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\begin{document}

\title{The Effect of Diabetes Mellitus on Disease Prognosis in Covid 19
Patients}



\author[1]{Zeynep Altın}%
\author[2]{Hamiyet Yilmaz}%
\affil[1]{Republic of Turkey Ministry of Health Izmir Provincial Health Directorate Izmir University of Health Sciences Tepecik Training and Research Hospital}%
\affil[2]{TC Sağlık Bakanlığı İzmir İl Sağlık Müdürlüğü İzmir Sağlık Bilimleri Üniversitesi Tepecik Eğitim ve Araştırma Hastanesi}%


\vspace{-1em}



  
  \date{May 21, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Aims: In this study, we aimed to evaluate and compare the clinical
characteristics, laboratory findings, outcomes of hospitalized patients
with and without diabetes along with poorly vs well-controlled diabetes.
Methods: A total of 341 hospitalized patients with covid-19 confirmed by
RT-PCR and/or chest imaging suggestive of covid-19 infection were
retrospectively included in this study. The patients were divided into 2
groups as diabetic (n = 120) and non-diabetic (n = 221). Demographic
data, symptoms, comorbidities, laboratory values were recorded. The
patients were classified according to the clinical stages defined by
guidance of WHO for covid-19. The percentage of patients with severe
disease was higher in diabetic group (n = 57) 47.5\% compared to
non-diabetic group(n=61) 27.8\% (p = 0.001). The percentage of patients
requiring oxygen therapy was significantly higher in 61 (51.2\%)
diabetic group than non-diabetic group 65 (29.4\%) (p = 0.001).The
median time of duration of hospitalization in diabetic group was 8 days,
{[}IQR 6-11.5{]} that was significantly higher than non-diabetic group 7
days {[}IQR 5-10{]} (p = 0.009). The median time of duration of
hospitalization in poorly controlled diabetic group was 9 days {[}IQR
6.00-16.00{]} that was significantly higher than well-controlled
diabetic group 8 days {[}IQR 6.00-11.00{]} (p = 0.006). Results:
Patients with diabetes were more susceptible to covid-19 infection and
the infection was more severe in patients with diabetes compared to
patients without diabetes. However, the mortality rate was similar
between diabetic and non-diabetic group. Diabetic covid-19 patients
without other comorbidities were not prone to severe infection.
Conclusion: Patients with diabetes and comorbidities, apart from the
glycemic control, should receive intensive monitoring and disease
management.%
\end{abstract}%



\sloppy


\textbf{The Effect of Diabetes Mellitus on Disease Prognosis in Covid 19
Patients}

\textbf{Abstract}

Aims: In this study, we aimed to evaluate and compare the clinical
characteristics, laboratory findings, outcomes of hospitalized patients
with and without diabetes along with poorly vs well-controlled diabetes.

Methods: A total of 341 hospitalized patients with covid-19 confirmed by
RT-PCR and/or chest imaging suggestive of covid-19 infection were
retrospectively included in this study. The patients were divided into 2
groups as diabetic (n = 120) and non-diabetic (n = 221). Demographic
data, symptoms, comorbidities, laboratory values were recorded. The
patients were classified according to the clinical stages defined by
guidance of WHO for covid-19. The percentage of patients with severe
disease was higher in diabetic group (n = 57) 47.5\% compared to
non-diabetic group(n=61) 27.8\% (p = 0.001). The percentage of patients
requiring oxygen therapy was significantly higher in 61 (51.2\%)
diabetic group than non-diabetic group 65 (29.4\%) (p = 0.001).The
median time of duration of hospitalization in diabetic group was 8 days,
{[}IQR 6-11.5{]} that was significantly higher than non-diabetic group 7
days {[}IQR 5-10{]} (p = 0.009). The median time of duration of
hospitalization in poorly controlled diabetic group was 9 days {[}IQR
6.00-16.00{]} that was significantly higher than well-controlled
diabetic group 8 days {[}IQR 6.00-11.00{]} (p = 0.006).

Results: Patients with diabetes were more susceptible to covid-19
infection and the infection was more severe in patients with diabetes
compared to patients without diabetes. However, the mortality rate was
similar between diabetic and non-diabetic group. Diabetic covid-19
patients without other comorbidities were not prone to severe infection.

Conclusion: Patients with diabetes and comorbidities, apart from the
glycemic control, should receive intensive monitoring and disease
management.

\textbf{What's already known about this topic?}

- Data on the role of glycemic control in the prognosis of - Covid-19
are conflicting and the risk factors affecting clinical progress and
outcome are still controversial. - It is difficult to decide whether
diabetes itself will increase susceptibility and affect the outcome of
infections.

\textbf{What does this article add?}

- The mortality rate due to Covid 19 is similar in diabetic and
non-diabetic groups.

- Diabetic Covid-19 patients without additional comorbidities are not
prone to serious infection.

- Clinical outcomes in patients with diabetes mellitus are similar
between well and poorly controlled diabetic subgroups.

- Patients with diabetes and comorbidities beyond glycemic control
should receive intensive follow-up and disease management.

