Clinical characteristics, laboratory results of 1331 COVID-19 patients divided into different groups
The characteristics of this study population at baseline are given in Table1.The median age was 54 years old (39-64) and 64 years old (56-70) in the non-diabetes and diabetes groups, respectively. Comorbidities such as hypertension (55.5% vs 21.4%), coronary heart disease (9.9% vs 3.5%), CVD (7.3% vs 2.2%), and CKD (4.7% vs 1.5%) were significantly more prevalent in diabetes group. Systolic blood pressure (SBP) was higher in diabetes group (128mmHg [120-140] vs 124mmHg [119-135]). Moreover, decreased blood oxygen saturation (lower than 93%) occurred more frequently in the diabetes group versus the non-diabetes group (19.8% vs 19.6%) on admission. Chest CT scan revealed that the incidence of bilateral lesions was higher (94% vs 80.1%) in the diabetes group compared to non-diabetes patients.
There were numerous differences of laboratory results between diabetes group and non-diabetes group with COVID-19 (Table2). FBG level was significant higher in the diabetes group compared to the non-diabetes group, as expected (9.1 mmol/L [6.5-11.63] vs 5.57 mmol/L [4.92-6.89]), with higher levels of HbA1c (7.87% [6.27-9.03] vs 5.9% [5.4-6.3]). Diabetic patients had higher white blood cell count (WBC) (5.93 × 109/L [4.49-7.53] vs5.35×109/L [4.1-6.95]), neutrophil count (NEU) (4.25×109/L [3.13-5.37] vs 3.45×109/L [2.46-5.07]), neutrophil lymphocyte ratio (NLR) (3.84 [2.45-6.37] vs 2.79 [1.88-4.93]), C-reaction protein (CRP) (29.84mg/L [5.26-75.66] vs 9.1mg/L [1.42-38.95]), lower lymphocyte count (LY)(1.04×109/L [0.72-1.43] vs 1.17×109/L [0.80-1.61]), compared with non-diabetes group. These results revealed that diabetes represented more severe inflammatory. The percentage of high level in prothrombin time (PT) and D-dimer among diabetes group was higher than that among non-diabetes group. The serum level of albumin (ALB) which was lower in diabetes group (35.7±5.5vs 38.5±5.7) than non-diabetes group. Meanwhile, the Urea nitrogen (BUN), marker of kidney function, was higher in diabetes group (4.68mmol/L [3.60-6.20] vs 3.90 mmol/L [3.10-5.13]. Non-diabetes participants had significantly lower serum level of lactate dehydrogenase (LDH) (201U/L [160-261] vs 229 U/L [180-341]). Compared with the non-diabetes group, the diabetes group had higher levels of total cholesterol (TCH) and lower high-density lipoprotein cholesterol (HDL-C).
In addition, between-group comparison with only diabetes group was performed. The baseline characteristic and radiological finding were also summarized in Table 1. Diabetes patients with comorbidities were the oldest among three groups . There was a significant difference in blood oxygen saturation, respiratory rate and SBP among three groups but no significant differences in the comparison of non-comorbidity group and only diabetes group or the comparison of diabetes only group and diabetes with comorbidities group. Chest CT scan indicated that diabetes only group had more incidences of bilateral lesions than non-comorbidity group.
Although numerous differences of laboratory findings among non-comorbidity group, diabetes only group and diabetes with comorbidities group (Table 2), only ten item had statistical significance between non-comorbidity group and diabetes only group, including ALB (39.3±5.9g/L vs 36.5±6.4),sodium (140 mmol/L [138,141.00] vs 138 mmol/L [136,141]), BUN(3.70 mmol/L[2.96, 4.66] vs 4.30 mmol/L [3.51, 5.07]), CRP (6.11 mg/L[1.0-27.66]) vs 13.2mg/L[3.0-61.47]), HDL-C (1.11±0.42 mmol/L vs0.97±0.26 mmol/L), certainly embraced FBG (5.37 mmol/L [4.83,6.50] vs 9.4 mmol/L [6.48,11.59]) and HbA1c (5.90% [5.44,6.20] vs 7.60% [5.64,8.98]). Such results combined with oxygen saturation indicated that there was no different in cardiac, liver, lung and coagulation function between both groups.
