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Review Article

COVID‑19, Hypertension, and Diabetes – Hunt for the Link!

Kaustav Saha, Shatavisa Mukherjee
Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India

Abstract
The recent pandemic outbreak of coronavirus disease 2019 (COVID‑19) has left everyone baffled. The exponential rise in deaths worldwide,
with such an extensive rapid spread, has made it a public health emergency. While the scientists at the frontier are untiringly putting their
utmost efforts to come up with evidence‑based pharmacological interventions, attempts have also been made to demystify the disease link
with associated comorbidities and further risk prognostication. The presence of comorbidities has been documented to be associated with
increased risk of developing acute respiratory diseases. Older hypertensives have been posed to be at greater risk of being affected, with
associated complications and severity in grade. Diabetic and obese individuals have also been shown to be in increased risk of infections
and other complications. Cytokine storm, a major complication of this disease, has also led to adverse renal outcomes. The present review
aimed to probe the possible link between COVID‑19 and various comorbidities.

Keywords: Comorbidities, coronavirus disease 2019, diabetes, hypertension

Introduction congestion, runny nose, sore throat, and diarrhea.[5] Current

In late December 2019, the first pneumonia cases of unknown
origin were identified in Wuhan, the capital city of Hubei
province in Central China.[1] The causative pathogen was
identified as a novel enveloped RNA betacoronavirus. Owing
to the phylogenetic similarity to the previously isolated severe
acute respiratory syndrome coronavirus (SARS‑CoV), the new
virus has been named SARS‑CoV‑2.[2] The rapid outbreak of
coronavirus disease 2019 (COVID‑19) has now become a
public health emergency of international concern contributing
to a huge adverse impact globally. There have been 3,221,029
laboratory‑confirmed cases and 228,252 deaths globally as
of April 30, 2020, with figures on an exponential rise daily.[3]
The World Health Organization (WHO) declared COVID‑19 a
pandemic health emergency. Person‑to‑person transmission of
this virus occurs mainly through close contact with an infected
person, primarily via respiratory droplets and after touching
contaminated objects.[4] The clinical spectrum of SARS‑CoV‑2
infection appears to be wide and heterogeneous, encompassing
asymptomatic infection, mild upper respiratory tract illness,
and severe viral pneumonia with respiratory failure and even
death. With severity varying from mild to moderate, mostly
symptoms mainly include fever, tiredness, and dry cough,
however, people have also experienced aches and pains, nasal
evidence suggests that the incubation period may last for
1–14 days, with a mean duration of 5–7 days.[6] The peak
viremia occurs at the end of the incubation period and before
the onset of symptoms, suggesting that transmission begins
1–2 days before the onset of symptoms.[7] One of the putative
mechanisms of viral entry depends on the binding of the viral
spike (S) proteins to angiotensin‑converting enzyme 2 (ACE2)
cellular receptors and on the S protein priming by the host
cellular serine protease TMPRSS2. The understanding of the
host‑virus immunologic interaction is still incomplete.[8]
The infection spread has been on exponential rise due
to transmission potential by asymptomatic or minimally
symptomatic patients.[9] India in combating this situation
has mainly focused on containment strategy which involves
quarantining individuals coming from a high transmission
area, isolation of infected individuals, contact tracing as well
Address for correspondence: Miss. Shatavisa Mukherjee,
Department of Clinical and Experimental Pharmacology, Calcutta School of
Tropical Medicine, Kolkata ‑ 700 073, West Bengal, India.
E‑mail: shatavisa100@gmail.com
Submitted: 01‑May‑2020 Revised: 20-Jun-2020
Accepted: 17-Aug-2020 Published: 31-Aug-2021

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DOI:
10.4103/jpcs.jpcs_40_20 How to cite this article: Saha K, Mukherjee S. COVID‑19, hypertension,
and diabetes – Hunt for the link!. J Pract Cardiovasc Sci 2021;7:108-12.

