We read with interest the discussion by Solerte et al. [1] on the various physiological processes on the immune system where dipeptidyl peptidase‐4 (DPP‐4) is involved. Besides, as hypothesized by the authors, the presence of DPP-4 in the respiratory tract may facilitate the entry of severe acute respiratory syndrome (SARS-CoV-2), the causative pathogen for coronavirus disease 2019 (COVID-19). Therefore, at first sight, it seems logical for the authors to propose that the use of DPP-4 inhibitors may be benficial in patients with COVID-19.
However, as the pathophysiology of COVID-19 being unraveled, we have now acknowledged the potential for a substantial number of patients with COVID-19 to be complicated by the development of venous thromboembolism, especially those admitted into intensive care units. To illustrate, despite the initiation of pharmacological thromboprophylaxis, 31% of patients with COVID-19 admitted into intensive care units still developed venous thromboembolic events [2]. Indeed, COVID-19 has now been recognized as a hypercoagulable state where the elevation of several circulating prothrombotic factors had been reported [3].
Therefore, we should be very careful to call on for DPP-4 inhibitors to be repurposed as one of the treatment options for patients with COVID-19 since DPP-4 inhibitors have the potential to induce a prothrombic state. Other than their actions on glucose homeostasis and immune homeostasis, DPP-4 also acts on the vascular system where it possesses anti-thrombotic properties and may act as an immobilized anticoagulant on endothelial cells. This is owing to their ability to inhibit fibrin polymerization and clot formation.
In vivo model has demonstrated a reduction in the expression and activity of DPP-4 within the infarction area of patients with acute myocardial infarction, which corresponded to an increase in pro-coagulant Tissue Factor expression, suggesting a shift toward a prothrombogenic status [4]. Furthermore, when human umbilical vein endothelial cells were treated with diprotin A which inhibits the activity of DPP-4, increased adherence of non-stimulated platelets under flow conditions was observed, corresponding to a sign of thrombogenicity [4].
Real-world data have also indicated a safety signal with DPP-4 inhibitors due to the increased reporting of venous thromboembolism events. A recent pharmacovigilance study [5] observed excess of reporting of venous thromboembolism events with DPP-4 inhibitors compared with other antidiabetic agents except for insulin, with a proportional reporting ratio of 2·0 (95% confidence interval 1.7–2.3). In the post hoc subgroup analysis considering separately sitagliptin and other DPP-4 inhibitors, sitagliptin was associated with a significantly higher probability of reporting of venous thromboembolism events, with a proportional reporting ratio of 3.2 (95% confidence interval 2.8–3.7).
Although no definite conclusion could be made to the effect of DPP-4 inhibitors in COVID-19 patients, it may be unwise to repurpose DPP-4 inhibitors for the treatment of COVID-19 which is associated with a hypercoagulability state. In addition, in the aforementioned pharmacovigilance study [5], almost 50% of venous thromboembolism events associated with DPP-4 inhibitors were co-reported with an infection, which demanded cautious use of DPP-4 inhibitors, especially sitagliptin, during an active infection such as COVID-19.
Funding
The publication of this article received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
References
- 1.Solerte SB, Di Sabatino A, Galli M, Fiorina P (2020) Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19 Acta Diabetol 57:779–783. [DOI] [PMC free article] [PubMed]
- 2.Hasan SS, Radford S, Kow CS, Zaidi STR (2020) Venous thromboembolism in critically ill COVID-19 patients receiving prophylactic or therapeutic anticoagulation: a systematic review and meta-analysis [published online ahead of print, 2020 Aug 3]. J Thromb Thrombolysis 1–8. [DOI] [PMC free article] [PubMed]
- 3.Maier CL, Truong AD, Auld SC, Polly DM, Tanksley CL, Duncan A. COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia? Lancet. 2020;395:1758–1759. doi: 10.1016/S0140-6736(20)31209-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Krijnen PA, Hahn NE, Kholová I, et al. Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients. Basic Res Cardiol. 2012;107:233. doi: 10.1007/s00395-011-0233-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Gouverneur A, Lair A, Arnaud M, et al. DPP-4 inhibitors and venous thromboembolism: an analysis of the WHO spontaneous reporting database. Lancet Diabetes Endocrinol. 2020;8:365–367. doi: 10.1016/S2213-8587(20)30112-1. [DOI] [PubMed] [Google Scholar]