key: cord-313829-pjscmen8
authors: Caballero, A.E.; Ceriello, A.; Misra, A.; Aschner, P.; McDonnell, M.E.; Hassanein, M.; Ji, L.; Mbanya, J.C.; Fonseca, V.A.
title: COVID-19 in people living with diabetes: An international consensus
date: 2020-07-06
journal: J Diabetes Complications
DOI: 10.1016/j.jdiacomp.2020.107671
sha: 
doc_id: 313829
cord_uid: pjscmen8

The COVID-19 pandemic has added an enormous toll to the existing challenge of diabetes care world-wide. A large proportion of patients with COVID-19 requiring hospitalization and/or succumbing to the disease have had diabetes and other chronic conditions as underlying risk factors. In particular, individuals belonging to racial/ethnic minorities in the U.S. and other countries have been significantly and disproportionately impacted. Multiple and complex socioeconomic factors have long played a role in increasing the risk for diabetes and now for COVID-19. Since the pandemic began, the global healthcare community has accumulated invaluable clinical experience on providing diabetes care in the setting of COVID-19. In addition, understanding of the pathophysiological mechanisms that link these two diseases is being developed. The current clinical management of diabetes is a work in progress, requiring a shift in patient-provider interaction beyond the walls of clinics and hospitals: the use of tele-medicine when feasible, innovative patient education programs, strategies to ensure medication and glucose testing availability and affordability, as well as numerous ideas on how to improve meal plans and physical activity. Notably, this worldwide experience offers us the possibility to not only prepare better for future disasters but also transform diabetes care beyond the COVID-19 era.

Chinese Geriatric Endocrine Society issued guidance to PLWD on coping with the situation. 19, 20 Expert recommendations on insulin treatment of hyperglycemia in patients affected with COVID-19 was also developed to guide hyperglycemia management in hospitalized patients. 21 Many endocrinologists offered free consultation to PLWD through internet-based consultation platforms. Based on the experience with SARS, it is predicted that this pandemic will be of short duration, so, advice has focused on how to discover and prevent hyperglycemic crisis. According to Chinese guidelines, a slight elevation of glucose above the recommended target is tolerable for a short period of time. But patients should be aware of early signs of significant hyperglycemia crisis and when to go to the hospital.

A very detailed guidance for PLWD was created on how to access certified internet-based medical services and medical supplies through smartphones. A location-based GPS diabetes pharmacy map was also developed, providing information on pharmacies with insulin to ensure that PLWD are able to access their medicines through non-hospital channels. The map has been viewed by more than 2.3 million people and its related information has reached 5 million.

For those PLWD urgently needing to see health care providers in hospital, information was J o u r n a l P r e -p r o o f based public media, such as Baidu (a Google equivalent) and WeChat, used by more than 800 million people living in China.

The mean prevalence of diabetes in Europe in people affected by COVID-19 has been reported to be 33% by the WHO Europe Region. 22 Italy was the first country in Europe affected by . The situation in the north of the country was dramatic while in the southern area it remained under control. The second country showing a similar trend was Spain; the epidemic was very serious in the areas of Madrid and Barcelona and less so in other parts.

Italy and Spain adopted the -lockdown‖ strategy quite quickly, closing almost all activities and keeping their citizens at home. This lockdown was also rapidly adopted in several other countries, possibly explaining why the disease left countries like Portugal and Greece virtually unaffected. Conversely, where the lockdown was adopted late in the appearance of COVID-19, the related morbidity was higher. For example, the UK experienced a high total number of cases, and Sweden a high number of cases as a proportion of their small population. Russia has a different story: at the beginning the situation was unclear but today this country displays the worst situation in Europe. The World Health Organization issues daily situation reports to communicate all updates by country and region. 23 J o u r n a l P r e -p r o o f but upon lifting the lockdown there has been a major surge. Mortality due to COVID-19 in India has remained lower than many other countries: ~3%.

India has a huge number of patients with diabetes; specifically, 18 million patients above 65 years of age who are particularly vulnerable to mortality due to COVID-19. These large numbers of patients pose a major challenge in prevention and management. 24 Further, during the lockdown, patients with diabetes have increased snacking/carbohydrate intake and decreased physical activity, resulting in weight gain, which may de-stabilize glucose control. 25 A simulation model analysis showed a significant association between the duration of the lockdown and loss of glycemic control as well as associated complications. The predicted increment in HbA1C from baseline at the end of 30 days and 45 days lockdown was 2.26% and 3.68% respectively. Similarly, the predicted percentage increase in complication rates at the end of 30day lockdown was 2.8% for retinopathy, 9.3% for microalbuminuria, 14.2% for proteinuria, 2.9% for peripheral neuropathy, 10.5% for lower extremity amputation, 0.9% for myocardial infarction, and 0.5% for stroke. 26 These data show a likely increase of patients with diabetesrelated complications, adding to already huge numbers. In addition, according to another recent analysis, a 7% increase in diabetes risk will occur consequent to weight gain during lockdown. 27 If this occurs, millions of new cases of diabetes will be diagnosed in the near future.

