key: cord-1017630-t6nepikd
authors: Zhu, Zheng; Mao, Yaqian; Chen, Gang
title: Predictive value of HbA1c for in-hospital adverse prognosis in COVID-19: a systematic review and meta-analysis
date: 2021-08-11
journal: Prim Care Diabetes
DOI: 10.1016/j.pcd.2021.07.013
sha: c1da0c0f911d043a52a74694460bbbd611f4f194
doc_id: 1017630
cord_uid: t6nepikd

Background and aims Clinical and laboratory predictors of adverse clinical course and death in COVID-19 patients urgently need to be identified. So far, the association between HbA1c and in-hospital mortality of COVID-19 remains a controversial issue. The aim of this study is to analyze predictive value of HbA1c for adverse prognosis in COVID-19. Methods Both Chinese and English databases were systematically searched using specific keywords associated with the aims until November 21th, 2020. The Newcastle-Ottawa Scale (NOS) was used for quality assessment. A Statistical analysis was carried out using Review Manager 5.3 and STATA 15.1. Results Nine clinical trials were included in this study involving 2577 subjects. The results indicate that the association between elevated HbA1c referred as a continuous variable and adverse prognosis of COVID-19 was not significant (OR, 1.02; 95%CI, 0.95-1.09). However, higher HbA1c levels regarded as a dichotomous variable contributed to an increase mortality of COVID-19 (OR, 2.300; 95%CI, 1.679-3.150). Results were stable in a sensitivity analysis. More studies are needed to demonstrate the effect of HbA1c on hospital mortality. Conclusion Prolonged uncontrolled hyperglycemia increases the risk of adverse prognosis in COVID-19. Patients with higher HbA1c should be monitored strictly to minimize the risk of adverse prognosis in COVID-19.

The epidemic of COVID-19 has spread rapidly worldwide [1] [2] [3] . The manifestations of severe cases with COVID-19 can develop into acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) [1] . Identifying the risk factors associated with the progress of COVID-19 is essential to guide clinicians to carry out targeted therapy. Data has showed that patients with poor glucose control have a higher mortality of other viral epidemics such as H1N1 flu and SARS [4] [5] . Currently, the inclusion of diabetes status estimation is strongly supported by the evidence on the risk management of COVID-19 patients. Glycosylated hemoglobin (HbA1c) is a stable index of long-term glucose control and provides an Two investigators (ZZ and YM) extract the following data from eligible studies: authors, journal, country, study period and sample size, the following potential risk factors were recorded independently: baseline demographic characteristics, glucose metabolic states (DM or all included), comorbidities (hypertension, cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease), number of patients in control or case group, maximally adjusted effect estimates (HR and OR) and corresponding 95% confidence intervals (95%CIs), and adjustment factors. The data mentioned were either extracted from the manuscript or converted from the tables and figures provided. Any variances were resolved by consensus.

The statistical analysis was carried out using Review Manager 5.3 and STATA 15.1. Because of the different statistical methods used in the collected studies, studies were analyzed that analyzed the measured HbA1c values as continuous variables and dichotomous variables, respectively. The maximally adjusted HR and OR with 95%CI were used to estimate the strength of the association between HbA1c levels and adverse outcome of COVID-19 by using the generic inverse variance method. If the ORs and 95% CIs were not published in the paper, the original data was used for the calculation of ORs. For studies reporting multiple HbA1c levels, this study extracted the number of events and patients with HbA1c＜ or ≥7%, and calculated the relative crude OR with 95% CIs. Chi-squared test (Chi2) and I-squared statistic (I2) were used to evaluate the degree of heterogeneity among the included studies [16] . For Chi2 test, a Cochrane's Qp value of <0.10 was considered significant. The I2 statistics thresholds of 75%, 50% and 25% were used to indicate high, moderate and low heterogeneity. When the I2 > 50%, the random-effect model (Inverse Variance) was chosen to calculate the pooled effect, otherwise the fixed-effect model(I-V) was used instead. The sources of heterogeneity were explored by subgroup analysis. In order to determine the stability of the summarized results, the sensitivity analysis of the in-hospital mortality was conducted using two techniques, respectively ignoring studies one by one, repeating meta-analysis by using a random-effects model. Publication bias was tested by Begg rank correlation test and Egger linear regression test [17] [18], with P<0.1 representing publication bias. The statistical significance level of the two-sided test was P<0.05 unless otherwise specified.

No patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of the results. We do plan to disseminate the results of the research to the relevant patient communities.

