Angioedema due to DPP-4 inhibitors
Question:
12/2/2020
My question is whether my patient has type three hereditary angioedema, if ordering Factor XII snp analysis is indicated, and treatment recommendations. He is a 62 year-old male with two severe episodes of angioedema. No new foods, pain meds/nsaids, latex, venom, or other exposures. He is not on an ACE-inhibitor. The first episode he had the flu vaccine eight hours prior and this was the suspected culprit. One month later, he reported tongue swelling, voice getting raspy, and the ED life flighted him to their main campus. Per ENT endoscopic visualization he did not require intubation. For several years, he has been on two diabetes medicines, sitagliptin and Januvia (Sitagliptin, a DPP-4 inhibitor) and Invokana (canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor). These were both stopped and he was sent to Allergy for drug allergy evaluation. In the literature (Annals of Int Med, 167(2); July 18, 2017, p.142-143), there is a case report of HAE type 3 with mutation of coagulation factor XII occurring after Sitagliptin administration. Bradykinin is also metabolized by DPP-4 (in addition to ACE, carboxypeptidase N and aminopeptidase P) so the addition of sitagliptin caused the severe reaction. In my patient, he has normal C4 (25 mg/dL), C1 esterase inhibitor level (26 mg/dL) and function (>100%), C1q (13.2 mg/dL), negative latex (<0.35 KU/L), negative allergy food screen skin test, and tryptase level (6.2 mcg/L). Do you think he has Type 3 HAE? Is the above genetic testing indicated? Do you agree it is the sitagliptin? Can Invokana (canagliflozin) be restarted? Should he have a rescue medicine like Firazyr or Ruconest on hand or should I wait for recurrence?
Answer:
HAE-normal C1INH (Type 3 HAE) is difficult to diagnose and remains a challenge for most of us. I reached out to HAE expert, Marc Riedl, MD, MS.
Angioedema associated with DPP-4 inhibitors, including sitagliptin, has been reported in a number of publications. Most, but not all of these have occurred when DPP-4 inhibitors are combined with ACE-I or ARB use. The true incidence of angioedema due to DPP-4 inhibitors is unknown, but given the role of DPP-4 in bradykinin and substance P degradation, and evidence of variable DPP-4 expression in humans (whether genetically determined or due to external factors such as immunosuppressants), a very plausible mechanism exists for non-histaminergic angioedema associated with this class of medications. So in this case, I would be first and foremost suspicious of sitagliptin as a causative factor.
Factor XII mutational analysis is a reasonable consideration if HAE-normal C1INH is suspected. In this case, I think a number of factors make the pre-test probability low: 1) ~90% of symptomatic HAE-normal C1INIH patients are female, 2) The age of onset in this case makes HAE unlikely, though HAE-normal shows a more variable age of symptom onset compared to HAE-C1INH deficiency, and 3) Current evidence suggests Factor XII mutations are found in a very small subset (<10%) of suspected HAE-normal patients tested in the U.S. Current guidelines recommend this genetic testing when the suspicion of HAE-normal C1INH is high and the testing is available, but the likelihood of a positive test in this case is low, in my opinion. That said, since C1INH lab results are normal, the Factor XII mutation analysis is the remaining readily available commercial test that could most definitively confirm a mechanism of angioedema.
I'm not aware of any available data suggesting an association or mechanism for canagliflozin causing angioedema, outside of rare post-marketing "allergic reactions" that are common to many drugs. I think it would be reasonable to cautiously restart canagliflozin if needed, though would avoid future DPP-4 inhibitor use in this patient. It's not clear from the case description whether the patient was treated with and clearly failed aggressive antihistamines/corticosteroids/epinephrine, which would be important to establish as clinical criteria for HAE-normal C1INH or idiopathic non-histaminergic angioedema. Given the significant airway involvement of his previous angioedema episodes, would want a clear acute treatment plan in place and consider at least short-term access to a bradykinin-specific rescue medication such as icatibant if histamine/mast cell targeted drugs have failed. The natural history of DPP-4 inhibitor associated angioedema is poorly defined and while it appears to be less common and severe than ACE-I associated angioedema, it's possible that similar to ACE-I associated angioedema symptoms could recur sporadically for a few months following medication discontinuation in some patients.
My sincere gratitude to Dr. Marc Riedl for his thoughtful and detailed response.
I hope you find this helpful.
Respectfully submitted,
Jeffrey G Demain, MD, FAAAAI