REVIEW ARTICLE

Dissecting the interaction between COVID-19

and diabetes mellitus
Ying Jie Chee1,* , Seng Kiong Tan1,2 , Ester Yeoh1,2
1
Division of Endocrinology, Department of Medicine, Khoo Teck Puat Hospital, Singapore, and 2Diabetes Center, Admiralty Medical Center, Singapore

Keywords ABSTRACT
COVID-19, Diabetes, SARS-CoV-2 Coronavirus disease 2019 (COVID-19) is a global pandemic that is caused by a novel coro-
navirus, severe acute respiratory syndrome coronavirus-2. Data from several countries have
*Correspondence shown higher morbidity and mortality among individuals with chronic metabolic diseases,
Ying Jie Chee such as diabetes mellitus. In this review, we explore the contributing factors for poorer
Tel.: +65-6555-8000 prognosis in these individuals. As a significant proportion of patients with COVID-19 also
Fax: +65-6602-3700 have diabetes mellitus, this adds another layer of complexity to their management. We
E-mail address:
explore potential interactions between antidiabetic medications and renin–angiotensin–al-
[email protected]
dosterone system inhibitors with COVID-19. Suggested recommendations for the use of
J Diabetes Investig 2020; 11: 1104– antidiabetic medications for COVID-19 patients with diabetes mellitus are provided. We
1114 also review pertinent clinical considerations in the management of diabetic ketoacidosis in
COVID-19 patients. In addition, we aim to increase clinicians’ awareness of the metabolic
doi: 10.1111/jdi.13326 effects of promising drug therapies for COVID-19. Finally, we highlight the importance of
timely vaccinations for patients with diabetes mellitus.

INTRODUCTION DIABETES MELLITUS AND OBESITY ARE RISK FACTORS

Coronavirus disease 2019 (COVID-19), caused by the severe FOR SEVERITY OF COVID-19 INFECTION
acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infec- Diabetes mellitus is a well-established risk factor for infections,
tion, was first reported in Wuhan, China, in December 20191. and the risk increases with poor glycemic control6. In general,
Similar to its counterparts, severe acute respiratory syndrome glycated hemoglobin (HbA1c) >9% has been shown to be asso-
coronavirus (SARS-CoV) and Middle East respiratory syn- ciated with 60% increased risk of severe bacterial pneumonia7.
drome coronavirus, SARS-CoV-2 is highly pathogenic, and can Although current evidence does not suggest that patients with
cause severe pneumonia, acute respiratory distress syndrome diabetes mellitus are at higher risk of contracting SARS-CoV-
and multiorgan failure. Furthermore, the rapid transmission of 28, diabetes mellitus has been listed as the third most prevalent
SARS-CoV-2 has caused a worldwide pandemic with >6 mil- comorbidity, behind cardio-cerebrovascular disease and hyper-
lion cases and 360,000 deaths since June 20202. tension9, and is also associated with a two- to threefold increase
Diabetes mellitus affects approximately 463 million people in adverse outcomes9. Similarly, obese individuals with body
worldwide3, while obesity inflicts nearly one-third of the world’s mass index >35 kg/m2 are at nearly sevenfold higher risk of
population4. The co-existence of obesity and diabetes mellitus, requiring mechanical ventilation10. A recent study suggested a
also known as “diabesity,” is yet another major pandemic that lower body mass index threshold of 25 kg/m2 for disease sever-
the world currently faces. Patients with diabesity are at signifi- ity stratification in the Asian population11. In addition, patients
cantly increased risk of developing severe infections and with microvascular and macrovascular complications of diabetes
impaired pulmonary function5. Furthermore, there are also mellitus, as well as obstructive sleep apnea, were found to be at
unique and complex interactions between antidiabetic medica- significantly higher risk of severe disease and mortality12. Fig-
tions and other commonly used agents for diabetes mellitus-re- ure 1 summarizes the diverse interactions between these two
lated comorbidities with COVID-19 infection. To further conditions.
complicate this interplay, some of the promising drug therapies
are also associated with metabolic effects. PATHOGENIC LINK BETWEEN DIABETES MELLITUS,
OBESITY AND INCREASED SEVERITY OF COVID-19
There are several mechanisms that predispose patients with dia-
betes mellitus to increased disease severity. Diabetes mellitus is
Received 11 May 2020; revised 10 June 2020; accepted 11 June 2020

