key: cord-0755017-yzd2th0o
authors: Shrestha, Dhan Bahadur; Budhathoki, Pravash; Raut, Sumit; Adhikari, Sugat; Ghimire, Prinska; Thapaliya, Sabin; Rabaan, Ali A; Karki, Bibodh Jung
title: New-onset diabetes in COVID-19 and clinical outcomes: A systematic review and meta-analysis
date: 2021-09-25
journal: World J Virol
DOI: 10.5501/wjv.v10.i5.275
sha: 7d9f045634db0201dcf196fab0d88f996286c058
doc_id: 755017
cord_uid: yzd2th0o

BACKGROUND: Diabetes mellitus (DM) is associated with adverse clinical outcomes and high mortality in patients with coronavirus disease 2019 (COVID-19). The relationship between diabetes and COVID-19 is known to be bidirectional. AIM: To analyze the rate of new-onset diabetes in COVID-19 patients and compare the clinical outcomes of new-onset diabetes, pre-existing diabetes, hyperglycemic, and non-diabetes among COVID-19 patients. METHODS: We used the Meta-analysis of Observational Studies in Epidemiology statement for the present meta-analysis. Online databases were searched for all peer-reviewed articles published until November 6, 2020. Articles were screened using Covidence and data extracted. Further analysis was done using comprehensive meta-analysis. Among the 128 studies detected after thorough database searching, seven were included in the quantitative analysis. The proportion was reported with 95% confidence interval (CI) and heterogeneity was assessed using I(2). RESULTS: Analysis showed that 19.70% (CI: 10.93-32.91) of COVID-19 patients had associated DM, and 25.23% (CI: 19.07-32.58) had associated hyperglycemia. The overall mortality rate was 15.36% (CI: 12.57-18.68) of all COVID-19 cases, irrespective of their DM status. The mortality rate was 9.26% among non-diabetic patients, 10.59% among patients with COVID-19 associated hyperglycemia, 16.03% among known DM patients, and 24.96% among COVID-19 associated DM patients. The overall occurrence of adverse events was 20.52% (CI: 14.21-28.70) among COVID-19 patients in the included studies, 15.29% among non-diabetic patients, 20.41% among patients with COVID-19 associated hyperglycemia, 20.69% among known DM patients, and 45.85% among new-onset DM. Meta-regression showed an increasing rate of mortality among new hyperglycemic patients, known diabetics, and new-onset DM patients in comparison to those without diabetes. CONCLUSION: A significantly higher rate of new onset DM and hyperglycemia was observed. Higher mortality rates and adverse events were seen in patients with new-onset DM and hyperglycemia than in the non-diabetic population.

The ongoing coronavirus disease 2019 (COVID-19) has infected 93 million patients and claimed the lives of 2.02 million people as of January 19, 2021 [1] . Extensive research has been conducted to study the comorbidities associated with increased severity of disease and worse clinical outcomes. Diabetes has consistently been associated with adverse clinical outcomes and high mortality in COVID-19 patients independent of or in association with other comorbidities [2] [3] [4] . Such findings have been linked to the alteration of immune and inflammatory responses caused by hyperglycemia among diabetic patients suffering from COVID-19 [5] . However, it is now known that the relationship between diabetes and COVID-19 is bidirectional [6] . Not only does having diabetes increase the risk of severe COVID-19, but severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is also known to have diabetogenic effects.

Multiple theories have been postulated to explain the increasing rate of new-onset diabetes in COVID-19 patients. One of the proposed mechanisms is that SARS-CoV-2 binds to the angiotensin-converting enzyme-2 (ACE-2) receptors expressed on adipose tissue, lungs, small intestine, kidneys, and pancreas. After endocytosis of the virus, downregulation of ACE-2 occurs, leading to overexpression of angiotensin II, which may impede insulin secretion. Similarly, it has been suggested that the direct entry of SARS-CoV-2 into the islet cells of the pancreas damages the beta cells, which normally secrete insulin [7, 8] .

In the light of new evidence and theories suggesting that there is increased susceptibility of worsening pancreas function and glucose homeostatic mechanisms in COVID-19 patients, the objective of this study is to analyze the rate of new-onset diabetes in COVID-19 patients and compare their clinical outcomes with those of other COVID-19 patients who had normal or increased blood sugar levels or a pre-existing diagnosis of diabetes.

