Published: 4 March 2021

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Vildagliptin and ACE inhibitors – increased risk of angioedema

Published: 4 March 2021
Prescriber Update 42(1): 5
March 2021

Background

Angioedema is the sudden localised swelling of the skin or mucous membranes caused by a transient increase in endothelial permeability and extravasation of plasma into the interstitial tissues.¹

Vildagliptin is a recently funded dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for the improvement of glycaemic control in type 2 diabetes.² Angiotensin-converting enzyme inhibitors (ACE inhibitors) are indicated for treatment of diabetic nephropathy, amongst other uses,³ and therefore these two medicines are often used together.

ACE inhibitor-induced angioedema

Angioedema is reported to occur in approximately 0.2 to 2.5 percent of patients taking an ACE inhibitor.¹ It may occur at any time during treatment.⁴

ACE inhibitor-induced angioedema predominantly affects the head and neck area, particularly the lips, tongue, face and upper airway, and thus may be life-threatening.⁴ Less commonly, the angioedema may present as acute abdominal pain associated with diarrhoea or other gastrointestinal symptoms, due to visceral involvement.⁴ It is not associated with itching or urticaria.⁴

Increased risk of angioedema with vildagliptin and ACE inhibitors

Angioedema is rarely seen in patients on vildagliptin monotherapy, but the risk is increased in patients who are also taking an ACE inhibitor.^2,5 While the absolute risk is small,⁵ it is likely that many patients prescribed vildagliptin will also be taking an ACE inhibitor. Consider this possible drug-drug interaction if a patient taking these medicines presents with angioedema.⁵

Check the medicine data sheets for more information. Patients may require additional monitoring for angioedema. Ask the patient to report back any symptoms.

Suggested mechanism

Substance P and bradykinin are vasodilators involved in the pathogenesis of angioedema. ACE and DPP-4 are involved in the degradation of substance P, and ACE is one of the enzymes that degrade bradykinin.^5,6

Compared with inhibition of ACE or DPP-4 alone, inhibition of both enzymes by the combined use of an ACE inhibitor and vildagliptin increases the risk of accumulation of substance P and bradykinin, resulting in angioedema.^5,6

New Zealand case reports

Since 2018, the Centre for Adverse Reactions Monitoring (CARM) has received four reports describing angioedema after starting vildagliptin (CARM IDs: 131257, 136882, 131241, 133491). In two cases, the patients were already taking an ACE inhibitor when vildagliptin treatment was initiated.

References

1. Rasmussen ER, Mey K and Bygum A. 2014. Angiotensin-converting enzyme inhibitor-induced angioedema – A dangerous new epidemic. Acta Derm Venereol 94(3): 260–4. DOI: 10.2340/00015555-1760 (accessed 3 February 2021).
2. Novartis New Zealand Limited. 2020. Galvus New Zealand Data Sheet 1 July 2020. URL: medsafe.govt.nz/profs/Datasheet/g/galvustab.pdf (accessed 9 December 2020).
3. New Zealand Formulary. 2020. New Zealand Formulary v102: Angiotensin-converting enzyme inhibitors 1 December 2020. URL: nzf.org.nz/nzf_1242 (accessed 9 December 2020).
4. Guyer A and Banerji A. 2020. ACE inhibitor-induced angioedema. In: UpToDate 1 June 2020. URL: uptodate.com/contents/ace-inhibitor-induced-angioedema (accessed 9 December 2020).
5. Brown NJ, Byiers S, Carr D, et al. 2009. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension 54(3): 516–23. DOI: 10.1161/HYPERTENSIONAHA.109.134197 (accessed 9 December 2020).
6. Scott SI, Andersen MF, Aagaard L, et al. 2018. Dipeptidyl peptidase-4 inhibitor induced angioedema – An overlooked adverse drug reaction? Curr Diabetes Rev 14(4): 327–33. DOI: 10.2174/1573399813666170214113856 (accessed 3 February 2021).