Factors influencing on development of COVID-19 pneumonia and association with oral anti-diabetic drugs in hospitalized patients with diabetes mellitus

Published:August 03, 2021DOI:https://doi.org/10.1016/j.pcd.2021.08.001

      Highlights

      • Factors affecting the development of COVID-19 pneumonia in patients with diabetes mellitus are not well known.
      • No oral anti-diabetics were associated with COVID-19 related death.
      • DPP-4 inhibitor use was associated with the risk of COVID-19 pneumonia.

      Abstract

      Background

      Diabetes mellitus (DM) increases mortality and morbidity in patients with coronavirus disease (COVID-19). In this study, it was aimed to assess factors influencing on COVID-19 pneumonia in hospitalized patients with diabetes and association with oral anti-diabetic drugs.

      Materials and methods

      This cross-sectional study included 432 patients with type 2 diabetes mellitus diagnosed with COVID-19. Data regarding clinical characteristics, demographic characteristics, intensive care unit (ICU) rate in patients admitted to ICU, laboratory results on day 1 and 7, thoracic computed tomography (CT) findings and oral anti-diabetic drugs used were extracted from medical records. In all patients, 75-days mortality was recorded. Data were assessed independently.

      Results

      There was pneumonia in 386 (89.4%) of 432 patients with diabetes. The risk for pneumonia was markedly higher in patients on DPP-4 inhibitors; however, there was no significant among other oral anti-diabetic groups and subgroups. In addition, elevated CRP was linked to the increased risk for pneumonia. Only patients in the pneumonia group had SGLT-2 inhibitor use. During follow-up, 91 patients died. In Cox regression analysis, low Glasgow Coma Scale score, and increased lactate dehydrogenase levels were identified as significant independent risk factors for mortality.

      Conclusion

      The study indicated that DPP-4 inhibitor used and elevated CRP level were associated with pneumonia development. Only patients in the pneumonia group had SGLT-2 inhibitor use. No oral anti-diabetics was found to be associated with COVID-19 related death.

      Graphical abstract

      Keywords

      1. Introduction

      Patients with diabetes mellitus (DM) are susceptible to various infections and sepsis [
      • Lin S.
      • Ge S.
      • He W.
      • Zeng M.
      Association between comorbid diabetes mellitus and prognosis of patients with sepsis in the intensive care unit: a retrospective cohort study.
      ]. Clinical experiences showed that the susceptibility is associated with fatal infections and adverse clinical outcomes due to factors including severe activation of pro-inflammatory cascade, impaired immune response and cellular dysfunction resulting from metabolic disorders and hyperglycemia [
      • Jafar N.
      • Edriss H.
      • Nugent K.
      The effect of short-term hyperglycemia on the innate immune system.
      ,
      • Bonyek-Silva I.
      • Nunes S.
      • Santos R.L.
      • et al.
      Unbalanced production of LTB4/PGE2 driven by diabetes increases susceptibility to cutaneous leishmaniasis.
      ,
      • Turina M.
      • Fry D.E.
      • Polk Jr., H.C.
      Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects.
      ].
      The Coronavirus disease 2019 (COVID-19), which affected 118 million people and caused more than 2.5 million deaths worldwide, has become an important clinical issue for patients with DM [
      • Guo W.
      • Li M.
      • Dong Y.
      • et al.
      Diabetes is a risk factor for the progression and prognosis of COVID-19.
      ,
      • Cheng X.
      • Liu Y.M.
      • Li H.
      • et al.
      Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
      ]. Many studies showed that DM caused an increase in the mortality in patients with COVID-19 pneumonia as similar to previous coronavirus outbreaks (SARS-CoV and MERS-CoV) [
      • Yang J.K.
      • Feng Y.
      • Yuan M.Y.
      • et al.
      Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS.
      ,
      • Kulcsar K.A.
      • Coleman C.M.
      • Beck S.E.
      • Frieman M.B.
      Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection.
      ]. However, mechanism underlying increased mortality has not been fully elucidated [
      • Mantovani A.
      • Byrne C.D.
      • Zheng M.H.
      • Targher G.
      Diabetes as a risk factor for greater COVID-19 severity and in-hospital death: a meta-analysis of observational studies.
      ].
      It is thought that patients with diabetes mellitus are more susceptible to COVID-19 pneumonia due to multiple immune disorders. However, it is controversial whether treatments for DM and clinical-laboratory differences have effect on the development of COVID-19 pneumonia in patients with diabetes [
      • Muniyappa R.
      • Gubbi S.
      COVID-19 pandemic, coronaviruses, and diabetes mellitus.
      ]. In the present study, it was aimed to assess factors affecting development of COVID-19 pneumonia and its relationship with oral anti-diabetic drugs in hospitalized patients with diabetes.

      2. Materials and methods

      The single-center, cross-sectional study was conducted at Kayseri City Training and Research Hospital. The study included 432 diabetes mellitus patients with the diagnosis of COVID-19 who were admitted to pandemic clinics between 1 March 2020 and 15 September 2020. The study was approved by Ethics Committee on Clinical Trials of Kayseri City Training and Research Hospital (195/2020). The study was conducted in accordance to tenets of Helsinki Declaration.

      2.1 Subjects

      The study included patients with type 2 diabetes mellitus (aged >18 years) with diagnosis of COVID-19. The cases in which SARS-CoV-2 RNA was detected in upper respiratory tract samples using a SARS-CoV-2 nucleic acid detection in accordance manufacturer’s instructions (Shanghai BioGerm Medical Biotechnology Co., Ltd.) were considered as PCR positive for SARS-CoV-2. The diagnosis of COVID-19 was made if SARS-CoV-2 PCR was positive or if there were compatible COVID-19 symptoms (loss of taste or smell, dyspnea, etc.) with typical ground glass appearance on thoracic computed tomography (CT) scan in the setting of an exposure risk and in the absence of other identifiable causes. The patients with diabetes was defined as patients using oral anti-diabetic drugs and having diagnosis of type 2 DM in medical records. The patients on oral anti-diabetic treatment for at least 3 months were included. In all patients, data regarding demographic characteristics (age, gender), clinical findings (comorbidities including hypertension, coronary artery disease, chronic obstructive pulmonary disease, asthma, chronic renal failure, congestive heart failure, hyperlipidemia, cerebrovascular disease, hypothyroidism), macro (coronary and peripheral artery disease and cerebrovascular disease) and microvascular complications (nephropathy, retinopathy and neuropathy), laboratory findings (C-reactive protein [CRP], blood urea nitrogen [BUN], creatinine, lactate dehydrogenase [LDH], ferritin, glomerular filtration rate [GFR], white blood cell [WBC] count], neutrophil count, lymphocyte count, platelet count, fibrinogen, activated partial thromboplastin time [aPTT], d-dimer, prothrombin time (PT), INR, HbA1c), severity scores (Glasgow Coma Scale, APACHE-II) and need for mechanical ventilation in patients admitted to intensive care unit (ICU), thoracic CT scan findings and oral anti-diabetic drugs used (active substance, subgroups, duration of use) were recorded. For routine laboratory tests, blood samples drawn on day 1 and 7 of admission were used. The severity scores within one hour after ICU admission were used.
      The first hospitalization was assessed in patients with multiple hospitalizations. The patients re-hospitalized on the day or next day of discharge, hospitalizations were combined in one hospitalization.
      The patients were stratified into 2 groups as patients with and without pneumonia according to thoracic CT scan findings. Data were compared between two groups. In all patients, 75-days mortality was recorded. Mortality-related markers were compared between survivors and non-survivor.
      The patients aged <18 years and >80 years, those with autoimmune disease or chronic infection and those with malignancy were excluded. In addition, the patients with diagnosis of DM on medical records but not using oral anti-diabetic drugs or those on oral anti-diabetic drugs less than 3 months were also excluded.

