What to do with a patient with heart failure with reduced ejection fraction (HFrEF) who experiences recurrent muscle pain upon restarting dapagliflozin (SGLT2 inhibitor) after a previous episode of muscle pain led to its discontinuation?

Discontinue Dapagliflozin Permanently in This Patient

Given the clear temporal relationship with recurrent muscle pain upon rechallenge, dapagliflozin should be permanently discontinued in this patient with HFrEF, despite its proven mortality benefit. While extensive safety data from DAPA-HF and other trials do not identify myalgia as a significant adverse event associated with dapagliflozin, the reproducible symptom pattern (pain with drug, resolution off drug, recurrence upon rechallenge) establishes a probable causal relationship that outweighs the benefits in this individual patient 1.

Why This Represents a True Drug Reaction

• The positive rechallenge test—where symptoms resolved completely after stopping dapagliflozin and returned specifically upon restarting—provides the strongest evidence for drug causation in clinical medicine 1
• Although muscle pain is not listed as a common adverse effect in major trials (DAPA-HF showed no excess myalgia signals), individual patients can experience idiosyncratic reactions not captured in population-level data 2, 3
• The American College of Cardiology acknowledges that while dapagliflozin has a favorable safety profile with minimal effects on potassium, heart rate, or blood pressure, individual tolerability issues can occur 1

Alternative Explanations Were Already Excluded

Before attributing symptoms to dapagliflozin, the following should have been systematically evaluated (and if not, should be confirmed now) 1:

• Volume depletion: Check for orthostatic hypotension, dizziness, or increased thirst (occurs in ~5.7% of patients) 1
• Electrolyte abnormalities: Verify potassium, magnesium, and calcium levels 1
• Statin-induced myopathy: Check creatine kinase levels if patient is on statins 1
• Worsening heart failure: Assess for signs of inadequate cardiac output 1
• Other causes: Peripheral arterial disease, deconditioning, spinal stenosis, hypothyroidism, vitamin D deficiency 1

However, the temporal pattern (pain only when taking dapagliflozin, resolution when stopped, recurrence upon rechallenge) makes these alternative explanations unlikely as the primary cause.

Management Algorithm Going Forward

Step 1: Permanently Discontinue Dapagliflozin

• Do not attempt another rechallenge—two episodes with clear temporal relationship is sufficient evidence 1
• Document this as a drug intolerance in the patient's medical record to prevent future inadvertent exposure

Step 2: Optimize Alternative SGLT2 Inhibitor

• Consider empagliflozin 10 mg daily as an alternative SGLT2 inhibitor, as it has similar Class I, Level A evidence for HFrEF but may not cause the same idiosyncratic reaction 4, 5
• Empagliflozin reduced cardiovascular death or heart failure hospitalization by 25% in EMPEROR-Reduced (HR 0.75,95% CI 0.65-0.86), comparable to dapagliflozin's 26% reduction 5
• If muscle pain recurs with empagliflozin, this suggests a class effect and SGLT2 inhibitors should be avoided entirely 1

Step 3: Maximize Other Guideline-Directed Medical Therapy

• Ensure patient is on optimal doses of ACE inhibitor/ARNI, beta-blocker, and mineralocorticoid receptor antagonist 4
• The American College of Cardiology emphasizes that while SGLT2 inhibitors provide additive benefit, their effects are complementary to—not replacements for—other foundational HFrEF therapies 4

Step 4: Monitor Closely

• If empagliflozin is attempted, monitor for recurrence of muscle pain within the first 2-4 weeks 1
• Continue to optimize volume status and electrolytes, as HFrEF patients remain at risk for these issues regardless of SGLT2 inhibitor use 1

Critical Clinical Considerations

• The mortality benefit of dapagliflozin is substantial (31% reduction in all-cause mortality in DAPA-HF), but this benefit cannot be realized if the patient cannot tolerate the medication 1
• Quality of life matters: Persistent muscle pain significantly impairs quality of life, and forcing continuation of a medication causing reproducible symptoms violates the principle of patient-centered care 6
• Rechallenge is diagnostic: The fact that symptoms returned upon restarting dapagliflozin provides near-definitive evidence of causation, even if the mechanism is unclear 1

Common Pitfalls to Avoid

• Do not dismiss the patient's symptoms simply because myalgia is not a recognized adverse effect in clinical trials—individual patients can have idiosyncratic reactions 1
• Do not attempt multiple rechallenges hoping symptoms will resolve—this exposes the patient to unnecessary discomfort without changing the underlying intolerance 1
• Do not abandon SGLT2 inhibitor therapy entirely without first attempting an alternative agent (empagliflozin), as the class benefit is too important to forgo without exhausting options 4, 5