Characteristics and outcomes of COVID‐19 in hospitalized patients with and without diabetes

1. INTRODUCTION

Since December 2019, more than 4 million persons have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and more than 280 000 have been killed by the resulting coronavirus disease 2019 (COVID‐19). Extrapolating these figures to the total number of people with diabetes worldwide (463 million in 2019 ¹ ) gives a conservative global estimate of 230 000 SARS‐CoV‐2 infections and 15 000 deaths due to COVID‐19 in this population. The actual numbers are probably higher because diabetes is generally reported in about 20% (7.4%‐33.8%) of hospitalized patients with COVID‐19. ² , ³ , ⁴ In some studies in China and the USA, diabetes appears to be associated with more severe course of the COVID‐19, ² , ⁵ including poor survival. ⁶ However, people with diabetes have higher prevalence of hypertension and obesity, and a greater burden of cardiovascular disease than non‐diabetic people. Indeed, hypertension and obesity are frequent among COVID‐19 patients (50% and 40%, respectively) ⁷ , ⁸ and are associated with more severe course of COVID‐19. ⁸ , ⁹ , ¹⁰ Cardiovascular disease is also associated with an elevated risk of inpatient death among inpatients with COVID‐19. ¹¹ Therefore, in order to characterize the probably complex associations between diabetes, co‐existing conditions, and COVID‐19, we decided to directly compare people with vs without diabetes within the same general population and same hospital context. In a rather small study from China, a comparison of 137 COVID‐19 patients without diabetes with 37 COVID‐19 patients with diabetes found that the disease was more severe in the diabetic group. ¹² However, the characteristics and outcomes of patients in China might not apply to patients from other countries because of differences in ethnicity, genetic backgrounds, lifestyles and demographics. The goal of the present study was therefore to assess the characteristics and outcomes of consecutive hospitalized patients with COVID‐19 as a function of the presence or absence of diabetes.

2. PATIENTS AND METHODS

3. RESULTS

From the start of the COVID‐19 epidemic until April 21st, 2020, 433 patients were admitted to Amiens University Hospital with COVID‐19. The patients' baseline characteristics are summarized according to the presence or absence of diabetes in Table 1. There were 115 patients with diabetes (26.6%), 317 patients without diabetes; and 1 patient whose diabetes status was unknown. The proportion of males was 63% in the diabetic group and 52% the non‐diabetic group. The mean ± SD age was 72 ± 14.3 years in the diabetic group (median: 72 years) and 70.6 ± 16.4 years in the non‐diabetic group (median: 73 years). Patients with diabetes had a significantly higher body mass index (BMI) than patients without diabetes. Furthermore, patients with diabetes were more likely to have hypertension, hyperlipidaemia, cardiovascular disease and chronic kidney disease and more likely to be treated with ARBs than those without diabetes. On admission, median glycaemia in the diabetic group (8.3 mmoL/L) was higher than in the non‐diabetic group (6.3 mmoL/L; P < .001), and the median GFR was lower (71.5 vs 85 mL/min/1.73 m², respectively; P < 0.001). The two groups did not differ with regard to the other laboratory results (WBC count, lymphocyte count and CRP).

The diabetic group was composed of 111 patients (96.5%) with type 2 diabetes, three patients with type 1 diabetes, and one patient with gestational diabetes. The mean duration of diabetes was 8 ± 9.4 years (median: 5 years) and mean HbA1c level was 7.5% ± 1.67 (median: 7.1%). Metformin was the most widely prescribed antidiabetic medication (used by 71 patients [61.7%]), followed by insulin (33 patients [28.7%]) and dipeptidyl peptidase 4 inhibitors (27 patients [23.5%]). Glinides, sulphonylureas, and glucagon‐like peptide‐1 analogues were employed much less frequently (by 17, 15 and 9 patients, respectively). Forty‐four patients were taking one antidiabetic medication (monotherapy), 32 were taking two medications, 16 were taking three medications, and four patients taking four medications. Lastly, 19 patients were being treated with lifestyle measures alone.

