Abstract
Highlights
Fasting blood glucose < 10 mmol/L was proposed as a target of glycemic control during the first week of hospitalization in patients with preexisting diabetes.
Poor HbA1c levels prior to coronavirus disease 2019 (COVID‐19) might not be associated with severity among patients with preexisting diabetes.
Mean blood glucose seemed not to be associated with poor prognosis of COVID‐19.
Keywords: COVID‐19, diabetes, fasting blood glucose, HbA1c
To the Editor:
Diabetes is one of the most common comorbidities in patients with coronavirus disease 2019 (COVID‐19) and a established risk factor of poor prognosis and mortality. 1 , 2 , 3 , 4 Clinical data has established the association between hyperglycemia and the poor prognosis of COVID‐19 in patients with preexisting diabetes. 5 , 6 However, data are still limited on the association of glycosylated hemoglobin (HbA1c) and the prognosis of COVID‐19 and the optimal target of glycemic control, especially during the early stage of hospitalization.
Therefore, we conducted this study to investigate the association of HbA1c and the outcome of COVID‐19 and determine the optimal glucose level during the early stage of their hospitalization among patients with preexisting diabetes, in a cohort of laboratory‐confirmed COVID‐19 patients in China.
1. METHODS
This was a multicenter observational study from “Construction of a bio‐information platform for novel coronavirus pneumonia (COVID‐19) patients follow‐up in Anhui” (ChiCTR2000030331). Data of hospitalized, laboratory‐confirmed COVID‐19 patients were obtained from 21 designated hospitals in 14 cities in Anhui, China, between 22 January to 16 April 2020. Epidemiological and clinical data of these patients were collected from medical records. Severe illness was defined according to the Chinese National guidelines. 7 Fasting blood glucose (FBG) was measured at fasting status in the morning. Postprandial blood glucose (PBG) were measured 2 hours after a meal. This study was approved by the institutional review board of the First Affiliated Hospital of University of Science and Technology of China (2020‐XG[H]‐009). All patients who participated in the study had provided written informed consent.
2. RESULTS
A total of 702 COVID‐19 patients were included in this study. Among them, 51(7.26%) had preexisting diabetes, all of them had type 2 diabetes mellitus (T2D). Compared with patients without diabetes (Table 1), those with diabetes were more likely to progress to severe illness (45.10% vs 8.91%, relative risk [RR] 5.06, 95% confidence interval [CI] 3.43‐7.48) and to be admitted to the intensive care unit (ICU) (31.37% vs 3.99%, RR 7.86, 95% CI 4.52‐13.67).
TABLE 1.
Characteristics and laboratory findings on admission of the 702 COVID‐19 patients
| All patients | Patients with preexisting diabetes | Nondiabetic patients | P value | |
|---|---|---|---|---|
| N | 702 | 51 | 651 | |
| Characteristics | ||||
| Age, years | 42.49 ± 15.50 | 58.40 ± 11.20 | 41.25 ± 15.11 | 0.001 |
| 0‐29, n(%) | 157(22.36) | 1(1.96) | 156(23.96) | 0.001 |
| 30‐50, n(%) | 318(45.30) | 11(21.57) | 307(47.16) | |
| ≥ 50, n (%) | 227(32.34) | 39(76.4) | 188(28.88) | |
| Male sex, n (%) | 384(54.70) | 35(68.63) | 349(53.61) | 0.041 |
| Body mass index, kg/m2 | 23.74 ± 3.79 | 24.18 ± 2.69 | 23.71 ± 3.86 | 0.391 |
| Current smoking, n(%) | 0.028 | |||
| Current smoker | 52(7.41) | 3(5.88) | 49(7.53) | |
| Former smoker | 14(1.99) | 4(7.84) | 10(1.54) | |
| Never smoked | 636(90.60) | 44(86.27) | 592(90.94) | |
| Coexisting disorder, n(%) | ||||
| Hypertension | 83(11.82) | 20(39.22) | 63(9.68) | 0.001 |