J o u r n a l P r e -p r o o f inability to access the online link, poor quality of picture, poor perception of sound, etc. 29 Indeed, many patients prefer telephone or smartphone-based tele-consults.

One of the widely debated questions regarding the COVID-19 epidemic is why overall mortality due to COVID-19 in India lower than other countries. Adverse factors which could lead to increase in mortality are all too pervasive in Asian Indians: poorly controlled diabetes and hypertension, high prevalence of cardiovascular diseases, increased baseline sub-clinical inflammation, and increasing obesity.

There could be other factors which could be protective but need research. Firstly, BCG vaccination may have a role in enhancing innate immunity. Countries which have a universal BCG vaccination (including India) have a lower mortality due to COVID-19 as compared to other nations. Second, cytokine storm, associated with high mortality in COVID-19 cases, may be muted in Indians due to previous recurrent infections (malaria, previous coronavirus, etc).

These and several other issues have been discussed in a recent review. 30

What will be the scenario for COVID-19 related mortality and hospitalization in the next 24 months? It is difficult to predict but some indicators are available from the model of Harpreet In summary, while overall mortality due to COVID-19 is lower in India than in other countries, the elderly population, where most patients with diabetes, hypertension and CVD are concentrated, remains at high risk. Several solutions are suggested in Table 1 . 32, 33 Perspective from the Middle East

The Middle East (ME) has a huge range of variability in wealth, strength of the health system as well as in density of the population, where some countries are <2 million in population while others are >100 million. Consequently, these variations are also reflected in the response to COVID-19 with regards to the ability to implement robust social distancing, effective and timely use of protective measures, and in the ability to test suspected cases. Many studies on COVID-19 are ongoing and the results of these studies are not yet published. However, recent data from Kuwait are now available, although not yet peer-reviewed. 34 In a single hospital where 100% of COVID-19 patients were admitted, the total number of admissions was 417 persons and case fatalities were 14.4%, with mean age 54.2±11.09. Male gender represented 90% of all fatalities and diabetes was diagnosed in 40% of those who died. This observation matches the recent announcement by the United Arab Emirates government spokesperson, where 40% of COVID-J o u r n a l P r e -p r o o f years in Kuwait (36.7%) and in those aged 60-69 years (62.8%) . 35 Future data from other Middle East countries are eagerly awaited.

One aspect was common across the ME: Ramadan fasting, as Ramadan this year started on 23 rd of April, which coincided with the peak of COVID-19 in many countries. While the majority of the ME population are Muslims, this issue extends to millions of Muslims globally where fasting during the month of Ramadan is something they await passionately each year.

The vast majority of PLWD fast safely during Ramadan. 36 However, for some there is increased risk of hypoglycemia, hyperglycemia, ketoacidosis, dehydration, and thrombosis. 37 Furthermore, many PLWD are treated with SGLT2 inhibitors (SGLT2-I) in view of the recent cardiovascular outcomes trials. However, some were concerned about the possibility of dehydration during Ramadan fasting for people treated with this class of medication, as well as the concern regarding diabetic ketoacidosis in those patients with COVID-19 on SGLT2-I. In response to the question of the safety of Ramadan fasting for PLWD, the Diabetes and Ramadan International Alliance has provided guidance that is available on the IDF website. 38 As the coronavirus epidemic spread throughout the ME, many clinicians and PLWD looked for 

Approximately 25% of all cases of COVID-19 in the world have been reported in the U.S.

