Angioedema associated with dipeptidyl peptidase-IV inhibitors

Abstract

Background Dipeptidyl peptidase-IV (DPP-IV) inhibitors, also known as gliptins, are a class of oral antidiabetic agents. Postmarketing reports have documented the occurrence of angioedema in patients treated with gliptins and it was found that these drugs increased the risk of angioedema in patients concurrently treated with angiotensin-converting enzyme inhibitors (ACEIs). The aim of this manuscript is to provide an overview of the risk of angioedema associated with gliptins. Methods The keywords used for the literature search in the PubMed database included “angioedema” and “dipeptidyl peptidase”, “gliptins”, or the name of each DPP-IV inhibitor. Articles in English published up to December 2020 were taken into consideration. Results The available data appear to rule out a higher risk of angioedema associated with gliptin monotherapy and have revealed an increased susceptibility in patients simultaneously treated with gliptins and ACEIs. However, one single multicenter phase IV trial and case reports, even if very limited in number, have shown that angioedema can also occur during treatment with DPP-IV inhibitors without the concomitant use of ACEIs. The involvement of other drugs and drug interactions has occasionally been suggested. In a few patients, deficiency of enzymes involved in bradykinin catabolism was detected and this finding can constitute a risk factor for angioedema exacerbated by treatment with DPP-IV inhibitors. Conclusions This risk of angioedema associated with the use of gliptins has mostly been related to the concurrent administration of ACEIs, and has been considered rare, but it might be underestimated and underreported. The role of additional risk factors or drug interactions deserves further investigations. Caution should be taken when considering the use of DPP-IV inhibitors in patients treated with ACEIs or presenting with other known risk factors for angioedema.

A Rare Case Report of Sitagliptin-Induced Angioedema

“…Bradykinin is also a substrate for DPP-4, inhibiting sitagliptin [4]. Several studies published so far have elucidated angioedema from sitagliptin occurring with concurrent use of ACE-I or ARB [5,6]. One case report showed angioedema from sitagliptin recently started for diabetes without using an ACE-I or ARB, similar to our patient [7].…”

Trends in Treatments With Disease-Specific and Interfering Drugs in Patients With Hereditary Angioedema in Sweden

“…39 This class of drugs may induce angioedema when used in combination with ACE inhibitors because they also participate in the degradation of bradykinin. 28 There were very few prescriptions for these drugs by patients with HAE in the current study (data not shown).…”

“…Treatment for comorbidities, including angiotensinconverting enzyme (ACE) inhibitors used to treat CVD may increase the risk of angioedema, and when used in combination with dipeptidyl peptidase-4 (DPP4) inhibitors (used to treat diabetes), the risk is further increased. 28 Both ACE and DPP4 participate in the degradation of bradykinin and substance P. 28,29 In women, the manifestations of HAE often start at puberty, indicating that estrogen is a promoter of angioedema. 30 Therefore, there is general consensus not to use oral contraceptives containing estrogens in patients with HAE.…”

Acute quadruple extremity compartment syndrome due to angio-oedema after polypharmacy overdose including olmesartan medoxomil, telmisartan and vildagliptin

“…Although the incidence of angio-oedema is not dose dependent at normal doses,6 the risk increases with concomitant use of drugs that inhibit the bradykinin pathway, such as DPP-4 inhibitors. While there are no data on ARBs, ACE inhibitors are known to significantly increase the risk of angio-oedema when used in combination with DPP-4 inhibitors, with some studies reporting a fourfold increase in risk 7 8. In this case, the potentiation of bradykinin activity was multifaceted: RAAS inhibitors limited bradykinin degradation, and DPP-4 inhibitors prevented its enzymatic degradation, thereby increasing the risk of bradykinin-mediated angio-oedema 9.…”