1104 J Diabetes Investig Vol. 11 No. 5 September 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution
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 REVIEW ARTICLE
http://wileyonlinelibrary.com/journal/jdi COVID-19 and diabetes mellitus

• Hand hygiene
• Avoid touching face
• Regular cleaning & disinfection of high touch surfaces
• Social distancing
• Vaccination

Stable/Well (Outpatient) Remdesivir

• Continue regular DM medications

• Regular self glucose +/- • Hepatotoxicity
ketone monitoring
• Access to usual DM medications Prevention
& supplies of COVID-19 Lopinavir-ritonavir
• Education on sick day management
• Outpatient support & clinic
• Insulin resistance
reviews with safe distancing
• Hypertriglyceridemia
measures or via telemedicine

Hospitalized (moderately ill) Interaction Metabolic Hydroxychloroquine/

Glycemic
between effects of cholroquine
• Insulin therapy control
COVID-19 COVID-19
• Discontinue selected oral glucose • Hypoglycemia
& DM treatment
lowering agents (e.g. SGLT2 inhibitors) • Arrhythmias
• Blood glucose monitoring
(capillary blood glucose or remote
IL-6 inhibitor
glucose monitoring)
• Aim inpatient glucose 4-10 mmol/L
• Variable effect on
Hospitalized (severelyill/DM crisis) blood glucose

• IV insulin (may require higher dose)

Type 1 IFN
• Electrolyte management-
may require more potassium Comorbids
supplementation
• Monitor fluid status • Thyroid dysfunction

Risk factors for poorer outcomes

• Advanced age
• Obesity
• Obstructive sleep apnea
• Pre-existing microvascular & macrovascular complications

Figure 1 | Interaction between coronavirus disease 2019 (COVID-19) and diabetes mellitus (DM). IFN, interferon; IL-6, interleukin-6; SGLT2, sodium–
glucose cotransporter 2.

associated with immune dysfunction13, increased susceptibility advanced glycation end-products could also inhibit the genera-
to inflammation14 and reduced viral clearance15. Furthermore, a tion of interferon gamma by T lymphocytes19. These could
possible association between SARS-CoV-2 and the renin–an- reduce antiviral activity and increase the severity of infection.
giotensin–aldosterone system (RAAS) might increase adherence The low T lymphocyte counts in diabetes mellitus patients
of SARS-CoV-2 to target cells and might worsen the severity of might blunt antiviral interferon responses20. Furthermore, the
COVID-1916, generating controversies about the use of RAAS co-existence of diabetes and obesity or “diabesity” is character-
blockers, which will be discussed further. ized by a pro-inflammatory state, driven by cytokines, such as
interleukin-6 (IL-6) and tumor necrosis factor alpha21,22. These
Diabetes mellitus is associated with immune dysfunction and patients are at increased risk of uncontrolled inflammation,
increased inflammation which could induce a cytokine storm and contribute to an
The immune system is dysregulated in hyperglycemia. The overall poor prognosis.
humoral system, which mediates immediate defense responses
by polymorphs, macrophages and dendritic antigen presenting Hyperglycemia and obesity are associated with alterations in
cells to pathogens, is attenuated in diabetes mellitus17. Defects pulmonary function and reduced viral clearance
in adaptive immunity are associated with impaired type 1 inter- Studies have shown that hyperglycemia can directly increase
feron production18. Furthermore, increased generation of glucose concentrations in the airways and affect pulmonary

