Abstract Body

Overall Diabetes Morbidity and Mortality with COVID-19

Viral N. Shah, MD

Associate Professor, Barbara Davis Center for Diabetes, University of Colorado Denver

On December 12, 2019, a pneumonia cluster of unknown causes was identified in Wuhan in the Hubei province of China. Later on, it was confirmed to be caused by novel coronavirus (COVID-19) probably linked to seafood wholesale market in Wuhan. Within three months of the first case in Wuhan, many countries reported cases of COVID-19.

There has been a large amount of publications since the first case of COVID-19 in December 2019. Per a PubMed search (using the search strategy COVID-19 [tiab]), in the year 2020 alone there were 79,593 publications related to COVID-19. Earlier publications from China and other countries reported a higher frequency of diabetes patients in the hospital setting. Earlier studies reported a two- to three-fold increased risk for severe disease and mortality in patients with diabetes compared to non-diabetic patients. This higher mortality among patients with diabetes was confirmed across different geographic locations, cross-sectional studies, as well as cohort or nationwide studies. Moreover, diabetes was associated with a higher risk for hospitalization, longer hospital stays, and ICU admissions.

The majority of earlier studies reported an association between diabetes and COVID-19 morbidity and mortality without specifying diabetes type. A large population-based study from the United Kingdom, mortality in patients with type 1 diabetes was three-fold higher (OR 3.51; 95% CI 3.16-3.90) and in patients with type 2 diabetes was two-fold higher (OR 2.03; 95% CI 1.97-2.09) compared to the general population. This suggested a higher mortality among patients with type 1 diabetes compared to type 2 diabetes. However, another population-based study from Sweden reported a two-fold increased but similar mortality between patients with type 1 diabetes and type 2 diabetes. Similarly, studies from the United States reported similar outcomes in patients with type 1 and type 2 diabetes.

The published studies suggest mortality and morbidity is higher among patients with diabetes compared to patients without diabetes. However, there are many limitations and confounders of which we should be cognizant. Timing and virus strain may have confounded the results of many studies. For example, during the first wave of COVID-19 in many countries, health care systems were unprepared to deal with the huge surge of this new viral infection leading to rationalization of health care. In addition, there were no drugs or vaccines available during the first wave leading to higher mortality in older adults with multiple comorbidities such as diabetes. Moreover, different strains of the virus overtime had varied infection severity. For example, the alpha and delta strains of the virus led to more severe infections and increased mortality compared to a wild virus and the newer omicron variant. Higher mortality in people with diabetes was attributed to old age (>70 years) and the presence of other comorbidities such as hypertension and cardiovascular diseases.

In summary, the present evidence indicates higher mortality and morbidities in patients with type 1 diabetes and type 2 diabetes. There is no data on morbidity and mortality of COVID-19 in patients with other types of diabetes such as monogenic diabetes. Higher mortality may be attributed to advanced age and presence of comorbidities. The COVID-19 disease is evolving and future studies will provide a greater understanding on the pathophysiology of COVID-19 in patients with diabetes and drugs to prevent disease severity in this patient population.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA beta-coronavirus responsible for the coronavirus disease 2019 (COVID-19). COVID-19 encompasses a large range of disease severity, from mild symptoms to severe forms with Intensive Care Unit admission and eventually death. The severe forms of COVID-19 are usually observed in high-risk patients, as those with type two diabetes mellitus. Acute hyperglycemia at hospital admission represents a risk factor for poor COVID-19 prognosis in patients with and without diabetes. Acute and chronic glycemic control are both emerging as major determinants of vaccination efficacy, disease severity, and mortality rate in COVID-19 patients. Mechanistically, it has been proposed that hyperglycemia might be a disease-modifier for COVID-19 through multiple mechanisms: 1- induction of glycation and oligomerization of ACE2, the main receptor of SARS-CoV-2; 2- increased expression of the serine protease TMPRSS2, responsible for S protein priming; 3- impairment of the function of innate and adaptive immunity despite the induction of higher pro-inflammatory responses, both local and systemic. Consistently, managing acute hyperglycemia through insulin infusion has been suggested to improve clinical outcomes while implementing chronic glycemic control positively affects the immune response following vaccination. Here, we review the available evidence linking acute and chronic hyperglycemia to COVID-19 outcomes, describing also the putative mediators of such interactions and proposing glycemic control as a potential route to optimize disease prevention and management.

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Background: SWEET (Better control in Pediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference), a large international multicentred pediatric diabetes registry for children with diabetes, was launched in 2008. Presently it contains data from 90,000 participants and 1 Million visits from 120 centers on all continents As the COVID-19 pandemic has been global, registries collecting data from around the world are particularly well suited for analyzing the impact and outcomes in children with established diabetes and on the cases of new-onset of type 1 diabetes (T1D).

Methods: Aggregated data per person with T1D ≤ 18 years of age were analysed in 2018 – first half of 2021. Hierarchic linear and logistic regression models were applied. Models were adjusted for gender, age- and diabetes duration-groups.

Results: Across all country quartiles of COVID-19 mortality in the background poulation, HbA1c and rate of severe hypoglycaemia remained comparable to the year prior to the first wave, while DKA rates increased significantly in the centres from countries with the highest mortality rate but returned to baseline after the first wave. CGM use decreased slightly during the first wave (53 vs. 51%) and increased significantly thereafter (55 vs. 63%, p<0.001).

The total number of new onset T1D cases in 88 centers worldwide increased from 3242 (2018), 3967 (2019) to 4302 in 2020. The average number of new-onset T1D per center increased from 11.5 [95%-confidence interval: 10.3-12.8] in 2018 to 16.8 [15.6-18.1] in 2020 in the youngest age group <6, from 13.6 [12.9-14.3] in 2018 to 21.5 [20.8-22.2] in 2020 in children 6 to <12 year and from 12.0 [11.4-12.6] to 19.3 [18.7-19.9] in adolescents 12 to 18 years (all p<0.001) These increases remained within the expected increase with the 95%-confidence interval of the regression line and tended to continue during the first half of 2021. However, in Europe and North America following the lockdown early in 2020, the typical seasonality of more cases during cold season was delayed with a peak during the summer and autumn months.

Conclusions: This real-world data analysis of the worldwide impact of the COVID-19 pandemic on pediatric T1D indicates that children cared for in large pediatric diabetes centres maintained glycemic control during the challenges of the first wave of the COVID pandemic. Possibly the widespread use of diabetes technology contributed to this. The major concern relates to the observed rise in DKA in those countries with the highest COVID-19 mortality. In contrast to other findings the slope of the rise in pediatric new-onset T1D in SWEET centers remained unchanged during the COVID pandemic in all age groups. However, the lockdown caused a change in the seasonality at onset possibly related to lockdown measures.

Trial Registration: NCT04427189