key: cord-0920642-zhxfzu4v authors: Alhakak, Amna; Butt, Jawad H.; Gerds, Thomas A.; Fosbøl, Emil L.; Mogensen, Ulrik M.; Krøll, Johanna; Pallisgaard, Jannik L.; Gislason, Gunnar H.; Torp‐Pedersen, Christian; Køber, Lars; Weeke, Peter E. title: Glycated haemoglobin levels among 3295 hospitalized COVID‐19 patients, with and without diabetes, and risk of severe infection, admission to an intensive care unit and all‐cause mortality date: 2021-12-05 journal: Diabetes Obes Metab DOI: 10.1111/dom.14604 sha: 22d5d45dc6e33de15985a456a4ac06143039f13e doc_id: 920642 cord_uid: zhxfzu4v AIM: To determine the risk of adverse outcomes across the spectrum of glycated haemoglobin (HbA1c) levels among hospitalized COVID‐19 patients with and without diabetes. MATERIALS AND METHODS: Danish nationwide registries were used to study the association between HbA1c levels and 30‐day risk of all‐cause mortality and the composite of severe COVID‐19 infection, intensive care unit (ICU) admission and all‐cause mortality. The study population comprised patients hospitalized with COVID‐19 (3 March 2020 to 31 December 2020) with a positive polymerase chain reaction (PCR) test and an available HbA1c ≤ 6 months before the first positive PCR test. All patients had at least 30 days of follow‐up. Among patients with diabetes, HbA1c was categorized as <48 mmol/mol, 48 to 53 mmol/mol, 54 to 58 mmol/mol, 59 to 64 mmol/mol (reference) and >64 mmol/mol. Among patients without diabetes, HbA1c was stratified into <31 mmol/mol, 31 to 36 mmol/mol (reference), 37 to 41 mmol/mol and 42 to 47 mmol/mol. Thirty‐day standardized absolute risks and standardized absolute risk differences are reported. RESULTS: We identified 3295 hospitalized COVID‐19 patients with an available HbA1c (56.2% male, median age 73.9 years), of whom 35.8% had diabetes. The median HbA1c was 54 and 37 mmol/mol among patients with and without diabetes, respectively. Among patients with diabetes, the standardized absolute risk difference of the composite outcome was higher with HbA1c < 48 mmol/mol (12.0% [95% confidence interval {CI} 3.3% to 20.8%]) and HbA1c > 64 mmol/mol (15.1% [95% CI 6.2% to 24.0%]), compared with HbA1c 59 to 64 mmol/mol (reference). Among patients without diabetes, the standardized absolute risk difference of the composite outcome was greater with HbA1c < 31 mmol/mol (8.5% [95% CI 0.5% to 16.5%]) and HbA1c 42 to 47 mmol/mol (6.7% [95% CI 1.3% to 12.1%]), compared with HbA1c 31 to 36 mmol/mol (reference). CONCLUSIONS: Patients with COVID‐19 and HbA1c < 48 mmol/mol or HbA1c > 64 mmol/mol had a higher associated risk of the composite outcome. Similarly, among patients without diabetes, varying HbA1c levels were associated with higher risk of the composite outcome. Coronavirus disease-2019 (COVID-19) infection, caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), was declared a global pandemic by the World Health Organization on 11 March 2020. 1, 2 In previous studies, in a non-COVID-19 setting, glycated haemoglobin (HbA1c) has been shown to be a clinically useful marker for predicting all-cause mortality among patients both with and without diabetes. [3] [4] [5] [6] In a COVID- 19 setting, many studies have demonstrated that diabetes mellitus is a substantial risk factor for increased severity of COVID-19 infection, admission to an intensive care unit (ICU), and COVID-19 related mortality. [7] [8] [9] [10] Patients with diabetes and higher levels of HbA1c or hyperglycaemia also have higher levels of inflammatory markers, which could indicate a more severe inflammatory response than those without diabetes or with normoglycaemia. [11] [12] [13] [14] [15] [16] However, to date, few studies have examined the relationship between varying HbA1c levels and the associated risk of mortality and adverse outcomes among COVID-19 patients, and these studies have conflicting results. [17] [18] [19] The studies focused primarily on the association between HbA1c and mortality among COVID-19 patients with diabetes. Previously, Holman et al 18 identified an independent association between high HbA1c levels and COVID-19-related mortality among over 3 million people with type 1 diabetes and type 2 diabetes. However, the absolute risk of mortality according to HbA1c level after COVID-19 infection was not reported, only patients with diabetes were included, and important outcomes such as severe COVID-19 infection or ICU admission were also not examined. In a COVID-19 setting, more information is needed on the association between varying HbA1c testing levels prior to a positive SARS-CoV-2 polymerase chain reaction (PCR) test and risk of mortality and, particularly, adverse outcomes among patients with and without diabetes. Thus, the purpose of the present Danish registry-based cohort study was to determine the risks of severe COVID-19 infection, ICU admission, or all-cause mortality among COVID-19 patients, with and without diabetes, associated with varying levels of HbA1c. Units coding system (see Appendix S1, Table S1 ). 