FBG and HbA1c in diabetes only group and diabetes with comorbidities group were almost at the same level. Compared with diabetes only group, diabetes with comorbidities group had lower LY (0.93 ×109/L [0.68-1.33] vs 1.27 ×109/L [0.84-1.73]), higher NLR (4.29 [2.62-7.3] vs 3.15 [2.08-5.06]) and CRP (39.9 [6.60-77.67] vs 13.2 [3.0-61.47]), which represented more severe inflammatory response.
Treatment and outcome of 1331 COVID-19 patients divided into different groups
As shown in Table 3, 1223 of the total 1331 patients (91.9%) were discharged from the hospital, the rate of mortality of diabetes group was higher than non-diabetes group (7.2% vs 13.6%). Kaplan-Meier survival analysis for all-cause mortality in COVID-19 patients is shown in Figure 2. The overall survival rate was significantly lower in the diabetes group (log-rank p< 0.01, Figure 2A).
Compared with non-diabetes group, the incidence of severe cases was more prevalent among the diabetes group (34.6% vs 21.7%). However, there were no significant in ICU admission, length of hospital stay and the duration from admission to ICU between both groups. Diabetes group had higher rate of ARDS (11% vs 5.7%) and hypoproteinemia (15% vs 6.5%). As regard other complications, ACI, AKI, secondary infection, shock, no observable difference was identified between diabetes group and non-diabetes group.
Treatment and primary outcome of non-comorbidity group and diabetes only group were no difference (Table 3), results for all-cause mortality were similar in both groups (log-rank p=0.59) (Figure 2B). As regard the second endpoint, there was no difference between both groups expect hypoproteinemia (5.0% vs 16.9%). Likewise, there was a similar frequency of COVID-19 pharmacological therapy in only diabetes patients versus diabetes with comorbidities patients, however, the latter was more likely to receive mechanical ventilation (10.8% vs 18.3%), had higher incidence of mortality (4.6% vs 18.3%), shock (0 vs 1.6%) and more severe cases (21.5% vs 41.3% ). The overall survival rate was lowest in the diabetes with comorbidities group (log-rank p< 0.0001) (Figure 2B).
Clinical characteristics, laboratory results of diabetic survivors and non-survivors with COVID-19
Diabetic survivors (n=165) and non-survivors(n=26) had a lot in common of basic characteristic except for decreased blood oxygen saturation (10.9% vs 26.9%) and rapid breathing (18.2% vs 26.9%) which were more frequently in non-survivors (Table S2), indicated that the latter had sever lung dysfunction. There were numerous differences of laboratory results between diabetic survivors and non-survivors with COVID-19 that reflected functions of different organs and systems (Table S2). Diabetic non-survivors had higher WBC (7.26×109/L [5.19-13.07] vs 5.91×109/L [4.42-7.29]), NEU (6.22 × 109/L [3.69-11.33] vs 4.09 [3.01-5.13]), NLR (10.43 [5.78-16.84] vs 3.50 [2.33-5.53]), CRP (115.3 [66.11-170.6] vs 25.4 [4.44-63.0]), IL-6 (83.47pg/ml [35.75-243.60] vs 3.09pg/ml [1.50-5.25]), lower LY (0.65 × 109/L [0.56-1.07] vs 1.08×109/L [0.78-1.48]) compare to diabetic survivors, reflecting that mortality patients had severe inflammatory response. Serum levels of PT(14.0s [11.6-15.4] vs 16.2s [13.5-18.9]), D-dimer(0.62mg/L [0.62-1.09] vs 5.40 mg/L [1.50-21.00]), ALT (21.3 U/L [15.3-32.3]vs31.0 U/L [(20.9-46.6]), AST(27.0 U/L[19.0-38.7] vs 43.0 U/L[31.0-60.5]), BUN(4.5 mmol/L [3.59-5.82] vs 6.51 mmol/L[4.92-17.45]), creatinine(64.0 umol/L [44.6-81.0] vs 73.0 umol/L [64.0- 129.6]), CK(61.0 U/L [36.5-111.0] vs 85.0 U/L [71.0-364.0]), LDH(216 U/L [172-219] vs 522 U/L [420-611]), all significantly higher in non-survivors which reflected more severe coagulation, liver, kidney, and cardiac dysfunction. Diabetic non-survivors reported higher average FBG (12mmol/L [9.4-12.81] vs 8.7 mmol/L [6.5-11.36]) compared with survivors.