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 5 September 2020 1105
REVIEW ARTICLE
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function, as well as alter pulmonary vascular permeability and and/or insulin might have to be reduced and adjusted accord-
alveolar epithelial function23. These factors might contribute to ingly to avoid hypoglycemia.
increased severity of respiratory infections. Furthermore, a In the next section, we review the different classes of oral
recent study has also shown delayed clearance of SARS-CoV-2 antidiabetic agents, and their effects on infection and inflamma-
in patients with diabetes mellitus15. tion, and provide recommendations on their use during acute
With regard to obesity, pulmonary function studies have illness.
shown a restrictive pattern and reduced lung volumes in obese
individuals10. The reduced cardiorespiratory reserve, coupled Metformin
with difficulty in ventilation, could account for the significant In stable patients with normal oral intake and who do not have
increased disease severity in these patients5,10,11. nausea and vomiting, metformin can be continued. Interest-
ingly, metformin has gained recent interest given its potential
Increased adherence of SARS-CoV-2 to target cells role in immunomodulation. Animal studies have shown
SARS-CoV-2 has glycoprotein spikes on its surface, which reduced expression of pro-inflammatory cytokines, such as
attach to angiotensin-converting enzyme 2 (ACE2) receptors tumor necrosis factor alpha and IL-6, associated with continued
on target cells. On binding to ACE2, the virus is processed by metformin use in sepsis30. Metformin has also been shown to
proteases, such as the transmembrane serine protease 2 and improve survival in mice infected with Legionella pneu-
furin, resulting in the internalization of the virion complex20. mophila31. However, in the critically ill patient with acute renal,
ACE2 and furin expression are increased in diabetes mellitus, hepatic injury or hemodynamic instability, metformin should
which might facilitate viral entry and replication20,24. be avoided due to the risk of lactic acidosis.

POTENTIAL EFFECTS OF SARS-COV-2 ON PANCREATIC Dipeptidyl peptidase-4 inhibitors

FUNCTION Concerns regarding the slight increased risk of nasopharyn-
The binding of SARS-CoV to the ACE2 receptors on pancre- geal32 and urinary tract infections33 have arisen from the use of
atic islets could potentially cause acute diabetes25. In a study by dipeptidyl peptidase-4 (DPP4) inhibitors. However, a meta-
Yang et al.25, just two of 39 patients with SARS-CoV and analysis by Cai et al.34 did not report significant differences in
labeled to have diabetes mellitus during admission continued to DPP4 inhibitor use with increased risk of upper respiratory
have diabetes mellitus after 3 years. Further characterization tract infections. Another cohort study also did not show an
showed significant immunostaining for ACE2 in the pancreatic association between DPP4 inhibitor and risk of pneumonia35.
islets, but this was weak in the exocrine tissues. In addition, In addition, DPP4 has been shown to be a receptor for cellu-
SARS-CoV-2 might be associated with elevated amylase, lipase lar entry of Middle East respiratory syndrome coronavirus36.
and focal changes to the pancreas, raising the possibility of pan- Whether this translates into increased susceptibility to certain
creatic injury26. Other viruses, such as enteroviruses, Cox- coronavirus infections or increases the severity of coronavirus
sackie B virus and cytomegalovirus, had previously been found infections is currently unclear. At present, the use of DPP4
to be associated with the development of type 1 diabetes melli- inhibitors did not show any difference in lymphocyte function
tus27. We recently reported a case of diabetic ketoacidosis or production of inflammatory cytokines in human studies37.
(DKA) precipitated by COVID-19 in a patient with newly diag- Further studies are required to elicit potential therapeutic bene-
nosed diabetes mellitus28. Similar to other acute illnesses that fits of DPP4 inhibitors in SARS-CoV-2 infection. In stable
necessitate hospitalization among patients with diabetes melli- patients with satisfactory oral intake, clinicians might elect to
tus, inpatient glycemic management and being alert to the continue DPP4 inhibitors.
potential risk of DKA are crucial. However, the long-term
effects of SARS-CoV-2 are unclear, and long-term follow up Glucagon-like peptide-1 receptor agonists
will be required to determine the magnitude of its impact on There is emerging evidence of the potential anti-inflammatory
pancreatic function and the consequent risk of developing dia- properties arising from glucagon-like peptide-1 (GLP-1) recep-
betes mellitus. tor signaling38. GLP-1 receptor agonist treatment in mice
infected with respiratory syncytial virus is associated with a sig-
MANAGEMENT OF DIABETES MELLITUS IN A PATIENT nificant reduction in inflammatory cytokine production and
WITH COVID-19 attenuation of inflammation in the respiratory epithelium39.
Glycemic control is important for all patients. Previous experi- Furthermore, GLP-1 receptor agonist therapy in the intensive
ences with SARS-CoV and current data with COVID-19 have care unit setting is associated with a reduction of hypoglycemia,
shown that hyperglycemia and diabetes mellitus are significant glucose variability and catabolism by suppressing glucagon40, all
risk factors for complications and mortality29. of which can be protective in these critically ill patients. How-
One of the main challenges in the management of acutely ever, delayed gastric emptying, which is common in the criti-
unwell COVID-19 patients with diabetes mellitus is the reduced cally ill, might affect the extent of the benefits of glycemic
oral intake. As such, the dosage of usual oral antidiabetic agents control. Its use is also relatively contraindicated in patients with