      2.2 Statistical analysis

      Statistical analyses were performed using SPSS version 22.0 (IBM Corp., Armonk, NY, USA). Data are presented as mean ± standard deviation (SD), the median (interquartile range) or count (percent). The normality and the homogeneity of the data were evaluated by Shapiro–Wilk test and Levene test, respectively. Comparisons between groups for continuous variables were performed using the Student t test (normal distribution) or the Mann–Whitney U test (non-normal distribution). Fisher test or the χ2 test was used for all categorical data. Logistic regression analysis was used to determine the relative risks of developing pneumonia. Only the variables with a statistically significant association in the simple logistic regression model were included in the multiple logistic regression model. Odds ratios (OR) and 95% confidence intervals (CI) were determined. Cox regression models were used to predict death. A p value <0.05 were considered as statistically significant.

      3. Results

      3.1 Patients characteristics

      In the study, 432 type 2 diabetes mellitus patients with diagnosis of COVID-19 were assessed. Of the patients 197 (45.6%) were men (Table 1). Overall, 382 patients (88.4%) had a comorbid condition. The hypertension was most common comorbid disease (74.1%); followed by hyperlipidemia (51.6%). The biguanides were the most commonly used oral anti-diabetic drugs (89.6%); followed by DPP-4 (dipeptidyl peptidase 4) inhibitors (56.9%). Of the patients, 161 (37.3%) were admitted to intensive care unit.
      Table 1Demographic and clinical findings of patients who with pneumonia and without pneumonia.
      TotalNo pneumoniaPneumoniap
      n = 432n = 46n = 386
      Age, year63.3 ± 10.359.6 ± 11.163.6 ± 10.10.011
      Male gender197 (45.6)22 (47.8)175 (45.3)0.749
      Female gender235 (54.4)24 (52.2)211 (54.7)
      Duration of diabetes, year6.2 ± 2.95.5 ± 3.26.2 ± 2.80.122
      Microvascular complications204 (47.2)17 (37)187 (48.4)0.140
      Macrovascular complications155 (35.9)13 (28.3)142 (36.8)0.254
      Comorbidities382 (88.4)39 (84.8)343 (88.9)0.462
      Hypertension320 (74.1)32 (69.6)288 (74.6)0.460
      Asthma38 (8.8)4 (8.7)34 (8.8)0.980
      Chronic obstructive pulmonary disease45 (10.4)5 (10.9)40 (10.4)0.915
      Coronary artery disease123 (28.5)9 (19.6)114 (29.5)0.157
      Chronic kidney disease20 (4.6)2 (4.3)18 (4.7)0.923
      Hyperlipidemia223 (51.6)20 (43.5)203 (52.6)0.242
      Cerebrovascular disease24 (5.6)3 (6.5)21 (5.4)0.762
      Hypothyroidism29 (6.7)2 (4.3)27 (7.0)0.498
      Anti-hypertensive treatment
      Angiotensin-converting enzyme inhibitors105 (24.3)12 (26.1)93 (24.1)0.766
      Angiotensin II receptor blockers120 (27.8)12 (26.1)108 (28)0.787
      Beta blockers119 (27.5)13 (28.3)106 (27.5)0.909
      Diuretics166 (38.4)23 (50)143 (37)0.088
      Diabetes treatment
      Oral antidiabetics only242 (56)30 (65.2)212 (54.9)0.184
      Oral antidiabetics + insulin190 (44)16 (34.8)174 (45.1)
      Oral antidiabetic drugs
      DPP-4 Inh246 (56.9)18 (39.1)228 (59.1)0.010
      Sulfonylureas66 (15.3)6 (13.0)60 (15.5)0.656
      Biguanides379 (89.6)44 (95.7)335 (88.9)0.154
      SGLT-2 Inh56 (13.0)0 (0.0)56 (14.5)0.006
      Glitazones27 (6.3)4 (8.7)23 (6.0)0.468
      Combinations of oral antidiabetic drugs
      DPP-4 Inh + biguanides133 (30.8)14 (30.4)119 (30.8)0.948
      DPP-4 Inh + sulfonylureas1 (0.2)01 (0.3)
      DPP-4 Inh + SGLT-2 Inh2 (0.5)02 (0.5)
      DPP-4 Inh + glitazones2 (0.5)02 (0.5)
      Biguanides + sulfonylureas18 (4.2)4 (8.7)14 (3.6)
      Biguanides + SGLT-2 Inh7 (1.6)07 (1.8)
      Biguanides + glitazones10 (2.3)2 (4.3)8 (2.1)
      Biguanides + DPP-4 Inh + sulfonylureas25 (5.8)2 (4.3)23 (6)
      Biguanides + DPP-4 Inh + SGLT-2 Inh27 (6.25)027 (7)
      Biguanides + DPP-4 Inh + glitazones3 (0.7)1 (2.2)2 (0.5)
      Biguanides + sulfonylureas + SGLT-2 Inh2 (0.5)02 (0.5)
      Biguanides + sulfonylureas + glitazones3 (0.7)03 (0.8)
      Biguanides + SGLT-2 Inh + glitazones1 (0.2)01 (0.3)
      Biguanides + DPP-4 Inh + sulfonylureas + SGLT-2 Inh8 (1.9)08 (2.1)
      Biguanides + DPP-4 Inh + sulfonylureas + glitazones2 (0.5)02 (0.5)
      Biguanides + DPP-4 Inh + glitazones + SGLT-2 Inh4 (0.9)04 (1)
      Biguanides + DPP-4 Inh + sulfonylureas + glitazones + SGLT-2 Inh1 (0.2)01 (0.3)
      Intensive care unit161 (37.3)4 (8.7)157 (40.7)<0.001
      Mechanical ventilation90 (55.9)2 (50)88 (56.1)0.810
      Mortality 75th day91 (21.0)1 (2.1)90 (23.3)0.001
      DPP-4 Inh, dipeptidyl peptidase 4 inhibitors; SGLT-2 Inh, sodium glucose co-transporter type 2 inhibitors. We provided the significant values as bold.

