Should I hold off on initiating dapagliflozin in a patient with heart failure who has not yet started taking their prescribed Angiotensin-Converting Enzyme (ACE) inhibitors and beta blockers?

Do Not Hold Dapagliflozin—Initiate It Now Alongside ACE Inhibitors and Beta-Blockers

You should initiate dapagliflozin immediately without waiting for ACE inhibitors and beta-blockers to be started first. Modern heart failure management has evolved beyond the traditional sequential approach, and SGLT2 inhibitors like dapagliflozin are now recognized as foundational therapy that can and should be started concurrently with other guideline-directed medical therapies 1.

Why Concurrent Initiation Is Appropriate

• Dapagliflozin demonstrated efficacy in patients already on optimal background therapy, with 94% of DAPA-HF trial participants receiving ACE inhibitors, ARBs, or ARNIs, and 96% on beta-blockers at baseline 1. However, this does not mean these medications must be started first—it simply reflects the trial population.

• The FDA label for dapagliflozin contains no requirement to initiate ACE inhibitors or beta-blockers before starting dapagliflozin 1. The drug's mechanism of action (SGLT2 inhibition promoting natriuresis and reducing cardiac workload) is independent of renin-angiotensin-aldosterone system blockade or beta-adrenergic blockade.

• Early initiation of dapagliflozin during heart failure hospitalization is being actively studied for its ability to facilitate decongestion and improve natriuresis, suggesting that waiting to optimize other therapies first may actually delay beneficial effects 2.

The Traditional Sequential Approach Is Outdated

• Historical guidelines recommended ACE inhibitors and beta-blockers as first-line therapy because these were the first medications proven to reduce mortality in heart failure 3, 4. The European Society of Cardiology traditionally recommended initiating ACE inhibitors first, followed by beta-blockers after clinical stabilization 4.

• However, this sequential approach was based on the chronological order of clinical trial evidence, not on pharmacological necessity. Beta-blockers were added to guidelines after ACE inhibitors simply because the trials came later 5.

• Modern evidence shows that beta-blockers can be safely initiated in-hospital before discharge, and early initiation improves long-term adherence and outcomes 6, 7. The same principle applies to dapagliflozin.

Practical Implementation Strategy

Start all three medications concurrently using this approach:

For ACE Inhibitors:

• Begin with low doses: enalapril 2.5 mg twice daily, lisinopril 2.5-5 mg once daily, or ramipril 2.5 mg once daily 4, 8.
• Check baseline blood pressure, creatinine, and potassium before initiation 8.
• Accept creatinine increases up to 50% above baseline or to 3 mg/dL (whichever is greater) and potassium up to 5.5 mmol/L 3, 4.
• Double the dose at minimum 2-week intervals until target dose is reached 4, 8.

For Beta-Blockers:

• Initiate only in stable patients without signs of acute decompensation, persistent congestion, or heart rate <60 bpm 3, 4.
• Start with bisoprolol 1.25 mg once daily, carvedilol 3.125 mg twice daily, or metoprolol succinate 12.5-25 mg once daily 4.
• If worsening congestion occurs during titration, double the diuretic dose first before reducing the beta-blocker 4.
• Check blood chemistry 1-2 weeks after initiation and after final dose titration 3.

For Dapagliflozin:

• Start at 10 mg once daily if eGFR ≥30 mL/min/1.73 m² 1.
• No specific titration required—the therapeutic dose is 10 mg daily 1.
• Monitor for volume depletion, especially if the patient is on high-dose diuretics 1.

Critical Cautions When Starting Multiple Medications

Avoid these common pitfalls:

• Do not delay dapagliflozin if ACE inhibitor initiation is complicated by borderline renal function or hyperkalemia. Dapagliflozin does not worsen hyperkalemia and may actually improve renal outcomes independently 1.

• If the patient is hemodynamically unstable or has persistent signs of congestion, delay beta-blocker initiation but proceed with ACE inhibitor and dapagliflozin 4, 3. Beta-blockers should be started after optimization of volume status and successful discontinuation of intravenous diuretics, vasodilators, and inotropic agents 4.

• Asymptomatic hypotension does not require intervention—only symptomatic hypotension (dizziness, confusion) warrants dose adjustment 4, 3, 9. If symptomatic hypotension occurs, reduce or eliminate non-essential vasodilators (nitrates, calcium channel blockers) before reducing ACE inhibitor or beta-blocker doses 4, 9.

• Monitor renal function and electrolytes 1-2 weeks after initiating ACE inhibitors, but do not stop ACE inhibitors for mild creatinine elevation 4, 8. Stopping ACE inhibitors leads to clinical deterioration and should be avoided 4.

Why This Matters for Outcomes

• Concurrent use of high-dose ACE inhibitors, beta-blockers, and additional evidence-based therapies provides incrementally greater reductions in mortality and hospitalization compared to ACE inhibitors alone 10. Patients receiving all proven therapies had 12% fewer deaths and hospitalizations at one year 10.

• Dapagliflozin reduced the composite endpoint of cardiovascular death and heart failure hospitalization by 26% in DAPA-HF (hazard ratio 0.74, p<0.0001), with benefits appearing early and continuing to diverge over time 1.

• Delaying any component of guideline-directed medical therapy denies patients proven mortality and morbidity benefits. The treatment gap in heart failure results from outdated perceptions that medications must be started sequentially 7.

In summary: Initiate dapagliflozin now. Start the ACE inhibitor and beta-blocker concurrently if the patient is stable. If beta-blocker initiation must be delayed due to instability, proceed with dapagliflozin and ACE inhibitor together—do not wait.