\textbf{Introduction:}

The coronavirus disease 2019 (COVID-19), caused by severe acute
respiratory syndrome coronavirus-2 (SARS-CoV-2), has lead to more than
130 million cases and 2900000 deaths worldwide by April 2021. In
previous studies patients with diabetes were found to be more
susceptible to Covid-19. The prevalence of diabetes was 8 \%,
hypertension 17 \% and cardiovascular disease 5 \% in patients infected
with Covid-19 as reported in a metanalysis (1,2). The infection was more
severe and mortality was higher in patients with diabetes (3,4). Wang et
al and Wu et al, found that diabetic patients with covid-19 were prone
to severe and critical disease (5-7). However, in another metaanalysis
there was no correlation between the severity of disease and diabetes
(5,8). In fact, diabetes itself is a chronic inflammatory condition.
Hyperglycemia and insulin resistance promote increased synthesis of
glycosylation end products (AGEs) and proinflammatory cytokines,
oxidative stress and adhesion molecules leading to tissue inflammation
(9). In addition to marked inflammatory response, increased levels of
clotting factors and inhibition of fibrinolysis promoting the
development of a hypercoagulable pro-thrombotic state in type 2 diabetes
(9).

Although some studies suggested that, diabetes, especially, poorly
controlled diabetes was associated with worse outcome and higher
mortality (1,3,10), other studies showed that patients with
well-controlled or poorly controlled diabetes did not differ
significantly in terms of clinical outcomes (11). Therefore the data
regarding the role of glycemic control in the prognosis of covid-19
infection is conflicting and risk factors affecting the clinical
progression and outcome are still a matter of debate. Also, it is
difficult to decide whether diabetes itself increases susceptibility and
impacts outcomes from infections or the cardiovascular and renal
comorbidities that are frequently associated with diabetes are the main
factors involved (9). In this study, we aimed to evaluate and compare
the clinical characteristics, laboratory findings, outcomes of
hospitalized patients with and without diabetes along with poorly vs
well-controlled diabetes from a single center in Turkey.

\textbf{Materials and Methods:}

This retrospective study included 341 consecutive patients with covid-19
infection that were hospitalized in the pandemic wards of Research and
Training Hospital, admitted between March 1, 2020 and May 31, 2020. All
covid-19 patients were hospitalized and were diagnosed in acoordance
with WHO interim guidance. The clinical outcomes of all these patients
were monitored.

The patients were classified according to the clinical stages defined by
interim guidance of WHO for covid-19 (12). The clinical stages were:
mild, moderate, severe and critical (12,13). During hospitalization
period, the most advanced clinical stages of the patients were accepted
for classification. Mild and moderate cases were defined as non-severe
group without signs of hypoxia and pneumonia, inspite of having cough,
dyspnea and fever having blood oxygen saturation
(SpO\textsubscript{2})\textgreater{}90\%. Severe and critical stages
were defined as severe group. For the diagnosis of severe cases at least
one of the criteria should be included: dyspnea with a respiratory rate
\textgreater{}30 breaths/min, blood oxygen saturation
SpO\textsubscript{2} [?] 90\% and with progression in lesion of more than
50\% within 24-48 hours in chest imaging. Critical cases were:
respiratory failure with mechanical ventilation need, shock and
dysfunction of other organs requiring ICU care (12). Diabetic patients
were identified based on patient's self-report or medical records
confirmed by endocrinologist. Diagnosed diabetes was defined accoringd
to WHO diagnostic criteria of fasting plasma glucose [?] 126mg/dl (10).
Antidiabetic medications before hospitalization and during
hospitalization were recorded from electronic medical record system.
Cases with HbA1C levels \textgreater{} 7\% were classified as poorly
controlled while those with [?]7\% were regarded as well-controlled.
Demographic data, signs and symptoms, comorbidities and laboratory
values were recorded from the electronic record system of the hospital.

Laboratory values of patients in the first 24-hours of admission to
hospital were evaluated. Complete blood count analysis were performed
using UniCel DxH 800 hematology analyzer (Beckman Coulter, Miami, FL,
USA). Glucose, creatinine, alanine aminotransferase (ALT), aspartate
aminotransferase (ALT), ferritine, uric acid, C-reactive protein (CRP)
and lipid parameters measured by enzymatic methods using an AU5800
autoanalyzer (Beckman Coulter, High Wycombe, UK). For high sensitive
troponin I (hs-TNI) ve procalcitonin, ADVIA Centaur XP immunoassay
analyzer (Siemens Healthineers, Erlangen, Germany) was used.~Prothrombin
time (PT) and activated partial prothrombin time (APTT), fibrinogen, d
dimer were measured by CS 2500 ACL coagulation analyzer system (Sysmex
Corporation, Kobe, Japan). HbA1c were analyzed by autoanalyzer HPLC
Variant II (Bio-Rad Laboratories, CA, USA). Diagnosis of covid- 19 was
confirmed by real time polymerase chain reaction (RT-PCR) (Bio-Speedy
COVID-19 RT-qPCR kiti, Bioeksen R\&D Technologies Ltd, \selectlanguage{polish}İ\selectlanguage{english}stanbul).

Continuous variables were presented as mean \selectlanguage{ngerman}± standart deviation (SD) or
median and interquartie range. Categorical variables were expressed as
frequencies and percentages (\%). Chi-square test was applied to compare
categorical variables and Student-t test and Mann-Whitney U test were
used for the comparison of continuous variables. For more than two-group
comparisons of continuous variables ANOVA was used. P\textless{}0.05 was
considered statistically significant. Statistical analysis was performed
with SPSS 24 statistical software.