      3.2 Clinical and laboratory findings associated with pneumonia

      The patients were stratified into 2 groups according to presence of diffuse ground glass areas on thoracic CT scan: patients with or without pneumonia. There was pneumonia in 386 patients (89.4%). Table 1 presents demographic and clinical characteristics of patients with or without pneumonia. Mean age was 63.6 ± 10.1 years in patients with pneumonia whereas 59.6 ± 11.1 years in patients without pneumonia. There was no significant difference in gender distribution and comorbid conditions between groups; however, mean age was significantly higher in patients with pneumonia than those without (p = 0.011). The ICU admission rate was higher in patients with pneumonia (p < 0.001). In additions, 75-days mortality was significantly higher in patients with pneumonia when compared to those without pneumonia (23.12% vs. 2.2%, p = 0.001).
      The DPP-4 inhibitor and SGLT-2 (sodium–glucose-cotransporter 2) inhibitor use was significantly more common among diabetes mellitus patients with pneumonia (p = 0.01 and p = 0.006, respectively) (Table 1); however, no significant difference was detected in the DPP-4 inhibitor (linagliptin, sitagliptin, vildagliptin, saxagliptin) and SGLT-2 inhibitor subgroups (dapagliflozin, empagliflozin) (p > 0.05; Table A1). The main combination of oral anti-diabetic drugs was DPP-4 inhibitor + biguanides in the whole group, however there was no significant difference between groups according to pneumonia (p = 0.948) (Table 1).
      Mean fasting glucose level, CRP, LDH and fibrinogen levels were significantly higher in pneumonia group than patients without pneumonia (p = 0.005, p < 0.001, p = 0.017 and p = 0.002; respectively). Other parameters including HbA1C were not different between groups (p > 0.05; Table A2).
      To identify risk for pneumonia, univariate and multivariate logistic regression analysis was performed and only the variables with a statistically significant association in the simple logistic regression model were included in the multiple logistic regression model (Table 2). SGLT-2 inhibitor use was not included in the regression analysis, because only patients in the pneumonia group had SGLT-2 inhibitor use. In age and gender adjusted model, the logistic regression showed that CRP elevation was associated with pneumonia development (Odd ratio [OR]: 1.030; 95% CI: 1.006−1.053; p = 0.012). The risk for pneumonia was significantly increased in patients on DPP-4 inhibitor (OR: 4.628; 95% CI: 1.189−18.013; p = 0.027).
      Table 2Results of multiple logistic regression analysis for risk factors associated with pneumonia in age and gender adjusted model.
      Risk factorsOR95% CIp
      Univariate analysis
      Hypertension1.2860.659−2.5090.461
      Angiotensin-converting enzyme inhibitors0.8990.447−1.8080.766
      Angiotensin II receptor blockers1.1010.550−2.2050.787
      Chronic obstructive pulmonary disease0.9480.354−2.5370.915
      Asthma1.0140.343−2.9990.980
      Duration of diabetes1.0860.978−1.2050.123
      Fasting glucose level1.0071.002−1.0120.005
      HbA1C1.1660.728−1.8670.522
      DPP-4 Inh2.2451.200−4.1980.011
      C-reactive protein1.0361.020−1.051<0.001
      Lactate dehydrogenase1.0091.003−1.0140.001
      Fibrinogen1.0011.000−1.0010.003
      Biguanides0.3630.085−1.5500.171
      Blood urea nitrogen1.0210.993−1.0510.139
      Multiple analysis
      Fasting glucose level1.0070.997−1.0160.154
      DPP-4 Inh4.6281.189−18.0130.027
      C-reactive protein1.0301.006−1.0530.012
      Lactate dehydrogenase1.0020.995−1.0090.536
      Fibrinogen1.0001.000−1.0010.374
      SGLT-2 Inh, sodium glucose co-transporter type 2 inhibitors; DPP-4 Inh, dipeptidyl peptidase 4 inhibitors; OR, odds ratio; CI, confidence interval. We provided the significant values as bold.

