Observational Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Clin Cases. Nov 26, 2020; 8(22): 5576-5588
Published online Nov 26, 2020. doi: 10.12998/wjcc.v8.i22.5576
No significant association between dipeptidyl peptidase-4 inhibitors and adverse outcomes of COVID-19
Jiang-Hua Zhou, Bin Wu, Wen-Xin Wang, Fang Lei, Xu Cheng, Juan-Juan Qin, Jing-Jing Cai, Xiao-Jing Zhang, Feng Zhou, Ye-Mao Liu, Hao-Miao Li, Li-Hua Zhu, Zhi-Gang She, Xin Zhang, Juan Yang, Hong-Liang Li
Jiang-Hua Zhou, Bin Wu, Wen-Xin Wang, Xu Cheng, Juan-Juan Qin, Ye-Mao Liu, Hao-Miao Li, Department of Cardiology, Renmin Hospital of Wuhan University, Basic Medical School, Wuhan University, Wuhan 430071, Hubei Province, China
Fang Lei, Xiao-Jing Zhang, Basic Medical School, Institute of Model Animal, Wuhan University, Wuhan 430071, Hubei Province, China
Jing-Jing Cai, Department of Cardiology, the 3rd Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
Feng Zhou, Medical Science Research Center, Zhongnan Hospital of Wuhan University, Institute of Model Animal, Wuhan University, Wuhan 430072, Hubei Province, China
Li-Hua Zhu, Zhi-Gang She, Juan Yang, Hong-Liang Li, Department of Cardiology, Renmin Hospital of Wuhan University; Institute of Model Animal of Wuhan University, Wuhan 430071, Hubei Province, China
Xin Zhang, Institute of Model Animal, Wuhan University, Department of Gastroenterology, Wuhan Third Hospital, Tongren Hospital of Wuhan University, Wuhan 430072, Hubei Province, China
Author contributions: Zhou JH, Wu B, and Wang WX contributed equally to the work, designed the study, collected and analyzed the data, and wrote the manuscript; Lei F, Cheng X, Qin JJ, Zhou F, Liu YM, and Li HM performed statistical analysis; Cai JJ, Zhang XJ, Zhu LH, and She ZG wrote the manuscript and provided valuable suggestions for study design and data analysis; Zhang X, Yang J, and Li HL contributed equally to the work, designed the project, edited the manuscript, and supervised the study; all authors have approved the final version of this paper.
Supported by National Key R&D Program of China, No. 2019YFC2004702 and No. 2020YFC0845500; the National Natural Science Foundation of China, No. 81970070 and No. 81970011; the Hubei Science and Technology Support Project, No. 2019BFC582 and No. 2018BEC473.
Institutional review board statement: The study was reviewed and approved by the Science and Research Office of Renmin Hospital and Zhongnan Hospital of Wuhan University (Wuhan).
Informed consent statement: Informed consent was waived by the ethics boards of the involved hospitals.
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement:  No additional data are available.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Hong-Liang Li, MD, PhD, Professor, Department of Cardiology, Renmin Hospital of Wuhan University; Institute of Model Animal of Wuhan University, No. 115 Donghu Road, Wuchang District, Wuhan 430071, Hubei Province, China. lihl@whu.edu.cn
Received: July 6, 2020
Peer-review started: July 6, 2020
First decision: August 8, 2020
Revised: August 20, 2020
Accepted: September 25, 2020
Article in press: November 26, 2020
Published online: November 26, 2020
Processing time: 141 Days and 23.9 Hours
ARTICLE HIGHLIGHTS
Research background

Diabetes is one of the most important comorbidities linked to the remarkably increased severity and mortality of coronavirus disease 2019 (COVID-19). Our most recent retrospective study based on one of the largest scale patient cohorts has demonstrated that glucose control is the key point to diminish COVID-19 mortality for patients with co-existing diabetes. Dipeptidyl peptidase 4 (DPP4) is commonly targeted for glucose lowering and has outstanding roles in inflammatory and immune regulation. As the well-established Middle East respiratory syndrome coronavirus cellular receptor, DPP4 was predicted to have a tight interaction with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein in the recent molecular modeling study.

Research motivation

The latest observations sparked intense debates about whether DPP4 inhibitors might be promising therapeutic agents against COVID-19 among patients with diabetes. However, there is no direct clinical evidence supporting the associations between DPP4i usage and COVID-19 prognosis so far.

Research objectives

To investigate the potential impacts of DPP4i on COVID-19 among patients with diabetes, and to clarify whether continuation of DPP4i for diabetes management among patients in the setting of COVID-19 is an appropriate option.

Research methods

We enrolled 15451 confirmed COVID-19 cases, including 2563 inpatients with type 2 diabetes from 16 hospitals in Hubei Province, between December 30, 2019 and April 23, 2020. After excluding those ineligible individuals, 142 patients receiving DPP4i and 1115 cases receiving non-DPP4i oral anti-diabetic were included in the subsequent analysis. Then we performed a strict propensity score matching (PSM) analysis where age, sex, comorbidities, number of oral hypoglycemic agents, heart rate, blood pressure, pulse oxygen saturation (SpO2) < 95%, CT diagnosed bilateral lung lesions, laboratory indicators, and proportion of insulin usage were matched. Finally, 111 participants treated with DPP4i were successfully matched with 333 non-DPP4i users. Then logistics linear model and mixed-effect Cox model were applied to analyze the associations between in-hospital use of DPP4i and adverse outcomes of COVID-19.

Research results

We found that there was no significant association between patients taking DPP4i vs other oral hypoglycemic drugs regarding the incidence or risk of 28-d all-cause death (adjusted hazard ratio = 0.44, 95%CI: 0.09-2.11, P = 0.31). Likewise, the incidences and risks of secondary outcomes including septic shock, ARDS, or acute organ (kidney, liver, and cardiac) injuries were also comparable between the DPP4i and non-DPP4i groups. And the performances of DPP4i on glucose control (e.g., the median level of fasting blood glucose and random blood glucose) and inflammatory regulation were all kept approximately equivalent in the DPP4i vs non-DPP4i group. Furthermore, we did not observe substantial side effects on uncontrolled glycaemia or acidosis due to DPP4i application compared to non-DPP4i agents in the study cohort.

Research conclusions

These data demonstrated that there are no significant correlations between DPP4i treatment and adverse clinical outcomes among COVID-19 patients with diabetes, and DPP4i does not show any other significant adverse effects on anti-diabetic treatment. Thus, DPP4i might be a relative safe option for managing pro-existing type 2 diabetes patients infected by SARS-CoV-2, which may provide certain reference value for clinical decision-making. Our study also paves the way for perspective studies and randomized controlled clinical trials on DPP4i therapy for COVID-19.

Research perspectives

Large-scale prospective cohort studies and randomized clinical trials with ethnically and geographically diverse cohorts are needed to better understand the effects of DPP4i agents on mortality, glycemic control, and side effects among COVID-19 individuals.