key: cord-0996503-cntn7txi authors: Strollo, Rocky; Maddaloni, Ernesto; Dauriz, Marco; Pedone, Claudio; Buzzetti, Raffaella; Pozzilli, Paolo title: Use of DPP4 inhibitors in Italy does not correlate with diabetes prevalence among COVID-19 deaths date: 2020-09-16 journal: Diabetes Res Clin Pract DOI: 10.1016/j.diabres.2020.108444 sha: c99d538bfb81ea0fabe7e56656a89cc63212e663 doc_id: 996503 cord_uid: cntn7txi nan In a nationwide study of 3,818 charts from patients with fatal COVID-19, we found that geographical differences in Dipeptidyl peptidase 4 (DPP4) inhibitors use did not correlate with diabetes prevalence among COVID-19 deaths, thus not supporting the hypothesis of a clinically relevant involvement of DPP4 in COVID-19 development and progression. Dipeptidyl peptidase 4 (DPP4) is a serine exopeptidase which regulates immune responses by acting as a co-stimulatory molecule on T-cells [1] . It is a pharmacological target of DPP4 inhibitors (DPP4i), a class of drugs widely used for the management of type 2 diabetes (T2D). It has been proposed that DPP4 might sterically interact with the S1 domain of the SARS-CoV-2 spike glycoprotein [2] . Moreover, DPP4i modulate inflammation by suppressing Th17 activity and proinflammatory cytokines [3] [4] [5] , two features of severe COVID-19 [6, 7] . In an experimental model of Acute Respiratory Distress Syndrome (ARDS), a main cause of COVID-19 death, DPP4 inhibition alleviated histological findings of lung injury by inhibiting proinflammatory cytokines IL-1β, TNFα, and IL-6 [8] . Therefore, DPP4 inhibition may have a role in limiting two steps of COVID-19 immunopathogenesis: 1) by altering a potential SARS-CoV-2/DPP4 interaction; 2) by halting disease progression towards hyperinflammation. Under the hypothesis that treatment with DPP4i could prevent COVID-19 progression in subjects with diabetes, the aim of this analysis is to examine the association between DPP4i use among those with diabetes and COVID-19 deaths across regions of Italy during the pandemic. A COVID-19 surveillance system was launched by the Italian National Institute of Health The total number of medical charts reviewed in each district did not correlate with the prevalence of diabetes among COVID-19 deaths (rho=0.002, p=0.99). The median percentage use of DPP4i among diabetic people in the sanitary districts was 11.4% [10.2-12.5] ; Sicily was the lowest (5.7%), while Bolzano and Sardinia showed the highest percentages (16.9% and 16.8%, respectively) ( Table S1 ). The percentage use of DPP4i in each district was unrelated to diabetes prevalence among those who died from COVID-19 (-0.247, p=0.29; Figure 1 ). No significant differences in the use of DPP4i were found between alive and In this study, over one third of individuals who died of COVID-19 had diabetes. Geographical differences in DPP4i use did not correlate with diabetes prevalence among COVID-19 deaths. Our data extend findings from two recent reports that evaluated the association between DPP4i treatment and COVID-19 fatality. In an Italian case-control study involving 85 T2D individuals hospitalized for COVID-19, previous DPP4i treatment (nine patients) was unrelated to COVID-19 death [10] . In the CORONADO study, a larger, nationwide observational study of 1,317 diabetic people hospitalized for COVID-19, DPP4i treatment before admission (285 subjects) did not improve the primary outcome (invasive respiratory support or death within seven days from admission) [11] . However, the small sample size stands out as major limitation in the former, while the latter study was not specifically designed to assess the relationship between DPP4i and COVID-19. Main strengths of our study include the large number of cases assessed nationwide and the use of hard endpoint which can be measured unambiguously. Due to its ecologic nature, our study is limited to the biases inherent these types of studies, and by the lack of data on glucose control and other comorbidities. In conclusion, our findings suggest that pharmacological inhibition of DPP4 may not have a role in preventing SARS-CoV-2 infection and/or COVID-19 progression. 7 and edited the manuscript. CP contributed to data analyses and data interpretation. All authors critically revised the manuscript for intellectual content. All authors have seen and approved the final draft. Table S1 -Prevalence of diabetes in the general population (presented in ascending order, as estimated by ISTAT) and among individuals died of COVID-19 (retrieved from medical chart review by ISS) and estimated percentage use of DPP4i among individuals with diabetes in each Italian region and Autonomous Province * . Diabetes Data about DPP4i use were estimated for each sanitary district upon data provided by IQVIA ® . The total number of patients on DPP4i in each district ( ) was then calculated as follows: where MS is the market share of sitagliptin, as provided by IQVIA ® The proportion of patients with diabetes using DPP4i in each sanitary district was then calculated as follows: where P is the total number of patients with diabetes. The "on-field" analysis provided by the "Osservatorio per la Salute" of the Autonomous Province Cut to the chase: a review of CD26/dipeptidyl peptidase-4's (DPP4) entanglement in the immune system Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26 Sitagliptin inhibit human lymphocytes proliferation and Th1/Th17 differentiation in vitro Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor-alpha concentrations: A systematic review and meta-analysis of controlled trials Targeting dipeptidyl peptidase IV (CD26) suppresses autoimmune encephalomyelitis and up-regulates TGF-beta 1 secretion in vivo Clinical and immunological features of severe and moderate coronavirus disease 2019 Pathological findings of COVID-19 associated with acute respiratory distress syndrome DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice Rome: Istituto Nazionale Di Statistica Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes: A case-control study Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study We thank Dr. Lorenza Nisticò and other members of the Italian National