\textbf{Results:}

A total of 341 hospitalized patients with covid-19 confirmed by RT-PCR
and/or chest imaging suggestive of covid-19 infection were
retrospectively included in this study. Among these patients, 120 cases
(35.2\%) had diabetes mellitus, 221 did not have diabetes. The
demographic and clinical characteristics of patients with and without
diabetes are shown in Table-\selectlanguage{english}I. Sex distribution was similar between the
diabetic and non-diabetic group. However median age was significantly
higher in patients with diabetes (60, {[}IQR{]} 49-71 years) compared to
non-diabetics (49, {[}IQR{]} 36-62 years) (p=0.001). The percentage of
patients with respect to having dry cough, fever, dyspnea, chest pain,
sore throat, headache, fatigue, myalgia and loss of smell and taste were
similar between the two groups. RT-PCR positivity was similar between
the groups. Considering the comorbidities, the ratios of patients with
pulmonary disease, chronic liver and kidney disease, venous
thromboembolic disorders, rheumatologic disease and malignancy were not
different between the two groups. But, the percentage of hypertension 84
(70.5\%) vs 75 (33.8\%) p=0.001 and cardiovascular disease 30 (25.6\%)
vs 28 (12.9\%) p=0.006 were significantly higher in the diabetic group.
Also chronic kidney disease was more prevalent in diabetic patients
(p=0.02).

\selectlanguage{english}\textbf{Table-I: Clinical Characteristics of hospitalized covid-19
patients}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Diabetes (120)} & \textbf{Non-diabetes (221)} &
\textbf{p-value}\tabularnewline
\textbf{Age (median,IQR)} & 60 (49-71) & 49 (36-62) &
0,001\tabularnewline
\textbf{Sex (M/F)(n)} & 62/58 & 124/97 & 0,302\tabularnewline
\textbf{Fever (n)\%} & 76(63,9\%) & 132 (60\%) & 0,880\tabularnewline
\textbf{Cough} & 60 (50,8\%) & 103(46,6\%) & 0,644\tabularnewline
\textbf{Dyspnea} & 38 (32\%) & 65(29,7\%) & 0,660\tabularnewline
\textbf{Fatigue} & 36(30,1\%) & 58(26,2\%) & 0,445\tabularnewline
\textbf{Myalgia} & 60(50,8\%) & 103(46,6\%) & 0,644\tabularnewline
\textbf{Taste/smell loss} & 5 (3,8\%) & 4 (1,6\%) & 0,291\tabularnewline
\textbf{Sore throat} & 16(13,1\%) & 24(11\%) & 0,553\tabularnewline
\textbf{Chest pain} & 4 (3,2\%) & 2 (0,8\%) & 0,165\tabularnewline
\textbf{Hypertension} & 84(70,5\%) & 75(33,8\%) & 0,001\tabularnewline
\textbf{CVD} & 30(25,4\%) & 25(11,6\%) & 0,001\tabularnewline
\textbf{Pulmonary disease} & 11(9,0\%) & 15(6,8\%) &
0,470\tabularnewline
\textbf{CKD} & 12(9,8\%) & 82(3,7\%) & 0,02\tabularnewline
\textbf{CLD} & 1(0,9\%) & 2(0,8\%) & 0,929\tabularnewline
\textbf{Thyroid disease} & 7(5,7\%) & 16(7,3\%) & 0,580\tabularnewline
\textbf{Rheumatic disease} & 2(1,6\%) & 2(0,9\%) & 0,551\tabularnewline
\bottomrule
\end{longtable}

CVD~=~Cardiovascular disease, CKD~=~Chronic kidney disease,
CLD~=~Chronic liver disease

P values indicate differences between diabetes and non-diabetes
patients. P \textless{} 0.05 was considered statistically significant

Laboratory values are shown in Table-II. Among the laboratory parameters
studied, diabetic patients had higher neutrophil (4.85 {[}IQR
3.62-8.17{]} vs 4.3 {[}IQR 3.0-6.1{]}; p=0.016) and thrombocyte count
(234x10\textsuperscript{3} {[}IQR 188-318x10\textsuperscript{3}{]} vs
205x10\textsuperscript{3} {[}IQR 161-253 x10\textsuperscript{3}{]};
p=0.001), higher CRP (40.45 {[}IQR 7.45-101.55{]} vs 12.90 {[}IQR
4.90-52.95{]}; p=0.001), ferritine (175.1 {[}IQR 67.50-409.70{]} vs 98.0
{[}IQR 55.0-241.0{]}; p=0.010), fibrinogen (427.6 {[}IQR 341.1-518.6{]}
vs 368.6 {[}IQR 280.6-444.1{]}; p=0.011) levels compared to non-diabetic
individuals. On the contrary, Hemoglobin levels were lower in diabetic
patients (12.65 {[}IQR 11.12-14.37{]} vs 13.70 {[}IQR 12.50-14.90{]};
p=0.001).

Treatments and clinical outcomes are shown in Table-II. Although the
percentage of patients that need oxygen treatment were significantly
higher in diabetic 61 (51.2\%) compared to non-diabetic group 65
(29.4\%) (p=0.001), the need for invasive mechanical ventilation was
similar. According to clinical staging, the percentage of patients with
severe disease was higher in diabetic group (n=57) 47.5 \% compared to
non-diabetic group (n=61) 27.8\% (p=0.001). The percentage of patients
that take antiviral (favipiravir), antibiotic therapy and
hydroxychloroquine were not different between the two groups. Plasma
therapy were administered to 5 patients and intravenous immunoglobulin
was administered to 4 patients without diabetes, Tocilizumab was given
to patients in the non-diabetic group. At that time, steroid treatment
were not widely used, so only 3 patients in diabetic and 2 in
non-diabetic received steroid therapy. The median time of duration of
hospitalization in diabetic group was 8 days, {[}IQR 6-11.5{]} that was
significantly higher than non-diabetic group 7 days {[}IQR 5-10{]} (p=
0.009). The mortality rate was similar between diabetic and non-diabetic
individuals.