      3.3 Clinical and laboratory findings associated with mortality

      Overall, 91 patients died during follow-up. Table 3 presents demographic and clinical characteristics of non-survivors. Mean age was significantly higher in non-survivors when compared to survivors (p < 0.001). The presence of pneumonia and comorbidity was significantly lower in survivors when compared to non-survivors (87.1% vs. 97.8%, p = 0.02 and 86.5% vs. 95.6%, p = 0.016, respectively). The presence of hypertension, asthma, coronary artery disease, congestive heart failure and chronic renal failure were found to be associated with increased mortality (p < 0.05). There was no significant difference in mortality among oral anti-diabetic drugs (p > 0.05); however, duration of diabetes was longer in non-survivors when compared to survivors (7.4 ± 2.6 vs. 5.8 ± 2.8; p < 0.001). Mean APACHE score was 18.1 ± 13.5 while mean GCS score was 10.9 ± 4.7 in non-survivors. The high APACHE II score and low GCS score were associated with mortality (p = 0.026 and p < 0.001, respectively).
      Table 3Characteristics associated with death in patients who had COVID-19.
      Non-survivorSurvivorp
      n = 91n = 341
      Age mean67.9 ± 8.261.9 ± 10.4<0.001
      Male gender49 (53.8)148 (43.4)0.077
      Female gender42 (46.2)193 (56.6)
      Duration of diabetes, year7.4 ± 2.65.8 ± 2.8<0.001
      Bilateral diffuse infiltration (pneumonia)89 (97.8)297 (87.1)0.002
      Comorbidities87 (95.6)295 (86.5)0.016
      Hypertension75 (82.4)245 (71.8)0.044
      Asthma3 (3.3)35 (10.3)0.037
      Chronic obstructive pulmonary disease11 (12.1)34 (10.0)0.564
      Coronary artery disease34 (37.4)89 (26.1)0.037
      Congestive heart failure12 (13.2)16 (4.7)0.007
      Chronic kidney disease8 (8.8)12 (3.5)0.047
      Hyperlipidemia51 (56.0)172 (50.4)0.348
      Cerebrovasculer disease7 (7.7)17 (5.0)0.309
      Hypothyroidism7 (7.7)22 (6.5)0.642
      Oral antidiabetic drugs
      DPP-4 Inh56 (61.5)190 (55.7)0.342
      Sulfonylureas14 (15.4)52 (15.2)1.000
      Biguanides74 (88.1)305 (90.0)0.689
      SGLT-2 Inh14 (15.4)42 (12.3)0.482
      Glitazones7 (7.7)20 (5.9)0.475
      APACHE II score on admission mean ± SD18.1 ± 13.513.6 ± 10.70.026
      GCS score on admission mean ± SD10.9 ± 4.714.7 ± 0.6<0.001
      Fasting glucose level, mg/dL253 ± 129192 ± 85.6<0.001
      Duration of biguanide use, year7,0 ± 2.65,7 ± 2,7<0.001
      HbA1C mean ± SD
      n = 6 for no pneumonia group and n = 99 for pneumonia group.
      8.4 ± 1.48.2 ± 2.00.665
      DPP-4 Inh, dipeptidyl peptidase 4 inhibitors; SGLT-2 Inh, sodium glucose co-transporter type 2 inhibitors; APACHE II, acute physiology, assessment and chronic health evaluation; GCS, glasgow coma scale; HbA1C, hemoglobin A1c. We provided the significant values as bold.
      a n = 6 for no pneumonia group and n = 99 for pneumonia group.
      The blood parameters on day 1 and 7 of admission were compared between survivors and non-survivors (Table 4). On day 1 and 7, mean CRP, BUN, LDH, ferritin, d-dimer levels and neutrophil count were significantly higher in non-survivors compared to survivors (p < 0.001). Again, mean GFR values on day 1 and 7 were found to be significantly lower in non-survivors (p < 0.001). Mean fibrinogen level was significantly higher on day 1 in non-survivors (p = 0.012); however, no significant difference was found between non-survivors and survivors on day 7 (p > 0.05). The mean creatinine level on day 7 was significantly higher in non-survivors (p < 0.001) but no significant difference was observed on day 1 (p > 0.05).
      Table 4Laboratory findings associated with death on day 1 and on day 7 in patients who had COVID-19.
      Laboratory measures of on 1th dayLaboratory measures of on 7th day
      Non-survivorSurvivorpNon-survivorSurvivorp
      n = 91n = 341n = 91n = 341
      C-reactive protein, mg/dL110.2 ± 94.760.7 ± 65.8<0.00191.3 ± 76.335.5 ± 45.5<0.001
      Blood urea nitrogen, mg/dL35.4 ± 22.919.0 ± 11.3<0.00150.5 ± 33.921.2 ± 13.4<0.001
      Creatinine, mg/dL2.4 ± 15.81.6 ± 1.20.6371.8 ± 1.60.9 ± 0.8<0.001
      Lactate dehydrogenase, U/L560.0 ± 453.0306.3 ± 155.5<0.001618.1 ± 301.6285.1 ± 108.5<0.001
      Ferritin, ng/mL880.8 ± 1369305.2 ± 363.5<0.001793.5 ± 479.6432.2 ± 427.2<0.001
      Glomerular filtration rate, mL/min53 ± 26.376.5 ± 25.1<0.00155.5 ± 33.582.6 ± 33.5<0.001
      Neutrophil, ×103/μL9.9 ± 14.75.6 ± 3.9<0.00110.7 ± 55.5 ± 2.9<0.001
      Lymphocyte, ×103/mL1.8 ± 3.81.5 ± 1.00.3342.0 ± 5.52.7 ± 150.724
      Platelet ×103/μL218.6 ± 96.6225.2 ± 83.90.525256.9 ± 92.7313.3 ± 2560.109
      Fibrinogen, mg/L5985 ± 18225312 ± 17640.0125568 ± 19565231 ± 17940.304
      Activated partial thromboplastin time, s34.8 ± 18.532.3 ± 32.70.53990.7 ± 401.085.1 ± 509.30.945
      d-dimer, ng/mL2669 ± 33251147 ± 1572<0.0013340 ± 35471110 ± 1580<0.001
      Prothrombin time, s16.1 ± 5.714.3 ± 7.00.04517.1 ± 7.914.6 ± 5.60.014
      INR1.2 ± 0.41.1 ± 0.50.0471.3 ± 0.61.1 ± 1.10.380
      To identify risk factors for mortality, Cox regression analysis was performed on all parameters found to be significant in Table 3, Table 4 (Table 5). Elevated LDH levels were identified as independent risk factors for mortality (OR: 1.001; 95% CI: 1.00–1.001; p = 0.009). In addition, high GCS scores were found to be associated with reduction in risk for mortality (OR: 0.901; 95% CI: 0.831−0.976; p = 0.011). No other parameter was found to be associated with risk for mortality.
      Table 5Results of Cox regression analysis for risk factors associated with death. We provided the significant values as bold.
      Risk factorsOR95% CIp
      Duration of diabetes0.9960.813–1.2200.968
      Asthma000.989
      Coronary artery disease0.5120.200–1.3120.163
      Chronic kidney disease000.981
      Age0.9880.932–1.0480.694
      APACHE II1.0000.963−1.0390.983
      GCS0.9010.831–0.9760.011
      Fasting glucose level1.0031.000−1.0060.097
      C-reactive protein1.0000.997−1.0040.833
      Blood urea nitrogen1.0170.997−1.0370.093
      Lactate dehydrogenase1.0011.000−1.0010.009
      Ferritin1.0000.999−1.0000.501
      d-dimer, ng/mL1.0001.000−1.0000.718
      Fibrinogen1.0001.000−1.0000.712
      OR, odds ratio; CI, confidence interval; APACHE II, acute physiology assessment and chronic health evaluation; GCS, glasgow coma scale. We provided the significant values as bold.

