What are the benefits and risks of dapagliflozin (Forxiga) for a patient with a history of type 2 diabetes or heart failure, considering their kidney function and overall health?

DECLARE-TIMI 58 Trial Summary for Hospital Patients

Trial Design and Patient Population

The DECLARE-TIMI 58 trial was a large cardiovascular outcomes study that randomized 17,160 patients with type 2 diabetes to dapagliflozin 10 mg daily versus placebo, with a median follow-up of 4.2 years. 1 The trial included patients with either established atherosclerotic cardiovascular disease (40.6% of participants) or multiple cardiovascular risk factors (59.4%), with a mean age of 64 years and median diabetes duration of 11 years. 1, 2

Primary Outcomes

Cardiovascular Safety (MACE)

• Dapagliflozin met the primary safety endpoint by demonstrating non-inferiority for major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, or ischemic stroke), with a hazard ratio of 0.93 (95% CI 0.84-1.03), meaning it did not increase cardiovascular risk. 1
• However, dapagliflozin did not show superiority for reducing MACE in the overall population. 1

Heart Failure and Cardiovascular Death

• Dapagliflozin significantly reduced the co-primary efficacy endpoint of cardiovascular death or hospitalization for heart failure by 17% (HR 0.83; 95% CI 0.73-0.95). 1, 3
• Hospitalization for heart failure alone was reduced by 27% (HR 0.73; 95% CI 0.61-0.88). 1, 3

Kidney Protection

• Dapagliflozin demonstrated a 47% reduction in composite renal events (sustained decrease in eGFR by 40%, progression to end-stage kidney disease, or renal death), with HR 0.53 (95% CI 0.43-0.66). 1, 3

Subgroup Findings

Patients with Prior Myocardial Infarction

• In the 3,584 patients with previous MI, dapagliflozin reduced MACE by 16% (HR 0.84; 95% CI 0.72-0.99), with an absolute risk reduction of 2.6%. 4
• The benefit appeared greatest within 2 years after the most recent acute event. 4

Blood Pressure Subgroups

• The cardiovascular and renal benefits were consistent across all baseline blood pressure categories, including normotensive patients (SBP <120 mm Hg), with no increased risk of volume depletion, amputation, or acute kidney injury at any blood pressure level. 2

Concurrent Cardiovascular Medications

• The benefits of dapagliflozin were consistent regardless of background use of ACE inhibitors/ARBs (81% of patients), beta-blockers (53%), diuretics (36%), or mineralocorticoid receptor antagonists (4%). 5
• In patients receiving triple therapy with ACE inhibitors/ARBs + beta-blockers + diuretics, dapagliflozin reduced cardiovascular death/heart failure hospitalization by 24% and kidney outcomes by 38%. 5

Safety Profile

Common Adverse Events

• Genital mycotic infections occurred more frequently with dapagliflozin (approximately 6% vs 1% with placebo). 6, 7
• Volume depletion events did not differ significantly between groups across all blood pressure categories. 2
• No significant increase in acute kidney injury, lower-limb amputations, or hyperkalemia was observed. 5

Serious Safety Concerns

• Diabetic ketoacidosis risk increased (2.2 vs 0.2 events per 1,000 patient-years with placebo), including euglycemic DKA. 1, 7
• Patients should withhold dapagliflozin during acute illness, reduced oral intake, or at least 3 days before major surgery. 6, 7

Clinical Implications for Your Patient

Indications Based on DECLARE-TIMI 58

• Dapagliflozin 10 mg daily is indicated for reducing hospitalization for heart failure in adults with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors. 7
• The medication provides significant kidney protection with a 47% reduction in adverse renal outcomes. 3

Dosing and Monitoring

• The fixed dose is 10 mg once daily, with no titration required. 6
• For glycemic control, dapagliflozin should not be initiated if eGFR <45 mL/min/1.73 m², though cardiovascular and renal benefits persist at eGFR 25-44 mL/min/1.73 m². 6
• Do not initiate if eGFR <25 mL/min/1.73 m², but may continue if already on treatment. 6

Key Safety Precautions

• Assess volume status before initiation and correct any depletion. 6
• Educate patients to stop dapagliflozin during acute illness, fever, vomiting, or diarrhea. 6
• Monitor for symptoms of ketoacidosis (nausea, vomiting, abdominal pain, fatigue) even with normal blood glucose. 7
• Consider reducing concurrent diuretic doses to prevent excessive volume depletion. 6