The results did not change in both the diabetic and non-diabetic group,
regarding the clinical characteristics, laboratory parameters and
clinical outcomes after excluding the effect of age.

\textbf{Table-II: Laboratory findings, treatments and clinical outcomes
of hospitalized covid-19 patients}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Diabetes (120)} & \textbf{Non-diabetes (221)} &
\textbf{p-value}\tabularnewline
\textbf{WBC 10\textsuperscript{3}/uL (median, IQR)} & 7.40 (5.25-10.40)
& 7 (5.20-8.80) & 0.739\tabularnewline
\textbf{Neutrophil, 10\textsuperscript{3}/uL} & 4.85 (3.62-8.17) & 4.30
(3.00-6.10) & 0.016\tabularnewline
\textbf{Lymphocyte, 10\textsuperscript{3}/uL} & 1.40 (1.00-1.90) & 1.40
(1.00-2.10) & 0.308\tabularnewline
\textbf{Platelet count 10\textsuperscript{3}/uL} & 234 (188.75-318.75) &
205 (161.00-253.00) & 0.001\tabularnewline
\textbf{Hemoglobin, g/dL} & 12.65 (11.12-14.37) & 13.70 (12.50-14.90) &
0.001\tabularnewline
\selectlanguage{greek}\textbf{Procalcitonin, µg/L}\selectlanguage{english} & 0.06 (0.01-0.31) & 0.03 (0.01-0.08) &
0.818\tabularnewline
\textbf{PTR, second} & 12.60 (12.00-13.10) & 12.50 (11.80-13.50) &
0.553\tabularnewline
\textbf{APTT, second} & 25.30 (23.30-27.20) & 24.80 (23.90-27.70) &
0.155\tabularnewline
\textbf{CRP, mg/L} & 40.45 (7.45-101.55) & 12.90 (4.90-52.95) &
0.001\tabularnewline
\textbf{LDH, U/L} & 243 (184-309.50) & 251 (203.50-299.0) &
0.774\tabularnewline
\textbf{Ferritin, g/L} & 175.10 (67.50-409.7) & 98.0 (55.0-241.0) &
0.010\tabularnewline
\textbf{Fibrinogen mg/dL} & 427.60 (341.1-518.6) & 368.6 (280.60-444.1)
& 0.011\tabularnewline
\selectlanguage{greek}\textbf{D-dimer, µg/L}\selectlanguage{english} & 640 (430-1410) & 610 (310-1200) &
0.760\tabularnewline
\textbf{Troponin, ng/L} & 2.83 (0.17-10.56) & 2.50 (0.19-5.50) &
0.137\tabularnewline
\textbf{Antibiotic therapy} & 94(78.60\%) & 157(70.90\%) &
0.071\tabularnewline
\textbf{Anti-viral therapy} & 69(57.90\%) & 122(55.20\%) &
0.168\tabularnewline
\textbf{Chloroquine therapy} & 110(92.10\%) & 209(94.90\%) &
0.394\tabularnewline
\textbf{Oxygen inhalation} & 61(51.20\%) & 65(29.40\%) &
0.001\tabularnewline
\textbf{Invasive MV therapy} & 12(9.80\%) & 11(4.90\%) &
0.068\tabularnewline
\textbf{Severe disease} & 57(47.50\%) & 61(27.80\%) &
0.001\tabularnewline
\textbf{Hospital stay, day} & 8 (6.0-11.50) & 7 (5.0-10.0) &
0.009\tabularnewline
\textbf{Death} & 2(4.20\%) & 2(2.80\%) & 0.479\tabularnewline
\bottomrule
\end{longtable}

WBC~=~White blood cell, PTR~=~prothrombin time, APTT~=~activated partial
thromboplastin time, CRP~=~C-reactive protein, LDH~=~lactate
dehydrogenase, MV ~= mechanical ventilation

P values indicate differences between diabetes and non-diabetes
patients. P \textless{} 0.05 was considered statistically significant

In diabetic group, median age and sex were similar between the
well-controlled (n=30) and poorly controlled (n=90) subgroups (Table-III).
The percentage of patients with respect to having dry cough, fever,
dyspnea, chest pain, sore throat, headache, fatigue, myalgia and loss of
smell and taste were similar between the two groups. RT-PCR positivity
was similar between the groups. Among the laboratory parameters; PT
(12.60 {[}IQR 12.10-13.70{]} vs 12.60 {[}IQR 12.10-13.10{]}; p=0.048)
and APTT (26.10 {[}IQR 23.90-27.20{]} vs 24.70 {[}IQR 22.80-27.40{]};
p=0.027) values were significantly higher in well-controlled diabetic
group with respect to poorly controlled diabetetic group.

The percentage of patients that need oxygen treatment or invasive
mechanical ventilation was similar between well-controlled and poorly
controlled diabetic group (Table-III). According to clinical staging, the
percentage of severe disease, as well as the percentage of all the
comorbidities evaluated were also similar between two groups. The
percentage of patients that take antiviral (favipiravir), antibiotic
therapy, hydroxychloroquine and anti-diabetic medication including oral
anti-diabetic drugs (metformin, dpp-4 inhibitors, pioglitazone, sglt-2
inhibitors, acarbose, gliclazide) and/or insulin were not different
between the two groups. The median time of duration of hospitalization
in poorly controlled diabetic group was 9 days, {[}IQR 6.00-16.00{]}
that was significantly higher than well-controlled diabetic group 8 days
{[}IQR 6.00-11.00{]} (p= 0.006). The mortality rate was similar between
well-controlled and poorly controlled diabetic group.

