Saudi Scientific Diabetes Society Position Statement: Management of Diabetes Mellitus in the Pandemic of COVID-19

About 10% coronavirus (COVID-19) infected patients are with diabetes comorbidity. Also, diabetes promotes severe progression in COVID-19 patients. Diabetes comorbidity is associated with significant mortality in those people with COVID-19. In this position statement, the management of diabetes in cases of COVID-19, has been presented. The impact of diabetes on the morbidity and mortality of COVID-19, as well as both the target glucose level and the method of blood glucose control have been presented in details.


Introduction
During our current era, the pandemic of coronavirus disease 2019 (COVID-19) has drawn the attention of every one all over the globe. In April 6 th 2020, globally, according to the World Health Organization (WHO), CoVID-19 affected 1,210,956 confirmed cases with 67,594 deaths, with its unprecedented challenges to the global public health system [1]. This pandemic has disrupted the flow of everyday life as we know it. Healthcare systems started to experience some failure which led to reallocation of its resource in a new setting because of this crisis with a great difficulties for both healthcare personals and patients. Of course, people with comorbid diseases like diabetes mellitus are at a great risk for the hazardous consequences of this pandemic. Thus, the Saudi Society of Diabetes How to cite this paper: Alshaikh, A., Alsifri, S., Alhozali, A., Mosli, H., Zawawi, T., Mira, S. and Issak, E.R. (2020) Saudi Scientific Diabetes Society Position Statement: Management of Diabetes Mellitus in the Pandemic of COVID-19. International Journal of Clinical Medicine, 11, 199-206. https://doi.org/10.4236/ijcm.2020.115020 would like to provide its recommendations for the clinical care of diabetes during this COVID-19 pandemic.

Diabetes Mellitus and COVID-19 Morbidity and Mortality
Diabetes promotes severe progression in COVID-19 patients, the presence of coexisting diabetes was more common among COVID-19 patients with severe disease than among those with non-severe disease (16.2% vs. 5.7%), (Figure 1). Data was extracted regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in China through January 29 th , 2020 [2]. Another nationwide analysis of comorbidity and its impact on 1,590 patients with COVID-19 in China, also, revealed thatCOVID-19 patients with diabetes had a worse prognosis ( Figure 2) [3].
Diabetes is considered as a risk factor for mortality in cases with COVID-19. A large national study showed that the mortality of patients with diabetes was significantly higher than that of non-diabetic patients, (10% vs 2.5% P <0.001) [3]. In addition, WHO Joint Mission claimed that patients who reported no comorbid conditions had a CFR of 1.4%, patients with comorbid conditions had  much higher rates-9.2% for diabetes [4]. Also, Chinese CDC declared that patients who reported no comorbid conditions had a case fatality rate (CFR) of 0.9%, while patients with comorbid conditions had much higher rates-7.3% for diabetes [5]. A research about clinical characteristics of 82 death cases with COVID-19 found that diabetic ketoacidosis is one of the causes of mortality [6].

How Does Diabetes Accentuate COVID-19 Morbidity?
High level IL-6, TNF-α and other inflammatory cytokines are expressed in the serum of individuals with diabetes [7]. Moreover, animal models suggested that diabetes significantly promoted the production of TLR4-induced IL-6 [8]. Also, studies have shown that coronavirus, including SARS, is highly likely to activate TLR3 and TLR4, leading to a runaway immune response [8], which in turn leads to Il-6-dominated cytokine storms, which have also been shown to be one of the leading causes of death from coronavirus pneumonia [9]. In addition, IL-6 were associated with death of COVID-19 patients, univariate regression showed increasing odds of in-hospital death associated with IL-6 (odds ratio 1.12, 95% CI 1.03 -1.23, Per 1 unit increase; p = 0.0080) [10]. Therefore, it can be speculated that over activation of TLR4 signaling ( Figure 3) in individuals with diabetes may contribute to the progression of the severity of the disease and even mortality.
Moreover, patients with diabetes may have bad glycemic control after viral Figure 3. The potential mechanism of high severe/died risk in diabetic patients [10].
infection. It was suggested that SARS-CoV may cause pancreatic islets pathology because of the expression of angiotensin converting enzyme 2 (ACE2), the functional receptor of SARS-CoV, in the exocrine and endocrine tissues of the pancreas [11]. In addition, a recent study in China have found that SARS-CoV-2 is able to efficiently use human ACE2 as a receptor for cellular entry, which could potentially facilitate human-to-human transmission [12].