Treatment and outcome of diabetic survivors and non-survivors with COVID-19
Undoubtedly, higher proportions of occurrence of complications including ARDS (3.0 vs 61.5%), ACI (5.5% vs 26.9%), shock (0 vs 11.5%), secondary infection (6.1% vs 46.2%]), AKI (0.6% vs 7.7%) and coagulopathy (15.8% vs 38.5%) were found in non-survivors (Table 5). Likewise, non-survivors group had greater incidence of severe cases (33.7% vs 100%), ICU admission (6.7% vs 42.3%), and more likely to receive corticosteroid (33.3% vs 73.1%). There was a significantly lower frequency of hypoglycemic medication in diabetic non-survivors vs diabetic survivor, including the usage of metformin(30.9 % vs 11.5%),sulfonylurea(21.8%vs 3.8%) and AGI (45.5% vs 7.7%), which might relate to the blood glucose controlled.
Clinical characteristics, laboratory results, treatment and outcome of diabetic COVID-19 patients using metformin and matched non-metformin user
Of 191 diabetic patients with COVID-19, 54 cases using metformin, after sex, age-matching, there was 50 patients using metformin and sex, age-matched 50 non-metformin user in this part. The frequency of fever (54% versus 78%) and fatigue (38% versus 18%) showed significant differences in clinical characteristics between diabetic COVID-19 patients using metformin and matched non-metformin users (Table S3). Laboratory finding (Table 6) revealed metformin user had lower level of LDH (237 ±115 U/L vs 304±162 U/L) and FBG (10.57±4.92 mmol/L vs 8.32±2.47 mmol/L), however the distribution of glucose was similar. Results which referred liver, kidney, cardiac, coagulation and inflammatory response were not statistically significant. Primary outcome, secondary outcome of patients who using metformin were comparable to matched non-metformin user (Table 7). The former group showed a higher need for antiviral (98% vs 84%), antibiotics (90% vs 74%). Insulin (52.0% vs 20%), sulfonylurea (36.0% vs 2%), AGI (56.0% vs 6%), thiazolidinedione (12% vs 0) were also applied significantly more frequently to the individuals using metformin.
Clinical characteristics, laboratory results, treatment and outcome of diabetic COVID-19 patients using AGI and matched non-AGI user
Of 191 diabetic patients with COVID-19, 77 cases using metformin, after sex, age-matching, there was 46 patients using metformin and sex, age-matched 46 non-metformin user in this part. Table S3 showed that the length about onset of symptom to hospital admission was longer in AGI group when compared with matched non-AGI group, which indicated that the symptoms in former patient might relatively mild.. Noteworthy, parts of inflammation response related laboratory results, such as WBC (4.83×109/L [4.04-6.68] vs 5.91 [4.42-9.35]), NLR(3.25 [2.05-4.41] vs 4.88 [2.50-12.32]), CRP (26.2 [3.7-52.2] vs 63.8[10.8-83.4]) were significant lower in AGI group (Table 6). Furthermore, these differences were not related to glucose control as serum level of both groups was comparable.
The mortality rate (2.2% vs 26.1%) was lower in AGI group (Table 7), and also the rate of ARDS (2.2%vs 17.4%) and shock (2.2% vs 21.7%). At the same time, patients who treated with AGI indicated a lower need treatment for corticosteroids (26.1% vs 47.8%), immunoglobin (23.9% vs 47.8%), mechanical ventilation (6.5% vs 21.7%), and insulin (50.0% vs 84.8%).
Independent risk factors for mortality of patient with COVID-19
Among the included 1131 patients, multivariable Cox regression (Table 8) showed that male sex (hazard ratio [HR] 2.59, 95% CI 1.63-3.99), hypertension (HR 1.75, 95% CI 1.18-2.6), CKD (HR 4.55, 95%CI 2.52-8.20), CVD (HR 2.35, 95%CI 1.27-4.33) were risk factors for the mortality of COVID-19. Age was also the risk factor for mortality of COVID. However, diabetes alone was not the independent risk factor for mortality of patients with COVID-19.