This study was conducted according to the Meta-analysis of Observational Studies in Epidemiology statement [9] . Our protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42021219284).

Investigators independently searched databases such as PubMed, PubMed Central, Scopus, Embase, and Google Scholar for all peer-reviewed articles published until November 6, 2020. The terms "New onset diabetes mellitus (DM)", "DM", "hyperglycemia", "SARS-Cov-2" and "COVID-19" connected with "OR" and "AND". Boolean operators were searched under the medical subject headings terms. The reference section of each study shortlisted from this process was checked to identify further studies not found in the previous database searches. Additional studies collected from this method were included if they fulfilled the inclusion and exclusion criteria. Electronic search details are provided in Supplementary Material 1.

The studies were selected based on the following criteria: Inclusion criteria: (1) Study type(s): Observational studies with a comparison of outcomes among individuals with new onset diabetes, pre-existing diabetes, hyperglycemic and non-diabetics with COVID-19 were included in this review; (2) Study participant(s): Individuals of any age, gender, or nationality diagnosed with COVID-19 and new-onset DM; and (3) Objective outcome(s): Mortality, mechanical ventilation/intubation, and intensive care unit (ICU) admission were defined as the primary outcomes of our study. Complications such as Acute Respiratory Distress Syndrome (ARDS), acute cardiac injury, acute liver injury, acute kidney injury, cerebrovascular accident, coagulopathy, and secondary infection were secondary outcomes. Exclusion criteria: (1) Inadequate or unclear descriptions; (2) Animal studies; (3) Review articles; (4) Full text unavailable; and (5) Studies published in a language other than English.

The titles and abstracts of studies retrieved in Covidence during the search were screened independently by two reviewers (PG and SR). The full-texts of potentially relevant studies were then reviewed by two reviewers (SA and SR) according to the eligibility criteria. Any conflict in the first phase of review was resolved by SA and in the second phase by PG. The included studies were then collated, and the three reviewers extracted the data using standardized data extraction formats. The extracted data included: First author, year of publication, country of study, study design, number of patients, age, sex, comorbidities, case definitions, inclusion and exclusion criteria, COVID-19 associated DM, COVID-19 associated hyperglycemia, outcomes, and follow-up duration. The outcomes were mortality and adverse events such as severe COVID-19, intubation, complications and ICU admission. All three reviewers matched their data with each other after extraction and revisited papers in case of disagreements. Discrepancies were resolved through consensus among the reviewers. Data analysis: The data were analyzed using comprehensive meta-analysis, employing a random effect model. Proportions were presented appropriately using 95% confidence intervals (CI). Forest plots were derived for a visual representation of the analysis. Sensitivity analysis was performed, excluding individual studies to gauge the impact of those studies on the overall results. Meta-regression was undertaken for mortality, considering diabetes status as a moderator among patients with hyperglycemia, patients with new-onset DM, patients with known diabetes, and the non-diabetic population.

We assessed the risk of bias using the JBI tool to evaluate the quality of case reports, case series, and retrospective studies (Tables 1,2, 3) [10] . Publication bias across the included studies was evaluated using funnel plot.

We imported 128 studies after a thorough database search and removed 27 duplicates. The title and abstract of 101 studies were screened, and we excluded 76 irrelevant studies. We assessed the full text of 25 studies and excluded 15 studies with definite reasons ( Figure 1 ). Finally, ten studies were included in our qualitative analysis (Table 4 ) and seven in our quantitative analysis.

A summary of the included studies including type of study, location, study population and the relevant outcomes is presented in Table 4 .

A total of 7 papers were included in the quantitative synthesis.

Pooling data from six studies that reported new-onset diabetes among COVID-19 cases using a random effect model showed that 19.70% (CI: 10.93-32.91, I 2 = 96.71) of COVID-19 cases were associated with DM ( Figure 2 ). Sensitivity analysis after 

Were the patient's demographic characteristics clearly described? Yes

Was the patient's history clearly described and presented as a timeline? Yes

Was the current clinical condition of the patient on presentation clearly described? Yes

Were diagnostic tests or assessment methods and the results clearly described? Yes

Was the intervention(s) or treatment procedure(s) clearly described 

Pooling data from five studies that reported hyperglycemia among COVID-19 cases using a random effect model showed that 25.23% (CI: 19.07-32.58, I 2 = 86.6) of COVID-19 cases were associated with hyperglycemia ( Figure 3 ). Sensitivity analysis after removing individual studies is shown in Supplementary Material 2, and Figures 2 and 3.