Over the study period, 181 patients met the primary endpoint: 51 in the diabetic group and 129 in the non‐diabetic group (OR [95%CI] for the diabetic group: 1.16 [0.75‐1.79]; P = .50; Table 2 ). A total of 114 patients were admitted to the ICU: 40 in the diabetic group (35.1% of those admitted to the ICU) and 73 in the non‐diabetic group (OR: 1.78 [1.12‐2.83]; P = .015). The diabetic and non‐diabetic groups did not differ with regard to the Simplified Acute Physiology Score on admission to the ICU. The mean age of people admitted to the ICU was 62.2 ± 12.6 (median [IQR]: 63.5 [55‐71]). Overall, 89 patients died: 20 in the diabetic group, 68 in the non‐diabetic group (OR: 0.77 [0.44‐1.32]; P = .36), and the patient whose diabetes status was unknown. Twenty‐one of the deaths (23.6%) occurred in the ICU. Overall, the mean age at death in hospital was 80.5 ± 10.9 (median [IQR]: 83 [73‐88]), which was considerably greater than the value for patients admitted to the ICU. Other outcomes are presented in Table 2. Patients with diabetes had higher risk of developing ARDS and acute renal injury, whereas the groups did not differ in terms of the incidence of cardiac injury and a documented secondary infection. The mean length of stay was 17.1 ± 11.7 days in the diabetic group and 13.5 ± 9.1 days in the non‐diabetic group. As of May 1, 2020, 30 non‐diabetic patients and 17 diabetic patients were still hospitalized.

Diabetes was not associated with the primary outcome in the non‐adjusted analysis or in the multivariable logistic regression analysis (OR [95%CI]: 1.12 [0.66‐1.90]; P = .67). Variables that were significant in the parsimonious model are shown in Figure 1. It should be noted that the removal of obesity from the parsimonious model did not modify the results significantly (Figure S1).

Diabetes was associated with ICU admission in the non‐adjusted analysis (OR [95%CI]: 1.78 [1.12‐2.83]; P = .015) and remained a significant factor in the multivariable model (OR [95%CI]: 2.06 [1.09‐3.92]; P = .027; Figure 2).

Diabetes was not associated with death in the non‐adjusted analysis or in the multivariable Cox model (HR [95%CI]: 0.73 [0.40‐1.34]; P = .32). Variables that remained significant in the final model are shown in Figure 3, and survival curves from the multivariable model (stratified by the presence/absence of diabetes) are shown in Figure S2. It is noteworthy that glycaemia on admission did not emerge as a significant outcome predictor in any of the multivariable models. Moreover, none of the antidiabetic medications was significantly associated with the primary endpoint in the univariable analysis (Table S1).

4. DISCUSSION

The main findings of our study are as follows. Firstly, diabetes was present in 26.6% of patients hospitalized with COVID‐19; this proportion is considerably higher than the prevalence of diabetes in Amiens University Hospital's referral area (5.53% in 2013 and ≈6% in 2016). Secondly, COVID‐19 with diabetes was significantly associated with a greater likelihood of admission to the ICU (relative to COVID‐19 without diabetes) but was not associated with increased mortality. Thirdly, COVID‐19 with diabetes was also associated with a higher risk of developing ARDS and acute renal injury, relative to COVID‐19 without diabetes. Lastly, the median length of stay was longer in COVID‐19 patients with diabetes than in COVID‐19 patients without diabetes.

Most cases of COVID‐19 are mildly symptomatic or even asymptomatic. As such, these cases may not be detected or are managed by a general practitioner or in an outpatient setting. However, pneumonia and severe symptoms occur in about 15% of cases of COVID‐19. ¹⁵ Patients with severe COVID‐19 are usually admitted to hospital for monitoring and treatment. Diabetes is one of the most common comorbidities in patients hospitalized with COVID‐19, since most large studies have reported that diabetes is present in 19% to 34% of this patient population. ⁴ , ⁶ Our results are in line with the literature data because the proportion of hospitalized COVID‐19 patients with diabetes in our cohort was significantly greater than the prevalence of diabetes in the local population. Another 5% of COVID‐19 patients develop critical disease with respiratory failure and/or multiple organ dysfunction. These patients typically require admission to the ICU. Our results confirm that diabetes is a common comorbidity among COVID‐19 patients admitted to the ICU (a third of all ICU admissions in our cohort). In a large study in the Lombardy region of Italy, diabetes was present in 17% of patients admitted to the ICU. ⁷ Interestingly, data on 7162 COVID‐19 patients from the United States showed that diabetes was present in 6% of non‐hospitalized patients, 24% of hospitalized patients, and 32% of those admitted to the ICU. ⁸

Our results show that diabetes is significantly associated with ICU admission and the development of ARDS and acute renal injury. At the time of ICU admission, diabetic and non‐diabetic patients had a similar Simplified Acute Physiology Score II; this suggests that the COVID‐19 was not more severe in the diabetic group and does not support the application of a lower threshold for ICU referral among diabetic patients. Indeed, type 2 diabetes is associated with obesity, insulin resistance, and low grade inflammation; these factors may result in immune dysregulation and more severe COVID‐19. In one study, mice were made susceptible to Middle East respiratory syndrome coronavirus (via the expression of human dipeptidyl peptidase‐4) and given a high fat diet to induce diabetes. The mice showed delayed but prolonged, severe inflammation of the lungs upon infection. ¹⁶ It remains to be seen whether these observations are of relevance to COVID‐19. Interestingly, people with diabetes have elevated urine levels of ACE 2, the SARS‐CoV‐2's co‐receptor for cell entry. ¹⁷

