Since the last article in this series appeared, the number of cases of Coronavirus Disease 2019 (COVID-19) have risen exponentially, with the latest total at 6.3 million¹. Studies have shown that advanced age, as well as comorbidities such as diabetes and hypertension, are significant risk factors for increased mortality in patients infected with COVID-19. However, there is a lack of data regarding the effect of glycemic levels on the prognosis of inpatients admitted for treatment of COVID-19^2,3. Hyperglycemia in inpatients is defined as a blood glucose level of > 140 mg/dl (7.8 mmol/L); moreover, studies conducted before the COVID-19 pandemic found that in patients with or without pre-existing diabetes, inpatient hyperglycemia is associated with increased risk of morbidity (including infection), mortality, and prolonged hospital stay^4,5. Additionally, those with newly diagnosed hyperglycemia were also found to have higher rates of both admission to intensive care and dependence on assisted care after discharge from hospital, as well as in-hospital mortality ⁶.

       Recent retrospective studies in the United States and China that looked at inpatient glycemic levels and patient outcomes for those admitted for COVID-19, have reported poorer outcomes in those with higher glucose levels. The first study published on this subject, by Bode et al, included a total of 1,122 patients in 88 hospitals in the United States; 451 patients with either diabetes or uncontrolled hyperglycemia had a mean blood glucose of more than 180 mg/dl (10mmol/L) over an average period of 37.8% patient days. Among 570 patients who died or were discharged, the mortality rate was 28.8% in patients with diabetes and/or uncontrolled hyperglycemia (n=184), compared with 6.2% mortality in patients without diabetes or hyperglycemia (n=386) (P < 0.001). Median length of stay was longer in patients with diabetes and/or uncontrolled hyperglycemia in comparison to those without these diagnoses (5.7 vs 4.3 days, P <0 .001). A subgroup analysis found that patients with uncontrolled hyperglycemia (but not diabetes) had an increased rate of mortality compared to those with pre-existing diabetes (41.7% vs 14.8%, P <0.001)⁷.

       In China, Zhu and colleagues studied 7,337 patients hospitalized for COVID-19. The prevalence of diabetes in this group was 13% and those with diabetes were almost a decade older than those without this disease, with a median age of 62 (55-68) years. In addition, patients with diabetes required more intensive in-hospital treatment and had a significantly higher in-hospital death rate (7.8% versus 2.7%, P < 0.001). The cohort of patients with diabetes were further divided into two groups, those with well controlled diabetes (glycemic variability between 70-180 mg/dl [3.9-10.0 mmol/L]) and poorly controlled disease (upper limit of glycemic variability >180mg/dl). In-hospital death rate was lower in the well-controlled group relative to the poorly controlled group (1.1% versus 11.0%, P<0.001) and complications, such as acute respiratory distress syndrome, septic shock, acute kidney injury and heart failure were lower⁸.

       In addition to learning more about who is most at risk during this pandemic, health care staff who are managing hyperglycemic emergencies such as diabetes ketoacidosis (DKA) and hyperosmolar hyperglycemic states are facing additional challenges. Personal protective equipment needs to be used rationally in hospitals facing shortages and the duration of staff exposure to patients needs to be considered. Insulin protocols using subcutaneous insulin instead of intravenous regimens have been proposed for management of mild DKA, with certain caveats for hospitals facing limitations of equipment such as infusion pumps⁹. The use of subcutaneous insulin is not a new concept, with studies reporting the use of short-acting analogue insulin as a safe and effective alternative in those with uncomplicated DKA^10,11. Continuous glucose monitoring devices have also emerged as a useful tool since they enable remote monitoring and therefore reduce health care workers’ exposure time to infected patients without compromising their care.

       A target glucose range between 140-180 mg/dl (7.8-10.0mmol/L) has been recommended for patients in the critical and non-critical care setting, as a tighter target has been associated with increased mortality¹². Insulin is often utilized to achieve this as glycemic control can be obtained more rapidly and dosing can be adjusted according to patient’s calorie intake and general condition. In addition, there are fewer limitations for use of insulin injections in acute illness than there are for use of oral agents; biguanides, for example, must be withheld from patients with renal insufficiency or those requiring imaging studies with contrast. However, because hypoglycemia is a potential and serious complication of insulin therapy, vigilant monitoring for this condition is essential.

       The use of dipeptidyl peptidase-IV (DPP4) inhibitors have been explored for inpatient use as the actions of these agents are glucose dependent and therefore prevent hypoglycemia. Pooled data from randomized controlled trials comparing the use of DPP4 inhibitors as monotherapy or in combination with a basal insulin, found that both regimens were comparable to basal bolus insulin in achieving blood glucose targets with a lower incidence of hypoglycemia¹³.

       Diabetes and hyperglycemia are associated with poorer outcomes in patients hospitalized for COVID-19. Therefore, it is important to keep glycemic goals in mind while managing this population and to use available technologies and medications to safely achieve those levels.

References:

1. Worldometer. COVID-19 Coronavirus Pandemic. https://www.worldometers.info/coronavirus/. Updated 2 June, 2020. Accessed 2 June, 2020.

2. Zhao X, Zhang B, Li P, et al. Incidence, clinical characteristics and prognostic factor of patients with COVID-19: a systematic review and meta-analysis. medRxiv. 2020. Accessed 28 May, 2020.

3. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The Lancet. March 11, 2020.

4. American Diabetes Association. 15. Diabetes care in the hospital: standards of medical care in diabetes—2019. Diab Care. 2019;42(Supplement 1):S173-81.

5. Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: An independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87(3):978-982.

6. Evans NR, Dhatariya KK. Assessing the relationship between admission glucose levels, subsequent length of hospital stay, readmission and mortality. Clin Med(Lond) 2012;12(2):137-139.

7. Bode B, Garrett V, Messler J, et al. Glycemic characteristics and clinical outcomes of COVID-19 patients hospitalized in the United States. J Diabetes Sci Technol. 2020:May 9;1932296820924469.

8. Zhu L, She ZG, Cheng X, et al. Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing Type 2 diabetes. Cell Metab. 2020;S1550-4131(20)30238-2.

9. Diabetes UK. COncise adVice on Inpatient Diabetes (COVID:Diabetes): FRONT DOOR GUIDANCE. https://abcd.care/sites/abcd.care/files/site_uploads/COvID_Front_Door_v2.0.pdf. April 20, 2020. Accessed May 14, 2020.

10. Umpierrez GE, Cuervo R, Karabell A, et al. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. Diab Care. 2004;27(8):1873-8.

11. Vincent M, Nobécourt E. Treatment of diabetic ketoacidosis with subcutaneous insulin lispro: a review of the current evidence from clinical studies. Diabetes Metab. 2013;39(4):299-305.

12. NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360:1283-97.

13. Lorenzo-González C, Atienza-Sánchez E, Reyes-Umpierrez D, et al.  Safety and efficacy of DDP4-inhibitors for management of hospitalized general medicine and surgery patients with type 2 diabetes. Endocr Pract. 2020;April 27.