| Cardiovascular disease | 18(2.56) | 3(5.88) | 15(2.30) | 0.136 |
| Chronic pulmonary disease | 11(1.57) | 2(3.92) | 9(1.38) | 0.188 |
| Chronic liver disease | 28(3.99) | 4(7.84) | 24(3.69) | 0.017 |
| Chronic renal disease | 5(0.71) | 0 | 5(0.77) | 1.000 |
| Autoimmune disease | 5(0.71) | 1(1.96) | 4(0.61) | 0.315 |
| Symptoms, n(%) | ||||
| Fever | 545(77.64) | 41(80.39) | 504(77.42) | 0.752 |
| Cough | 425(60.54) | 35(68.63) | 390(59.91) | 0.001 |
| Sputum production | 206(29.34) | 15(29.41) | 191(29.34) | 0.016 |
| Fatigue | 112(15.95) | 9(17.65) | 103(15.82) | 0.309 |
| Gastrointestinal symptoms | 53(7.55) | 8(15.69) | 45(6.91) | 0.046 |
| Severity, n(%) a | 0.001 | |||
| Mild | 55(7.83) | 0 | 55(8.45) | |
| Moderate | 566(80.63) | 28(54.90) | 538(82.64) | |
| Severe | 81(11.54) | 23(45.10) | 58(8.91) | |
| Admission to ICU, n(%) | 42(5.98) | 16(31.37) | 26(3.99) | 0.001 |
| Death, n(%) | 1(0.14) | 1(1.96) | 0(0.00) | |
| Time from onset of symptom to hospital admission (days) | 5.89 ± 4.61 | 7.39 ± 6.54 | 5.77 ± 4.41 | 0.018 |
| Time from onset of symptom to outcome (days) | 22.80 ± 7.47 | 26.57 ± 9.35 | 22.51 ± 7.23 | 0.003 |
| Time from hospital admission to outcome (days) | 17.04 ± 6.49 | 18.98 ± 7.44 | 16.89 ± 6.39 | 0.027 |
| SpO2, % | 97.71 ± 1.84 | 96.61 ± 3.76 | 97.80 ± 1.57 | 0.063 |
| SBP, mm Hg | 126.94 ± 14.70 | 131.37 ± 14.93 | 126.59 ± 14.63 | 0.013 |
| DBP, mm Hg | 81.28 ± 11.35 | 81.53 ± 10.11 | 81.26 ± 11.45 | 0.939 |
| Laboratory findings | ||||
| White blood cell count, × 109/L | 5.36 ± 2.35 | 6.06 ± 2.24 | 5.30 ± 2.35 | 0.001 |
| Neutrophil, % | 62.81 ± 14.84 | 67.65 ± 22.37 | 62.43 ± 14.03 | 0.001 |
| Lymphocyte, % | 26.43 ± 11.65 | 17.71 ± 11.07 | 27.12 ± 11.42 | 0.001 |
| <20% (lymphopenia), n (%) | 215(30.63) | 33(64.71) | 182(27.96) | 0.001 |
| Hemoglobin, g/L | 135.06 ± 17.94 | 136.86 ± 16.33 | 134.92 ± 18.07 | 0.555 |
| Platelet count, × 109/L | 187.90 ± 73.96 | 175.88 ± 71.35 | 188.85 ± 74.13 | 0.209 |
| PT, s | 13.15 ± 2.58 | 13.05 ± 2.01 | 13.16 ± 2.62 | 0.935 |
| APTT, s | 34.40 ± 9.77 | 34.29 ± 7.60 | 34.41 ± 9.95 | 0.877 |
| ALT, U/L, median (IQR) | 25.30(15.00,38.00) | 23.70(16.00,30.30) | 26.00(15.00,38.05) | 0.413 |
| AST, U/L, median (IQR) | 25.00(20.00,34.00) | 24.00(20.13,33.50) | 25.00(20.00,34.00) | 0.843 |
| Total bilirubin, μmol/L | 14.22 ± 8.98 | 16.67 ± 9.40 | 14.02 ± 8.93 | 0.023 |
| Creatinine, μmol/L | 64.54 ± 18.24 | 66.05 ± 18.12 | 64.42 ± 18.27 | 0.633 |
| BUN, mmol/L | 4.14 ± 2.05 | 4.76 ± 1.81 | 4.09 ± 2.06 | 0.001 |
| Blood glucose, mmol/L | 6.28 ± 2.20 | 10.11 ± 4.29 | 5.90 ± 1.41 | 0.001 |
| Procalcitonin, ng/mL, median (IQR) | 0.06(0.03,0.11) | 0.10(0.02,0.18) | 0.05(0.03,0.10) | 0.094 |
| C reactive protein, mg/L, median (IQR) | 10.51(2.50,30.10) | 33.75(13.35,77.30) | 9.60(2.10,27.90) | 0.001 |
| CK, U/L, median (IQR) | 59.20(42.00,87.75) | 68.00(48.00,80.70) | 59.00(42.00,88.00) | 0.328 |
| CK‐MB, U/L, median (IQR) | 9.00(3.16,13.00) | 9.05(4.00,16.70) | 9.00(3.00,13.00) | 0.272 |
| IL‐6, pg/ml, median (IQR) | 16.80(5.23,31.05) | 32.95(22.59,56.97) | 13.30(4.93,25.63) | 0.001 |
| Urine protein (+ or ++), n(%) | 53//368(14.40) | 3//22(13.64) | 50//346(14.45) | 0.204 |
| Abnormalities on chest CT, n(%) | 647//702(92.17) | 51//51(100.00) | 596//651(91.55) | 0.026 |
Abbreviations: ALT, alanine aminotransferase; APTT, activated partial thromboplastin time; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CK, creatinine kinase; CK‐MB, creatinine kinase‐MB; DBP, diastolic blood pressure; ICU, intensive care unit; IL‐6, interleukin 6; IQR, interquartile range; PT, prothrombin time; SBP, systolic blood pressure; SpO2, saturation of oxygen.
