COVID‐19 in a country with a very high prevalence of diabetes: The impact of admission hyperglycaemia on mortality

Abstract Aims To evaluate the frequency of diabetes and admission hyperglycaemia in Mexican COVID‐19 patients, to describe the clinical and biochemical characteristics of patients with admission hyperglycaemia and to determinate the impact of diabetes and admission hyperglycaemia on COVID‐19 severity and mortality. Methods A multicentric study was performed in 480 hospitalized patients with COVID‐19. Clinical and biochemical characteristics were evaluated in patients with admission hyperglycaemia and compared with non‐hyperglycaemic patients. The effect of diabetes and admission hyperglycaemia on severity and risk of death were evaluated. Results Age was 50.7 ± 13.6 years; 68.3% were male. Some 48.5% (n = 233) had admission hyperglycaemia; 29% (n = 139) of these patients had pre‐existing diabetes. Patients with admission hyperglycaemia had more requirement of invasive mechanical ventilation (IMV), higher levels of urea, D‐dimer and neutrophil‐lymphocyte ratio (NLR), as well as lower lymphocyte count. An association between admission hyperglycaemia with IMV and D‐dimer with glucose was found. Age ≥50 years (OR 2.09; 95%CI 1.37–3.17), pre‐existing diabetes (OR 2.38; 95%CI 1.59–5.04) and admission hyperglycaemia (OR 8.24; 95%CI 4.74–14.32) were risk factors for mortality. Conclusions Admission hyperglycaemia is presented in 48.5% of COVID‐19 patients. Diabetes and admission hyperglycaemia are associated with the severity of disease and mortality. This study shows the devastating conjunction of hyperglycaemia and COVID‐19. Clinical trial registration: Clinical characteristics of patients with COVID‐19, DI/20/204/04/41 (Hospital General de Mexico) and NR‐13‐2020 (Hospital Regional de Alta Especialidad Ixtapaluca).


| INTRODUC TI ON
Coronavirus disease 2019  is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). 1 The highest proportion of severe cases occurs in adults ≥60 years of age, and in patients with diabetes, hypertension, obesity, chronic obstructive pulmonary disease, and cardiovascular, renal, and cerebrovascular diseases. [1][2][3] The SARS-CoV-2 accesses host cells via the binding of its spike glycoprotein to angiotensinconverting enzyme 2 (ACE2), sialic acid receptor, transmembrane serine protease 2 (TMPRSS2), extracellular matrix metalloproteinase inducer (CD147), cathepsin B and L; all of these factors are expressed in endothelial cells. Endothelial dysfunction is a determinant of COVID-19. 4 The main complications of COVID-19 include acute respiratory distress syndrome (ARDS), cardiac injury, liver dysfunction, acute kidney injury, bacteraemia, diffuse intravascular coagulation and hyperglycaemia. Hyperglycaemia is common in patients with COVID-19, predominantly in severe cases. 3 Hyperglycaemia in hospitalized patients, irrespective of its cause, is associated with adverse outcomes. 3 Hyperglycaemia could be present in patients with known or undiagnosed diabetes, or during acute illness (termed 'stress hyperglycaemia'). 5 Stress hyperglycaemia has two scenarios: patients with undiagnosed diabetes or impaired glucose tolerance, and patients who develop hyperglycaemia as a result of the severe stress and increased counterregulatory hormones. 6 Diabetes and hyperglycaemia are associated with a poor outcome (higher severity and mortality) in patients with COVID-19. 7 Admission hyperglycaemia has been observed as a predictor of radiographic imaging of SARS-CoV2, regardless of previous diabetes diagnosis. 8 Diabetes is one of the most common causes of morbidity and mortality around the world. 9 In 2019, 463 million people had diabetes, with an expectation that this number will rise to 578 million people worldwide by 2030 and 700 million by 2045. 9 In the top 10 countries with more cases of diabetes, Mexico ranks 6th worldwide, with 12.8 million people affected. 9 The specific mechanisms of hyperglycaemia in COVID-19 are not clear. 10 A relation between SARS-CoV-2 and ACE2 receptor, expressed in the liver and in the endocrine pancreas, has been proposed. 10 Hepatocytes and pancreatic beta cells could be infected by SARS-CoV-2 through glycosylated ACE2 receptor, promoting the development of insulin resistance and impaired insulin secretion, inducing hyperglycaemia. 10 The impairment in β-cell insulin secretion may worsen pre-existing diabetes or determine the appearance of hyperglycaemia in cases of non-diabetes. 10 A vicious circle has been proposed: SARS-CoV-2 decreases insulin secretion and promotes the appearance/worsening of insulin resistance, inducing hyperglycaemia, which, in turn, may further damage β-cells, with a worsening of insulin resistance. 11 In low-and middle-income countries, there is little information about the frequency of hyperglycaemia in COVID-19 patients and its impact on outcome severity. In our population, there is a high rate of diabetes, hypertension, overweight and obesity, which are risk factors for severe disease in SARS-CoV-2 infection. 12 A study in Mexican population has shown that diabetes, particularly earlyonset diabetes, is a risk factor for COVID-19 lethality and mortality; however, the effect of diabetes and hyperglycaemia on adverse outcomes in a clinical setting is not yet understood. 13 The aims of our study were to evaluate the frequency of diabetes and admission hyperglycaemia in Mexican COVID-19 patients, to evaluate the clinical and biochemicals characteristics of patients with admission hyperglycaemia and compare with non-hyperglycaemia patients, and to determinate the impact of diabetes and admission hyperglycaemia on severity and mortality in a population of a low/ middle-income country.