1106 J Diabetes Investig Vol. 11 No. 5 September 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
 REVIEW ARTICLE
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renal impairment. Currently, there is insufficient evidence to supporting the postulation that b-cell dysfunction might be
support for or against the use of GLP-1 receptor agonists in induced by SARS-CoV-2.
the context of the coronavirus infection. The classes of antidiabetic medications, their effects in the
context of COVID-19 and the recommendations during acute
Thiazolidinedione, sulphonylurea, meglitinide and sodium– illness are summarized in Table 1.
glucose cotransporter 2 inhibitors
Studies have suggested increased ACE2 expression associated PRACTICAL CONSIDERATIONS FOR INPATIENT
with thiazolidinedione use, raising concerns about possible GLYCEMIC CONTROL IN PATIENTS WITH COVID-19
increased susceptibility to SARS-CoV-2 infection41. However, in Maintaining good glycemic control is important for these
view of the adverse effects, such as fluid retention, which is patients. In a retrospective study by Bode et al.44 examining the
commonly associated with thiazolidinedione, it should be dis- outcomes of inpatient glycemic control of 1,122 patients with
continued in acutely ill patients. Similarly, sulphonylureas and COVID-19, uncontrolled hyperglycemia (defined as ≥2 episodes
sodium- glucose cotransporter 2 inhibitors are generally unfa- of blood glucose >10 mmol/L) was associated with a nearly
vorable in the setting of acute illness. Sulphonylurea and megli- fivefold increase in mortality and increased length of hospital-
tinide increase the risk of hypoglycemia in the presence of poor ization. Zhu et al.45 showed that inpatients whose blood glucose
oral intake. was maintained between 3.9 and 10 mmol/L had significantly
Sodium–glucose cotransporter 2 inhibitors are associated lower rates of complications and all-cause mortality. Frequent
with increased risks of dehydration and euglycemic DKA, par- monitoring of blood glucose is essential with the aim of main-
ticularly in the setting of an acute illness. taining blood glucose levels within the recommended target of
4–10 mmol/L43. Furthermore, it is important to emphasize that
Insulin inpatient diabetes management is highly dynamic. The titration
Insulin has been the treatment of choice for optimization of of antidiabetic medications needs to be guided by ongoing glu-
glycemic control in acutely ill patients. Several landmark studies cose measurements and trends, illness severity, route of nutri-
have shown mortality and morbidity benefits associated with tion and concomitant medications that might affect glucose
the use of intensive insulin therapy. Intravenous insulin can be levels, such as glucocorticoids. The need for frequent inpatient
administered as a continuous infusion that allows rapid titra- blood glucose monitoring increases exposure of healthcare
tion. Furthermore, insulin has been shown to downregulate workers to SARS-CoV-2. Besides donning personal protective
ACE2 receptors42, but more research is required to identify equipment and strict adherence to recommendations from the
direct clinical benefits of insulin in the context of COVID-19. Centers for Disease Control and Prevention in preventing
In addition, observational studies have reported significantly transmission of pathogens during glucose monitoring46, addi-
higher insulin requirements among COVID-19 patients43, tional care needs to be taken to reduce the spread of COVID-

Table 1 | Summary of antidiabetic medications, effects on coronavirus disease 2019 and recommendations on their use during acute illness

Antidiabetic medication Effects on infection Recommendations during acute illness

