What is the recommended management plan for patients with type 2 diabetes at high risk for cardiovascular events, considering the latest Cardiovascular Outcomes Trial (CVOT) on dapagliflozin (DAPA)?

Latest Cardiovascular Outcomes Trial on Dapagliflozin

DECLARE-TIMI 58: The Definitive CVOT for Dapagliflozin

The DECLARE-TIMI 58 trial (2018) is the largest and most recent cardiovascular outcomes trial for dapagliflozin, demonstrating a 17% reduction in the composite of cardiovascular death or heart failure hospitalization (HR 0.83,95% CI 0.73-0.95), driven primarily by a 27% reduction in heart failure hospitalization (HR 0.73,95% CI 0.61-0.88). 1

Trial Design and Population

• DECLARE-TIMI 58 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 uniquely enrolled a broader population than other SGLT2 inhibitor CVOTs: 40.6% had established cardiovascular disease while 59.4% had multiple risk factors only (age ≥55 years in men or ≥60 years in women plus at least one additional CV risk factor) 1
• Mean baseline characteristics: HbA1c 8.3%, eGFR 85.2 mL/min/1.73 m², 10% with history of heart failure 1

Primary Cardiovascular Outcomes

Dapagliflozin demonstrated cardiovascular non-inferiority for MACE (cardiovascular death, MI, or ischemic stroke) with HR 0.93 (95% CI 0.84-1.03), meeting the pre-specified non-inferiority margin of 1.3. 1

• The incidence of MACE was 2.30 events per 100 patient-years with dapagliflozin versus 2.46 with placebo 1
• Dapagliflozin was superior to placebo for the co-primary endpoint of cardiovascular death or heart failure hospitalization: HR 0.83 (95% CI 0.73-0.95, p=0.0035) 1
• The benefit was driven by a 27% reduction in heart failure hospitalization (HR 0.73,95% CI 0.61-0.88) with no significant change in cardiovascular death alone 1

Subgroup Analysis: 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, p=0.039) with an absolute risk reduction of 2.6%, whereas there was no MACE benefit in patients without prior MI (HR 1.00,95% CI 0.88-1.13). 2

• The benefit appeared greatest within 2 years after the last acute MI event (p for interaction trend=0.007) 2
• For cardiovascular death/heart failure hospitalization, absolute risk reductions were 1.9% in patients with prior MI versus 0.6% in those without 2

Renal Outcomes

• Dapagliflozin significantly reduced the composite renal endpoint of sustained ≥40% decline in eGFR, end-stage kidney disease, or renal/cardiovascular death by 24% (HR 0.76,95% CI 0.67-0.87) 1
• At baseline, 23.5% had microalbuminuria and 6.8% had macroalbuminuria 1

Subsequent Heart Failure Trials

DAPA-HF Trial (2019)

The DAPA-HF trial enrolled 4,744 patients with heart failure and reduced ejection fraction (LVEF ≤40%), demonstrating a 26% reduction in cardiovascular death or worsening heart failure (HR 0.74,95% CI 0.65-0.85) over 18 months, with benefits independent of diabetes status. 1, 3

• 55% of patients did not have diabetes, establishing dapagliflozin as the first SGLT2 inhibitor proven effective in heart failure regardless of diabetes 3
• Hospitalization for heart failure was reduced by 30% (HR 0.70,95% CI 0.59-0.83) 1
• The treatment effect curves separated early and continued to diverge throughout the trial 1

DELIVER Trial (2022)

• DELIVER enrolled 6,263 patients with heart failure and preserved ejection fraction (LVEF >40%), showing an 18% reduction in cardiovascular death, heart failure hospitalization, or urgent heart failure visits (HR 0.82,95% CI 0.73-0.92) over 28 months 1
• This established dapagliflozin's efficacy across the entire spectrum of heart failure phenotypes 1

DAPA-CKD Trial (2020): Renal Protection

The DAPA-CKD trial demonstrated that dapagliflozin reduced the primary composite renal endpoint (≥50% sustained eGFR decline, ESKD, or renal/cardiovascular death) by 39% (HR 0.61,95% CI 0.51-0.72) in patients with CKD and albuminuria, regardless of diabetes status. 1, 4

• The trial enrolled patients with eGFR 25-75 mL/min/1.73 m² and UACR 200-5000 mg/g 4
• 67.5% had diabetes and 32.5% did not, with consistent benefits in both groups 5
• The kidney-specific composite was reduced by 44% (HR 0.56,95% CI 0.45-0.68) 1
• Cardiovascular death or heart failure hospitalization was reduced by 29% (HR 0.71,95% CI 0.55-0.92) 1

Clinical Implications from Guidelines

Current ESC and ADA guidelines recommend dapagliflozin (along with empagliflozin and canagliflozin) in patients with type 2 diabetes and established cardiovascular disease or very high/high cardiovascular risk to reduce cardiovascular events, independent of glycemic control needs. 6

• The 2019 ESC Guidelines give a Class I, Level A recommendation for SGLT2 inhibitors including dapagliflozin in patients with type 2 diabetes and CVD or at very high/high CV risk 6
• Dapagliflozin is recommended at a fixed dose of 10 mg once daily for cardiovascular and renal protection, regardless of eGFR level (as long as ≥25 mL/min/1.73 m²) 4
• For glycemic control, dapagliflozin should not be initiated if eGFR <45 mL/min/1.73 m², but cardiovascular and renal benefits persist at lower eGFR levels 4

Key Safety Considerations from CVOTs

• Genital mycotic infections occurred in approximately 6% of patients versus 1% on placebo 4
• Dapagliflozin should be withheld at least 3 days before major surgery or procedures requiring prolonged fasting to prevent postoperative ketoacidosis 4
• Volume depletion risk is higher in elderly patients and those on concurrent diuretics, requiring assessment before initiation 4
• An initial reversible eGFR dip of 3-5 mL/min/1.73 m² typically occurs within 1-4 weeks, followed by long-term renal protection 4