      4. Discussion

      We investigated association between pneumonia development and clinical data by selecting a specific study population including 432 type 2 diabetes mellitus patients with a diagnosis of COVID-19. Our results indicate that only DPP-4 inhibitor use and elevated CRP levels were independent risk factors for development of pneumonia in diabetes mellitus patients with COVID-19. In addition, in Cox regression analysis, low GCS score and elevated LDH levels were linked with 75-days mortality.
      In coronavirus infections, initial response is created by submucosal mast cells of respiratory tract [
      • Malone R.W.
      • Tisdall P.
      • Fremont-Smith P.
      • et al.
      COVID-19: famotidine, histamine, mast cells, and mechanisms.
      ]. The mast cell degranulation is regulated by stromal cell-derived factor-1 (SDF-1) which is inactivated by DPP-4 [
      • Elmansi A.M.
      • Awad M.E.
      • Eisa N.H.
      • et al.
      What doesn’t kill you makes you stranger: dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands.
      ]. However, growing evidence shows mast cells release bioactive molecules which exacerbate clinical course of disease while neutralizing these pathogens [
      • Malone R.W.
      • Tisdall P.
      • Fremont-Smith P.
      • et al.
      COVID-19: famotidine, histamine, mast cells, and mechanisms.
      ,
      • Ricke D.O.
      Two different antibody-dependent enhancement (ADE) risks for SARS-CoV-2 antibodies.
      ]. The dual activity of mast cells in viral infection has led debates about COVID-19 pneumonia and DPP-4 inhibitors [
      • Dalan R.
      Is DPP4 inhibition a comrade or adversary in COVID-19 infection.
      ,
      • Iacobellis G.
      COVID-19 and diabetes: can DPP4 inhibition play a role?.
      ,
      • Barchetta I.
      • Cavallo M.G.
      • Baroni M.G.
      COVID-19 and diabetes: is this association driven by the DPP4 receptor? Potential clinical and therapeutic implications.
      ,
      • Strollo R.
      • Pozzilli P.
      DPP4 inhibition: preventing SARS-CoV-2 infection and/or progression of COVID-19?.
      ].
      In our study, DPP-4 inhibitor use was found to be associated with pneumonia development in diabetes mellitus patients with diagnosis of COVID-19, which differs from results reported by studies in the literature. In previous studies comparing patients using or not using DPP-4 inhibitor, it was reported that the need for mechanical ventilation was less common among patients on DPP-4 inhibitor [
      • Mirani M.
      • Favacchio G.
      • Carrone F.
      • et al.
      Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a case series from an academic hospital in Lombardy, Italy.
      ,
      • Solerte S.B.
      • D’Addio F.
      • Trevisan R.
      • et al.
      Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study.
      ]. Among these, in the study on 90 patients by Mirani et al., only 12% were on DPP-4 inhibitor [
      • Mirani M.
      • Favacchio G.
      • Carrone F.
      • et al.
      Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a case series from an academic hospital in Lombardy, Italy.
      ]; the number of patients was smaller than that in our study. In the study by Solerte et al., only sitagliptin was investigated [
      • Solerte S.B.
      • D’Addio F.
      • Trevisan R.
      • et al.
      Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study.
      ]. In a study by Kim et al., no significant association was found between DPP-4 inhibitor use and severity of pneumonia [
      • Kim M.K.
      • Jeon J.H.
      • Kim S.W.
      • et al.
      The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea.
      ]. However, above-mentioned studies excluded COVID-19 patients without pulmonary involvement on thoracic CT scans; thus, they are inadequate to assess factors predisposing to pneumonia.
      For DPP-4 use, the mechanisms underlying risk for potential infection haven't been fully elucidated. A membrane-bound form of DDP-4, namely CD26, is present in several cell types including T lymphocytes, B lymphocytes, natural killer cells and macrophages [
      • Mulvihill E.E.
      • Drucker D.J.
      Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors.
      ]. The CD26 is N-terminal dipeptide that cleaves a protease from polypeptides and involved in some biological processes that may potentially modify immune function [
      • Elmansi A.M.
      • Awad M.E.
      • Eisa N.H.
      • et al.
      What doesn’t kill you makes you stranger: dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands.
      ]. Thus, the CD26/DPP4-mediated cleavage of immunoregulatory substrates such as regulatory peptides, neuropeptides and chemokines may influence on immune activity or function [
      • Mortier A.
      • Gouwy M.
      • Van Damme J.
      • Proost P.
      • Struyf S.
      CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology.
      ]; thereby, CD26 inhibition by DPP-4 inhibitors may alter immune function.
      In a meta-analysis, all-causes infections showed a significant increase with sitagliptin therapy but no significant increase was found with vildagliptin therapy [
      • Richter B.
      • Bandeira-Echtler E.
      • Bergerhoff K.
      • Lerch C.
      Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes.
      ]. However, no significant increase was observed in risk for respiratory tract infections with DPP-4 inhibitors when results from several safety analyses of clinical trials on sitagliptin and vildagliptin were compared with placebo [
      • Williams-Herman D.
      • Engel S.S.
      • Round E.
      Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes.
      ]. In a study on association between oral anti-diabetics and community-acquired pneumonia, no increase was observed in risk for pneumonia by DPP-4 inhibitor use [
      • Gorricho J.
      • Garjón J.
      • Alonso A.
      • et al.
      Use of oral antidiabetic drugs and risk of community-acquired pneumonia: a nested case-control study.
      ]. A case-control study on Vigibase database of World Health Organization (WHO), it was found that reports of infections were increased after introduction of DPP-4 inhibitors [
      • Willemen M.J.
      • Mantel-Teeuwisse A.K.
      • Straus S.M.
      • Meyboom R.H.
      • Egberts T.C.
      • Leufkens H.G.
      Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase.
      ]. Kawasaki et al. demonstrated that sitagliptin diminished pulmonary damage caused by LPS in rats [
      • Kawasaki T.
      • Chen W.
      • Htwe Y.M.
      • Tatsumi K.
      • Dudek S.M.
      DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice.
      ]. There is no evidence for similar findings in human lung. Thus, it is unknown whether DPP-4 inhibition will affect immune function or whether it will increase risk for infection in human. Based on our current results, the finding of the increased risk for pneumonia in diabetes mellitus patients with COVID-19 using DPP-4 inhibitor indicate potential role of DPP-4 in COVID-dipeptide 19 pneumonia.
      DPP-4 was previously defined as a functional receptor for MERS-CoV [
      • Lu G.
      • Hu Y.
      • Wang Q.
      • et al.
      Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26.
      ,
      • Raj V.S.
      • Mou H.
      • Smits S.L.
      • et al.
      Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC.
      ]. In some studies, it was shown that there was correlation between DPP-4 and angiotensin converting enzyme (ACE)-2 [
      • Cao Z.
      • Wang L.T.
      • Liu Z.M.
      Homologous modeling and binding ability analysis of Spike protein after point mutation of severe acute respiratory syndrome coronavirus 2 to receptor proteins and potential antiviral drugs.
      ,
      • Sun J.
      • Ye F.
      • Wu A.
      • et al.
      Comparative transcriptome analysis reveals the intensive early stage responses of host cells to SARS-CoV-2 infection.
      ]. This has led the hypothesis that SARS-CoV-2 might use DPP-4 as a functional receptor in addition to ACE-2 [
      • Cao Z.
      • Wang L.T.
      • Liu Z.M.
      Homologous modeling and binding ability analysis of Spike protein after point mutation of severe acute respiratory syndrome coronavirus 2 to receptor proteins and potential antiviral drugs.
      ,
      • Vankadari N.
      • Wilce J.A.
      Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26.
      ]. In a study quantifying DPP-3 levels in COVID-19 patients, Schlicht et al. found that DPP-4 levels were found to be decreased as similar to MERS-CoV [
      • Schlicht K.