Metformin Reduces inflammatory cytokines Avoid in the setting of renal, hepatic failure or critically ill
May reduce viral replication due to risk of lactic acidosis
DPP4-inhibitor May be associated with disease severity in More data needed for the acutely ill patient. May consider
MERS-CoV, but effect on SARS-CoV-2 continuing in patients who are well with satisfactory oral
not defined intake
GLP-1 receptor agonist Significant reduction in inflammatory More data needed for the acutely ill patient. May consider
responses in animal models continuing in patients who are well with satisfactory oral
intake
Thiazolidinediones May be associated with increased ACE2 Discontinue in acutely ill patients due to risk of fluid
expression, but clinical implication is unclear retention
Sulphonylurea/meglitinides No apparent direct effect in SARS-CoV-2 Discontinue in patients with poor oral intake due to
hypoglycemia risk
SGLT-2 inhibitors No apparent direct effect in SARS-CoV-2 Discontinue in acute illness due to risk of euglycemic DKA
and further dehydration
Insulin May downregulate ACE2 receptors Treatment of choice in acutely ill patients to achieve
glycemic targets with dose titration based on glucose
levels

ACE2, angiotensin-converting enzyme 2; DKA, diabetic ketoacidosis; DPP4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; MERS-CoV, Middle
East respiratory syndrome coronavirus; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; SGLT-2, sodium–glucose cotransporter 2.

ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd J Diabetes Investig Vol. 11 No. 5 September 2020 1107
REVIEW ARTICLE
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19 during capillary glucose monitoring, as viable SARS-CoV-2 However, after SARS-CoV-2 entry, the expression of ACE2
might be present on contact surfaces. It is therefore important was found to be significantly downregulated, which could be
to clean and disinfect the glucometer after each and every use, associated with significant lung injury20. This can be attributa-
and to use disposable safety lancets. Where possible, the ble to the physiological action of ACE2, which catalyzes the
responsibility for routine cleaning and disinfection should be breakdown of angiotensin II to angiotensin (1-7), the latter
assigned to appropriately-trained personnel47. having anti-inflammatory and anti-oxidant properties that pro-
If resources permit, the use of remote glucose monitoring tects the lungs against acute respiratory distress syndrome51.
might prove beneficial. Real-time continuous glucose monitor- With regard to the effects of RAAS inhibitors on ACE2 expres-
ing has been reported as a useful alternative for COVID-19 sion in humans, studies have shown conflicting results.
patients with diabetes mellitus, allowing rapid titration of insu- Although Ferrario et al.52 previously reported that lisinopril
lin doses, while minimizing the risk of staff exposure. and losartan are associated with a significant increase in ACE2
levels, others did not report an effect on ACE2 among patients
MANAGEMENT OF DIABETIC EMERGENCIES IN COVID- treated with RAAS inhibitors16,53. At this point, there is insuffi-
19 cient evidence to conclude whether RAAS inhibition is benefi-
Patients who are acutely ill are at risk of diabetic emergencies. cial or harmful in COVID-19.
In a study involving a cohort of 174 Chinese patients with Despite these uncertainties, abrupt cessation of RAAS inhibi-
COVID-19, 37 had diabetes mellitus, of which two developed tors might be associated with more harm. Many diabetes melli-
DKA49. tus patients have concomitant cardiovascular diseases and are