108 © 2021 Journal of the Practice of Cardiovascular Sciences | Published by Wolters Kluwer - Medknow
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Saha and Mukherjee: COVID-19, hypertension and diabetes
as reducing the movement of people in areas that have a high
caseload.[10] Regarded as a voluntary measure taken up by a
person himself or in advice of his/her health‑care professionals,
self‑isolation is a condition when a person experiencing any
cardinal symptoms stays at home and does not go to work,
school, or public places. For all confirmed cases, self‑isolation
for 14 days, even after the disappearance of symptoms, has
been advocated as a precautionary measure. However, owing
to the unknown nature of the virus, it is quite unknown as
to how long people remain infectious even after they have
recovered. Abiding by the national advice in such cases has
been advocated. For reduction of SARS‑CoV‑2 transmission,
nonpharmacological interventions comprising repeated hand
hygiene, respiratory etiquettes, and social distancing have
been advocated. The WHO recommended maintaining at
least a 1‑m (3 feet) distance between oneself and others, as a
protective measure.
As reported till date, severity of this illness has been observed
to be majorly skewed toward the geriatric population, with a
higher prevalence of cardiovascular (CV) complications such
as hypertension and diabetes. Since this culprit virus largely
infects human cells via ACE2 receptor that acts on the renin–
angiotensin–aldosterone system (RAAS), sufficient suspicion
upsurges a keen hunt for link between hypertension and severe
COVID‑19 infection. This present narrative review tried to
explore possible links between COVID‑19 and other CV
risks. An extensive literature search was conducted using the
main online databases (PubMed, Google Scholar, MEDLINE,
UpToDate, Embase, and Web of Science) with keywords such
as “COVID‑19,” “SARS‑CoV‑2,” “Hypertension,” “Diabetes,”
and “Obesity.”
COVID and Comorbidities
Studies have demonstrated that the presence of any
commodities has been associated with a 3.4‑fold increased risk
of developing this acute respiratory distress syndrome (ARDS)
in affected patients. Patients with at least one comorbidities
have been associated with poor clinical outcomes. The most
common comorbidities associated with poorer prognosis
included diabetes, hypertension, respiratory diseases, cardiac
diseases, pregnancy, renal diseases, and malignancy.[11] Huang
et al. reported the clinical features of 41 confirmed patients and
indicated that 32% of them had underlying diseases including
cardiovascular disease (CVD), diabetes, hypertension,
and chronic obstructive pulmonary disease (COPD). [12]
Subsequently, Wang et al. reported findings from 138 cases
of COVID‑19 of which 46.4% had comorbidities. Almost
72.2% admitted to the intensive care units had comorbidities,
thus suggesting that comorbidities may be risk factors for
adverse outcomes.[13] Like other avian influenza, COVID‑19
is more readily predisposed to respiratory failure and death in
susceptible patients. Older age and male sex have been some
of the significant clinical predictors of worse COVID‑19
prognosis.[14] Studies commenting on the association suggest
that hypertension carries a nearly 2.5‑fold higher risk of
Journal of the Practice of Cardiovascular Sciences ¦ Volume 7 ¦ Issue 2 ¦ May-August 2021
developing severe disease or dying from SARS‑CoV‑2
infection. This is in comparison to other comorbidities,
such as COPD (over 5‑fold higher risk) or chronic kidney
disease (over 3‑fold higher risk).[15] Researches indicated that
SARS‑CoV infections led to immune dysregulation which
explains the escalated risk of cardiac diseases, bone diseases,
and malignancy, thus suggesting immune dysregulation and
prolonged inflammation to be potential drivers of the poor
clinical outcomes in COVID‑19 patients, though it awaits
robust verification with further studies. Thus, assessment
of the prevalence of various underlying conditions is the
basis for mitigating complications in patients infected with
SARS‑CoV‑2.[16]
Data collected by the newly created COVID‑19‑Associated
Hospitalization Surveillance Network (COVID‑NET) showed
that almost 90% of hospitalized patients have some type of
underlying condition, with the hospitalization rate being
4.6 per 100,000 populations. The hospitalization rate is shown
to be increasing with increasing patients’ age, and those aged
65 years and older also were the most likely to have one
or more underlying conditions.[17] Women are less likely to
be affected by many bacteria and viruses than men, partly
because of their more robust innate and adaptive immune
responses.[18] Elderly people and severe patients are more
susceptible to SARS‑CoV‑2, which may be associated with a
higher frequency of comorbidities.[19]
Hypertension
Hypertension was the most common comorbidity among
the oldest patients, with a high prevalence rate of 72.6%,
followed by CVD at 50.8% and obesity at 41%. In the
two younger groups, obesity was the condition most often
seen in COVID‑19 patients, with prevalences of 49% in
50–64‑year‑olds and 59% in those aged 18–49 years.[20] A
meta‑analysis of the comorbidities suggested that hypertension
was prevalent in approximately 21.1% of the patients, while
diabetes, CVD, and respiratory system disease were present
in 9.7%, 8.4%, and 1.5% of the cases, respectively. Older
hypertensive individuals are at greater risk of being affected
with COVID‑19, with associated complications and severity
in grade. However, it is unclear whether uncontrolled blood
pressure is a risk factor for acquiring COVID‑19, or whether
controlled blood pressure among patients with hypertension
is or is not less of a risk factor.[21]
Diabetes
Diabetes is a risk factor for hospitalization and mortality of
the COVID‑19 infection. Studies have suggested that diabetes
has been comorbidity in 22% of 32 nonsurvivors in a study of
52 intensive care patients. In another study of 173 cases with
severe disease, 16.2% had diabetes, and in further study of
140 hospitalized patients, 12% had diabetes. When comparing