      • Rohmann N.
      • Geisler C.
      • et al.
      Circulating levels of soluble Dipeptidylpeptidase-4 are reduced in human subjects hospitalized for severe COVID-19 infections.
      ], supporting the hypothesis.
      In our study, only patients in pneumonia group were receiving SGLT-2 inhibitor. Therefore we could not clearly reveal the role of SGLT-2 inhibitor’s role in COVID-19. In a retrospective cohort study, it was reported that SGLT-2 inhibitor use did not predispose COVID-19 development [
      • Sainsbury C.
      • Wang J.
      • Gokhale K.
      • et al.
      Sodium-glucose co-transporter-2 inhibitors and susceptibility to COVID-19: a population-based retrospective cohort study.
      ]. However, data regarding SGLT-2 inhibitors are limited; thus, our study will add literature in this context. Further randomized, controlled studies are needed to understand the role of SGLT-2 inhibitor roles in COVİD-19. In addition, although advanced age and elevated CRP, LDH and fibrinogen levels were found to be associated with pneumonia, only CRP elevation resulted in increased risk for pneumonia in multiple analysis. This finding is in agreement with literature [
      • Chen Y.
      • Yang D.
      • Cheng B.
      • et al.
      Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.
      ].
      In studies about mortality, data regarding DPP-4 inhibitor are controversial. Some authors reported better outcomes in COVID-19 patients using DPP-4 inhibitor [
      • Solerte S.B.
      • D’Addio F.
      • Trevisan R.
      • et al.
      Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study.
      ] while other authors reported inconclusive results on the issue [
      • Chen Y.
      • Yang D.
      • Cheng B.
      • et al.
      Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.
      ,
      • Bonora B.M.
      • Avogaro A.
      • Fadini G.P.
      Disentangling conflicting evidence on DPP-4 inhibitors and outcomes of COVID-19: narrative review and meta-analysis.
      ,
      • Fadini G.P.
      • Morieri M.L.
      • Longato E.
      • et al.
      Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes: a case-control study.
      ,
      • Pérez-Belmonte L.M.
      • Torres-Peña J.D.
      • López-Carmona M.D.
      • et al.
      SEMI-COVID-19 Network. Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
      ,
      • Wargny M.
      • Potier L.
      • Gourdy P.
      • et al.
      CORONADO investigators. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.
      ]. In another study, it was reported in-hospital DPP-4 use decreased mortality but pre-hospital use had no association with mortality [
      • Pal R.
      • Banerjee M.
      • Mukherjee S.
      • Bhogal R.S.
      • Kaur A.
      • Bhadada S.K.
      Dipeptidyl peptidase-4 inhibitor use and mortality in COVID-19 patients with diabetes mellitus: an updated systematic review and meta-analysis.
      ]. Our results are supportive for previous studies, without significant increase in mortality by DPP-4 inhibitor use.
      Many studies have defined markers for mortality in COVID-19. The parameters consistent with literature including comorbidity, asthma, coronary artery disease, chronic renal failure, advanced age, high APACHE II score and low GCS score were more common among non-survivors [
      • Wargny M.
      • Potier L.
      • Gourdy P.
      • et al.
      CORONADO investigators. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.
      ,
      • Ramos-Rincon J.M.
      • Buonaiuto V.
      • Ricci M.
      • et al.
      SEMI-COVID-19 network. Clinical characteristics and risk factors for mortality in very old patients hospitalized with COVID-19 in Spain.
      ,
      • Corona G.
      • Pizzocaro A.
      • Vena W.
      • et al.
      Diabetes is most important cause for mortality in COVID-19 hospitalized patients: systematic review and meta-analysis.
      ]. In addition, fasting glucose level and duration of diabetes was linked with death. In our study, non-survivor patients had higher duration of biguanide use. This may be secondary to prolonged diabetes mellitus duration since, as presented in our study, metformin is most commonly used oral anti-diabetic agent worldwide and it is generally used as first-line treatment [
      • Lazarus G.
      • Suhardi I.P.
      • Wiyarta E.
      • Rasyidah R.A.
      • Barliana J.D.
      Is there a need to reconsider the use of metformin in COVID-19 patients with type 2 diabetes mellitus?.
      ,
      • Cheng X.
      • Liu Y.M.
      • Li H.
      • et al.
      Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
      ].
      To determine alteration in mortality-related factors during course of disease, we assessed blood parameters on day 1 and 7. In agreement with literature, elevated CRP, BUN, LDH, ferritin, d-dimer and neutrophil count and low GFR level were found to be associated with mortality [
      • Kim M.K.
      • Jeon J.H.
      • Kim S.W.
      • et al.
      The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea.
      ,
      • Wargny M.
      • Potier L.
      • Gourdy P.
      • et al.
      CORONADO investigators. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.
      ,
      • Corona G.
      • Pizzocaro A.
      • Vena W.
      • et al.
      Diabetes is most important cause for mortality in COVID-19 hospitalized patients: systematic review and meta-analysis.
      ,
      • Cai R.
      • Zhang J.
      • Zhu Y.
      • Liu L.
      • Liu Y.
      • He Q.
      Mortality in chronic kidney disease patients with COVID-19: a systematic review and meta-analysis.
      ,
      • Cheng Y.
      • Luo R.
      • Wang K.
      • et al.
      Kidney disease is associated with in-hospital death of patients with COVID-19.
      ]. Mean fibrinogen level was significantly higher on day 1 in non-survivors; however, no significant difference was found between non-survivors and survivors on day 7. This may be affected by COVID-19 treatment initiated at hospital admission. Similarly, the mean creatinine level on day 7 was significantly higher in non-survivors but no significant difference was observed on day 1. The change in creatinine levels on day 7 can be explained by COVID-19 progression and nephrotoxic effects of available treatments [
      • Kolhe N.V.
      • Fluck R.J.
      • Selby N.M.
      • et al.
      Acute kidney injury associated with COVID-19: a retrospective cohort study.
      ,
      • Adapa S.
      • Chenna A.
      • Balla M.
      • et al.
      COVID-19 pandemic causing acute kidney injury and impact on patients with chronic kidney disease and renal transplantation.
      ]. However, in our study, only elevated LDH levels were identified as significant independent risk factors for mortality in agreement with previous studies [
      • Kim M.K.
      • Jeon J.H.
      • Kim S.W.
      • et al.
      The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea.
      ,
      • Chen Y.
      • Yang D.
      • Cheng B.
      • et al.
      Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.
      ,
      • Corona G.
      • Pizzocaro A.
      • Vena W.
      • et al.
      Diabetes is most important cause for mortality in COVID-19 hospitalized patients: systematic review and meta-analysis.
      ].
      The all studies including ours delineate a complex picture for interaction between DM and COVID-19 pneumonia. Diabetes mellitus leads immune disorder and various metabolic disorders. Together with effects of DM on immune system DM therapies may alter response to and clinical outcomes of COVID-19 pneumonia. On contrary to other studies, our study emphasizes factors influencing on development of COVID-19 pneumonia in patients with diabetes. This paves the way for protective measures that may be implemented in diabetes mellitus patients with well-known predisposition to infections. However, further randomized, controlled studies are needed to better understand factors involved in the development of pneumonia in diabetes mellitus patients with a diagnosis of COVID-19.
      This study has some limitations. Due to deficiencies of infrastructure and training of healthcare providers, the documentation about history of COVID-19 exposure and laboratory tests were incomplete. In particular, HbA1c values were missing in a considerable proportion of subjects; thus, our analysis regarding association between degree of glycemic control and severity and mortality of COVID-19 was limited. Although we had age adjusted regression analysis, we could not totally exclude age effect on relationship between pneumonia and oral anti-diabetics.

