FROM: Diabetic Research and Clinical Practice
Should anti-diabetic
medications be reconsidered amid COVID-19 pandemic?
Published:April 10, 2020DOI:https://doi.org/10.1016/j.diabres.2020.108146
Keywords
·
COVID-19
·
T2DM
Ever since its outbreak in December 2019,
the novel coronavirus disease (COVID-19), caused by severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) has spread to more than 200 nations,
affecting over 509,000 individuals and inflicting over 23,000 fatalities
globally . Although the overall mortality rate is low, ranging from 1.4% to
7.2%, people with diabetes mellitus (DM) tend to have more severe disease,
acute respiratory distress syndrome and increased fatality . Of the 1099
confirmed COVID-19 patients reported from China, 173 had severe disease; DM was
more prevalent in those with severe disease (16.2%) as compared to those with
non-severe disease (5.7%)
In addition, DM has been reported to be
associated with poor prognosis in other viral infections, notably seasonal
influenza, pandemic influenza A H1N1 (2009), Severe Acute Respiratory Syndrome
(SARS) and Middle East Respiratory Syndrome (MERS). Proposed mechanisms for
this apparent association between COVID-19 and DM include impaired innate
immune system in people with DM. In addition, angiotensin-converting enzyme
inhibitors (ACEi) and angiotensin-receptor blockers (ARBs), used so widely in
people with DM have been implicated as a connecting link between COVID-19 and
DM. ACEi/ARBs leads to upregulation of angiotensin-converting enzyme 2 (ACE2),
a type 1 integral membrane glycoprotein that is constitutively expressed in the
lungs, heart, intestine, kidney and vascular endothelium. SARS-CoV-2 utilizes
ACE2 as a receptor for entry into host pneumocytes, hence, upregulation of ACE2
by ACEi/ARBs might explain the severe and fatal consequences of COVID-19
Considering the
high-risk, persons with DM should take extra precautions amid COVID-19
pandemic. Strict social distancing and proper hang hygiene should be the norm.
Good glycemic control should be of at most importance as it has been shown to
boost the innate immune system. Although it would be wise to stick to the
ongoing therapy or intensify the same, physicians may however consider
reviewing the prescription (Table 1).
Table
1Table showing
commonly prescribed anti-diabetic drugs and concerns regarding their use during
COVID-19 pandemic. ACE2 (angiotensin-converting enzyme 2) acts as a receptor
for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Thus, any
anti-diabetic drug that upregulates ACE2 directly or indirectly by inhibition
of ADAM-17 (a disintegrin and metalloproteinase-17, an enzyme that cleaves and
inactivates ACE2) is theoretically expected to promote SARS-CoV-2 infection.
|
Anti-diabetic drug
|
Data from animal studies
|
Data from human studies
|
Concerns for use during COVID-19 pandemic
|
|
Insulin
|
Reduces
renal ADAM-17 expression in diabetic mice thereby reducing urinary ACE2
shedding and increasing intrarenal ACE2 expression
|
–
|
No human
data to support poor outcome
|
|
Metformin
|
–
|
–
|
No concern
|
|
Sulfonylureas
|
–
|
–
|
No concern
|
|
Pioglitazone
|
Upregulation
of ACE2 in insulin-sensitive tissues of rats
|
Downregulation
of ADAM-17 in human skeletal muscles
|
Theoretical
risk of poor outcome, however, no data on human pulmonary ACE2 expression
|
|
Liraglutide
|
Upregulates
ACE2 in cardiac and pulmonary tissues of diabetic rats
|
–
|
Theoretical
risk of poor outcome, however, no data on human pulmonary ACE2 expression
|
|
SGLT2 inhibitors
|
–
|
Promotion
of renal ACE2 activity
|
Theoretical
risk of poor outcome, however, no data on human pulmonary ACE2 expression
|
|
DPP4 inhibitors
|
DPP4H/M mice develops severe disease
with MERS-CoV
DPP4i do not alter ACE2 activity in diabetic mice |
DPP4i
might exert overall anti-inflammatory role
|
Theoretically,
DPP4 modulation might help offset the cytokine-mediated acute respiratory
complications of COVID-19
|
|
Hydroxychloroquine
|
–
|
Reduction
of viral load in COVID-19
|
Can be
considered as a third-line add on drug in patients with poor glycemic control
|
COVID-19:
Coronavirus disease 2019; ACE2: Angiotensin-converting enzyme 2; ADAM-17: a
disintegrin and metalloproteinase-17; SGLT2: Sodium-glucose transporter 2;
DPP4: Dipeptidyl peptidase 4; DPP4H/M: Transgenic diabetic mice expressing human DPP4; MERS-CoV: Middle East
Respiratory Syndrome – Coronavirus.