The data in this section represented the highest severity level assessed of a patient during hospitalization.
To investigate the potential contribution of blood glucose to the progression of COVID‐19, we divided the patients with diabetes, who were all nonsevere upon admission, into the severe group or the nonsevere group according to their final diagnosis. Two patients in the nonsevere group were excluded from analysis because of the unavailability of blood glucose data during hospitalization. We found that upon admission, there was no significant difference in HbA1c (severe vs nonsevere, 7.90 ± 1.73% vs 8.01 ± 1.35%, P = 0.792), suggesting that glycemic control before infection might not be associated with progression to severe illness. Within 1 week of admission, patients who progressed to severe illness had higher FBG (11.37 ± 3.75 mmol/L vs 9.52 ± 3.25 mmol/L, P = 0.001, Figure 1A) and higher 2‐hour PBG (17.16 ± 5.87 mmol/L vs 12.80 ± 4.06 mmol/L, P = 0.002, Figure 1B) compared with patients in the nonsevere group.
FIGURE 1.
Dynamics of fasting blood glucose, mean 2‐hour postprandial blood glucose of coronavirus disease 2019 (COVID‐19) patients with preexisting diabetes. This figure depicts the average values of (A) fasting blood glucose, (B) daily mean 2‐hour postprandial blood glucose of COVID‐19 patients with preexisting diabetes. Red lines represent the patients with preexisting diabetes who progressed to severe illness during admission (n=23), and blue lines represent those with preexisting diabetes who stayed nonsevere (n=26)
Based on these findings, we established RR regression models and found that only mean FBG over the first week of admission ≥10 mmol/L was significantly associated with a higher risk of progression to severe illness (adjusted RR 2.09, 95% CI 1.05 to 4.14), adjusted for age, sex, smoking status, and blood pressure. 2‐hour PBG and mean blood glucose during the first week of admission also did not demonstrate independent association with progression to severe illness at levels ≥7.8 mmol/L, ≥10.0 mmol/L or ≥ 13.4 mmol/L. There was no significant association between HbA1c and progression of COVID‐19, adjusted for potential confounders.
3. COMMENT
In this study, we found that better FBG within the first week of admission was significantly associated with the reduced risk of progression to severe illness. Notably, we found that FBG≥10 mmol/L could serve as an upper limit of FBG control for COVID‐19 patients with diabetes. That might be caused by inflammatory responses following the viral infection, which was also observed in previous studies. 5 Also, hyperglycemia during early admission may directly accelerate the damage or promotes the life cycle of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), so as to propel progression to severe illness. 8 But mean blood glucose seemed not to be associated with poor prognosis. A possible reason may be different food administering pattern between patients of different severity.
Besides, HbA1c upon admission represents the glycemic status prior to SARS‐CoV‐2 infection. A previous report of 132 COVID‐19 patients indicated that HbA1c was associated with systemic inflammation, hypercoagulability, and poor prognosis, but these results are not adjusted for known risk factors of age, sex, or body mass index. 9 But in a multicenter study in France, association between HbA1c and the outcome of tracheal intubation for mechanical ventilation and/or death within 7 days of admission was not observed among COVID‐19 patients with diabetes. 10 In our study, we added the evidence that glycemic control prior to the infection was not associated with increased risk of progression of COVID‐19.
Collectively, hyperglycemia prior to the infection of SARS‐CoV‐2 might not play a significant role, but special attention should be paid to diabetic patients with suboptimal glucose control (≤10.0 mmol/L) during the early stage of hospitalization, especially within the first week.
DISCLOSURE
None declared.