| SUBJEC TS , MATERIAL S AND ME THODS
A cross-sectional, retrospective, observational study was conducted in 480 patients hospitalized with COVID-19 in three medical institutions of Mexico: General Hospital of Mexico Eduardo Liceaga, Regional Hospital of High Specialty Ixtapaluca and General Hospital of Cuatitlán Vicente Villada. These hospitals are responsible for the treatment of patients with COVID-19, assigned by the government of Mexico. Patients were attended from March to July 2020.
-The results of present study denote the devastating conjunction of two pandemics, diabetes and COVID-19, in a country with a very high prevalence of metabolic diseases.
-Early detection of hyperglycaemia in patients with COVID-19, both with and without diabetes, timely treatment and the restoration of normoglycaemia are essential.
Inclusion criteria were patients aged 18-80 years, clinical syndromes associated with SARS-CoV-2 infection that required hospitalization (mild and severe pneumonia, Acute Respiratory Distress Syndrome [ARDS], sepsis and sepsis shock), 14 and positive SARS-CoV-2 testing (real-time PCR). Pregnant women were not eligible for the study. Patients with incomplete data in medical records were excluded ( Figure 1). All participating subjects were informed of the aim of the study and provided oral informed consent.
The clinical history, vital signs and laboratory data, obtained from electronic medical records, were analysed and evaluated.
Information was collected on age, sex, morbidity and body mass index (BMI). The laboratory data collected were routine blood, blood glucose, lipid, liver and renal function, fibrinogen and Ddimer levels.
Admission hyperglycaemia was defined as blood glucose levels ≥140 mg/dl occurring within a 24-h period since the hospital admission. 5,15 Pre-existing diabetes was confirmed by reviewing patients' The diagnosis of pneumopathy was established with radiography chest plus thoracic ultrasonography or computed tomography. 16 All patients were treated with standard protocol, including hydroxychloroquine, antiviral drugs or tocilizumab. Non-critically ill patients with pre-existing diabetes and glucose levels between 110 and 180 mg/dl continued with oral antidiabetic drugs. Sulphonylureas were discontinued in all cases. If glucose levels were above 180 mg/ dl, an insulin regimen with basal-bolus-correction established.
Critically ill patients and patients with hyperglycaemia on admission were treated with an insulin regimen and basal-bolus-correction (NPH, glargine and lispro).
The primary outcomes were presence of severe pneumonia, which was defined by the use of IMV and in-hospital mortality.