Our comprehensive retrieval identified 798 records from the electronic databases, and 467 studies were remained after removing duplications. After scanning the titles, abstracts, reading full texts and handsearching the reference lists of articles, this study finally got 9 retrospective studies [7] [25] (flow diagram and the detailed reasons for the exclusion were shown in Figure 1 ) including a total of 2577 COVID-19 to evaluate the associations between HbA1c level and their in-hospital mortality and/or intubation rate. As the location and study period of the two studies overlapped [10] [6] , the one with a larger sample size were included [10] . One excluded study contained J o u r n a l P r e -p r o o f multiple HbA1c levels without original data, and approximately one-third of the studied population did not provide data on HbA1c [11] .

The characteristics of eligible studies were summarized in Table1. All studies derived the data from the electronic health records of institutions or hospitals. Three studies were conducted in Europe [20] [24] [25] , two in the USA[10] [23] , and remaining four in Asia [7] [19] [21] [22] . The study period of eligible studies ranged from 7 [25] to 118 [24] days. The sample size of eligible study ranged from 29 [19] to 1279 [10] . The mean age of participants included in the studies varied from 63.6 years [7] to 68.0 years [23] . The proportion of male in each study ranged from 48.3% [19] to 62% [7] . Most of the eligible studies were of high quality with an average quality score as 7.11 (Supplementary Table S1 [25] , and their effect values at least adjusted for confounders of age. The two studies also adjusted the confounding factors of hypertension [10] [21] . Three studies only involved patients with diabetes (n=1520), and the other six included 427 patients with diabetes and 711 patients without diabetes. Among them, one study reported that 36.4% of patients in the high HbA1c group were not previously known to have diabetes [23] .

In addition, the baseline characteristics and laboratories values of the high and low HbA1c groups after admission were shown in tables 2 [19] [20] [21] [22] [23] [24] . All P-values > 0.05, which meant that there was no significant difference in indicators between the two groups, which might be related to the lack of available data.

However, only from the numerical value, the high HbA1c group had a higher proportion of comorbidities and the elderly than low HbA1c group. Patients with the high HbA1c levels had more fever, cough, and higher levels of inflammation markers (i.e. C-reactive protein，procalcitonin，ferritin，interleukin-6，tumor necrosis factor-a), D-dimer and fibrinogen. Most notably, the frequencies of ICU admission and mechanical ventilation were significantly higher in high HbA1c group than low HbA1c group. In addition, indicators with different units were not pooled together. In these researches [20] [21] [22] , compared with the low HbA1c group, leukocytes, neutrophils increased and lymphocytes decreased in the high HbA1c group.

When HbA1c was regarded as a continuous variable [7] [10] [19] [21] [25] , the pooled analysis without statistical heterogeneity across different studies (I2=0%; p=0.63) did not find the correlation between the higher HbA1c and the reduced adverse prognosis of COVID-19 (OR 1.02 [0.95-1.09]; p=0.63) (Supplementary Figure 2A) . However, six studies referred HbA1c as a dichotomous variable, involving a sum of 1180 subjects and 301 deaths, and showed that higher HbA1c was significantly related to increased hospital mortality compared with groups with lower HbA1c (OR 2.300 [1.679-3.150]; p=0.000, I2=48%; p=0.087) (Supplementary Figure 2B) . Because of the moderate heterogeneity, sensitivity analysis was carried out. After ignoring studies one by one, there was no substantial alterations in the pooled ORs, confirming that this result was robust and reliable (Supplementary Figure 1S ). Pooled ORs from the fixed-effects model and random-effects model were virtually similar (Supplementary Figure 2S ).

Because there were moderate differences between individual studies, this research conducted a subgroup analysis in accordance with the study period, sample size, age, sex, diabetic status, incidence of hypertension (Table 3 ). Significant correlations between higher HbA1c and adverse prognosis remained in age subgroups. Subgroup analysis by diabetic status and the incidence of hypertension showed that HbA1c level was associated with adverse prognosis among COVID- 19 . Subgroup analysis categorized by study period did not show any significant relation between HbA1c and primary outcome among studies period <30days. Similarly, the significant relation could not be replicated among female patients or from smaller sample size studies.

No publication bias was found by Begg's and Egger's test among the studies (all p > 0.05) (Supplementary Figure 3SA , 3SB).