The relationship between diabetes and our present study endpoints was independent of obesity (as a categorical variable) and BMI (as a continuous variable). Indeed, obesity is one of the main underlying conditions in patients with COVID‐19, and is associated with an elevated risk of hospital admission ¹⁸ and with worse inpatient outcomes ¹⁹ (eg, invasive mechanical ventilation ⁹ and mortality ²⁰ ). The mechanisms responsible for the poor prognosis in obese people with COVID‐19 include obesity‐related respiratory dysfunction, low‐grade systemic inflammation, and complement system hyperactivation. Moreover, it has been suggested that adipose tissue accumulation within the lungs has a detrimental local effect. ²¹

Our most striking finding is that diabetes was not associated with greater risk of in‐patient death, despite a longer hospital stay. In a small study from China, diabetes was associated with an increased risk of death in a univariable analysis (OR [95%CI]: 2.85 [1.35‐6.05]; P = .0062) but was not selected for multivariable analysis. ⁶ Notably, the patients' median age was 56 years in the Chinese study and 72 in the present study. Furthermore, a recent meta‐analysis and systematic review found that diabetes was associated with an elevated relative risk (RR) [95%CI] of death (2.12 [1.44‐3.11]). The review's authors suggested that the RR was lower in studies with a median age ≥ 55 years than in studies with a median age < 55. ²² It is therefore possible that the RR of death in patients with COVID‐19 and diabetes falls with age ‐ a phenomenon that is also encountered for diabetes‐related cardiovascular disease, cardiovascular death, ²³ and overall mortality. ²⁴ In our cohort, patients who died were considerably older than those admitted to the ICU; this suggests that younger patients with co‐existing diseases (including diabetes) were more frequently referred to the ICU, whereas elder patients were not. This is supported by the fact that more than 75% of deaths in our study (regardless of diabetes status) occurred outside the ICU. In our multivariable analyses, age was positively associated with death but negatively associated with ICU admission.

The main strength of our study relates to its inclusive nature: the inclusion of consecutive patients gave us a true, precise picture of COVID‐19 in our region. The fact that the study was undertaken in only one tertiary hospital is also a strength because the criteria for admission to the hospital in general and to the ICU in particular were relatively homogenous. Furthermore, the diabetic group was relatively homogenous, as almost all of the patients had type 2 diabetes.

Our study had the limitations inherently associated with observational studies. Firstly, causality cannot be inferred from an association between variables, and the absence of a statistically significantly association does not rule out clinical relevance. Secondly, there were some missing data for important variables, such as BMI and smoking status. Other measures of adiposity (such as waist circumference and neck circumference) were not available. In a recent multicentre study performed in Italy, neck circumference was significantly associated with the need for invasive mechanical ventilation in COVID‐19 patients. ²⁵ Thirdly, and despite our adjustment for a large number of variables, residual confounding cannot be ruled out. Lastly, the observational design prevented us from prespecifying the statistical power, and so our results should be considered as being indicative only.

In conclusion, our observational study of all consecutive patients hospitalized with COVID‐19 in a tertiary referral centre found that diabetes was present in a quarter of admissions and was associated with a greater risk of ICU admission and a longer length of stay but not with mortality (relative to non‐diabetic patients). Further investigations of the relationship between COVID‐19 and diabetes are now warranted, with a focus on (i) the RR of death in COVID‐19 patients with vs without diabetes and (ii) the interaction between age and/or diabetes duration on one hand and COVID‐19 mortality and other outcomes on the other.

CONFLICT OF INTEREST

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

AUTHOR CONTRIBUTIONS

Abdallah Al‐Salameh and Jean‐Daniel Lalau designed the study and drafted the manuscript which was revised and then approved by all authors; Abdallah Al‐Salameh and Jean‐Daniel Lalau had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Analysis and interpretation of data: Abdallah Al‐Salameh, Benoit Vaysse, Rachel Desailloud, Olivier Ganry, Jean‐Daniel Lalau. Patient recruitment: Jean‐Philippe Lanoix, Youssef Bennis, Claire Andrejak, Etienne Brochot, Guillaume Deschasse, Hervé Dupont, Vincent Goeb, Maité Jaureguy, Sylvie Lion, Julien Maizel, Julien Moyet, Benoit Vaysse, Rachel Desailloud, Olivier Ganry, and Jean‐Luc Schmit.

Supporting information

Al‐Salameh A, Lanoix J‐P, Bennis Y, et al. Characteristics and outcomes of COVID‐19 in hospitalized patients with and without diabetes. Diabetes Metab Res Rev. 2021;37:e3388. 10.1002/dmrr.3388