Introduction
Coronavirus disease 2019 (COVID-19) is caused by severe acute
respiratory syndrome coronavirus 2 (SARS-CoV-2, earlier known as
2019-nCoV) (1). The outbreak of COVID-19
rapidly caused a global health crisis (2),
(3) and the World Health Organization has
announced COVID-19 as a pandemic.
Diabetes mellitus (DM) is one of the most frequent comorbidities
reported in patients infected with COVID-19. The inflammatory process
associated with DM and chronic high levels of glucose in the blood can
lead to low immunity response which aggravate infections in diabetic
patients (4). There are several evidences
of increased incidence and severity of COVID-19 in patients with DM
reported with higher risk for intensive care unit (ICU) admission and
substantial mortality (5). In addition,
obesity has been associated with disease severity and guidelines
recommend that obese patients especially those with severe obesity
should take extra measures to avoid COVID-19 infection
(6). It has been reported that compared
with non-ICU patients, ICU patients have a higher proportion of
diabetes. Additionally, it is also suggested that DM may affect the
clinical manifestations and patient’s disease progression
(7).
A recent retrospective study suggested that Type 2 DM and obesity may
have contributed to disease severity and mortality in COVID-19
critically ill patients (8). Another
retrospective cross-sectional study conducted in United Kingdom reported
that hospitalized COVID-19 patients with DM had longer LOS in hospital
than patients without DM. Same study also documented that elder COVID-19
patients with DM and patients without diabetic ketoacidosis were less
likely to survive compared to younger patients and patients with
diabetic ketoacidosis, respectively (9).
Similar to these findings, another cohort study conducted in China,
retrospectively reviewed 258 consecutive hospitalized COVID-19 patients
with or without DM suggested that DM is associated with increased
disease severity and a higher risk of mortality in patients infected
with COVID-19. In addition, impaired fasting glucose and diabetes at
admission were significantly associated with higher risks of adverse
outcomes among COVID-19 infected patients
(10). Few observational studies suggested
that diabetes was significantly associated with higher risks of
composite adverse endpoints (death, ICU admission, and mechanical
ventilation) (10).
The increased rate of those suffering from diabetes combined with the
prevalence of COVID-19 suggest that the care for diabetic patients must
be increased in order to reduce any further complications and the risk
of death. The poor outcomes of patients with diabetes and COVID-19
indicated that more supervision is required in these patients. Hence
with the high global burden of diabetes and the increasing number of
COVID-19 cases, there is a need to understand the association of
diabetes and COVID-19 related outcomes in COVID-19 infected patients.
To date no meta-analysis conducted
to explore possible risk factors and resource utilization in DM patients
infected with in COVID-19. Therefore, we aimed to conduct a
meta-analysis to find out association between DM and poor outcomes in
patients with COVID-19 infection.
Materials and methods
This systematic literature review and meta-analysis was performed in
accordance with the Preferred Reporting Items for Systematic Reviews and
Meta-analyses (PRISMA) statement (11) and
it was prospectively registered on Prospective Register of Systematic
Reviews (PROSPERO) (CRD42020213791).
Data sources and search
strategy
Databases, the Medical Literature Analysis and Retrieval System Online
(MEDLINE)/PubMed, and Web of
Science were searched using a comprehensive search strategy to identify
eligible studies published in the English language from inception
to January 2021. Search terms used
were “diabetes mellitus”, “diabetes”, “Coronavirus”, “COVID-19”,
and “SARS-CoV-2. Additionally, manual searches were performed on Google
Scholar and bibliographies of relevant articles and previous systematic
review (12) were also screened to
identify other significant studies.
Study selection and data
extraction
Two reviewers independently performed the selection of study based on an
initial screening of identified titles and abstracts followed by second
screening of full-text articles. Studies were considered eligible if
they met the following criteria: (i) studied subjects were diabetic and
non-diabetic exposed with
COVID-19; (ii) outcome of interest reported
comorbidities, clinical
manifestations of COVID-19; (iii) studies using
observational study design
(retrospective cohort, case-control, prospective cohort, and
cross-sectional studies).
Two independent authors performed study screening and data extraction
judiciously according to inclusion criteria. Any discrepancies were
resolved through discussion of the third author until consent was
achieved. A standard data extraction format was used to capture the
study information, including name of the first author, year of the
publication, country, study design, age, gender, settings, country,
database used, study population, no. of comorbidities/symptoms reported,
and other relevant information.
Quality
assessment
Two authors independently assessed the quality of the methodology for
each study using the Newcastle-Ottawa scale (NOS)
(13). The NOS comprised of three scales;
selection (maximum of four stars), comparability (maximum of two stars),
exposure/outcome (maximum of three stars) and graded out of 9 points
(stars). This assessment critically appraised the internal (systematic
error) and external validity of the studies. We consider studies with a
score of 6 or greater as high quality. Any disagreement was resolved
through consensus.
Data
analysis
We carried out meta-analysis to calculate the pooled
estimates of odds ratio/mean
difference (OR)/(MD) and 95% confidence intervals (CI). Random effects
model (DerSimonian and Laird) was used for the overall pooled estimate
meta-analysis.