Nine clinical trials were included in this study involving 2577 subjects. The study did pooled analysis of all studies of in-hospital mortality or critical illnesses for COVID-19, and found that elevated HbA1c levels contributed to an increase in-hospital mortality in patients with COVID-19，when it was regarded as a dichotomous variable. Incidence of hypertension and diabetic status were the main source of moderate heterogeneity. However, when HbA1c was referred as a continuous variable, this association was not significant.

The meta-analysis of HbA1c as a dichotomous variable has the moderate heterogeneity, but the I2 < 50% was acceptable, and the sensitivity analysis showed that the result was robust and reliable. In two previous population-based studies, one showed that COVID-19-related mortality was higher in people with HbA1c>7.5% [26] , and another identified that mortality in people with type 1 and type 2 diabetes was significantly and independently related to the HbA1c [8] . In addition, a study of 80 patients with type 2 diabetes from India even found that COVID-19 patients with HbA1c > 8% exhibited a excessive uncontrolled inflammatory responses, hypercoagulable state, and severe symptomatic presentation [27] . Besides, A similar outcome was found in 44 COVID-19 patients admitted to an intensive care unit in Austria [28] .

From another point of view，based on the results of a study of 806 diabetes patients in Saudi Arabia, it was found that high HbA1c level were independently associated with hospitalization, compared with low HbA1c level [29] . This evidently indicated that patients especially of the poorly-controlled group associated to a significantly higher risk of severe COVID-19 requiring hospitalization.

Severe COVID-19 could be accompanied by fatal complications, such as acute respiratory distress syndrome, pneumonia, disseminated intravascular coagulation, and eventually lead to death [30] [31] . In the present study, more severe lung involvement and higher levels of coagulation and inflammation markers were more specific in the high HbA1c group. Similarly, a previous study conducted by Wang et al. pointed out J o u r n a l P r e -p r o o f that HbA1c was associated with low SaO2, hypercoagulability, and inflammation in COVID-19 patients [6] .

Fever and cough occurred more often in the higher HbA1c group, and the fundamental cause of such manifestation might be the early and extensive lung involvement of COVID-19 infection caused by glucose variability [27] . Moreover, compared with patients with controlled glucose, increased leukocytes, neutrophils and decreased lymphocytes in patients with uncontrolled glucose, suggesting that viral infection was more serious and was easy to be accompanied by bacterial infection [22] . It is widely known that, in the pathophysiological process of severe infection, the increased cytokines released by elevated neutrophils could lead to cytokine storms and multiple organ dysfunction [32] [33] [34] . The elevated neutrophils were positively correlated with the increased risk of death of COVID-19 [34] [35] . Meanwhile, the absolute count of lymphocytes among COVID-19 was negatively correlated with viral RNA load, occurrence of ARDS, need of ICU care, severity and mortality [34] [35] [36] [37] . A study conducted by Evangelos et al. showed that the elevated CRP was positively related with the occurrence of ARDS, myocardial injury and death, and the increase of ferritin was related to the poor prognosis of COVID-19 [38] . Simultaneously, it is reported that hyperglycemia aggravates inflammation by raising the release of TNF-α and interleukin [39] [40] [41] , which can result in inflammatory storm, and is judged to be one of the principal causes of poor prognosis in patients with COVID-19 [42] . Therefore, the causality between the characteristics of HbA1c groups and the pooled ORs of this study could be explicated. Some biological mechanisms have been raised to explain the potential causal relationship between prolonged uncontrolled hyperglycaemia and increased mortality in COVID-19 patients. Impaired immune response to viral infections is the main cause [43] . Particularly, hyperglycemia may inhibit intracellular destruction of microbes, neutrophil chemotaxis, and phagocytosis, thereby providing higher affinity for cellular binding and effective virus entry, and reducing viral clearance [44] . In addition, it can also cause direct glycosylation of proteins, thus changing the structure of complements [45] [46] . Chronic hyperglycemia downregulates the expression of ACE2 possessing anti-inflammatory property through glycosylation, making cells vulnerable to viral inflammation and destruction, which might interpret higher predisposition of COVID-19 with chronic hyperglycemia to ARDS [47] [48] . Furthermore, endotheliitis might be a possible mechanism leading to organ dysfunction causing critical illness in COVID-19, which might be exacerbated by endothelial dysfunction associated with chronic hyperglycemia [49] . Notably, HbA1c is as much a marker of ambient glucose as it is of oxidative stress. It is an early step in the production of advanced glycation end products.

Perhaps the sickest of the ICU/intubated COVID-19 patients had a great deal of oxidative stress. High HbA1c may be associated with a large amount of oxidative stress for critical illness in COVID-19.

