What is the likely cause of tongue swelling in a 28-year-old patient with a history of heart failure, currently being treated with Entresto (sacubitril/valsartan), carvedilol, and furosemide, and could it be due to Entresto or amyloidosis?

Tongue Swelling in a 28-Year-Old on Entresto: Likely Cause

The tongue swelling is almost certainly due to Entresto (sacubitril/valsartan), not amyloidosis, and requires immediate discontinuation of the medication. This represents angioedema, a potentially life-threatening adverse effect that can cause airway obstruction and death.

Why Entresto is the Culprit

Entresto carries a significant risk of angioedema, particularly affecting the tongue, lips, pharynx, and throat, which can lead to fatal airway compromise. 1 The FDA drug label explicitly warns about "serious allergic reactions causing swelling of your face, lips, tongue, and throat (angioedema) that may cause trouble breathing and death" and instructs patients to "get emergency medical help right away" if these symptoms occur. 1

• The mechanism involves neprilysin inhibition, which increases bradykinin levels—a potent mediator of angioedema. 2
• Black patients have a higher risk of angioedema with Entresto compared to non-Black patients. 1
• Patients with any prior history of angioedema (from any cause) have substantially elevated risk when taking Entresto. 1
• The 2021 ACC Expert Consensus specifically notes that neprilysin inhibitors are not combined with ACE inhibitors precisely because of the heightened angioedema risk. 2

Why Amyloidosis is Extremely Unlikely

Cardiac amyloidosis causing isolated tongue swelling (macroglossia) in a 28-year-old would be extraordinarily rare and would present with additional characteristic features that are absent in this case.

• Amyloid-related macroglossia typically occurs in AL (light chain) amyloidosis, not ATTR amyloidosis (the type associated with cardiac involvement in younger patients). 2

• If amyloidosis were causing tongue enlargement, you would expect to see: 2

  • Gradual, progressive tongue enlargement over months to years (not acute swelling)
  • Indentations from teeth on the lateral tongue borders
  • Difficulty with speech and swallowing that develops slowly
  • Other systemic manifestations (peripheral neuropathy, carpal tunnel syndrome, autonomic dysfunction, nephrotic syndrome)
  • Restrictive cardiomyopathy with preserved ejection fraction initially, not the reduced ejection fraction typically treated with Entresto

• The 2023 ACC Expert Consensus on Cardiac Amyloidosis describes neuropathy management extensively but does not characterize acute tongue swelling as a presenting feature. 2

• At age 28, hereditary ATTR amyloidosis (ATTRv) would be the only plausible amyloid type, and this typically presents with peripheral neuropathy and autonomic dysfunction first, not isolated macroglossia. 2

Immediate Management Required

Stop Entresto immediately and do not rechallenge—the FDA label explicitly states "Do not take Sacubitril and Valsartan Tablets again if you have had angioedema during treatment." 1

• Assess airway patency urgently; look for stridor, difficulty breathing, or inability to swallow secretions. 1, 3
• Angioedema from ACE inhibitors and ARNIs can be fatal through asphyxiation—seven deaths from tongue angioedema related to ACE inhibitors were documented in a forensic series, with massive tongue swelling confirmed at autopsy. 3
• Administer emergency treatment if airway compromise is present: epinephrine, antihistamines, corticosteroids, and secure the airway if necessary. 1
• The risk of recurrent angioedema persists for weeks after stopping the medication due to the long half-life of neprilysin inhibition effects. 2

Alternative Heart Failure Therapy

After stopping Entresto, transition to an ACE inhibitor or ARB (but wait at least 36 hours after the last Entresto dose to avoid overlapping neprilysin and RAAS inhibition, which increases angioedema risk). 2, 1

• The 2021 ACC Expert Consensus recommends ACE inhibitors or ARBs as alternative GDMT for HFrEF when ARNIs cannot be used. 2
• Continue beta-blocker (carvedilol) and diuretic (furosemide) therapy without interruption. 2
• Consider adding a mineralocorticoid receptor antagonist (spironolactone or eplerenone) and SGLT2 inhibitor to optimize guideline-directed medical therapy. 2

Critical Pitfall to Avoid

Do not attribute new-onset tongue swelling in a patient on Entresto to other causes without first stopping the medication—this is a medical emergency with potential for fatal airway obstruction. The temporal relationship between Entresto use and tongue swelling, combined with the known high-risk adverse effect profile, makes drug-induced angioedema the diagnosis until proven otherwise. 1, 3