To provide a quantitative estimate of the association of the
symptoms/complication of interest with severity outcomes (ICU admission,
length of stay (LOS) or need for mechanical ventilation) or deaths were
calculated from crude frequency of exposed and non-exposed cases.
Heterogeneity among studies was assessed with the Cochran chi-square
(χ2) and quantified with the I2 and
tau-square (𝜏2). Statistical heterogeneity was
reported using the I2 statistic, with results ranging
from 0 to 100% and values of 25, 50 and 75% representing low, moderate
and high level of heterogeneity, respectively. All the statistical
analysis was conducted using
Review Manager 5.3 (Nordic
Cochrane Centre, Cochrane Collaboration, 2014). A p values of
<0.05 was considered statistically
significant.
Results
Literature search and study
inclusion
The PRISMA flow diagram summarizing the process of study selection is
shown in Figure 1. The electronic search identified 1237 potentially
relevant records, of which 1100 were excluded after screening the title
and abstract. The remaining 61 full-text articles were assessed for
eligibility and 47 were further excluded due no information on COVID-19
infected non diabetes patients, mortality, resource utilization, and
study design. Total 14 articles were included for the systematic review
and meta-analysis.
Study characteristics and quality
assessment
Of 14 included observational studies, all studies were retrospective.
The general characteristics of included studies are reported in Table 1.
Among included 14 studies, 12 were conducted in China, 1 in USA, and 1
in England. This meta-analysis involved 5697 patients (diabetic=1428 and
non-diabetic=3644).
The quality assessment of the included studies is shown in supplementary
Table S1. The NOS results showed that the average score was 7.2 (range
6-9) for all included studies. Therefore, the quality of included
studies suggested good (14).
Symptoms associated with DM and
COVID-19
infection
Out of 14 included studies, total 11 studies reported symptoms including
fatigue, fever, headache, myalgia, nausea/vomiting, anorexia, cough,
diarrhoea, dyspnoea, palpitation, pharyngalgia, shortness of breath,
polypnea, sore throat, sputum, chest pain and expectoration. Fever and
cough followed by fatigue and diarrhoea were most commonly reported
symptoms across the included studies.
Results from the pooled meta-analysis found non-significant symptoms
trends in DM patients infected with COVID-19 compared to non-diabetic
COVID-19 patients infected. However, dyspnoea was significantly
association with DM [2.30 (1.37, 3.84); p value=0.001;I 2=72%; p value=0.003] compared with
non-diabetic patients infected with COVID-19 (Table 2).
Comorbidity associated with DM and
COVID-19
infection
Total 11 studies reported comorbidities/complications including
hypertension, CLD, COPD, thyroid disease, AKI, cancer, cerebrovascular
disease, CKD, digestive disease, septic shock, and AKI. COPD, CVD, and
hypertension followed by cerebrovascular disease, cancer and CKD were
most commonly reported co-morbidities/complications across the included
studies.
From reported co-morbidities, CVD, hypertension, AKI, cerebrovascular
disease, AKI and ARDS were significantly associated with DM in COVID-19
infected patients compared to non-diabetic patients (2.91 [2.34,
3.63], p<0.00001; 2.19 [1.39, 3.46], p=0.0008; 3.59
[1.46, 8.84], p=0.005; 2.09 [1.22, 3.61], p=0.008; and 3.01
[1.63, 5.58], p=0.0005; and 3.40 [2.09, 5.55],
p<0.00001; respectively). However, no significant association
was observed with CLD, COPD, thyroid disease, cancer, CKD, digestive
disease, and septic shock in DM patients infected with COVID-19 compared
to non-diabetic patients (Figure 2. and supplementary Table S2).
Diabetes and
outcome
It includes mortality, recovery, length of stay (LOS), mechanical
ventilation, need for ICU, discharge from hospital, and hospitalization
(Figure 3. and supplementary Table S3).
Association between
mortality/recovery and DM in COVID-19 infected
patients
Total 12 and 5 studies reported outcome as mortality and recovery
respectively. Pooled results from meta-analysis found significant
association between mortality and DM compared to non-diabetic patients
infected with COVID-19 (2.46 [1.68, 3.58], p <0.00001;I2 : 62%; p=0.002). However, no significant
association was found between recovery with DM compared to non-diabetic
COVID-19 infected patients (0.48 [0.21, 1.07], p=0.07;I2 : 85%; p <0.00001) (Figure 3).
Association between healthcare
utilization and DM in COVID-19 infected
patients
LOS and hospitalization were not significantly differing between
diabetes and non-diabetes patients infected with COVID-19 (1.91
[-1.12, 4.94], p= 0.22; I2:91%, p <
0.00001 and 1.45 [0.51, 4.08], p= 0.49; I2: 59%,
p=0.12 respectively) (Figure 4). However, discharge from hospital was
significantly higher in non-diabetic patients infected with COVID-19
compared to diabetic patients (0.52 [0.34, 0.81], p = 0.004;
I2: 6%, p=0.35). On the other hand, ICU admission and
use of mechanical ventilation was significantly associated with DM and
COVID-19 infected patients compared to non-diabetic patients (2.79
[1.79,4.34], p < 0.00001; I2: 0%,
p=0.53 and 3.33 [2.05, 5.42], p < 0.00001;
I2: 48%, P=0.09, respectively) (Figure 3).
