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Covid-19 ve Diyabet: Antidiyabetik İlaçlar ile Fark Var COVID-19 and Diabetes Mellitus: Are there any Differences in Outcomes with Anti-Diabetic Drugs?

Aim: This study aims to analyze the effect of diabetes and diabetes drugs on the outcome of COVID-19 patients. Material and Methods: All the patients with diabetes hospitalized for COVID-19 between March 15, 2020 and June 15, 2020 at Istanbul University Faculty of Medicine were screened. Outcomes of the patients were compared with patients without diabetes. Results: Among six hundred fourteen patients (59.8% male, n=367) there were 151 patients with diabetes (24.5%). Patients with diabetes were hospitalized longer than patients without (12.1±10.3 vs. 10.2±7.3, p=0.037 in days), had higher intensive care unit (ICU) hospitalization rate (20.5% (n=31) vs. 12.0% (n=56), p=0.016, OR:1.8 (1.1-2.9)) and mortality rate (15.8% (n=24) vs. 7.7% (n=36, p=0.007), OR:2.1(1.2-3.8)). There was no difference in admission to ICU between patients who use metformin, basal insulin or bolus insulin regarding admission to ICU compared to patients who don’t (p= 0.32, p=0.22 and p=0.64, respectively). No patient on sodium-glucose co-transporter-2 treatment was treated in ICU. Death rate didn’t differ between patients regarding their treatment modalities. Conclusion: Patients with diabetes had worse outcomes than non-diabetic patients, and according to our findings and no anti-diabetic drug has a beneficial or harmful effect.


INTRODUCTION
Novel coronavirus disease 2019 (COVID- 19) has caused a global pandemic and affected millions of people worldwide (1). Patients with advanced age, co-morbidities and immunosuppression are reported to be at greater risk of morbidity and mortality (2,3). Whether diabetes poses a higher risk for disease progression, hospitalization and death is still at question.
Various reports have shown an increased risk of death from diabetes for COVID-19 patients. Guan et al. reported that there were more patients with diabetes in their cohorts who experienced serious illness than the normal population (4). Guo et al. has shown increased inflammatory response in patients with COVID-19 and diabetes compared to patients without (5). Guo et al. has reported increased mortality among patients with diabetes compared to patients with other co-morbidities (6).
As the first line pharmacologic treatment of diabetes, metformin is under investigation for its effects on COVID-19 patients (7,8). Insulin and other drug classes are tested for their impact on the outcome of COVID-19 patients. This study aims to analyze the effect of diabetes and diabetes drugs on outcome of COVID-19 patients.

Ethics
Approval for the study was obtained from both Turkish Ministry of Health (2020-05-14T12_59_48) and -blinded for peer review Faculty of Medicine Ethics Committee (rule number: 08/06/2020-91658). Rules of Helsinki Declaration were followed through the study.

Subjects
All the patients hospitalized for COVID-19 between March 15, 2020 and June 15, 2020 at -blinded for peer review Faculty of Medicine were screened. Patients demographic characteristics were recorded from their medical records and patient history in their files. Patients were excluded if they were younger than 18 years. Patient files were screened for (1) diabetes drugs patients used until the hospitalization (drug changes necessary during the hospitalization were not included to the analysis), (2) hospitalization outcomes (discharge, intensive care unit (ICU), death etc.). Outcomes were compared with patients without diabetes (control group). Patients' admission laboratory data were compared regarding their diabetes status.

Statistical Analysis
Statistical analysis was performed using the SPSS software version 16. Normality of the variables were tested using visual (histogram) and analytic methods (Kolmogorov-Smirnov/Shapiro-Wilk's test).. Kruskal-Wallis and Mann-Whitney U tests were conducted to compare parameters among groups. Pearson and Spearman correlation methods were used to test correlations. Chi square test was used to determine an association between two categorical values. And correlation of a nominal and a categorical data were analyzed with the Eta value. An overall 5% type-I error level was used to infer statistical significance.

RESULTS
Six hundred fourteen patients (59.8% male, n=367) were included. There were 151 patients with diabetes (24.5%). Patients with diabetes were significantly older than patients without (63.2±12.5 vs. 55.4±15.9, p<0,001 in years) ( There was no difference in admission to ICU between patients who use metformin and patients who don't (p=0.32), (Table 3). No difference was observed between patients who use basal insulin or bolus insulin regarding admission to ICU compared to patients who don't use these agents (p=0.22 and p=0.64, respectively). No patient on SGLT-2 inhibitor treatment (12 patients were on SGLT-2 inhibitor treatment) was treated in ICU. Death rate didn't differ between patients who use metformin, basal insulin, bolus insulin, pioglitazone, sulfonylureas, DPP-4 inhibitors and SGLT-2 inhibitors (Table 3).

DISCUSSION
This study reports that death and ICU admission rate of patients with diabetes were significantly higher than patients without diabetes in a university hospital.
Outcomes of COVID-19 patients with diabetes differ significantly according to region, country, ethnicity and available treatments. A cohort from a New York Hospital reports (9) death rate as 10.2%, whereas another report from USA with a cohort from different states (10) has higher death rate as 28%. In a report from Italy this rate is as high as 48% (11). Their cohort was relatively older than our patients. Our death rate is 15,8% among patients with diabetes and it's almost twice the rate of patients without diabetes. A meta-analysis with 83 studies has revealed twofold increase in severe/clinical illness (12) compatible with our results and our OR.
Also, because our cohort is from a tertiary university hospital where our control patients (patients without diabetes) had other morbid disorders such malignancies, chronic kidney disease etc., these results can be interpreted as an understatement of the real risk. Holman et al. showed increased mortality rate with HbA1c levels > 7.6% compared to levels lesser (13). In our study mean HbA1c was 7,2%. This could have also affected our results.
Patients on metformin did not have different mortality or morbidity rate compared to patients without this treatment. Role of metformin on COVID-19 related morbidities is not clear yet. There are reports of improved outcomes with metformin as well as without significant difference (14). SGLT-2 inhibitors are also among drugs which are under attention. Dalan et al. reported lower risk of mechanical ventilation with SGLT-2 inhibitors (15). Whether this beneficial effect is the result of cardiovascular protection obtained with these agents or an unknown pleiotropic effect, is the question of a larger randomized trial. There is an ongoing clinical trial to investigate the effects of dapagliflozin in COVID-19 which can hopefully address these inquiries and calculate euglycemic ketoacidosis risk with these agents can bring to COVID-19 infection. In our study patients on SGLT-inhibitors had relatively lower rate of ICU admission and mortality, however this difference didn't reach statistical significance due to small sample size.
In our cohort insulin use was not associated with better or worse outcomes. Yu et al. has reported that insulin use was associated with enhanced inflammation (16). Riahi et al. has reported that insulin therapy increased mortality risk in both inpatients and outpatients (17). These findings are not unexpected due to the conditions in which insulin is used. Patients on insulin are often patients with poor glycemic control and/or patients with advanced age and diabetes duration in need for insulin therapy.
DPP-4 inhibitors had no effect on mortality or ICU admission. Our cohort had relatively small number of   (18). From real life data, Strollo et al. has reported no difference with DPP-4 inhibitors in prevention or progression of COVID-19 (19).
Limitations of our trial include observational nature of the study. Also, our results are from a tertiary unit, therefore our results may not be reflecting general population. Our analysis includes drugs used in preadmission, thus any changes of diabetes drugs during COVID-19 therapy is no reflected in our report.
As a result, diabetic patients had worse outcomes than nondiabetic patients, and according to our findings and no antidiabetic drug has a beneficial or harmful effect.