      5. Conclusion

      The DPP-4 inhibitor uses and elevated CRP level increased risk for pneumonia in diabetes mellitus patients with a diagnosis of COVID-19. Only patients in the pneumonia group had SGLT-2 inhibitor use. No oral anti-diabetics were found to be associated with COVID-19 related death.

      Research funding

      During this study, any pharmaceutical company that has a direct connection with the subject of the research, a company that provides and/or produces medical tools, equipment, and materials, or any commercial company, during the evaluation process of the study, financial and/or no moral support was received.

      Author contributions

      All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

      Disclosure

      Regarding this study, the authors and/or their family members do not have a scientific and medical committee membership or relationship with their members, consultancy, expertise, working status in any company, shareholding, or similar situations with a potential conflict of interest.

      Declaration of interests

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Appendix A

      Table A1Subgroup analysis for DPP-4 inhibitors and SGLT-2 inhibitors in patients with and without pneumonia.
      DPP-4 inhibitors sub-groupsTotalNo pneumoniaPneumoniap
      n = 246n = 18n = 228
      Linagliptin53 (21,5)2 (11.1)51 (22.4)0.521
      Saxagliptin2 (0,8)0 (0.0)2 (0.9)
      Sitagliptin98 (39,8)7 (38.9)91 (39.9)
      Vildagliptin93 (37,8)9 (50.0)84 (36.8)
      SGLT-2 inhibitors sub-groupsTotalNo pneumoniaPneumoniap
      n = 56n = 0n = 56
      Dapagliflozin25 (44.6)0 (0.0)25 (44.6)
      Empagliflozin31 (55.4)0 (0.0)31 (55.4)
      DPP-4 Inh, dipeptidyl peptidase 4 inhibitors; SGLT-2 Inh, sodium glucose co-transporter type 2 inhibitors.
      Table A2Laboratory findings of patients who with pneumonia and without pneumonia.
      Laboratory measures of on admission dayNo pneumoniaPneumoniaP
      n = 46n = 386
      Fasting glucose level, mg/dL164 ± 59.6209 ± 1010.005
      HbA1C, %
      n = 6 for no pneumonia group and n = 99 for pneumonia group HbA1C: hemoglobin A1c.
      7.8 ± 1.48.3 ± 1.90.524
      C-reactive protein, mg/dL7 (16.45)55.3 (85.43)<0.001
      Blood urea nitrogen, mg/dL19.5 (9.25)19 (16)0.136
      Creatinine, mg/dL0.99 (0.26)1.1 (0.69)0.532
      Lactate dehydrogenase, U/L235 (102.3)321 (226)0.017
      Ferritin, ng/mL117 (379)226 (437)0.505
      Glomerular filtration rate, mL/min76.5 ± 24.571 ± 27.30.366
      White blood cell count, ×109/L5.6 (2.9)7.6 (6.1)0.30
      Neutrophil (PMN), ×103/μL2.8 (3.3)5.8 (5.9)0.071
      Lymphocyte, ×103/μL1.8 (1.3)1.2 (0.8)0.412
      Platelet ×103/μL214.6 ± 52.5224.8 ± 89.80.452
      Fibrinogen, mg/L4022 ± 12195563 ± 17920.002
      Activated partial thromboplastin time (aPTT), s30.6 ± 12.633.0 ± 30.50.753
      d-dimer, ng/mL660 (547)1090 (1500)0.346
      Prothrombin time (PT), s12.9 (2)14 (2.5)0.075
      a n = 6 for no pneumonia group and n = 99 for pneumonia group HbA1C: hemoglobin A1c.