DKA occurs as a result of insulin deficiency and increased at risk of decompensation if these medications are stopped. At
counterregulatory responses, which favor the production of present, professional societies worldwide have therefore recom-
ketones. The unique interactions between SARS-CoV-2 and the mended continuation of RAAS inhibitors54.
RAAS might provide yet another mechanism in the pathophysi-
ology of DKA. First, as alluded to earlier, direct entry of SARS- METABOLIC COMPLICATIONS OF TREATMENTS OF
CoV-2 into pancreatic islet cells might worsen b-cell injury25. COVID-19
Second, downregulation of ACE2 after viral entry can lead to Moving forward, there are currently numerous trials underway
unopposed angiotensin II, which might impede insulin secre- in search of effective treatments for this infection. We aim to
tion50. provide a summary of the current treatments, mechanisms of
In addition, the relationship between SARS-CoV-2 and the actions, and highlight some of these agents that are associated
RAAS can complicate DKA management. As angiotensin II with the effects on glucose and/or lipid metabolism.
increases pulmonary vascular permeability and worsens damage In brief, the SARS-CoV-2 replication cycle starts by gaining
to lung parenchyma16, fluid replacement needs to be adminis- host entry through the S protein, facilitated by host transmem-
tered judiciously to avoid aggravating pulmonary injury. This brane serine protease 220. Viral polyproteins are synthesized by
also raises the importance of careful assessment of fluid status ribonucleic acid polymerase, followed by assembly of structural
through objective hemodynamic parameters to determine the proteins and release of new viral particles. There are several
amount of fluid replacement. drug targets that might interfere with the replication cycle of
Another important aspect in DKA management is that of SARS-CoV-2, including chloroquine and hydroxychloroquine,
monitoring and correcting electrolyte abnormalities. As which reduce viral entry; lopinavir–ritonavir, which inhibit pro-
angiotensin II stimulates aldosterone secretion and increases teolysis; and tocilizumab, which disrupts IL-6 signaling. Other
renal potassium loss, this can potentiate the risk of hypokale- potential candidates include the transmembrane serine pro-
mia, which might necessitate additional potassium supplemen- tease 2 inhibitor, camostat mesylate, which has been shown to
tation in order to continue intravenous insulin to suppress prevent viral cell entry, as well as remdesivir, which inhibits
ketogenesis28. ribonucleic acid polymerase55. Type 1 interferon might interfere
with viral replication and minimize systemic inflammation56.
USE OF RAAS INHIBITORS IN COVID-19 As the use of these medications is likely to increase with the
Many patients with diabetes mellitus have other comorbidities growing number of COVID-19 cases, we highlight three agents
and are taking RAAS inhibitors. The complex relationship with accompanying metabolic effects, which might be beneficial
between the RAAS and SARS-CoV-2 has led to controversies or detrimental by exacerbating the underlying metabolic comor-
surrounding the use of these agents. bidities already established in some of these patients.
As ACE2 is the key receptor that facilitates entry of SARS-
CoV-2, it is postulated that ACE inhibition could lead to a Chloroquine and hydroxychloroquine
compensatory increase in the ACE2 expression with concerns These two agents inhibit SARS-CoV-2 entry, proteolytic pro-
that this might provide increased binding sites for viral entry cessing and might also have immunomodulatory effects by
into pneumocytes16. reducing cytokine production55.

