by Marie E. McDonnell, MD

In the COVID-19 pandemic, health systems around the world have had to rapidly adapt hospital and ICU-specific protocols to address severe respiratory failure while simultaneously addressing the unique challenges of marked insulin resistance, hyperglycemia and obesity-related morbidity in a disproportionate number of patients. The practical impact on the international community of physicians, nurses, and health care workers has been enormous (1) and the final impact has yet to be measured. In this Endocrine society virtual symposium, Dr. Daniel Drucker contributes to this global collaboration by summarizing key insights and emphasizing the importance of guiding clinicians and patients to employ established knowledge about the pandemic as well as our need to learn more through the scientific community.

Dr. Drucker sets the stage by highlighting the fact that our therapeutic armamentarium has expanded over the past 10 years, which has allowed for patient tailored approaches. Given the established cardiovascular, anti-inflammatory and renal benefits of some of these agents, it incites the question as to whether there is an optimal "COVID" diabetes regimen that may offer some protection from serious outcomes. While we are not close to knowing if this is possible, several are asking this important question, for example the DARE-19 trial with the SGLT2 inhibitor dapagliflozin. He also importantly sheds light on the current science that in total does not support the idea that DPP4 inhibitors could alter the natural history of COVID-19 infection, and there currently is no indication that any medication can. (2)

Dr. Drucker is also careful to direct our attention to the true unknowns and to redirect us away from old confounders. For example, we are also starting to see the previously seen association between insulin and mortality,(2) which almost certainly reflects baseline disease complexity and duration as has been seen in many (?all) large retrospective population studies of people with diabetes.

As he skillfully reviewed for us relatively early in the Northamerican COVID-19 experience (3), Dr. Drucker asserts that COVID-19 is not just an infectious disease, but rightfully an Endocrine disease in so much as the receptors it modulates. We are called upon as Endocrinologists to review the ACE2 receptor, a key enzyme that modulates levels of the angiotensin peptides and the key to permit both cardioprotective and deleterious effects of the RAS system. He challenges us to recall that the membrane protease TMPRSS2, which is also integral in SARS-COV2 binding, is highly regulated by androgens. These two key findings have inspired several clinical trials that are in development and/or ongoing.

As clinicians continue to receive practical guidance in real-time by the experts like Dr. Drucker and others,(4,5) more light is being shed on the unknown factors linking COVID19, diabetes and obesity. For example, we understand COVID-19 is unique in that it significantly impacts the endothelium, presumably the root cause of the arterial and venous thromboembolic complications now being increasingly reported. The most consistent finding among COVID-19 patients is that severe disease is accompanied by high levels of inflammatory markers, which are also elevated in the setting of severe states of insulin insufficiency independent of accompanying illness.(6,7) IL-6 in particular has been highlighted as likely playing a role in a maladaptive immune response to the SARS-CoV-2 virus and has been proposed as a possible treatment target.(8) This link may be important as we consider the best therapeutic approaches for treating patients who have hyperglycemia in the setting of COVID-19.

Dr. Daniel Drucker finally addresses head-on the important question of glucose control and its impact on outcomes in COVID-19. This question has been tackled by several observational studies comparing outcomes in individuals with normoglycemia compared with varying degrees of hyperglycemia in those with and without preexisting diabetes. Studies have consistently indicated that in COVID-19, hyperglycemia predicts poor outcomes in both diabetes and those without preexisting diabetes(11,12), and insulin therapy may be beneficial(13). Until we have more information on the details, Dr. Drucker appropriately directs the clinical team to rely on the current state of the evidence on glycemic targets in the ICU, namely the results of the NICE SUGAR trial. In this pragmatic, large multinational randomized trial including medical and surgical ICU patients with hyperglycemia, the moderate glycemic target of 180mg/dl or less prevailed over 81-108 mg/dL. Clinicians should take special care to prevent hypoglycemia, which carries with it its own host of inflammation, cardiac dysrhythmias and other negative sequelae. 