Advanced age, hypertension and diabetes are not only risk factors for poor prognosis of COVID-19, but also confounding factors for HbA1c [23] . Among patients with severe COVID-19, more non-survivors were male [22] . Thus, age, sex, diabetic status, and the incidence of hypertension are possible effect modifiers of the HbA1c-mortality association. However, the results of our age-stratified subgroup analysis did not furnish evidence to support this hypothesis. There was moderate heterogeneity among these studies, which was solved according to diabetic status and the incidence of hypertension through subgroup analysis. Some of the inconsistencies in these findings could partly be explained by discrepancy in dietary patterns, lifestyle habits, antidiabetic or antihypertensive drugs, ICU length of stay, and better compliance with doctor's advice before and after infection with COVID-19. Besides, compared with studies of large sample size, small sample size studies were more likely to be affected by selection bias. Similarly, the significant relation could not be replicated among female patients or short study periods. Therefore, these results should be explicated with caution to a certain extent. Significantly, stress hyperglycemia (HbA1C < 6.5%, transient hyperglycemia) may have a worser outcome than previously diagnosed diabetes [50] . Limited studies have ruled out our attempt to study admission glucose as a potential modifier through subgroup analysis. Therefore, more research is needed to determine whether stress hyperglycemia can change the correlation of HbA1c-mortality.

Nevertheless, when HbA1c was referred as a continuous variable, this association was not significant. Several reasons should be considered. First of all, there may be several confounding factors that interfere with this result, such as age, sex, diabetic status, and the incidence of hypertension. Secondly, as reported by Agarwal et al. [10] , when the mortality rate in the cohort was such high, the effect of glucose control on mortality might be relatively too small to be detected. Thirdly, the HbA1 might have an effect on in-hospital glucose levels and could not independently predict mortality, which may be affected by hospitalization factors, such as hospitalization insulin treatment, other hyperglycemia-inducing hospital interventions, and severity of illness, and need to be further investigated. Last but not least, a small number of patients with relatively short study periods should be taken into consideration, as HbA1c is generally considered to be a long-term predictor of mortality in patients with diabetes.

The current meta-analysis has some inevitable limitations. Firstly, although this study extracted the adjusted OR (if they are available), confounding factors such as demographic characteristics, BMI ， comorbidities, and post-hospital treatment might still interfere with the results due to the inability to obtain data for individual participants. Therefore, this result should be interpreted carefully in clinical practice. Besides, excluding several studies that did not report the necessary data for HbA1c-mortality analysis may lead to publication bias. Lastly, due to the inherent limitations of observational studies, this research failed to establish a causal link between HbA1c and adverse outcome of COVID-19, when HbA1c was referred as a continuous variable. More studies are needed to use HbA1c as a continuous variable to demonstrate its effect on hospital mortality. The number of included studies was relatively small to reach a definite conclusion. Further studies need to be conducted through highly powered, multi-centered, prospective controlled trials.

While recognizing the built-in limitations of the original data, we insist that this meta-analysis has its merits and clinical significance. In this study, we searched 8 databases for the relationship between HbA1c and poor prognosis of COVID-19, and there was no language restriction. In addition, the stabilization and reliability of this results were further verified by the sensitivity analysis. For all we know, this study is the first systematic review and meta-analysis of the predictive value of pre-admission hba1c on the short-term prognosis of COVID-19. Though there is a resemble review regarding a mixed population with and without diabetes [51] , it only included in two studies and all patients of them were Chinese. According to this metaanalysis, we proposed people at high-risk of COVID-19 without (known) diabetes to control and monitor HbA1c levels. The effect of HbA1c on the hospitalization rate, in-hospital glucose levels, the glucose variation, and the influence of new-onset diabetes on the prognosis of COVID-19 are worth exploring in the future. The elevation of HbA1c is a predictor of COVID-19 's in-hospital mortality. The COVID-19 high-risk population with elevated HbA1c should comply with doctor's advice, strictly monitor and control hyperglycemia. For clinicians, HbA1c can represent a clinical tool for early risk assessment of COVID-19, which is vital for targeted therapy and needs more attention. As for researchers, further prospective studies and much larger samples size are needed to verify these findings.

Gang Chen conceived and designed this study. ZZ and YM collected the data and performed the literature search. ZZ was involved in the writing of this paper. All of the authors read and approved the final version of this paper.

None.

Not required.

The authors declare no conflict of interests. 

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We thank all patients and their families involved in the study.

We will disseminate our findings to patient organisations and media outlets.

No additional data available.