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Hydroxychloroquine has been shown to improve insulin and IL-6 receptor antagonist
glucose metabolism. Studies have shown a significant reduction Tocilizumab is a biological agent that binds to the IL-6
in HbA1c and reduction in insulin doses57. Although the exact receptor, interferes with IL-6 signaling and attenuates the
mechanisms remain to be elucidated, the improvements in gly- “cytokine storm” in severe COVID-19 infection55. More com-
cemic control are likely associated with reduced insulin degra- monly used in rheumatic conditions, tocilizumab has been
dation58, increased insulin binding to its receptor with an shown to be associated with contrasting effects on glucose
increase in the half-life of the insulin receptor complex59,60 and metabolism in different tissues. IL-6 has been shown to have
increases insulin secretion61. Given the potential benefits of an unfavorable effect on glucose metabolism by increasing
hydroxychloroquine/chloroquine on glucose metabolism, close hepatic insulin resistance78,79. The use of tocilizumab is asso-
glycemic monitoring in diabetes mellitus patients, timely reduc- ciated with a small, but significant, improvement in HbA1c
tion of the dosages of antidiabetic medications and insulin in at 1 and 3 months of initiation of tocilizumab in patients
patients who receive these treatments is essential to avoid hypo- with rheumatoid arthritis, reflecting improved insulin sensitiv-
glycemia. ity from IL-6 inhibition80. However, IL-6 has a complex role
Although in vitro studies have shown antiviral activity of in modulating insulin sensitivity, being both an enhancer
hydroxychloroquine/chloroquine against SARS-CoV-262,63, and inhibitor of insulin action on different tissues, and hav-
observational studies did not show a significant reduction in ing differential roles in regulating metabolism in individuals
the need for intubation or mortality64,65. Furthermore, there is with diabetes, as compared with individuals with normal glu-
concern about the cardiovascular safety associated with this cose tolerance. It has been postulated that the higher circu-
class of medication66. Electrophysiological studies suggest that lating levels of IL-6 in patients with diabetes mellitus serves
hydroxychloroquine/chloroquine use might interfere with car- as a compensatory mechanism to promote glucose uptake in
diac channels, lead to prolongation of action potential and skeletal muscle, and thus, the use of IL-6 inhibitors might
cause life-threatening arrhythmias67. Thus, the efficacy and adversely impact glucose homeostasis in skeletal muscles81.
safety of hydroxychloroquine/chloroquine in the treatment of Nevertheless, the impact of short-term use of IL-6 receptor
COVID-19 are currently inconclusive and await further confir- antagonist for treatment of COVID-19 on glucose metabo-
mation with randomized controlled trials. lism is currently unclear and needs to be corroborated by
further research.
Lopinavir–ritonavir
Lopinavir–ritonavir are protease inhibitors used in the treat- Type 1 interferon
ment of human immunodeficiency virus. The mechanism of Thyroid dysfunction is a common side-effect of interferon ther-
action is thought to inhibit 3-chymotrypsin-like protease in apy, and its prevalence has been reported to be up to 35%82.
viral ribonucleic acid processing55. The development of thyroid dysfunction does not appear to be
Protease inhibitors have been shown to inhibit glucose related to the dose of interferon therapy83. However, among
uptake68. Euglycemic, hyperinsulinemia clamp studies showed a those who develop thyroid dysfunction and with positive thy-
reduction in glucose disposal with lopinavir–ritonavir use69. roid autoantibodies, 50% continue to carry the antibodies after
The increase in peripheral insulin resistance might be secondary interferon therapy is stopped, necessitating the need for long-
to dysregulation in insulin signaling, by causing inhibition of term follow up84.
glucose uptake70 and phosphorylation of the insulin receptor71. Interferon-induced type 1 diabetes mellitus has been
With regard to lipid metabolism, among HIV patients taking reported, but its occurrence is rare. Most of these cases occur
lopinavir–ritonavir, triglyceride levels nearly doubled within in patients who test positive for the glutamic acid decarboxy-
3 months of initiation72. Another study showed that hyper- lase antibody85,86. Checking for glutamic acid decarboxylase
triglyceridemia can occur within 2 weeks of therapy73. positivity might be worthwhile before initiation of interferon
Protease inhibitors stimulate hepatic triglyceride synthesis74, therapy.
and inhibit chylomicron uptake and triglyceride clearance75. As
severe hypertriglyceridemia is a risk factor for acute pancreatitis, Remdesivir
it is important to monitor the lipid levels of patients initiated Remdesivir use is associated with clinical improvement in
on this treatment, especially for diabetes mellitus patients, who >50% of patients with COVID-19 and shortens the time to
are at higher risk of developing severe hypertriglyceridemia. recovery87,88. Remdesivir attenuates hepatic lipid deposition and
The efficacy of lopinavir–ritonavir is currently inconclusive. insulin resistance in mice89. Paradoxically, hepatotoxicity is one
Its use was previously reported to be associated with reduced of its major adverse effects in humans, and needs to be used
mortality at 28 days, and shortened intensive care unit admis- with caution in patients with underlying liver disease or receiv-
sions and duration of viral shedding76. However, a more recent ing statin therapy87.
randomized controlled trial involving 199 patients with The mechanism of action and metabolic effects of the
COVID-19 infection treated with lopinavir–ritonavir did not medications used to treat COVID-19 are summarized in
show a mortality benefit77. Table 2.