Race/ethnicity has been recorded in only 48% of them. 41 Among these cases, racial/ethnic minorities stand out as being disproportionately affected by COVID-19. For example, 21.3% of COVID-19 cases are in Blacks, 34.3% in Latinos/Hispanics and 34.7% in non-Hispanic Whites while they represent 13.4%, 18.3% and 60.4% of the general U.S. population respectively. 41, 42 Most cases have been reported in people ages 18 to 44 years, followed by those ages 45 to 64 years. However, most hospitalizations indicating severe disease have been in individuals above 75 years. 41 The prevalence of diabetes is on the rise in the U.S. At the present time, it is estimated that at least 1 in 10 individuals above 18 years of age has diagnosed diabetes. However, among those Journal Pre-proof J o u r n a l P r e -p r o o f between 65-74 and among those above 75, approximately 2 in 10 have diagnosed diabetes. 43 It is not surprising then that diabetes has been frequently reported as an underlying condition in people diagnosed with COVID-19 but even more significantly among those who have been hospitalized and in those who have died from COVID-19. 11, 12 The COVID-19 pandemic is a reminder of a previous major disaster to hit the U.S.: Hurricane Katrina, during and after which PLWD were seriously affected by not having access to healthy meals, medications like insulin, etc. 44 Major disasters usually lead to worse diabetes control among most PLWD. People with lower socio-economic status and access to health care are often affected in a more impactful manner. 45 In response, the American Diabetes Association formed a disaster preparedness task force that made recommendations about diabetes management when faced with an emergency (Table 3) . 46 Clinicians should be reminded to access and use these resources, freely available online.

Just as we teach all our patients that they should prepare for an emergency, so should healthcare provider organizations ensure that direct patient medical care will continue in some way, and that patients are aware of means by which they can access their medication-including experimental medications.

There is no doubt that people with diabetes are not only widely affected by COVID-19 but very often have a more severe form of the disease. 4 We have learned that in addition to the presence of co-morbidities, the level of hyperglycemia during the disease can seriously affect the outcomes. 47, 48 The survival rate in hospitalized patients with type 2 diabetes with well-controlled J o u r n a l P r e -p r o o f blood glucose is almost 99% (considering a threshold of glycemia <10 mmol/L or <180 mg/dL), while above this threshold the survival rate is only 11%. 47 In the same study, hyperglycemia was associated with worse prognosis of COVID-19 in both people with and without diabetes.

Hyperglycemia, particularly severe hyperglycemia, is often a marker of the severity of the underlying comorbidities. Thus, hyperglycemia can serve as a marker of high risk of morbidity and mortality in the COVID-19 infected patient, as was similarly observed for the SARS epidemic in 2006. 49 There is some evidence suggesting how hyperglycemia is generated or worsened during COVID-19, depicted in Figure 3 . SARS-CoV-2 may affect β-cells, causing a reduction of insulin secretion. 50 SARS-CoV-2 infection is also accompanied by a significant production of cytokines, which can induce insulin resistance. Both reduced insulin secretion and insulin resistance may result in hyperglycemia, which in turn may further decrease insulin secretion and increase insulin resistance. 50 Hyperglycemia also generates non-enzymatic glycosylation. Glycosylation of the ACE2 receptor can facilitate the entry of the SARS-CoV-2 into host cells. 50 Furthermore, acute hyperglycemia, either directly or through cytokine production, may provoke endothelial dysfunction and thrombus formation, which in turn can lead to organ damage and fatal outcome of the disease. 50 This hypothesis is consistent with the evidence of high levels of D-dimer in people with diabetes, particularly people with poor glycemic control, during the course of COVID-19. 48 J o u r n a l P r e -p r o o f Several important pathways have been linked between COVID-19 and diabetes that could be considered as targets for therapy related to diabetes and comorbidities. 51 The first is DPP-4, a known receptor for coronaviruses including MERS and SARS but not SARS-CoV-2. However, even though DPP-4 is involved in the inflammatory cascade, its role is minimal. There is currently no evidence that DPP-4 inhibitors (DPP-4I) have any beneficial effect on COVID-19infected patients.

A second, interesting pathway is the enzyme angiotensin converting enzyme-2 (ACE2), which does function as a receptor of coronavirus, including SARS-CoV-2. It is known that ACE is involved in conversion of Angiotensin I to Angiotensin II and ACE inhibitors are commonly used in the management of hypertension. It's also known that ACE2 acts on Ang II to produce a fragment that is beneficial, as it is involved in increasing blood flow, is cardio-protective and decreases insulin resistance. ACE2 is also present in the pancreas, where its role in diabetes is unclear. A rational hypothesis is that in binding to ACE2 the virus may affect organs where it is present and thereby the SARS-CoV-2 virus may be affecting the pancreas and causing hyperglycemia. 51 Obesity is an additional contributing factor to the deleterious outcomes in PLWD and COVID-19 as its state of low-grade, chronic inflammation seems to be amplified following SARS-CoV-2 infection. We still need to better understand this effect before we can effectively target this exacerbated inflammatory state and its frequent coagulation response that seems to be the trigger for severe disease and mortality.

