injury, or hyperkalemia 7