After excluding the patients with hypertension and/or cardiovascular
disease in diabetic group, we found no difference between the patients
with diabetes and without diabetes in terms of clininical
characteristics, laboratory parameters and clinical outcomes, except
glucose and HbA1c values. As expected, HbA1c (7.60 {[}IQR 6.73-8.70{]}
vs 5.40 {[}IQR 4.96-6.43{]}; p=0.011) and glucose (135.6 {[}IQR
122.10-166.70{]} vs 100.5 {[}IQR 86.10-120.10{]}; p=0.012) values were
higher in diabetic group with respect to non-diabetic group.

\textbf{Table-III: Clinical Characteristics, laboratory parameters and
treatments of the diabetic patients with covid-19}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Well-controlled diabetes (30)} & \textbf{poorly-controlled
diabetes (90)} & \textbf{p-value}\tabularnewline
\textbf{Age(median,IQR)} & 56 (49.25-70.25) & 61 (48-72) &
0.925\tabularnewline
\textbf{Sex (Male/Female)(n)} & 14/16 & 48/42 & 0.567\tabularnewline
\textbf{Hypertension} & 23(77.80\%) & 59(65.90\%) & 0.249\tabularnewline
\textbf{CVD} & 7(22.20\%) & 24(26.80\%) & 0.874\tabularnewline
\textbf{CKD} & 3(11.10\%) & 9(10.70\%) & 0.452\tabularnewline
\textbf{Pulmonary disease} & 3(11.0\%) & 6(7.30\%) &
0.584\tabularnewline
\textbf{WBC 10\textsuperscript{3}/uL median,IQR)} & 7.15 (4.57-10.20) &
7.50 (5.90-12.30) & 0.912\tabularnewline
\textbf{Neutrophil count, 10\textsuperscript{3}/uL} & 4.25 (2.62-8.10) &
5.20 (3.70-9.20) & 0.950\tabularnewline
\textbf{Lymphocyte, 10\textsuperscript{3}/uL} & 1.40 (1.00-1.77) & 1.30
(0.90-2.00) & 0.644\tabularnewline
\textbf{Platelet count 10\textsuperscript{3}/uL} & 215 (166-303) & 244
(194.25-352.25) & 0.503\tabularnewline
\textbf{Hemoglobin, g/dL} & 13.0 (11.10-14.50) & 12.60 (11.25-13.95) &
0.847\tabularnewline
\selectlanguage{greek}\textbf{Procalcitonin, µg/L}\selectlanguage{english} & 0.03 (0.01-0.06) & 0.08 (0.04-0.24) &
0.886\tabularnewline
\textbf{PTR, second} & 12.60 (12.10-13.70) & 12.60 (12.10-13.10) &
0.048\tabularnewline
\textbf{APTT, second} & 26.10 (23.90-27.20) & 24.70 (22.80-27.40) &
0.027\tabularnewline
\textbf{CRP, mg/L} & 11 (2.45-136.37) & 40.10 (7.31-112.60) &
0.667\tabularnewline
\textbf{LDH, U/L} & 259 (201.25-450.75) & 231 (199-295.0) &
0.183\tabularnewline
\textbf{Ferritin, g/L} & 115.01 (31.50-450) & 211.40 (75.30-450.0) &
0.268\tabularnewline
\textbf{Fibrinogen mg/dL} & 423.4 (341.7-506.0) & 441.60(379.1-529.4) &
0.846\tabularnewline
\selectlanguage{greek}\textbf{D-dimer, µg/L}\selectlanguage{english} & 450 (420-1520) & 660 (445-1375) &
0.686\tabularnewline
\textbf{Troponin, ng/L} & 3.02 (0.01-11.12) & 4.49 (0.02-12.94) &
0.537\tabularnewline
\textbf{Antibiotic therapy} & 25(85.20\%) & 69(76.80\%) &
0.626\tabularnewline
\textbf{Anti-viral therapy} & 23(77.40\%) & 52(58.20\%) &
0.268\tabularnewline
\textbf{Chloroquine therapy} & 27(92.60\%) & 82 (91.50\%) &
0.259\tabularnewline
\textbf{Oxygen inhalation} & 17(55.60\%) & 42(46.30\%) &
0.556\tabularnewline
\textbf{Invasive MV therapy} & 3(11.10\%) & 10(11.0\%) &
0.452\tabularnewline
\textbf{Severe disease} & 17(55.60\%) & 42(46.30\%) &
0.556\tabularnewline
\textbf{Hospital stay, day} & 8 ( 6.0-11.0) & 9( 6.0-16.0) &
0.006\tabularnewline
\textbf{Death} & 1(3.70\%) & 3(4.10\%) & 0.693\tabularnewline
\bottomrule
\end{longtable}

CVD~=~Cardiovascular disease, CKD~=~Chronic kidney disease, WBC~=~White
blood cell, PTR~=~prothrombin time, APTT~=~activated partial
thromboplastin time; CRP~=~C-reactive protein, LDH~=~lactate
dehydrogenase; MV ~= mechanical ventilation

P values indicate differences between well-controlled diabetes and
poorly-controlled diabetes patients. P \textless{} 0.05 was considered
statistically significant

\textbf{Discussion:}

In this retrospective study that included 341 patients, we evaluated the
clinical characteristics, laboratory parameters and clinical outcomes of
patients with covid-19 infection. All these parameters were compared
between covid-19 patients with diabetes mellitus and without diabetes
mellitus. Also we evaluated them in both well-controlled and poorly
controlled diabetic subgroups.

