At the time of this writing, 210 countries and territories have been affected by the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), with two million cases of COVID-19 (the disease caused by the virus) diagnosed and 134,616 deaths recorded1, though the actual numbers may be considerably higher. Many countries are under lockdown and our day-to-day lives have been changed by this pandemic. There are seven different human coronaviruses. The SARS-CoV-2 belongs to the β-coronavirus and, when compared to Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), has a higher rate of infectivity2. Despite a lower mortality rate than SARS and MERS, due to the infectious nature of SARS-CoV-2, the number of patients afflicted has overwhelmed the health care system in many countries, including the United States, Italy and Spain, which have the highest number of cases. Given the scope of this disease and the large number of patients worldwide diagnosed with diabetes, it is important to understand how this pandemic can affect patients with both conditions.
Poorly controlled diabetes mellitus not only leads to micro- and macrovascular damage, but due to its effect on the immune system, also increases susceptibility to infection. Reduction in T-cell response and neutrophil function, disorder of the humoral immune response and reduced inflammatory response have been found in individuals with diabetes. Moreover, human and animal studies have shown that in the presence of diabetes, there is a predominance of proinflammatory macrophages from regulatory or anti-inflammatory macrophages and T-cells in adipose tissue3. When compared to an age and gender matched cohort, patients with type 1 and type 2 diabetes were at higher risk for all infections, particularly those affecting the bones and joints, as well as sepsis and cellulitis. Risk of hospitalization following infection was higher for patients with type 1 diabetes compared to those with type 2 diabetes (3.71 versus 1.88)4. In terms of respiratory tract infections, patients with diabetes were found to be six times more likely than healthy individuals to be hospitalized during a flu epidemic5.
In past viral pandemics, patients with diabetes were found to have poorer outcomes than the general population. During the 2002-2003 SARS outbreak, diabetes was an independent risk factor for mortality and morbidity6,7. In 2009, during the H1N1 influenza pandemic, patients with diabetes had three times the risk of being hospitalized and were four times as likely to be admitted to the intensive care unit. The role of hyperglycemia in increasing the severity of influenza infections remains unclear. Possible links include: glycemic variability leading to endothelial dysfunction, increased viral load secondary to raised pulmonary glucose concentration, and immune system dysfunction in patients with diabetes8. Three years after the H1N1 influenza outbreak, MERS emerged in Saudi Arabia. The MERS infection had a higher case fatality rate compared to SARS (41.8% versus 9.6%)9. Investigators also found that comorbidities such as diabetes, hypertension, renal, cardiac and respiratory disease were clinical predictors of death in patients with MERS10.
The prevalence of diabetes amongst patients infected with COVID-19 varies among countries. China reported a prevalence of 8-11%; similarly, the United States reported a prevalence of 11%, while in Italy the prevalence was reported to be higher at 36%11-14. The global case fatality rate for all patients infected with the virus has been reported to be 3.4%15. Since the outbreak began in December 2019 in Wuhan China, numerous studies have been conducted to identify risk factors for disease severity and death. In a systemic review of 53,000 patients, older age (>50 years), male gender, smoking, as well as underlying comorbidities (chronic kidney disease, chronic obstructive airway disease, cerebrovascular disease) were predictors for severe COVID-19 disease. The same review identified age greater than 60 years (relative risk [RR]=9.45), cardiovascular disease (RR=6.75), hypertension (RR=4.48), and diabetes (RR=4.43), as factors that are independently associated with COVID-19 mortality16. Analysis of a case series of 174 individuals with diabetes (and no comorbidities) revealed that patients had a higher risk of severe pneumonia (based on computed tomography imaging score). Patients with diabetes also had an excessive inflammatory response with raised interleukin-6, C-reactive protein and ferritin levels, as well as hypercoagulable state as confirmed by raised coagulation index and D-dimer. This may suggest that patients with diabetes are more susceptible to cytokine storm leading to rapid deterioration17.
Owing to their mechanisms of action, concerns have been raised about some frequently prescribed medications in patients with diabetes. It has been suggested that the use of angiotensin-converting enzyme (ACE) inhibitors may result in an increased expression of the ACE-2 receptor, potentially leading to increased uptake of the virus. The SARS CoV-2 virus enters the cell via ACE-2 receptors, which are expressed by the alveolar cells in the lungs as well as the vascular endothelia, renal and cardiovascular tissue, small intestine and pancreas18,19. However there is no clinical data to support this phenomenon. Moreover, one study of 112 patients with COVID-19 and cardiovascular disease found that the use of ACE inhibitors or angiotensin II-receptor blockers (ARB) did not increase mortality20. A joint statement by the American Heart Association, the American College of Cardiology, and the Heart Failure Society of America has advised that patients on ACE inhibitors or ARBs should continue taking their medication21.
Because the dipeptidyl peptidase-4 (DPP-4) enzyme is a transmembrane protein expressed in many tissues including the immune cells, it also plays a role in immune regulation particularly by T-cell activation. Animal studies have found that expression of DPP-4 on diabetic mice infected with MERS-CoV had a prolonged infection and delayed recovery 22. How this finding would translate in human studies is uncertain. The use of DPP-4 inhibitors was previously reported to be associated with an increase in upper respiratory infections such as nasopharyngitis and sinusitis while there was no increase in the incidence of pneumonia 23. However a more recent meta-analysis did not find any increase in the overall risk of infection (including respiratory tract infections) with the use of DPP-4 inhibitors in comparison to placebo and active drug comparators24.