Pooling data among COVID-19 cases using a random effect model showed a 9.26% mortality rate among non-diabetic (CI: 6. Figure 4 ). Zhou et al [16] , 2020

Retrospective study 

Pooling data for the occurrence of adverse events among COVID-19 cases using a random effect model showed 15.29% occurrence among non-diabetic patients (CI: 9.06-24.65, I 2 = 84.47), 20.41% among those with COVID-19 associated hyperglycemia (CI: 6.20-49.86, I 2 = 93.41), 20.69% among known DM patients (CI: 8.12-43.50, I 2 = 90.14), and 45.85% among those with new-onset DM (CI: 22.23-71.50, I 2 = 94.21). The overall occurrence of adverse events was 20.52% (CI: 14.21-28.70, I 2 = 93.53) among all COVID cases irrespective of their DM status ( Figure 5 ).

Meta-regression showed an increasing rate of mortality among newly hyperglycemic patients, known diabetic patients, and new-onset DM compared to non-diabetic patients ( Figure 6 and Table 5 ).

Publication bias across the included studies was evaluated using Egger's test to evaluate funnel plot asymmetry. Publication bias reporting new-onset DM showed some publication bias depicted by the asymmetry of the funnel plot (Supplementary Material 2 and Figure 4) . Similarly, publication bias for mortality outcome is shown in Supplementary Material 2 and Figure 5 .

Our meta-analysis is the first to pool the prevalence of new-onset DM and compare mortality and adverse events among patients with new-onset DM vs patients with hyperglycemia, pre-existing DM, or no DM. Prior meta-analyses have shown DM to be associated with mortality, severe COVID-19, ARDS, and disease progression [11] [12] [13] . However, there was a paucity of data to compare the outcomes among infected patients with pre-existing diabetes compared to new-onset DM. We found the pooled September 25, 2021 Volume 10 Issue 5 prevalence of COVID-19 associated DM (new-onset) to be 19.7%, while the prevalence of COVID-19 associated hyperglycemia was 25.23%. Angiotensin II has been shown to increase hepatic glucose production and decrease insulin sensitivity. A multitude of explanations have been proposed for impaired blood glucose levels among patients infected with COVID-19, including downregulation of ACE-2 receptors leading to increased angiotensin II and defective insulin secretion as well as direct damage to beta cells of islets of the pancreas [7, 8] . Infection with the virus itself leads to oxidative stress, resulting in hypoxia and inflammation, which aggravates glucose homeostasis [14] . Additionally, damage to key organs involved in glucose metabolism such as the kidney and the liver resulting in abnormal blood glucose levels, has been observed in cases of COVID-19 infection. The use of corticosteroids is common among COVID-19 patients, especially those with severe COVID-19 [15] . However, in our meta-analysis, only one study [16] included patients receiving steroids, which eliminates steroid use as a possible cause of hyperglycemia. The mortality rate was highest among patients with new-onset DM (24.96%), followed by known DM patients (16.03%), patients with COVID-19 associated hyperglycemia (10.59%), and non-diabetic patients (9.26%). The September 25, 2021 Volume 10 Issue 5 higher prevalence in patients with new-onset DM could be explained by the masked presence of organ damage due to ongoing diabetes, which cannot be accounted for during statistical analysis in contrast to cases of pre-existing diabetes in which organ damage is accounted for statistically [17] . Similarly, metabolic inflammation caused by high blood sugar levels affects the body's immune system and healing process prolonging recovery [14] . Hyperglycemia has been found to affect lung volume and diffusion capacity, causing respiratory deterioration and a decrease in PaO 2 /FiO 2 ratio [17] . Chronic hyperglycemia causes down regulation of ACE-2, which has a protective effect against inflammation and in turn leads to inflammatory damage by the virus and potential cytokine storm. These are the reasons for increased mortality among patients with diabetes and hyperglycemia compared to non-diabetic patients. The pooled mortality of 16.03% among diabetic patients was lower than that shown in Shang's meta-analysis (21.4%) and higher than that in Miller et al [11] 