Recent data propose that patients with diabetes, hypertension and
kardiovascular disease are more prone to covid-19 infection. In a
meta-analysis that included 46,248 covid-19 patients the prevalence of
diabetes, hypertension and cardiovascular disease were 8\%, 17\% and
5\%, respectively.\textsuperscript{2,5} However in an Italian study, the
prevalence of diabetes was 35\% (5,14). Likewise, in our study cohort,
the prevalence of diabetes, hypertension and kardiovascular disease were
35.2\%, 46.5\% and 15.8\%, respectively. The difference from the resulst
of the above mentioned meta-analysis, might be explained by that, in our
hospital generally covid-19 patients with comorbidities were
hospitalized.

In case of clinical features of covid-19 infection such as; dry cough,
fever, dyspnea, chest pain, sore throat, headache, fatigue, myalgia and
loss of smell and taste, diabetic and non-diabetic patients were
similar.\textsuperscript{3,15} Also, in our study these symptoms were
similar between diabetics and non-diabetics.

Diabetic patients with covid-19 were found to have higher neutrophil and
leucocyte and decreased lymphocyte count in previous studies. It was
suggested that these findings might result from that diabetic patients
had more severe viral infection and were more susceptible to bacterial
infections (4,15). Also, inflammatory markers such as CRP and
erythrocyte sedimentation rate were more pronounced in diabetic patients
(9,10). In consistence with these findings, in our study we observed
higher neutrophil and leucocyte counts and CRP levels in diabetic
patients. In addition we found increased ferritine levels that was again
the result of severe infection and increased fibrinogen levels that
might reflect the hypercoagulable state that might be derived from
systemic activation of coagulation cascade due to the severe viral
infection (5,16).

While in some studies diabetes mellitus was found to be associated with
more severe or critical covid-19 infection (5,8), other studies found
that odds ratio for severe covid-19 infection was not higher in diabetic
patients compared to non-diabetic (2,5,10). In diabetes mellitus, in
addition to usual mechanisms such as impaired neutrophil chemotaxis and
phagocytosis, some specific factors were proposed to be responsible for
severe covid-19 infection: increased ACE-2 expression, increased Furin
which is a type-1 membrane-bound protease and involved in the entry of
coronaviruses into the cell, impaired T-Cell function and increased
Interleukin-6 (IL-6) (5). The higher rate of severe disease in patients
with diabetes was attributed to higher incidence of complications and
coexistence of other comorbidities, especially obesity and hypertension.
Even, further analysis revealed that diabetic patients without these
comorbidities were also more susceptible to severe disease and death
compared ton on-diabetics (10). In our study, we found that the
percentage of patients with severe disease was higher in diabetic group
compared to non-diabetic group. However, in contrast to previous
findings, after excluding the patients with hypertension and/or
cardiovascular disease in diabetic group, we found no difference between
the two groups in terms of clinical outcomes. This might be explained by
that, in our study we did not evaluate obesity which would affect the
results.

The data about the mortality of diabetic patients with covid-19 is
conflicting. Whereas it was reported to be higher in some studies
(17-19), it was similar between diabetics and non non-diabetics in other
studies (7,20). In our study, we found similar mortality rate between
diabetics and non-diabetics.

Recently, the clinical outcomes of well-controlled and poorly controlled
diabetic patients with covid-19 were also evaluated. Zhu et al, reported
that well-controlled diabetic patients had lower death rate, compared
with poorly controlled diabetics (21). However CORONADO study and Raoufi
et al, found no association between HbA1C and death rate (11,22). The
authors suggested that, these inconsistent results might arise from that
acute viral infections lead to decreased insulin sensitivity and
increased fasting plasma glucose levels even in diabetic patients with
Hba1c \textless{}7\%. In our study, we also found no difference in terms
of clinical outcomes in well-controlled vs poorly controlled diabetic
patients. This might suggest that diabetes with other comorbidities, is
associated with severe covid-19 infection irrespective of glycemic
control.

This study had limitations; since the data were collected
retrospectively from electronic medical records of our hospital,
information about the body mass index was absent. However, the large
sample size was the strength of the study.

\textbf{Conclusions:}

In conclusion, patients with diabetes were more susceptible to covid-19
infection and the infection was more severe in patients with diabetes
compared to patients without diabetes. However, the mortality rate was
similar between diabetic and non-diabetic group. Diabetic covid-19
patients without other comorbidities were not prone to severe infection.
Considering the patients with diabetes mellitus, clinical outcomes were
similar between well-controlled and poorly controlled diabetic
subgroups. Patients with diabetes and comorbidities, apart from the
glycemic control, should receive intensive monitoring and disease
management.

\textbf{Compliance with ethical standards}

\textbf{Conflict of interest:} The authors declare that they have no
confict of interest.

\textbf{Ethics approval:} The study was approved by local ethics
committee of Research and Training Hospital (Decision Date:25.01.2021;
Decision No:82021/01-13). Written informed consent was not regarded as
necessary bt the committee due to the retrospective nature of the study
and the patient data anonymity.

\textbf{Funding:} This study received no financial support.