Finally, the increase in blood glucose levels associated with COVID-19 described above could potentially occur not only in people with known diabetes but also in those with undiagnosed diabetes, prediabetes or with major predisposition to the disease. The potential deleterious effects of SARS-CoV-2 on ß-cells and on insulin resistance may partially explain the COVID-19-related new-onset diabetes cases identified in several countries/regions. 52 Understanding the precise mechanisms leading to this phenomenon will be extremely important in order to generate corresponding clinical management guidelines.

As previously stated, PLWD are more prone to a serious form of COVID-19. Optimizing glycemic control is key to reducing the risk of serious disease as well as successfully treating people who have been hospitalized with COVID-19. 53 The comprehensive management of associated comorbidities and the evaluation of biomarkers for cardiovascular risk are equally important during this critical time. 54, 55 The principles of managing diabetes in association with any acute illness apply in those affected with COVID-19, with a few caveats. 56 The biggest challenge is for health care systems to manage seriously ill patients in isolation, with limited staff and the well-known challenges regarding the availability of personal protective equipment. These conditions limit the ability to implement glucose monitoring and intravenous administration of insulin and fluids.

Despite these challenges, it seems prudent to target blood glucose levels below 10 mmol/L or 180 mg/dL as in most hospitalized patients with diabetes. Clinical studies to demonstrate this strategy is in fact conducive to better patient outcomes in the setting of COVID-19 are needed.

Insulin therapy is the preferred strategy to improve glycemic control in hospitalized patients, and reducing the risk for ketoacidosis and hypoglycemia is a core goal. Insulin schemes either using subcutaneous basal-bolus therapy or intravenous continuous infusion can be used. Insulin doses may be higher than usual due to augmented insulin resistance in these patients. In light of a possible mortality benefit from the glucocorticoid dexamethasone in those with respiratory failure due to COVID-19 57 , the adoption of specific insulin strategies to address steroid-induced hyperglycemia is also needed. 58 Oral anti-diabetes medications can be used in mild COVID-19 cases without severe hyperglycemia as long as they are not contraindicated. As previously stated, there is insufficient evidence to specifically recommend DPP-4I for the treatment of diabetes in the setting of COVID-19. While metformin and SGLT-2I may have a beneficial effect in heart failure, and epidemiologic studies suggest a possible survival advantage among those treated with metformin 59 , these medications need to be tested in randomized clinical trials in the setting of COVID-19 before making any formal recommendations. Furthermore, clinicians should be very cautious about the risk of lactic acidosis or ketoacidosis in patients who are severely ill and not eating or hydrating themselves well while on these medications. Dehydration could also impose J o u r n a l P r e -p r o o f could interfere with ACE2 to decrease its breakdown, which in turn would facilitate the penetration of SARS-CoV2 into host cells. 60 However, the clinical implication is highly questionable to the point that several international organizations have made a very clear statement that providers should encourage patients to continue to use these medications if needed. 61, 62 Tracking blood glucose levels in hospitalized patients is key to achieving effective diabetes control. Until the epidemic hit, hospital continuous glucose monitoring (CGM) had not been approved by the U.S. Food and Drug Administration (FDA). Insufficient data as well as concerns about subcutaneous blood flow and the lag between true blood glucose and subcutaneous interstitial fluid glucose precluded its approval. However, further data supporting a reasonable correlation between CGM and a point-of-care blood glucose testing in non-ICU patients, 63 and between flash glucose monitoring and capillary blood glucose testing in hospitalized patients, 64 along with the urgent need to better manage patients with diabetes and COVID-19, prompted the FDA to grant approval for the use of CGM systems in the hospital. Adoption of CGM for inpatient use requires careful consideration and expertise, and more guidance would be beneficial for hospital-based clinicians. 58

The COVID-19 and diabetes pandemics have imposed an unprecedented challenge on the lives of millions of people around the world. Improving diabetes control in the outpatient setting at We have the obligation as health care professionals to raise awareness and address to the best of our abilities all social determinants of health that clearly increase the risk of diabetes, COVID-19 and many other health threats. We also have the opportunity to improve the lives of PLWD beyond the COVID-19 era by addressing patients as a whole, beyond the usual biomedical model. 65 The management of chronic diseases like diabetes has long been an enormous challenge. The current model of health care based on patients receiving services at clinics and hospitals has been effective for many but not all PLWD. The -forced‖ used of telemedicine or virtual care during this pandemic has been beneficial to many PLWD and other chronic conditions. Although it is clear that this option of care is not available to most people around the world, exploring how to improve the communication between providers and patients and families at home, in their own communities facing day to day challenges, may prove to be a more effective approach to managing the disease well beyond the COVID pandemic. Indeed, rather than going back to the pre-COVID-19 diabetes care model, we should take advantage of what we are learning and innovating during this time to improve diabetes care strategies in the post-COVID-19 era. In addition, this experience will help us be better prepared for future disasters (Figure 4 ).