The pooled prevalence of COVID-19 associated DM was 19.70%, and for COVID-19 associated hyperglycemia was 25.23%. Among COVID-19 patients, higher mortality rates and adverse events were seen in patients with new-onset DM compared to those with pre-existing diabetes, those with COVID-19 associated hyperglycemia, and those without diabetes. September 25, 2021 Volume 10 Issue 5 Figure 6 Meta regression of diabetes status and mortality.

Diabetes has been shown to be associated with worsening severity of disease and poor prognosis in coronavirus disease 2019 (COVID-19). Interestingly, various cases of new onset diabetes mellitus (DM) were seen in patients with COVID-19. The virus is believed to bind to angiotensin-converting enzyme-2 receptors leading to increased angiotensin II and subsequent decreased insulin secretion.

In relation to various theories and proposed mechanisms of how COVID-19 may lead to abnormal glucose homeostasis, our study was conducted to evaluate new onset DM in COVID-19.

The study aimed to pool the prevalence of new onset DM and hyperglycemia in COVID-19 patients and compare various outcomes such as mortality, intubation and complications among infected patients who had hyperglycemia or preexisting DM or new onset DM or normal blood sugar levels.

Meta-analysis of Observational Studies in Epidemiology was used for the metaanalysis. Studies were screened using Covidence after searching various databases including PubMed, PubMed Central, Embase and Scopus. Comprehensive metaanalysis software was used for data analysis.

The results showed that 19.70% and 25.23% of patients had COVID-19 associated DM and hyperglycemia, respectively. The mortality rate was highest among COVID-19 associated DM patients (24.96%) followed by patients with preexisting DM (16.03%), and was least in non-diabetic patients (9.29%). The occurrence of adverse events was highest among COVID-19 associated new-onset DM patients followed by patients with preexisting DM, COVID-19 associated hyperglycemia and non-diabetic patients.

COVID-19 was associated with hyperglycemia and new-onset DM. Infected patients with new onset DM had worse prognosis in terms of mortality and adverse events.

The findings of this study should alarm clinicians that new onset diabetes and

COVID-19) Dashboard

Pan P; medical team from Xiangya Hospital to support Hubei, China. Association of diabetes mellitus with disease severity and prognosis in COVID-19: A retrospective cohort study

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

The Lancet Diabetes Endocrinology. COVID-19 and diabetes: a co-conspiracy?

COVID-19 and diabetes mellitus: from pathophysiology to clinical management

Redefining vulnerability in the era of COVID-19

New-Onset Diabetes in Covid-19

Diabetic ketoacidosis precipitated by Covid-19 in a patient with newly diagnosed diabetes mellitus

Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group

Diabetes mellitus increases the risk of hospital mortality in patients with Covid-19: Systematic review with meta-analysis

Diabetes Mellitus is Associated with Severe Infection and Mortality in Patients with COVID-19: A Systematic Review and Meta-analysis

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia -A systematic review, meta-analysis, and meta-regression

Newly diagnosed diabetes is associated with a higher risk of mortality than known diabetes in hospitalized patients with COVID-19

Is diabetes mellitus associated with mortality and severity of COVID-19?

Clinical Features of COVID-19 Patients with Diabetes and Secondary Hyperglycemia

Newly-diagnosed diabetes and admission hyperglycemia predict COVID-19 severity by aggravating respiratory deterioration

Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China

Impaired glucose metabolism in patients with diabetes, prediabetes, and obesity is associated with severe COVID-19

Glycosylated hemoglobin is associated with systemic inflammation, hypercoagulability, and prognosis of COVID-19 patients

Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study

Newly diagnosed diabetes mellitus, DKA, and COVID-19: Causality or coincidence

Short term follow-up of patients presenting with acute onset diabetes and diabetic ketoacidosis during an episode of COVID-19

Blood Glucose Is a Representative of the Clustered Indicators of Multi-Organ Injury for Predicting Mortality of COVID-19 in Wuhan

Type 1 diabetes onset triggered by COVID-19