Insulin is a safe choice under most circumstances and
remains the sole therapy for people with type 1 diabetes mellitus and can be
considered as a superior alternative in people with type 2 diabetes mellitus
(T2DM) having poor glycemic control. Although no direct effect on ACE2 is
reported, insulin treatment has been shown to attenuate renal ADAM-17 (a
disintegrin and metalloproteinase-17) expression in diabetic Akita mice . In
normal physiology, ADAM-17 cleaves ACE2, thereby inactivating the enzyme.
Whether the same phenomenon is replicated in human pneumocytes is not known.
Metformin and sulfonylureas exhibits no interaction with either ACE2 or ADAM-17
and can be safely continued. On the contrary, pioglitazone has been shown to
upregulate ACE2 in insulin-sensitive tissues in rats and reduce ADAM-17 activity
in human skeletal muscles . Similarly, liraglutide, a glucagon-like
peptide 1 (GLP1) analogue, increases cardiac and pulmonary ACE2 expression in
Type 1 diabetic rats . Data also supports promotion of ACE2 activity by
sodium-glucose transporter 2 inhibitors (SGLT2i); this has been proposed as a
plausible mechanism of renoprotection with this class of drugs .
The use of
dipeptidyl peptidase 4 inhibitors (DPP4i) in the present scenario merits
detailed discussion. DPP4i target the enzymatic activity of DPP4, a type II
transmembrane glycoprotein, expressed ubiquitously in many tissues, including
immune cells. Apart from breaking down circulating GLP1, DPP4 activates
T-cells, upregulates CD86 expression and NF-κβ pathway, thereby promoting inflammation. Hence, inhibition of DPP4 has
given rise to concerns regarding a possible increase in the risk of infections.
A few meta-analyses have identified an increased risk of nasopharyngitis and
urinary tract infection while others have negated this finding. In addition,
human DPP4 acts as a functional receptor for MERS-CoV (MERS-Coronavirus).
Transgenic diabetic mice expressing human DPP4 (DPP4H/M mice) developed a prolonged phase
of severe disease and delayed recovery upon infection with MERS-CoV. Although
SARS-CoV-2 does not require DPP4, the potential anti-inflammatory role of DPP4i
raises questions as to whether DPP4 modulation might help offset the
cytokine-mediated acute respiratory complications of COVID-19 . Nonetheless,
DPP4i do not alter ACE2 expression as shown in diabetic mice.
Although rarely
used, hydroxychloroquine can be good choice under present circumstances.
Hydroxychloroquine, at a dose of 400 mg once a day, is approved by the Drug
Controller General of India (DCGI) as a third-line add-on anti-diabetic drug
after metformin and sulfonylurea in people with T2DM . The drug acts by raising
intracellular pH that inhibits enzymatic degradation of insulin, resulting in
recirculation of substantial proportion of insulin in active form. Consistent
with its immunomodulator property, hydroxychloroquine also reduces pro-inflammatory
cytokines, notably TNFα and IL6, thereby decreasing insulin
resistance. Interestingly, hydroxychloroquine has also been found to be
effective against SARS-CoV-2 in-vitro and in
reducing viral load in COVID-19 patients. Mechanisms of action include impaired
binding between host ACE2 and SARS-CoV-2 spike protein and increased
intracellular/endosomal pH that inhibits antigen-presentation, T-cell
activation, cytosolic Toll-like receptor (TLR)-signaling and transcription of
pro-inflammatory cytokines, thereby, averting a cytokine storm . The drug has
even been used as a prophylaxis against COVID-19 in many countries and the
Indian Council of Medical Research (ICMR) has recently approved the
prophylactic use of this drug in high-risk groups including healthcare workers
at risk of infection.