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Table 2 | Mechanism of action and metabolic effects of medications used to treat coronavirus disease 2019

Name of medication Mechanism of action Metabolic effects

Chloroquine/hydroxychloroquine Inhibit SARS-CoV-2 entry and viral replication Improves glycemic control and may even cause
hypoglycemia
May be associated with increased risk of
arrhythmias
Lopinavir–ritonavir Inhibit 3-chymotrypsin-like protease in viral Increases triglyceride synthesis leading to
RNA hypertriglyceridemia
processing with antiviral activity against Inhibits glucose uptake, which may result in
SARS-CoV-2 hyperglycemia
IL-6 receptor antagonist Interferes with IL-6 signaling and attenuates Improves hepatic insulin sensitivity
“cytokine storm” May worsen skeletal muscle insulin resistance
Type 1 interferon Interferes with viral replication Thyroid dysfunction
Minimizes inflammation Rarely associated with type 1 diabetes mellitus
Remdesivir Inhibits viral RNA polymerase May cause hepatotoxicity

IL-6, interleukin-6; RNA, ribonucleic acid; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

PREVENTION OF COVID-19 IN DIABETES MELLITUS this group of vulnerable individuals93. McElhaney et al.94
PATIENTS showed that antibody titers did not differ between elderly
General recommendations patients with and without diabetes mellitus who were vacci-
The prevention of COVID-19 includes maintaining good hand nated against influenza. Long-term antibody titers and antibody
hygiene, abiding by social distancing measures and avoiding persistence were also similar in patients with and without dia-
close contact with people who are unwell. Diabetes mellitus betes mellitus for at least up to 6 months95. In clinical practice,
patients should be encouraged to continue regular self-monitor- Wang et al.96 showed reductions in hospitalizations, respiratory
ing of blood glucose, maintain healthy nutrition, keep physically failure and mortality among elderly patients with diabetes mel-
active with home-based exercises, and have an adequate supply litus who were vaccinated against influenza. Similar results were
of and access to diabetes mellitus medications and supplies. also shown in a meta-analysis involving 170,924 participants,
Diabetes mellitus patients should also be educated on sick day although there were multiple confounders that weakened the
rules by their healthcare team. evidence97. With regard to pneumococcal infections, vaccina-
The use of remote consultation has also enabled care to be tions have also shown mortality benefit in bacteremic pneumo-
delivered to diabetes mellitus patients while minimizing their coccal infection98.
exposure to SARS-CoV-2. The use of telemedicine has recently The efficacy of vaccinations might be of concern among
been shown to be effective in the management of even high- patients with type 1 diabetes mellitus, as it has been speculated
risk diabetes mellitus patients, such as those with newly diag- that they might not be able to mount sufficient immunological
nosed type 1 diabetes mellitus90. Before the COVID-19 pan- response99. Nevertheless, the overall response to vaccination
demic, a Cochrane review by Flodgren et al.91 showed that exceeds 70% among patients with diabetes mellitus, with type 2
interactive telemedicine can effectively assist physicians in the diabetes mellitus patients showing similar immune responses to
management of diabetes mellitus. Patients allocated to telemedi- controls98. As of 30 May 2020, there were 10 candidate vacci-
cine consultations had a lower HbA1c compared with usual nes for COVID-19 under investigation100.
care at a median of 9 months’ follow up. The COVID-19 pan-
demic is expected to accelerate the transformation of healthcare CONCLUSIONS
delivery and increase the use of telemedicine in the manage- With the exponential increase in the number of new COVID-
ment of chronic diseases. 19 cases, it has been postulated that this pandemic might per-
sist for the next few months and could even recur seasonally.
Vaccinations in diabetes mellitus patients The coexistence of two global pandemics – COVID-19 and dia-
Vaccinations have major public health benefits by providing betes mellitus – has significant clinical implications, and
direct protection to those who are vaccinated, as well as indirect impacts on morbidity and mortality. It is therefore crucial for
protection to the unvaccinated, but susceptible, individuals92. clinicians caring for people with diabetes mellitus and COVID-
In patients with diabetes mellitus, their innate cellular 19 to be aware of the metabolic risk factors associated with dis-
immune response is decreased, which increases their risk of ease severity, and keep abreast of the latest developments
developing infections. Despite this, influenza vaccination is emerging on the metabolic interactions between antidiabetic
effective in diabetes patients and it is important to vaccinate agents, RAAS inhibitors and potential drug treatments for

1110 J Diabetes Investig Vol. 11 No. 5 September 2020 ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
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http://wileyonlinelibrary.com/journal/jdi COVID-19 and diabetes mellitus

COVID-19 (Figure 1). Last, but not least, we highlight the 14. Tsalamandris S, Antonopoulos AS, Oikonomou E, et al. The
importance of timely vaccinations for individuals with diabetes role of inflammation in diabetes: current concepts and
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ening infection. The evidence on COVID-19 is evolving rapidly, delay the viral clearance in COVID-19 patients. medRxiv
and further metabolic interactions, both acute and long-term 2020. https://doi.org/10.1101/2020.03.22.20040774
outcomes, will surface with increasing data made available. 16. Vaduganathan M, Vardeny O, Michel T, et al. Renin-
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