J o u r n a l P r e -p r o o f Finally, we recognize that as we all continue to learn about COVID-19 and its consequences, sharing our collective experience is critical to the ultimate goal of developing evidence-based recommendations to better guide the management of diabetes during this challenging time and beyond.

J o u r n a l P r e -p r o o f 

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical characteristics of coronavirus disease 2019 in China

Clinical characteristics and outcomes of patients with severe covid-19 with diabetes

Prognostic factors in patients with diabetes hospitalized for COVID-19: Findings from the CORONADO study and other recent reports

COVID-19 and endocrine diseases. A statement from the

Diabetes in COVID-19: prevalence, pathophysiology, prognosis and practical considerations

Predicting mortality due to SARS-CoV-2: a mechanistic score relating obesity and diabetes to COVID-19 outcomes in

Diabetes and COVID-19: more than the sum of two morbidities

Diabetic patients with COVID-19 infection are at higher risk of ICU admission and poor short-term outcome

Covid-19: Black people and other minorities are hardest hit in US

Is ethnicity linked to incidence or outcomes of COVID-19?

Disparities in the population at risk of severe illness from COVID-19 by race/ethnicity and income

Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China

Expert recommendations for diabetes management in primary care during the COVID-19 pandemic

Guidance on diabetes management in the elderly during the COVID-19 pandemic

Recommendations on insulin treatment in diabetes patients affected with COVID-19

COVID-19 weekly surveillance report: data for the week of 8 -14

World Health Organization. Coronavirus disease (COVID-2019) situation reports

Clinical considerations for patients with diabetes in times of COVID-19 epidemic

Estimation of effects of nationwide lockdown for containing coronavirus infection on worsening of glycosylated haemoglobin and increase in diabetes-related complications: a simulation model using multivariate regression analysis

Increase in the risk for type 2 diabetes due to lockdown for COVID19 pandemic in India: a cohort analysis

Telemedicine for diabetes care in India during COVID19 pandemic and national lockdown period: guidelines for physicians

Roadblock in application of telemedicine for diabetes management in India during COVID19 pandemic

The links between COVID-19 and diabetes, known and unknown

Diabetes during the COVID-19 pandemic: a global call to reconnect with patients and emphasize lifestyle changes and optimise glycemic and blood pressure control

COVID-19 pandemic and challenges for socio-economic issues, healthcare and National Health Programs in India

Clinical characteristics of Coronavirus Disease 2019 (COVID-19) patients in Kuwait

The prevalence of pre-diabetes and diabetes in the Kuwaiti adult population in 2014

Diabetes and Ramadan: practical guidelines

International Diabetes Federation E-library. Diabetes and Ramadan: practical guidelines

Available at: www.diabetesatlas.org/en

The Hurricane Katrina aftermath and its impact on diabetes care: observations from "ground zero": lessons in disaster preparedness of people with diabetes

Impact of a natural disaster on diabetes: exacerbation of disparities and long-term consequences

American Diabetes Association statement on emergency and disaster preparedness: a report of the Disaster Response Task Force

Association of blood glucose control and outcomes in patients with COVID-19 and pre-existing type 2 diabetes

Outcomes in patients with hyperglycemia affected by Covid-19: can we do more on glycemic control? Diabetes Care

Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS

Why is hyperglycemia worsening COVID-19 and its prognosis? Diabetes Obes Metab

Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications

New-onset diabetes in Covid-19

Hyperglycemia and the worse prognosis of COVID-19. Why a fast blood glucose control should be mandatory

Diabetes and Cardiovascular Disease (D&CVD)

Issues of cardiovascular risk management in people with diabetes in the COVID-19 era

COVID-19 and diabetes management: What should be considered?

Practical recommendations for the management of diabetes in patients with COVID-19

Pragmatic Approach to Inpatient Diabetes Management during the COVID-19 Pandemic

Metformin Treatment was Associated with with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?

European Society of Cardiology. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers

Heart Failure Society of America, and American College of Cardiology. Patients taking ACE-i and ARBs who contract COVID-19 should continue treatment, unless otherwise advised by their physician

Continuous glucose monitoring in insulin-treated patients in non-ICU settings

Implementation of continuous glucose monitoring

This work was based on a livestreamed educational conference organized by the Postgraduate Medical Education department at Harvard Medical School and supported by an educational grant from Sanofi. The sponsor had no involvement in the conference content or in the development of this manuscript. We appreciate the assistance provided by Karen J. Kuc, MPH in the compilation and editing of the manuscript.