While we continue to accumulate knowledge and guidance from the front lines, there is much to learn about why COVID19 produces much more severe disease in the setting of dysmetabolism. On a final, positive note, thanks to modern technology allowing global connectivity, information and learnings are being disseminated faster than in any pandemic in the past. While at once taking great advantage of this for the welfare of all, the scientific community must also balance hope with caution and continue to advocate testing new therapies and approaches in high-quality randomized trials.

 

---

References

1. Caballero AE, Ceriello A, Misra A, Aschner P, McDonnell ME, Hassanein M, Ji L, Mbanya JC, Fonseca VA. COVID-19 in people living with diabetes: An international consensus. J Diabetes Complications 2020:107671
2. Cariou B, Hadjadj S, Wargny M, Pichelin M, Al-Salameh A, Allix I, Amadou C, Arnault G, Baudoux F, Bauduceau B, Borot S, Bourgeon-Ghittori M, Bourron O, Boutoille D, Cazenave-Roblot F, Chaumeil C, Cosson E, Coudol S, Darmon P, Disse E, Ducet-Boiffard A, Gaborit B, Joubert M, Kerlan V, Laviolle B, Marchand L, Meyer L, Potier L, Prevost G, Riveline JP, Robert R, Saulnier PJ, Sultan A, Thebaut JF, Thivolet C, Tramunt B, Vatier C, Roussel R, Gautier JF, Gourdy P, investigators C. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: the CORONADO study. Diabetologia 2020; 63:1500-1515
3. Drucker DJ. Coronavirus infections and type 2 diabetes-shared pathways with therapeutic implications. Endocrine reviews 2020;
4. Korytkowski M. A-LK, Drincic A, Hirsch IB, McDonnell ME, Rushakoff R, Muniyappa R. . A Pragmatic Approach to Inpatient Diabetes Management during the COVID-19 Pandemic. JCEM 2020; accepted, in press
5. Hamdy O, Gabbay RA. Early Observation and Mitigation of Challenges in Diabetes Management of COVID-19 Patients in Critical Care Units. Diabetes Care 2020; 43:e81-e82
6. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (London, England) 2020; 395:1054-1062
7. Stentz FB, Umpierrez GE, Cuervo R, Kitabchi AE. Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. Diabetes 2004; 53:2079-2086
8. Chen X, Zhao B, Qu Y, Chen Y, Xiong J, Feng Y, Men D, Huang Q, Liu Y, Yang B, Ding J, Li F. Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients. Clin Infect Dis 2020;
9. Korytkowski M. A-LK, Drincic A., Hirsch I, McDonnell ME, Rushakoff R, Muniyappa, R. A Pragmatic Approach to Inpatient Diabetes Management during the COVID-19 Pandemic. The Journal of clinical endocrinology and metabolism 2020;
10. Moghissi ES, Korytkowski MT, DiNardo MM, Einhorn D, Hellman R, Hirsch IB, Inzucchi SE, Ismail-Beigi F, Kirkman MS, Umpierrez GE. American Association of Clinical Endocrinologists and American Diabetes Association Consensus Statement on Inpatient Glycemic Control. Diabetes Care 2009; 32:1119-1131
11. Bode B, Garrett V, Messler J, McFarland R, Crowe J, Booth R, Klonoff DC. Glycemic Characteristics and Clinical Outcomes of COVID-19 Patients Hospitalized in the United States. Journal of diabetes science and technology 2020; 14:813-821
12. Wang S, Ma P, Zhang S, Song S, Wang Z, Ma Y, Xu J, Wu F, Duan L, Yin Z, Luo H, Xiong N, Xu M, Zeng T, Jin Y. Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study. Diabetologia 2020;
13. Sardu C, D'Onofrio N, Balestrieri ML, Barbieri M, Rizzo MR, Messina V, Maggi P, Coppola N, Paolisso G, Marfella R. Outcomes in Patients With Hyperglycemia Affected by COVID-19: Can We Do More on Glycemic Control? Diabetes Care 2020; 43:1408-1415