Discussion
This systematic review and meta-analysis of 14 studies aimed to evaluate
the association between DM and COVID-19 infected patients. Results from
current study showed that mortality, ICU, ARDS, mechanical ventilation,
discharge from hospital, hospitalization and co-morbidities (CVD,
hypertension, AKI, cerebrovascular disease, acute cardiac injury) are
significantly associated with DM in COVID-19 infected patients.
Diabetes is one of the most frequent comorbidities reported in patients
with COVID-19. The prevalence of diabetes among patients with COVID-19
varied in different studies. Studies in Chinese patients reported
prevalence rates ranged from 5.3 to 8.2% (3-5), while a recent study
involved 5,700 patients reported that 33.8% had diabetes (6). Several
studies have reported that diabetes and uncontrolled glycemia were
significant predictors of severity and mortality in patients infected
with lower respiratory tract infections
(10).
Previous studies found increased severity of COVID-19, caused by
infection with SARS-CoV-2 in patients with DM. Interacting with other
risk factors; hyperglycaemia might modulate immune and inflammatory
responses, thus predisposing patients to severe COVID-19 and possible
lethal outcomes. Potential pathogenetic links between COVID-19 and DM
include effects on glucose homeostasis, inflammation, altered immune
status and activation of the renin-angiotensin-aldosterone system
(15).
Presence of DM and the individual degree of hyperglycaemia seem to be
independently associated with COVID-19 severity and increased mortality
(12, 16).
Furthermore, the presence of typical complications of DM (CVD, heart
failure and CKD) also increases COVID-19 mortality (11,19). In current
meta-analysis we found higher mortality rate in DM COVID-19 infected
patients compared to non-DM COVID-19 infected patients.
COVID-19 can progress to ARDS, which requires positive pressure oxygen
and intensive care therapy (9). Previous systematic review and
meta-analysis conducted by Huang et al. (2020)
(17) showed that ARDS and disease
progression was significantly associated with DM in COVID-19 infected
patients. In addition, a retrospective case study conducted by Chen et
al. (2020) reported that SARS-CoV-2 can cause both pulmonary and
systemic inflammation, leading to multi-organ dysfunction in patients at
high risk (18). ARDS, respiratory
failure, sepsis, acute cardiac injury, and heart failure were the most
common critical complications during exacerbation of COVID-19
(18). In line with previous finding, our
meta-analysis also found significant association between DM and ARDS and
other co-morbidities in COVID-19 infected patients compared to non-DM
COVID-19 infected patients. In addition, various studies reported that
patients with diabetes are more likely than healthy people to develop
COVID-19 disease and complications such as ARDS and even death
(19-22).
Study reported the overall symptoms of COVID-19 in all patients are sore
throat, fever, dry cough, fatigue, and diarrhoea
(23, 24).
To support our findings, international diabetes federation (IDF)
statement reported that symptoms in diabetes patients not different with
other COVID-19 patients (25). But there
is an agreement that symptoms are more developed among diabetic patients
(26, 27).
Another study conducted in Greece reported that Type 2 diabetes and
obesity may have contributed to disease severity and mortality in
COVID-19 critically ill patients (8).
HbA1c is associated with inflammation, hypercoagulability, and low SaO2
in COVID-19 patients, and the mortality rate (27%) is higher in DM
patients (28).
In a case-report on a patient with both COVID-19 and diabetes, the
patient was discharged from the hospital after 15 days. The survival
term of the non-survivors is likely to be within 1–2 weeks after ICU
admission. The severity of SARS-CoV-2 pneumonia poses great strain to
hospital critical care resources, especially if they are not adequately
staffed or resourced (29). In a
retrospective cohort of 312 patients with COVID-19, we found that
diabetes was associated with higher risks of composite adverse endpoints
(mechanical ventilation, admission to ICU, or death) and mortality, and
IFG was also associated with higher risk of mortality. Similarly, in the
current meta-analysis we also observed that ICU admission, mechanical
ventilation, discharge from hospital and hospitalizations are
significantly associated with DM COVID-19 infected patients compared to
non-DM COVID-19 infected patients. This finding could be a potential
outcome to support development of health economics model for the use of
diabetic medication in DM COVID-19 infected patients and help decision
making process.
Association between DM and COVID-19 was also explored in the previous
published systematic review and meta-analysis, but these studies
considered limited studies and low sample size (references).
Interestingly, no studies yet compared DM COVID-19 infected patients and
non-DM COVID-19 infected patients. To best of our knowledge this is the
only largest meta-analysis to evaluate risk factors and resource
utilization associated with DM COVID-19 infected patients compared to
non-DM COVID-19 infected patients.