22 The Danish National Prescription Registry provides detailed information on all dispensed drug prescriptions from Danish pharmacies according to the Anatomic Therapeutic Chemical (ATC) Classification System since 1995. 23 The Danish Civil Registration System holds information on birth date, sex and vital status (ie, whether a person is alive and a citizen in Denmark, emigrated, or dead, along with the date of these events). 24 The Danish registries are of high quality and complete, and the definitions and codes obtained from the registries have been previously validated. 20 Patients with diabetes were identified according to diabetes-related hospital admissions or outpatient contacts (ICD-8 code: 250 and ICD-10 codes: E10-E14) any time before index date or by dispensed prescriptions for an antidiabetic drug (ATC code: A10) or HbA1c ≥ 48 mmol/mol (6.5%) ≤ 6 months before index date. Patient comorbidity was determined from the Danish National Patient Registry using hospital admissions or outpatient contacts (ie, primary or secondary diagnosis codes) any time prior to index date (Table S2 ). Concomitant pharmacotherapy was identified from the Danish Prescription Registry as a dispensed prescription within 6 months prior to index date (Table S3) . Patients with hypertension were identified from combination treatment with at least two dispensed antihypertensive drug prescriptions, as described previously. 27 The primary study outcome was a composite of COVID-19 severe acute respiratory syndrome (ie, severe COVID-19 infection [ICD-10 code: B972A]), ICU admission (NCSP codes: NABE, NABB, BGDA), or all-cause mortality. The secondary study outcome was all-cause mortality. All patients included had at least 30 days of potential follow-up from the first positive PCR test result. Patients were followed from the day of the first positive PCR test until the occurrence of a study outcome, death, or end of study (31 January 2021), whichever came first. Continuous variables are presented as medians with interquartile ranges (IQRs), and differences were assessed by the Kruskal-Wallis test. Categorical variables are presented as numbers with proportions, and differences were assessed using the chi-squared test. To test the association of varying HbA1c levels among patients with and without diabetes separately, we performed stratified analyses according to diabetes status. Patients with diabetes were grouped according to the HbA1c thresholds used by the International Diabetes Federation and the American Diabetes Association 28-31 : <48 mmol/mol (6.5%), 48 to 53 mmol/mol (6.5% to 7.0%), 54 to 58 mmol/mol (7.1% to 7.5%), 59 to 64 mmol/mol (7.5% to 8.0%), and >64 mmol/mol (8.0%). For this analysis, HbA1c 59 to 64 mmol/mol (7.5% to 8.0%) was used as the comparative reference as the International Diabetes Federation recommended this HbA1c target among patients using multiple medications, including glucose-lowering drugs, who have a reduced life expectancy (eg,<10 years) and multiple comorbidities. 31 Among patients without diabetes, HbA1c was stratified into <31 mmol/mol (5.0%), 31 to 36 mmol/mol (5.0% to 5.4%; reference), 37 to 41 mmol/mol (5.5% to 5.9%), and 42 to 47 mmol/mol (6.0% to 6.5%), as done previously. 4, 32 Using working Cox regression models, we standardized the 30-day risks of all-cause mortality and the composite outcome in the aforementioned HbA1c groups among patients with and without diabetes, according to the distribution of sex, age as a continuous variable, history of ischaemic heart disease, heart failure, atrial fibrillation, stroke, peripheral artery disease, hypertension, chronic obstructive pulmonary disease, cancer, chronic renal disease and use of cholesterol-lowering drugs, beta-blockers, calcium channel blockers, renin-angiotensin system inhibitors, aspirin, and anticoagulants in the study population. We report 30-day standardized absolute outcome risks and risk differences with 95% confidence intervals (CIs) of outcomes. 33 To test the robustness of our results, we performed several sensitivity analyses. First, the model assumptions of the working Cox regression model (proportional hazards, linearity of effects and absence of interactions) were tested, estimating standardized 30-day outcome risks based on a random survival forest model among patients with and without diabetes, respectively. 