Although there
is no dearth of animal data, robust human studies in the field of COVID-19 and
use of anti-diabetic medications are lacking. Hence, in the absence of strong
evidence, it would be extremely unwise to consider one drug over the other.
Good glycemic control should be the goal, no matter what drugs are being used.
However, considering the low-cost, widespread availability, modest HbA1c
reduction, once-daily dosing and relatively good tolerability,
hydroxychloroquine may be a good add-on drug during this outbreak for patients
with poor glucose control. Presence of diabetic retinopathy and cardiomyopathy
should be investigated prior to recommending hydroxychloroquine.
Funding
None.
Declaration
of Competing Interest
The authors declare that they have no
conflicts of interest.
Acknowledgement
None.
References
1.
Coronavirus disease 2019 (COVID-19) Situation Report -
67. Accessed March 28, 2020. Available from: https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200327-sitrep-67-covid-19.pdf?sfvrsn=b65f68eb_4.
2.
Guan W, Ni Z, Hu Y,
Liang W, Ou C, He J, et al. Clinical Characteristics of Coronavirus Disease 2019
in China. N Engl J Med [Internet]. 2020 [cited 2020 Mar 20]; Available from: http://www.nejm.org/doi/10.1056/NEJMoa2002032.
3.
Fang L, Karakiulakis G, Roth M. Are patients with
hypertension and diabetes mellitus at increased risk for COVID-19 infection?
Lancet Respir Med [Internet]. 2020 [cited 2020 Mar 20]; Available from: https://linkinghub.elsevier.com/retrieve/pii/S2213260020301168.
4.
o Salem E.S.B.
o Grobe N.
o Elased K.M.
Insulin
treatment attenuates renal ADAM17 and ACE2 shedding in diabetic Akita mice.
Am J Physiol-Ren Physiol. 2014; 306: F629-F639
o PubMed
o Crossref
5.
o Tripathy D.
o Daniele G.
o Fiorentino T.V.
o Perez-Cadena Z.
o Chavez-Velasquez A.
o Kamath S.
o et al.
Pioglitazone
improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in
type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled,
mechanistic study.
Diabetologia. 2013; 56: 2153-2163
o PubMed
o Crossref
6.
o Romaní-Pérez M.
o Outeiriño-Iglesias V.
o Moya C.M.
o Santisteban P.
o González-Matías L.C.
o Vigo E.
o et al.
Activation of
the GLP-1 receptor by liraglutide increases ACE2 expression, reversing right
ventricle hypertrophy, and improving the production of SP-A and SP-B in the
lungs of type 1 diabetes rats.
Endocrinology. 2015; 156: 3559-3569
o PubMed
o Crossref
7.
o Kawanami D.
o Matoba K.
o Takeda Y.
o Nagai Y.
o Akamine T.
o Yokota T.
o et al.
SGLT2
inhibitors as a therapeutic option for diabetic nephropathy.
Int J Mol Sci. 2017; 18: 1083
o Crossref
8.
o Iacobellis G.
COVID-19 and
diabetes: can DPP4 inhibition play a role?.
Diabetes Res Clin Pract. 2020; 162: 108125
o PubMed
o Abstract
9.
o Baidya A.
o Ahmed R.
Effect of early
addition of hydroxychloroquine in type 2 diabetic patients inadequately
controlled on metformin and sulfonylurea combination therapy.
Int J Res Med Sci. 2018 Jul; 25: 2626
o Crossref
10.
Zhou D, Dai S-M, Tong Q. COVID-19: a recommendation to
examine the effect of hydroxychloroquine in preventing infection and
progression. J Antimicrob Chemother [Internet]. 2020 [cited 2020 Mar 25];
Available from: https://academic.oup.com/jac/advance-article/doi/10.1093/jac/dkaa114/5810487.
Article
Info
Publication
History
Published online: April 10, 2020
Accepted: April 4, 2020
Received: April 3, 2020
Identification
Copyright
© 2020 Elsevier B.V. All rights
reserved.