      References

        • Lin S.
        • Ge S.
        • He W.
        • Zeng M.
        Association between comorbid diabetes mellitus and prognosis of patients with sepsis in the intensive care unit: a retrospective cohort study.
        Ann. Transl. Med. 2021; 9: 22
        • Jafar N.
        • Edriss H.
        • Nugent K.
        The effect of short-term hyperglycemia on the innate immune system.
        Am. J. Med. Sci. 2016; 351: 201-211
        • Bonyek-Silva I.
        • Nunes S.
        • Santos R.L.
        • et al.
        Unbalanced production of LTB4/PGE2 driven by diabetes increases susceptibility to cutaneous leishmaniasis.
        Emerg. Microbes Infect. 2020; 9: 1275-1286
        • Turina M.
        • Fry D.E.
        • Polk Jr., H.C.
        Acute hyperglycemia and the innate immune system: clinical, cellular, and molecular aspects.
        Crit. Care Med. 2005; 33: 1624-1633
        • Guo W.
        • Li M.
        • Dong Y.
        • et al.
        Diabetes is a risk factor for the progression and prognosis of COVID-19.
        Diabetes Metab. Res. Rev. 2020; : e3319
        • Cheng X.
        • Liu Y.M.
        • Li H.
        • et al.
        Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
        Cell Metab. 2020; 32 (537–547.e3)
        • Yang J.K.
        • Feng Y.
        • Yuan M.Y.
        • et al.
        Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS.
        Diabet. Med. 2006; 23: 623-628
        • Kulcsar K.A.
        • Coleman C.M.
        • Beck S.E.
        • Frieman M.B.
        Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection.
        JCI Insight. 2019; 4e131774
        • Mantovani A.
        • Byrne C.D.
        • Zheng M.H.
        • Targher G.
        Diabetes as a risk factor for greater COVID-19 severity and in-hospital death: a meta-analysis of observational studies.
        Nutr. Metab. Cardiovasc. Dis. 2020; 30: 1236-1248
        • Muniyappa R.
        • Gubbi S.
        COVID-19 pandemic, coronaviruses, and diabetes mellitus.
        Am. J. Physiol. Endocrinol. Metab. 2020; 318: E736-E741
        • Malone R.W.
        • Tisdall P.
        • Fremont-Smith P.
        • et al.
        COVID-19: famotidine, histamine, mast cells, and mechanisms.
        Front Pharmacol. 2021; 12: 633680
        • Elmansi A.M.
        • Awad M.E.
        • Eisa N.H.
        • et al.
        What doesn’t kill you makes you stranger: dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands.
        Pharmacol. Ther. 2019; 198: 90-108
        • Ricke D.O.
        Two different antibody-dependent enhancement (ADE) risks for SARS-CoV-2 antibodies.
        Front. Immunol. 2021; 12640093
        • Dalan R.
        Is DPP4 inhibition a comrade or adversary in COVID-19 infection.
        Diabetes Res. Clin. Pract. 2020; 164108216
        • Iacobellis G.
        COVID-19 and diabetes: can DPP4 inhibition play a role?.
        Diabetes Res. Clin. Pract. 2020; 162108125
        • Barchetta I.
        • Cavallo M.G.
        • Baroni M.G.
        COVID-19 and diabetes: is this association driven by the DPP4 receptor? Potential clinical and therapeutic implications.
        Diabetes Res. Clin. Pract. 2020; 163108165
        • Strollo R.
        • Pozzilli P.
        DPP4 inhibition: preventing SARS-CoV-2 infection and/or progression of COVID-19?.
        Diabetes Metab. Res. Rev. 2020; 36: e3330
        • Mirani M.
        • Favacchio G.
        • Carrone F.
        • et al.
        Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a case series from an academic hospital in Lombardy, Italy.
        Diabetes Care. 2020; 43: 3042-3049
        • Solerte S.B.
        • D’Addio F.
        • Trevisan R.
        • et al.
        Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study.
        Diabetes Care. 2020; 43: 2999-3006
        • Kim M.K.
        • Jeon J.H.
        • Kim S.W.
        • et al.
        The clinical characteristics and outcomes of patients with moderate-to-severe coronavirus disease 2019 infection and diabetes in Daegu, South Korea.
        Diabetes Metab. J. 2020; 44: 602-613
        • Mulvihill E.E.
        • Drucker D.J.
        Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors.
        Endocr. Rev. 2014; 35: 992-1019
        • Mortier A.
        • Gouwy M.
        • Van Damme J.
        • Proost P.
        • Struyf S.
        CD26/dipeptidylpeptidase IV-chemokine interactions: double-edged regulation of inflammation and tumor biology.
        J. Leukoc. Biol. 2016; 99: 955-969
        • Richter B.
        • Bandeira-Echtler E.
        • Bergerhoff K.
        • Lerch C.
        Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes.
        Vasc. Health Risk Manag. 2008; 4: 753-768
        • Williams-Herman D.
        • Engel S.S.
        • Round E.
        Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes.
        BMC Endocr. Disord. 2010; 10: 7
        • Gorricho J.
        • Garjón J.
        • Alonso A.
        • et al.
        Use of oral antidiabetic drugs and risk of community-acquired pneumonia: a nested case-control study.
        Br. J. Clin. Pharmacol. 2017; 83: 2034-2044
        • Willemen M.J.
        • Mantel-Teeuwisse A.K.
        • Straus S.M.
        • Meyboom R.H.
        • Egberts T.C.
        • Leufkens H.G.
        Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase.
        Diabetes Care. 2011; 34: 369-374
        • Kawasaki T.
        • Chen W.
        • Htwe Y.M.
        • Tatsumi K.
        • Dudek S.M.
        DPP4 inhibition by sitagliptin attenuates LPS-induced lung injury in mice.
        Am. J. Physiol. Lung Cell Mol. Physiol. 2018; 315: L834-L845
        • Lu G.
        • Hu Y.
        • Wang Q.
        • et al.
        Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26.
        Nature. 2013; 500: 227-231
        • Raj V.S.
        • Mou H.
        • Smits S.L.
        • et al.
        Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC.
        Nature. 2013; 495: 251-254
        • Cao Z.
        • Wang L.T.
        • Liu Z.M.
        Homologous modeling and binding ability analysis of Spike protein after point mutation of severe acute respiratory syndrome coronavirus 2 to receptor proteins and potential antiviral drugs.
        Beijing Da Xue Xue Bao. 2020; 53: 150-158
        • Sun J.
        • Ye F.
        • Wu A.
        • et al.
        Comparative transcriptome analysis reveals the intensive early stage responses of host cells to SARS-CoV-2 infection.
        Front. Microbiol. 2020; 11593857
        • Vankadari N.
        • Wilce J.A.
        Emerging COVID-19 coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26.
        Emerg. Microbes Infect. 2020; 9: 601-604
        • Schlicht K.
        • Rohmann N.
        • Geisler C.
        • et al.
        Circulating levels of soluble Dipeptidylpeptidase-4 are reduced in human subjects hospitalized for severe COVID-19 infections.
        Int. J. Obes. (Lond.). 2020; 44: 2335-2338
        • Sainsbury C.
        • Wang J.
        • Gokhale K.
        • et al.
        Sodium-glucose co-transporter-2 inhibitors and susceptibility to COVID-19: a population-based retrospective cohort study.
        Diabetes Obes. Metab. 2021; 23: 263-269
        • Chen Y.
        • Yang D.
        • Cheng B.
        • et al.
        Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.
        Diabetes Care. 2020; 43: 1399-1407
        • Bonora B.M.
        • Avogaro A.
        • Fadini G.P.
        Disentangling conflicting evidence on DPP-4 inhibitors and outcomes of COVID-19: narrative review and meta-analysis.
        J. Endocrinol. Invest. 2021; : 1-8
        • Fadini G.P.
        • Morieri M.L.
        • Longato E.
        • et al.
        Exposure to dipeptidyl-peptidase-4 inhibitors and COVID-19 among people with type 2 diabetes: a case-control study.
        Diabetes Obes. Metab. 2020; 22: 1946-1950
        • Pérez-Belmonte L.M.
        • Torres-Peña J.D.
        • López-Carmona M.D.
        • et al.
        SEMI-COVID-19 Network. Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study.
        BMC Med. 2020; 18: 359
        • Wargny M.
        • Potier L.
        • Gourdy P.
        • et al.
        CORONADO investigators. Predictors of hospital discharge and mortality in patients with diabetes and COVID-19: updated results from the nationwide CORONADO study.
        Diabetologia. 2021; 64: 778-794
        • Pal R.
        • Banerjee M.
        • Mukherjee S.
        • Bhogal R.S.
        • Kaur A.
        • Bhadada S.K.
        Dipeptidyl peptidase-4 inhibitor use and mortality in COVID-19 patients with diabetes mellitus: an updated systematic review and meta-analysis.
        Ther. Adv. Endocrinol. Metab. 2021; 12 (2042018821996482)
        • Ramos-Rincon J.M.
        • Buonaiuto V.
        • Ricci M.
        • et al.
        SEMI-COVID-19 network. Clinical characteristics and risk factors for mortality in very old patients hospitalized with COVID-19 in Spain.
        J. Gerontol. A Biol. Sci. Med. Sci. 2021; 76: e28-e37
        • Corona G.
        • Pizzocaro A.
        • Vena W.
        • et al.
        Diabetes is most important cause for mortality in COVID-19 hospitalized patients: systematic review and meta-analysis.
        Rev. Endocr. Metab. Disord. 2021; : 1-22
        • Lazarus G.
        • Suhardi I.P.
        • Wiyarta E.
        • Rasyidah R.A.
        • Barliana J.D.
        Is there a need to reconsider the use of metformin in COVID-19 patients with type 2 diabetes mellitus?.
        Int. J. Diabetes Dev. 2021; : 1-6
        • Cheng X.
        • Liu Y.M.
        • Li H.
        • et al.
        Metformin is associated with higher incidence of acidosis, but not mortality, in individuals with COVID-19 and pre-existing type 2 diabetes.
        Cell Metab. 2020; 32 (537.e3–547.e3)
        • Cai R.
        • Zhang J.
        • Zhu Y.
        • Liu L.
        • Liu Y.
        • He Q.
        Mortality in chronic kidney disease patients with COVID-19: a systematic review and meta-analysis.
        Int. Urol. Nephrol. 2021; : 1-7
        • Cheng Y.
        • Luo R.
        • Wang K.
        • et al.
        Kidney disease is associated with in-hospital death of patients with COVID-19.
        Kidney Int. 2020; 97: 829-838
        • Kolhe N.V.
        • Fluck R.J.
        • Selby N.M.
        • et al.
        Acute kidney injury associated with COVID-19: a retrospective cohort study.
        PLoS Med. 2020; 17e1003406
        • Adapa S.
        • Chenna A.
        • Balla M.
        • et al.
        COVID-19 pandemic causing acute kidney injury and impact on patients with chronic kidney disease and renal transplantation.
        J. Clin. Med. Res. 2020; 12: 352-361