34 Second, we report hazard ratios (HRs) with 95% CIs during complete follow-up among patients with and without diabetes, respectively. Third, to visualize the association between continuous HbA1c and the rates of the study outcomes, we fitted a Cox regression model, which used restricted cubic splines with three knots to illustrate the association between HbA1c and the outcome rates adjusted for all other variables of the main analysis. Fourth, to assess if HbA1c per se has a significant biological effect, we compared patients with and without diabetes but with the same range of HbA1c levels. The combined population was stratified into the following groups: HbA1c < 39 mmol/mol (5.7%) without diabetes, HbA1c < 39 mmol/mol with diabetes, HbA1c 39 to 47 mmol/mol (5.7% to 6.5%) without diabetes, HbA1c 39 to 47 mmol/ mol with diabetes, 48 to 53 mmol/mol, 54 to 58 mmol/mol, 59 to 64 mmol/mol, and >64 mmol/mol (Table S8) . Fifth, a sensitivity analysis was conducted to assess if random blood glucose at the time of admission plays a critical role in the prognosis of COVID-19 patients in terms of allcause mortality or the composite outcome. Sixth, to determine possible generalizability of the present study findings, we compared patient characteristics for the included study patients with COVID-19 patients with no information on HbA1c levels according to diabetes status. Seventh, to test if time of diagnosis influenced our findings, the populations with and without diabetes were stratified in two periods before and after 1 August 2020, and the main analyses were repeated. Eighth, to test whether time of HbA1c measurement prior to index date would influence our results, sensitivity analyses using HbA1c obtained 3 months before index date instead of 6 months were performed for both study outcomes among patients with and without diabetes as the main analyses. The main statistical coding was conducted using the SAS (version 9.4; SAS Institute Inc., Cary, North Carolina), and all statistical analyses were obtained using R (version 4.0.3). The level of statistical significance was set at 5%. In Denmark, registry-based studies using de-identifiable data do not require ethical approval. The present study was approved by the data responsible institute (the Capital Region of Denmark-Approval number:P-2019-191) in accordance with the General Data Protection Figure 1] ). Furthermore, Figure S1 shows the adjusted HRs from the Cox regression analysis for all-cause mortality among patients with diabetes. Illustrated in Figure S2 is a restricted cubic spline reporting the continuous association between HbA1c and the mortality rate among patients with diabetes. with diabetes are depicted in Figure S5 . A restricted cubic spline reporting the continuous association between HbA1c and the rate of the composite outcome among patients with diabetes is illustrated in Figure S6 . The model assumptions of the Cox regression analysis, based on a random survival forest model, were fulfilled for both study outcomes among COVID-19 patients with and without diabetes (Tables S4 and S5 , respectively). The comparison between patients with and without diabetes with the same range of HbA1c levels in a pooled population showed that having diabetes and an HbA1c level 39 to 47 mmol/mol or an HbA1c level > 64 mmol/mol was associated with a higher risk of the composite outcome ( Figure S9 ). However, an increased risk of the composite outcome was not observed in patients without diabetes. According to baseline characteristics, a dose-response relationship was identified between increasing levels of HbA1c groups and median levels of blood glucose among patients with and without diabetes (Tables 2 and 3 ). Among patients with diabetes, blood glucose levels 11.1 to 13.0 mmol/L and blood glucose levels > 13.0 mmol/L were associated with a higher risk of the composite outcome ( Figure S10 ). A dose-response relationship was identified between increasing blood glucose levels and the composite outcome among patients without diabetes ( Figure S11) . Overall, few differences were observed in baseline characteristics in hospitalized COVID-19 patients with diabetes according to available HbA1c value (Table S6 ). Baseline differences among hospitalized COVID-19 patients but without diabetes are listed in Table S7 . To test whether time affected our findings, we performed sensitivity analyses for the periods from 3 March 2020 to 1 August 2020 and 1 August 2020 to 31 December 2020 according to diabetes status for both study outcomes, which all yielded similar results to the main analyses (data not shown). To test whether time of HbA1c collection affected our findings, we performed sensitivity analyses using HbA1c measurements collected at <3 months prior to index date according to diabetes status. These analyses yielded the same results as the main analyses for both study outcomes (data not shown). In this Danish registry-based cohort study, we examined the associa- The HbA1c measurements were obtained up to 6 months prior to the index date, which may have influenced our findings, although sensitivity analyses using HbA1c levels gathered up to 3 months before the index date yielded the same results as for the main analyses. In addition, we were not able to confidently distinguish type 1 and type 2 diabetes, which may have influenced our study findings. In conclusion, in the present registry-based observational study, None declared. The final version of the manuscript was approved by all authors. Amna Alhakak is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The peer review history for this article is available at https://publons. com/publon/10.1111/dom.14604. 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