The care of patients with diabetes during the COVID-19 pandemic is fraught with challenges. Countries worldwide are imposing lockdowns and patients may have difficulty accessing health care facilities or obtaining their medications. Dietary patterns may also differ from the usual –depending on availability of specific foods–and physical activity may be limited. While we await the development of vaccines to slow the spread of the virus and for the decline of new cases, the care of our patients must evolve and adapt to the situation. Virtual health care or telemedicine is now more vital than ever to communicate with patients and ensure continuity of care. With the ongoing pandemic requiring the focused attention of the global health care community, our responsibility to managing patients with diabetes—who are at an elevated risk for virus-related morbidity and mortality—continues to be an important priority. To those on the frontlines worldwide, who have been tirelessly battling this pandemic, thank you and stay safe!
1. Worldometer. COVID-19 Coronavirus Pandemic. https://www.worldometers.info/coronavirus/. Updated 16 April, 2020. Accessed 16 April, 2020.
2. Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak–an update on the status. Mil Med Res. 2020;7(1):11.
3. Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: A review of pathogenesis. Indian J Endocrinol Metab. 2012;16 Suppl 1:S27–S36.
4. Carey IM, Critchley JA, DeWilde S, et al. Risk of infection in type 1 and type 2 diabetes compared with the general population: a matched cohort study. Diabetes Care. 2018 1;41(3):513-21.
5. Klekotka RB, Mizgała E, Król W. The etiology of lower respiratory tract infections in people with diabetes. Pneumonol Alergol Pol. 2015;83(5):401-8.
6. Yang JK, Feng Y, Yuan MY, et al. Plasma glucose levels and diabetes are independent predictors for mortality and morbidity in patients with SARS. Diabet Med. 2006;23(6):623-8.
7. Booth CM, Matukas LM, Tomlinson GA, et al. Clinical features and short-term outcomes of 144 patients with SARS in the greater Toronto area. JAMA. 2003;289(21):2801-9.
8. Hulme KD, Gallo LA, Short KR. Influenza virus and glycemic variability in diabetes: A killer combination? Front Microbiol. 2017;8:861.
9. Hui DS, Memish ZA, Zumla A. Severe acute respiratory syndrome vs. the Middle East respiratory syndrome. Curr Opin Pulm Mede. 2014;20(3):233–241.
10. Matsuyama R, Nishiura H, Kutsuna S, et al. Clinical determinants of the severity of Middle East respiratory syndrome (MERS): a systematic review and meta-analysis. BMC Public Health. 2016;16(1):1203.
11. Singh AK, Gupta R, Misra A. Comorbidities in COVID-19: Outcomes in hypertensive cohort and controversies with renin angiotensin system blockers. Diabetes Metab Syndr.2020;9(14):283-287.
12. Yang J, Zheng Y, Gou X, et al. Prevalence of comorbidities in the novel Wuhan coronavirus (COVID-19) infection: a systematic review and meta-analysis. Int J Infect Dis. 2020. doi.org/10.1016/j.ijid.2020.03.017.
13. Onder G, Rezza G, Brusaferro S. Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy. JAMA. Published online March 23, 2020. doi:10.1001/jama.2020.4683.
14. CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019 – United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382–386.
15. World Health Organization. WHO Director-General’s opening remarks at the media briefing on COVID-19 – 3 March 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19—3-march-2020. 3 March, 2020. Accessed 15 April, 2020.
16. 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. doi.org/10.1101/2020.03.17.20037572
17. Guo W, Li M, Dong Y, et al. Diabetes is a risk factor for the progression and prognosis of COVID‐19. Diabetes Metab Res Rev. 2020. doi: 10.1002/dmrr.3319.
18. Zheng YY, Ma YT, Zhang JY, Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020;5:1-2.
19. Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med. 2020. doi.org/10.1016/S2213-2600(20)30116-8.
20. Peng YD, Meng K, Guan HQ, et al. Clinical features and outcome of 112 cases of novel coronavirus pneumonia in cardiovascular patients infected by 2019-nCoV (in Chinese). Chin J Cardiol. 2020;48. doi: 10.3760/cma.j.cn112148-20200220-00105.
21. Patients taking ACE-i and ARBs who contract COVID-19 should continue treatment, unless otherwise advised by their physician: Statement from the American Heart Association, the Heart Failure Society of America and the American College of Cardiology [press release]. 2020 Mar 17.
22. Iacobellis G. COVID-19 and Diabetes: can DPP4 inhibition play a role?. Diabetes Res Clin Pract. 2020:108125.
23. Willemen MJ, Mantel-Teeuwisse AK, Straus SM, et al. Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase. Diabetes Care. 2011;34(2):369-74.
24. Yang W, Cai X, Han X, Ji L. DPP‐4 inhibitors and risk of infections: a meta‐analysis of randomized controlled trials. Diabetes Metab Res Rev. 2016;32(4):391-404.
Pei Lin Chan, MBBS (IMU), MRCP (UK)
Read previous columns from Dr. Chan.