\textbf{References}

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\emph{https://doi.org/10.1007/s00125-020-05180-x}

\textbf{Table-I: Clinical Characteristics of hospitalized covid-19
patients}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Diabetes (120)} & \textbf{Non-diabetes (221)} &
\textbf{p-value}\tabularnewline
\textbf{Age (median,IQR)} & 60 (49-71) & 49 (36-62) &
0,001\tabularnewline
\textbf{Sex (M/F)(n)} & 62/58 & 124/97 & 0,302\tabularnewline
\textbf{Fever (n)\%} & 76(63,9\%) & 132 (60\%) & 0,880\tabularnewline
\textbf{Cough} & 60 (50,8\%) & 103(46,6\%) & 0,644\tabularnewline
\textbf{Dyspnea} & 38 (32\%) & 65(29,7\%) & 0,660\tabularnewline
\textbf{Fatigue} & 36(30,1\%) & 58(26,2\%) & 0,445\tabularnewline
\textbf{Myalgia} & 60(50,8\%) & 103(46,6\%) & 0,644\tabularnewline
\textbf{Taste/smell loss} & 5 (3,8\%) & 4 (1,6\%) & 0,291\tabularnewline
\textbf{Sore throat} & 16(13,1\%) & 24(11\%) & 0,553\tabularnewline
\textbf{Chest pain} & 4 (3,2\%) & 2 (0,8\%) & 0,165\tabularnewline
\textbf{Hypertension} & 84(70,5\%) & 75(33,8\%) & 0,001\tabularnewline
\textbf{CVD} & 30(25,4\%) & 25(11,6\%) & 0,001\tabularnewline
\textbf{Pulmonary disease} & 11(9,0\%) & 15(6,8\%) &
0,470\tabularnewline
\textbf{CKD} & 12(9,8\%) & 82(3,7\%) & 0,02\tabularnewline
\textbf{CLD} & 1(0,9\%) & 2(0,8\%) & 0,929\tabularnewline
\textbf{Thyroid disease} & 7(5,7\%) & 16(7,3\%) & 0,580\tabularnewline
\textbf{Rheumatic disease} & 2(1,6\%) & 2(0,9\%) & 0,551\tabularnewline
\bottomrule
\end{longtable}

CVD~=~Cardiovascular disease, CKD~=~Chronic kidney disease,
CLD~=~Chronic liver disease

P values indicate differences between diabetes and non-diabetes
patients. P \textless{} 0.05 was considered statistically significant

\textbf{Table-II: Laboratory findings, treatments and clinical outcomes
of hospitalized covid-19 patients}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Diabetes (120)} & \textbf{Non-diabetes (221)} &
\textbf{p-value}\tabularnewline
\textbf{WBC 10\textsuperscript{3}/uL median, IQR)} & 7.40 (5.25-10.40) &
7 (5.20-8.80) & 0.739\tabularnewline
\textbf{Neutrophil, 10\textsuperscript{3}/uL} & 4.85 (3.62-8.17) & 4.30
(3.00-6.10) & 0.016\tabularnewline
\textbf{Lymphocyte, 10\textsuperscript{3}/uL} & 1.40 (1.00-1.90) & 1.40
(1.00-2.10) & 0.308\tabularnewline
\textbf{Platelet 10\textsuperscript{3}/uL} & 234 (188.75-318.75) & 205
(161.00-253.00) & 0.001\tabularnewline
\textbf{Hemoglobin, g/dL} & 12.65 (11.12-14.37) & 13.70 (12.50-14.90) &
0.001\tabularnewline
\selectlanguage{greek}\textbf{Procalcitonin, µg/L}\selectlanguage{english} & 0.06 (0.01-0.31) & 0.03 (0.01-0.08) &
0.818\tabularnewline
\textbf{PTR, second} & 12.60 (12.00-13.10) & 12.50 (11.80-13.50) &
0.553\tabularnewline
\textbf{APTT, second} & 25.30 (23.30-27.20) & 24.80 (23.90-27.70) &
0.155\tabularnewline
\textbf{CRP, mg/L} & 40.45 (7.45-101.55) & 12.90 (4.90-52.95) &
0.001\tabularnewline
\textbf{LDH, U/L} & 243 (184-309.50) & 251 (203.50-299.0) &
0.774\tabularnewline
\textbf{Ferritin, g/L} & 175.10 (67.50-409.7) & 98.0 (55.0-241.0) &
0.010\tabularnewline
\textbf{Fibrinogen mg/dL} & 427.60 (341.1-518.6) & 368.6 (280.60-444.1)
& 0.011\tabularnewline
\selectlanguage{greek}\textbf{D-dimer, µg/L}\selectlanguage{english} & 640 (430-1410) & 610 (310-1200) &
0.760\tabularnewline
\textbf{Troponin, ng/L} & 2.83 (0.17-10.56) & 2.50 (0.19-5.50) &
0.137\tabularnewline
\textbf{Antibiotic therapy} & 94(78.60\%) & 157(70.90\%) &
0.071\tabularnewline
\textbf{Anti-viral therapy} & 69(57.90\%) & 122(55.20\%) &
0.168\tabularnewline
\textbf{Chloroquine therapy} & 110(92.10\%) & 209(94.90\%) &
0.394\tabularnewline
\textbf{Oxygen inhalation} & 61(51.20\%) & 65(29.40\%) &
0.001\tabularnewline
\textbf{Invasive MV therapy} & 12(9.80\%) & 11(4.90\%) &
0.068\tabularnewline
\textbf{Severe disease} & 57(47.50\%) & 61(27.80\%) &
0.001\tabularnewline
\textbf{Hospital stay, day} & 8 (6.0-11.50) & 7 (5.0-10.0) &
0.009\tabularnewline
\textbf{Death} & 2(4.20\%) & 2(2.80\%) & 0.479\tabularnewline
\bottomrule
\end{longtable}