Glucose Level Fluctuation in Patients with COVID-19
Glucose level is fluctuating in patients with diabetes and COVID-19 because of irregular diet, reduced exercise, increased glucocorticoids secretion due to stress, the use of glucocorticoids in treatment, the interruption or non-standard treatment with oral antidiabetic drugs (OAD) in isolation wards. Also, COVID-19 can cause human body to produce a large number of inflammatory cytokines and lead to extreme stress in some severe and critical patients [13].

Glycemia Target in Patients with COVID-19
Stratification of cases with COVID-19 according to severity is the first step for better glucose management. For mild and moderate non-elderly COVID-19 patients, stick with strict high control target (Table 1). For mild and moderate elderly patients, or patients who have been using glucocorticoid, set up a low or strict control target. For severe and critical patients, elderly patients, hypoglycemia intolerable patients, or patients who have organ dysfunction or serious cardiovascular and cerebrovascular diseases, set up a low control target (Table 1). Also, hypoglycemia occurrence should be minimized during glucose management in diabetes patients with COVID-19. Medical care should be performed in time if hypoglycemia occurs [13].

Therapeutic Principle of Glucose Management in Patients with COVID-19
Insulin treatment is the first choice if diabetes combined with severe infection. For non-critical patients, insulin sc. injection is recommended, and basic dosage can refer to the out-of-hospital dosage. For critical patients, CSII is recommended. In case of serious glucose metabolism disorder with water and electrolyte and acid-base disorders, IV insulin treatment should be started, in combination with aggressive fluid infusion. If the clinical condition is stable and eating pattern is regular, patients can continue OAD treatment as before admission. Using NPH and long-acting insulin is recommended during glucocorticoid treatment to control the glucose level. Also, measure 7 point glucose (if necessary, plus nocturnal glucose) during insulin treatment [13]. Antidiabetic drugs and their use are shown in Table 2.

Management Plan of Diabetes in Patients with COVID-19 according to Disease Severity
Severity of COVID-19 can be based on the clinical classification released by the National Health Commission of China as shown in Table 3 [14].

1) Mild cases
There is no need to adjust the original regime too much. Both OAD and insulin treatment can be maintained. The progress of COVID-19 can be rapidly,  and can be worsen with hyperglycemia, thus, it is strongly recommend to increase the frequency of glucose monitoring, and consult with physicians to adjust treatment regime whenever needed even in diabetes patients with mild COVID-19.

2) Moderate cases
Original treatment regime is to be maintainedif patient's cognitive condition, appetite and glucose control are within normal range. In patients with obvious COVID-19 symptoms who cannot eat regularly, OAD is to be switched to insulin. Premix insulin regime is to be switched to basal-bolus regime or insulin pump for better flexibility of glucose management.
3) Severe and critical cases Intravenous insulin injection should be the first-line treatment. For patients who are in process of continuous renal replacement therapy (CRRT), the proportion of glucose and insulin in the replacement solution should be increased or decreased according to glucose monitoring result to avoid hypoglycemia and severe glucose fluctuations.

Management Plan of for Different Types of Diabetes in Patients with COVID-19
1) Type 1DM Insulin pump or basal plus bolus insulin treatment is the optimal regimen. Insulin analogues are recommended as first choice. Insulin treatment regimenis to be individualized according to individual's profile.
2) Type 2DM For mild COVID-19 patients with low-moderate glucose increase, non-insulin diabetes drugs can be used. For patients with fever or treated by glucocorticoid, insulin treatment is the first choice. For critical patients, insulin IV injection is recommended.
3) Glucocorticoid-associated diabetes Glucocorticoids-induced glucose increase often occurs between after-lunch and before-sleep. Therefore, it is important to monitor blood glucose after lunch and before dinner. Insulinisthe first choice.

Glucose Management of COVID-19 and Diabetes Treated with Glucocorticoids
Effect of glucocorticoids in COVID-19 is uncertain. However, some centers reported that glucocorticoids can be used in critical patients, or patients with fever and sporadic lesion in lungs, to reduce inflammatory lung injury. Thus, special consideration should be taken in management of glucose level in those cases [13].

Recommendations
• Because of the more fluctuations of blood glucose level, strengthened dynamic glucose monitoring is necessary. • As disease conditions of COVID-19 and diabetes can change rapidly, it is recommend to apply insulin therapy as soon as possible according to glucose level, and actively adjust treatment regime, to control glucose to a relatively ideal level.
• Insulin IV injection should be the first-line treatment in severe and critical patients.
• For fasting patients, the suggested ratio of glucose to insulin in IV infusion fluid is 2 -4 G glucose: 1U insulin.
• Too much and too long course of glucocorticoid treatment are main risk factor for glucose deterioration.
• When gradually reduce glucocorticoid treatment, we should also pay attention to glucose fluctuation, and adjust insulin dosage according to glucose level.
• In principle, it is recommended to measure blood glucose 7 times a day.