糖尿病是新型冠状病毒性肺炎(COVID‐19)患者最常见的合并症之一, 与疾病进展及死亡率有关。临床数据显示高血糖和已经患有糖尿病的COVID‐19患者的疾病进展有关。但糖化血红蛋白(HbA1c)水平和COVID‐19进展关系不明确, 血糖控制程度, 特别是入院早期血糖控制目标也没有得到充分探讨。
本研究旨在探究COVID‐19合并糖尿病患者的HbA1c和入院后血糖控制对COVID‐19进展的影响。
本研究是一项来自“安徽省新型冠状病毒性肺炎患者随访的生物信息平台建设”的多中心观察性研究(临床注册号:ChiCTR2000030331)。收集从2020年1月22日至4月16日安徽省21家定点医院的702名COVID‐19患者的人口学特征、既往病史、每日病情记录、实验室检查、治疗情况、影像学特征以及临床结局数据。本研究受到了中国科学技术大学附属第一医院伦理委员会的支持[(2020‐XG(H)‐009], 所有纳入研究的患者都提供了知情同意。
研究共纳入702名确诊COVID‐19患者, 51名(7.3%)患者合并糖尿病, 均为2型糖尿病患者。与无糖尿病组的患者相比, COVID‐19合并糖尿病组进展成重症的风险[45.1% vs 8.9%, 相对危险度(RR)5.06, 95% CI 3.43~7.48]和入住重症监护病房的风险 [31.37% vs 3.99%, RR 7.86, 95% CI 4.52~13.67] 均显著增高。
为了探究血糖控制对糖尿病合并COVID‐19患者疾病进展的影响, 我们依据病情进展将糖尿病患者分为重症组和非重症组, 2例糖尿病患者因没有住院期间血糖数据而未纳入分析。重症组和非重症组之间HbA1c没有明显差异(7.90%±1.73% vs 8.01%±1.35%, P=0.792), 提示感染前的血糖控制可能对COVID‐19进展没有影响。但是进展成重症的患者入院一周内的空腹血糖水平[(11.37±3.75)mmol/L vs (9.52±3.25)mmol/L, P=0.001]以及餐后2 h血糖水平[(17.16±5.87)mmol/L vs (12.80±4.06) mmol/L, P=0.002]显著高于非重症组患者。
基于以上发现我们进行了相对风险回归分析, 结果显示校正年龄、性别、吸烟状态和高血压后, 入院一周内的空腹血糖水平≥10 mmol/L, 增加重症风险2.09倍(95% CI 1.05~4.14)。入院一周内餐后2 h血糖以及平均血糖在≥7.8 mmol/L、≥10.0 mmol/L或≥13.4 mmol/L水平均未显示和疾病重症进展独立相关。校正可能的影响因素后, HbA1c和COVID‐19进展也没有显著相关性。
在这个研究中, 我们发现入院一周内较好的空腹血糖与COVID‐19重症风险降低显著相关。值得注意的是, 我们发现空腹血糖10 mmol/ L可以作为COVID‐19糖尿病患者空腹血糖控制的上限。住院早期的高血糖直接加重了疾病对机体的损伤或延长了SARS‐CoV‐2病毒的生命周期, 进而加速了疾病的进展。但是平均血糖似乎和重症疾病进展没有显著关系, 可能是因为患者饮食管理方式不相同。
此外, 入院时的HbA1c代表患者感染SARS‐CoV‐2之前的血糖状态。一项纳入132名COVID‐19患者的研究表明, HbA1c与全身性炎症和高凝状态以及预后不良有关, 但这些结果并未根据年龄、性别或BMI等危险因素进行校正。但法国一项纳入COVID‐19糖尿病患者的多中心研究未观察到HbA1c与入院7天内气管插管导致机械通气和/或死亡的结果之间的相关性。我们的研究进一步表明感染前的血糖控制与COVID‐19进展风险无关。
综上所述, SARS‐CoV‐2感染前的高血糖可能对COVID‐19进展没有显著影响。但在住院初期, 尤其是在入院一周内, 应特别注意严格控制糖尿病患者的血糖在10.0 mmol / L以内, 以减少疾病进展风险。
ACKNOWLEDGEMENT
This study is funded by the Fundamental Research Funds for the Central Universities (Grant number. YD9110004001, YD9110002002, and YD9110002008).
Ling P, Luo S, Zheng X, Cai G, Weng J. Elevated fasting blood glucose within the first week of hospitalization was associated with progression to severe illness of COVID‐19 in patients with preexisting diabetes: A multicenter observational study. Journal of Diabetes. 2021;13:89–93. 10.1111/1753-0407.13121
Ping Ling and Sihui Luo contributed equally to this work.
Funding information Fundamental Research Funds for the Central Universities, Grant/Award Numbers: YD9110002002, YD9110002008, YD9110004001
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