WBC~=~White blood cell, PTR~=~prothrombin time, APTT~=~activated partial
thromboplastin time, CRP~=~C-reactive protein, LDH~=~lactate
dehydrogenase, MV ~= mechanical ventilation

P values indicate differences between diabetes and non-diabetes
patients. P \textless{} 0.05 was considered statistically significant

\textbf{Table-III: Clinical Characteristics, laboratory parameters and
treatments of the diabetic patients with covid-19}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Well-controlled diabetes (30)} & \textbf{poorly-controlled
diabetes (90)} & \textbf{p-value}\tabularnewline
\textbf{Age(median,IQR)} & 56 (49.25-70.25) & 61 (48-72) &
0.925\tabularnewline
\textbf{Sex (Male/Female)(n)} & 14/16 & 48/42 & 0.567\tabularnewline
\textbf{Hypertension} & 23(77.80\%) & 59(65.90\%) & 0.249\tabularnewline
\textbf{CVD} & 7(22.20\%) & 24(26.80\%) & 0.874\tabularnewline
\textbf{CKD} & 3(11.10\%) & 9(10.70\%) & 0.452\tabularnewline
\textbf{Pulmonary disease} & 3(11.0\%) & 6(7.30\%) &
0.584\tabularnewline
\textbf{WBC 10\textsuperscript{3}/uL median, IQR)} & 7.15 (4.57-10.20) &
7.50 (5.90-12.30) & 0.912\tabularnewline
\textbf{Neutrophil, 10\textsuperscript{3}/uL} & 4.25 (2.62-8.10) & 5.20
(3.70-9.20) & 0.950\tabularnewline
\textbf{Lymphocyte, 10\textsuperscript{3}/uL} & 1.40 (1.00-1.77) & 1.30
(0.90-2.00) & 0.644\tabularnewline
\textbf{Platelet 10\textsuperscript{3}/uL} & 215 (166-303) & 244
(194.25-352.25) & 0.503\tabularnewline
\textbf{Hemoglobin, g/dL} & 13.0 (11.10-14.50) & 12.60 (11.25-13.95) &
0.847\tabularnewline
\selectlanguage{greek}\textbf{Procalcitonin, µg/L}\selectlanguage{english} & 0.03 (0.01-0.06) & 0.08 (0.04-0.24) &
0.886\tabularnewline
\textbf{PTR, second} & 12.60 (12.10-13.70) & 12.60 (12.10-13.10) &
0.048\tabularnewline
\textbf{APTT, second} & 26.10 (23.90-27.20) & 24.70 (22.80-27.40) &
0.027\tabularnewline
\textbf{CRP, mg/L} & 11 (2.45-136.37) & 40.10 (7.31-112.60) &
0.667\tabularnewline
\textbf{LDH, U/L} & 259 (201.25-450.75) & 231 (199-295.0) &
0.183\tabularnewline
\textbf{Ferritin, g/L} & 115.01 (31.50-450) & 211.40 (75.30-450.0) &
0.268\tabularnewline
\textbf{Fibrinogen mg/dL} & 423.4 (341.7-506.0) & 441.60(379.1-529.4) &
0.846\tabularnewline
\selectlanguage{greek}\textbf{D-dimer, µg/L}\selectlanguage{english} & 450 (420-1520) & 660 (445-1375) &
0.686\tabularnewline
\textbf{Troponin, ng/L} & 3.02 (0.01-11.12) & 4.49 (0.02-12.94) &
0.537\tabularnewline
\textbf{Antibiotic therapy} & 25(85.20\%) & 69(76.80\%) &
0.626\tabularnewline
\textbf{Anti-viral therapy} & 23(77.40\%) & 52(58.20\%) &
0.268\tabularnewline
\textbf{Chloroquine therapy} & 27(92.60\%) & 82 (91.50\%) &
0.259\tabularnewline
\textbf{Oxygen inhalation} & 17(55.60\%) & 42(46.30\%) &
0.556\tabularnewline
\textbf{Invasive MV therapy} & 3(11.10\%) & 10(11.0\%) &
0.452\tabularnewline
\textbf{Severe disease} & 17(55.60\%) & 42(46.30\%) &
0.556\tabularnewline
\textbf{Hospital stay, day} & 8 ( 6.0-11.0) & 9( 6.0-16.0) &
0.006\tabularnewline
\textbf{Death} & 1(3.70\%) & 3(4.10\%) & 0.693\tabularnewline
\bottomrule
\end{longtable}

CVD~=~Cardiovascular disease, CKD~=~Chronic kidney disease, WBC~=~White
blood cell, PTR~=~prothrombin time, APTT~=~activated partial
thromboplastin time; CRP~=~C-reactive protein, LDH~=~lactate
dehydrogenase; MV ~= mechanical ventilation

P values indicate differences between well-controlled diabetes and
poorly-controlled diabetes patients. P \textless{} 0.05 was considered
statistically significant

\textbf{Hosted file}

\verb`tables.docx`  available at \url{https://authorea.com/users/390918/articles/710307-the-effect-of-diabetes-mellitus-on-disease-prognosis-in-covid-19-patients}

\selectlanguage{english}
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