Mortality in patients with diabetes by COVID 19 a systematic review.

Background: Diabetes mellitus might be associated with severity and death in patients with COVID-19; but its mechanisms are still unknown. Objective: to carry out a systematic review of what has been published so far on mortality in patients with COVID-19 associated with diabetes comorbidity. Methods: A search was carried out in PubMed, Ovid MEDLINE, EMBASE and EMBASE Classic and Google Scholar databases; up to April 2020 using the search medical subheadings (MeSH) terms : "mortality from Coronavirus", "mortality from COVID-19" and "mortality in patients with diabetes by COVID-19". Enrolled studies were assessed independently by two blinded researchers. Studies quality was assessed using the Jedad scale. The articles score equal or greater than two points were considered highly methodological quality. Results: Initially, 65 articles were found and 46 were excluded for not meeting the eligibility criteria. Among the 10 remaining, 3 were excluded because had Jedad score lower than two points. Among the remaining seven, two were excluded because they were meta-analysis. Eventually, ve articles remained for nal analysis. For all, mortality among patients with diabetes was higher than without diabetes. The risk of global mortality among diabetes patients was 8.9 times higher (p<0.0001) than without diabetes The time of diagnosis could be more determining for mortality, meanwhile HB1Ac level was not determining Conclusion: Mortality risk observed by COVID-19 is higher among diabetes patients than healthy age matched peers. This result can be partially explained by hormonal signaling changes, such as blood clotting and abnormal pancreas functioning.


Introduction
Since december, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease  and, in severe cases, developing into the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID- 19 have been reported but risk factors for mortality in patients with prior diabetes mellitus cormobidity and a detailed clinical illness course, including viral shedding, have not been well described 1, 2 .
On April 7, 2020, the World Health Organization (WHO) reported 2,287,836 con rmed cases of COVID-19 worldwide. Also 160,323 deaths were reported, 7% death rate worldwide. The United States of American has most of cases with 733,921 and 39,019 deaths (0.053 death rate), followed by Spain with 191,726 cases and 20,043 deaths (0.101 death rate). Surprisingly, Italy does not have as much number of cases as reported in other contries (175,925 con rmed casa and 23,227 deaths), however, it presents the higher mortality rate (0.132) seen up to this date 3 .
A retrospective cohort study investigated several risk factors for death in adults with COVID-19 4 . In particular, older age, d-dimer levels greater than 1 μg/mL and higher SOFA score prior to hospital admission were associated with higher odds of in-hospital death. Additionally, elevated levels of blood IL-6, high-sensitivity cardiac troponin I, lactate dehydrogenase and lymphopenia were more commonly seen in severe COVID-19 illness 4 . Similar results have already been shown by other studies 5,6,7 .
Although the clinical manifestations of COVID-19 are surrogates of respiratory symptoms 8, 9 some patients with diabetes commonly develop severe illness 10 . In addition, these patients might have increased death risk 11 . The coronavirus 2019 disease (COVID-19) currently represents a serious public health issue worldwide. As well known, diabetic patients are at higher risk of infection especially during period of poor glycaemic control 11 . Recent investigations have reported that diabetes mellitus (DM) is one of the most common comorbidity accompanied the COVID-19 infection, 12 , 1 3 . Additionally, some studies have suggested that these subjects seem to have a higher mortality risk during the infection 14,15 .
Therefore, understanding the damage caused by SARS-CoV-2 to the diabetes patients,as well as its underlying mechanisms, is of great importance, , so that the treatment of these patients can be promptly and effective towards mortality reduction. According to this, our study aimed to carry out a systematic review of what has been published so far on mortality from COVID-19 in diabetes patients.

Method
Search strategy and selection criteria Studies search was carried out in the PubMed, Ovid MEDLINE, EMBASE and EMBASE Classic andGoogle Scholar databases up to April 2020 using the search medical subheading (MeSH) terms : "mortality from coronavirus", "mortality from COVID-19" and "mortality in patients with diabetes by COVID-19 ". The search was limited to written english manuscripts. At rst studies analysis, general characteristics of the study sample and COVID-19 mortality in diabetes patients was necessary to be reported. Manuscripts published as review articles, letters, case studies, editorials, conference abstracts, family-based studies and articles without abstracts were excluded.
Studies supplied by the database search strategy were assessed independently by two blinded researchers. Study quality was assessed using the Jedad scale 16 . The Jedad scale has a maximum score of ve points, it is subdivided into three topics: randomization, blind and an account of all patients. The score of the articles is, thus, distributed as explained below.
Randomization : 1 point if randomization is mentioned; 1 additional point if the method of the randomization was accomplished using a computer-based randomization software, generated appropriately by random number list, coin toss or well-shu ed envelopes. Deduct 1 point if the method of randomization is inappropriate (minimum 0). Initially, the researchers were trained to standardize the methodological application, which consisted of discussing the Jedad scale items and summarizing the articles; two researchers applied the scale independently and any disagreements between them were solved by discussing and reaching a consensus. The articles that obtained a score equal or greater than two points on the scale were considered as having high methodological quality.