| Statistical analysis
The Kolmogorov-Smirnov test was applied to determine the type of distribution of the continuous variables. Measures of central tendency and dispersion were calculated: mean ± standard deviation (SD) for parametric data or median and interquartile range (IQR) values for nonparametric data. Categorical variables were given as frequency rates and percentages. Mann-Whitney U test or t-test was used to compare quantitative measurements. In correlation analysis, Pearson correlation coefficient was used for the variables of normal distribution and Spearman correlation coefficient for those of skewed distribution.
The comparison of the proportion of the variables such as obesity, IMV and mortality was analysed with X 2 test. Risk estimation was through the odds ratio and 95% confidence interval (OR, 95%CI). All the analyses were carried out with the statistical program Statistical Package for the Social Sciences (SPSS) version 20.
p < .05 was considered significant.

| Association between COVID-19 severity, mortality and diabetes
In this study, a positive association was found between the severity of the disease, assessed by the need for IMV with admission hyperglycaemia (p = .009), and sex (p = .04 and hypertension as risk factors for mortality in our series ( Figure 2).

| DISCUSS ION
In this multi-centre study, we observed the elevated frequency of diabetes and admission hyperglycaemia, and their association with the severity of disease and mortality, in Mexican COVID-19 patients.
The pre-existence of certain comorbidities, such as diabetes, has been known as a risk factor for fatality hazard. 3,7 In our series, at hospital admission of COVID-19 patients, we noted a high frequency of diabetes (29%); however, when we evaluated the presence of hyperglycaemia, independently of the pre-existence diagnosis of diabetes, the frequency increased to 48.5%, which is an alarming datum.
Hyperglycaemia has been reported in more than a third of patients admitted to a hospital and is considered an important marker of poor clinical outcomes and increased mortality, not only in critical patients admitted to the intensive care unit, but also in patients admitted to general medicine and surgery wards, in particular in patients without a history of diabetes. Patients with new hyperglycaemia during hospitalization had a significantly higher mortality rate and lower functional outcomes than patients with a known history of diabetes or normoglycaemia. 6 A proposed mechanism for the increased morbidity and mortal- were risk factors for lethality. 13 They reported that early-onset diabetes conferred an increased risk of hospitalization and a higher risk of mortality in younger patients, which was similar to older patients with comorbidities and only exceeded by older patients with diabetes. The co-existence of obesity and diabetes, particularly early-onset diabetes, was a risk factor for COVID-19 mortality in Mexicans. In addition to diabetes and obesity, other factors associated with lethality were age >65 years, immunosuppression and hypertension. 13 In contrast, our study was performed in a clinical setting and included only COVID-19 patients that required hospitalization. It was observed that diabetes and admission hyperglycaemia were associated with a higher severity of disease, a worst outcome as the Yan et al. 31 showed that patients with COVID-19 and diabetes had more comorbidities such as cardiovascular, cerebrovascular disease or hypertension, had a longer length of hospital stay, were more likely to receive mechanical ventilation and admission to ICU, and had a higher mortality. Biochemically, these patients had higher levels of leucocyte count, neutrophil count, hsCRP, ferritin, IL-2 receptor, IL-6, IL-8, TNFα, D-dimer, fibrinogen and N-terminal pro-brain natriuretic peptide (NT-proBNP).
On the other hand, a possible relation of specific blood group and the association with an increased risk of SARS-CoV-2 infection has been proposed. A meta-analysis demonstrated that blood type A might be more susceptible to SARS-CoV-2 infection, while blood type O might be less susceptible; there was no correlation between ABO blood group and severity or demise of COVID- 19. 32 In patients of the present study, no ABO group differences were observed. However, the initial objective was not to study the association between blood groups and COVID-19. In Mexico, the distribution of blood types varies compared with other populations, so that group O predominates and the proportion of the population with group A is lower. 33 More studies focussed on the relation between ABO group and clinical outcome are required.
The limitations of our study include the retrospective design and the lack of resources for biochemical evaluation of parameters such as HbA1c or interleukin profile which is a non-routine measure- F I G U R E 2 Forest Plot using association of risk factors for mortality, by Odds Ratio and 95% of confidence interval (OR, 95%CI)