Results
Initially 53 articles were found with the mesh terms "mortality from Coronavirus", "mortality from COVID-19" and "mortality in patients with diabetes by COVID-19". Then a second search round was performed based on the references of the rst studies found; 12 additonal articles were found, 3 were duplicated. Among the 62 full text found, 46 were excluded for not meeting the eligibility criteria (none of those included the mortality rate for diabetes patients). Among the 10 articles that met the criteria, 3 were excluded because both evaluators rated a Jedad score lower than two points. Among the remaining seven, two were excluded because they were meta-analysis. Final analysis comprised ve full text studies ( Figure 1).
The table 1 shows studies general characteristics such as authors names, studies' objectives, place of recruitment, study type and conclusion.  (Figure 2).
Based on the nal studies analysis, a global average mortality risk from COVID-19 in patients with diabetes was assessed. It was seen that the mortality risk was 8.9 times higher for patients with diabetes than individuals without diabetes ( Figure 2).

Discussion
The aim of this systematic review was to identify COVID-19 mortality rate and risk among patients with diabetes. Our review showed that mortality rate due to COVID-19 varied widely according to each study, however, in all the mortality rate was higher among patients with diabetes. Nevertheless, while evaluating the average mortality risk for patients with diabetes in relation to non-diabetics patients, OR was 8.9 times higher. The new nding that o HB1Ac level and diagnosis time can contribute to higher mortality.
In one of the rst published studies evaluating the mortality risk of COVID-19, the authors showed that older age, high SOFA score and ddimer greater than 1 μg / mL could help clinicians to identify patients with poor prognosis at an early stage 17 . Also is known that the age-dependent defects in T-cell and B-cell functioning and the excess production of type 2 cytokines could lead to a de ciency in viral control replication and more prolonged proin ammatory responses, potentially leading to poor outcome 18 . It is known that the sofa severity scale is also a good marker of mortality in patients with sepsis 19; it has been shown that sepsis occurs in about 40% of patients with COVID-19 due to pneumonia 20 .
After these ndings, other studies began to evaluate other prognostic factors, such as heart disease, arterial hypertension, chronic obstructive lung Ddsease, chronic kidney disease and carcinoma 21,22,23  Most recently a meta-analysis showed that diabetic patients with COVID-19 infection have an higher risk of ICU admission and higher mortality risk 27 . A relationship between diabetes and infection has long been clinically recognized 28 . Infections -particularly in uenza and pneumonia -are common and more serious in older people with type 2 diabetes mellitus 28 , However, there is no evidence whether diabetes itself increases susceptibility of infections developing in these patients. Still, remains uncertain how exactly the in ammatory and immune response occurs in patients COVID-19, as well as whether hyper or hypoglycemia may alter the SARS-CoV-2 virulence or the virus itself interferes with insulin secretion or glycemic control.
There are several hypotheses for which the patient with diabetes has complications due to COVID-19. Chronic in ammation, increased coagulation activity, immune response impairment and potential direct pancreatic damage by SARS-CoV-2 might be among the underlying pathophysiological mechanisms contributing to the increased morbidity and mortality of COVID-19 in people with diabetes 29 .
Another possibility is that diabetes is a chronic in ammatory condition characterized by multiple metabolic and vascular abnormalities that can affect it response to pathogens 30 . Hyperglycemia and insulin resistance promote increased synthesis of the end of glycosylation oxidative stress products (AGEs), and proin ammatory cytokines; in addition, it stimulates the production of adhesion molecules that mediate tissue in ammation 14,15 . This in ammatory process may be part of the underlying mechanism that leads to a greater propensity to infections -worse results in patients with diabetes 31 .
Insulin resistance and T2DM are associated with endothelial dysfunction and increased platelet aggregation and activation. These abnormalities predispose the hypercoagulable prothrombotic state development 32 . It is possible that coagulation disorders are one of the main mechanisms that increase mortality from COVID-19 among patients with diabetes. Coronavirus inoculation has already been found in pancreatic islets. Therefore, although more evidence is needed, pancreatic damage may also be present in patients with COVID-19, possibly contributing to a higher risk of mortality in diabetic patients 33 .
Although diabetes is associated with worse prognosis for COVID-19 patients, the susceptibility to COVID-19 infection does not appear to be greater than non-diabetic individuals. According to several studies, the prevalence of diabetes in people infected with the virus is about the same as overall population, even slightly lower 34 .
The limitations of this study are related to the fact that we did not carry out risk analysis corrected by age and sex; as it is already known that age, as well as, male gender can in uence higher mortality rates. Nevertheless, this study has important clinical applications related to the fact that the increase in mortality in diabetic patients may be related to coagulation disorders and pancreatic changes.

Conclusion
According to the presented analyzes, we can concluded that mortality risk and mortality observed in COVID-19 disease is higher among patients with diabetes than individuals without diabetes. This can be partially explained by changes in its disease mechanism, such as blood clotting and abnormal pancreas functioning.
Declarations COI (Con ict of Interest statement) "The authors declared that they have no con ict of interest"  Figure 1 Global mortality risk of from COVID-19 in patients with diabetes Forest plot of studies investigating mortality risk in patients diabetes mellitus Systematic literature review process. The ow diagram describes the systematic review of the literature for the mortality by COVID-19 in diabetes patients.