intensive care and nonintensive care patients with COVID‑19,
there appears to be a two‑fold increase in the incidence of
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Saha and Mukherjee: COVID-19, hypertension and diabetes
patients in intensive care having diabetes.[22] Individuals
with diabetes are at increased risk of infections, including
influenza, and for related complications such as secondary
bacterial pneumonia. The same can be postulated as diabetes
patients have impaired immune response to infection both in
relation to cytokine profile and to changes in immune responses
including T‑cell and macrophage activation. Poor glycemic
control impairs several aspects of the immune response to
viral infection and also to the potential bacterial secondary
infection in the lungs.[23] Moreover, diabetic complications
such as diabetic kidney disease and ischemic heart disease
may complicate the situation in COVID patients, increasing
the severity and the need for acute dialysis. Furthermore,
COVID‑19 could cause acute myocardial injury with heart
failure, leading to impaired circulation.
Both hypertension and diabetes are often treated with ACE
inhibitors. There has been a considerable uproar in finding links
between the use of ACE inhibitors and COVID‑19.
COVID–Hypertension–Diabetes – Angiotensin-
Converting Enzyme Inhibitors Linked?
SARS‑CoV and SARS‑CoV‑2 bind to their target cells through
ACE2, expressed by epithelial cells of the lung, intestine,
kidney, and blood vessels. In patients with hypertension
or type 1/2 diabetes, who are treated with ACE inhibitors
and angiotensin II type I receptor blockers (ARBs), the
expression of ACE2 receptor are substantially increased. ACE2
receptor can also be increased by antidiabetic agents like
thiazolidinediones and nonsteroidal anti‑inflammatory drug
like ibuprofen. Studies thus hypothesized that treatment with
ACE2‑stimulating drugs increases the binding of SARS‑Cov‑2
to the lung surface and in this way leads to lung injury and risk
of developing severe and fatal COVID‑19. On the contrary,
experimental studies have shown ACE2 to be protective against
lung injury. ACE2 forms angiotensin 1–7 from angiotensin II,
and thus reduces the inflammatory action of angiotensin II,
and increases the potential of the anti‑inflammatory effects
of angiotensin 1–7. Accordingly, by reducing either
formation of angiotensin II in the case of ACE inhibitors,
or by antagonizing the action of angiotensin II by blocking
angiotensin AT1 receptors in the case of ARBs, these agents
could actually contribute to reduced inflammation systemically
and particularly in the lung, heart, and kidney. Hence, drugs
acting on RAAS may reduce the potential for development
of complications such as ARDS, acute kidney injury (AKI),
and myocarditis in COVID‑19 patients.[24,25] In fact, ARBs
have been suggested as a treatment for COVID‑19 and its
complications. Increased soluble ACE2 in the circulation
could bind SARS‑CoV‑2, reducing its ability to injure the
lungs and other ACE2‑bearing organs. Recombinant ACE2
could be a potential therapeutic approach in reducing viral
load by binding circulating SARS‑CoV‑2 and reducing their
potential attachment to tissue ACE2. None of these possibilities
have, however, been demonstrated in patients yet. A study
110 Journal of the Practice of Cardiovascular Sciences ¦ Volume 7 ¦ Issue 2 ¦ May-August 2021
from China included 42 hospitalized COVID‑19 patients on
antihypertensive therapy.[26] Results showed that those on ACE
inhibitor/ARB therapy had a lower rate of severe disease and
a trend toward a lower level of interleukin (IL)‑6 in peripheral
blood. In addition, patients on ACE inhibitor/ARB therapy
had increased CD3+ and CD8+ T‑cell counts in peripheral
blood and decreased peak viral load compared with other
antihypertensive drugs.
A study by Juyi Li published in JAMA Cardiology reported
on a case series of 1178 patients hospitalized with COVID‑19
at the Central Hospital of Wuhan in China, between January
15 and March 15, 2020. Of the 1178 patients, 30.7% had a
diagnosis of hypertension. These patients were older in age
and had a greater prevalence of chronic diseases. Patients
with hypertension also had more severe manifestations of
COVID‑19 compared to those without hypertension, including
higher rates of ARDS and inhospital mortality. 31.8% of total
hypertension cases were on ACE inhibitors or ARBs and had
similar comorbidities to those not taking these medications,
with similar laboratory profile results including blood counts,
inflammatory markers, renal and liver function tests, and
cardiac biomarkers, although those taking ACE inhibitors/
ARBs had higher levels of alkaline phosphatase.[27]
Researchers are also probing genetic predisposition for an
increased risk of SARS‑CoV‑2 infection, which might be due
to ACE2 polymorphisms that have been linked to diabetes
mellitus, cerebral stroke, and hypertension, specifically in Asian
populations. Monitoring of ACE2‑modulating medications,
such as ACE inhibitors or ARBs, has been suggested in patients
with CV comorbidities on ACE2‑increasing drugs who might
be at higher risk for severe COVID‑19 infection.[24]
Obesity
Many patients with type 2 diabetes are obese, and obesity is
also a risk factor for severe infection. It was illustrated during
the influenza A H1N1 epidemic in 2009 that the disease was
more severe and had a longer duration in about two‑fold more
patients with obesity who were then treated in intensive care
units compared with the background population. Especially,
metabolic active abdominal obesity is associated with higher
risk. The abnormal secretion of adipokines and cytokines such
as tumor necrosis factor‑alpha and interferon characterizes a
chronic low‑grade in abdominal obesity and may induce an
impaired immune response. People with severe abdominal
obesity also have mechanical respiratory problems, with
reduced ventilation of the basal lung sections increasing the
risk of pneumonia as well as reduced oxygen saturation of
blood.[28] Obese patients also have an increased asthma risk, and
those patients with obesity and asthma have more symptoms,
more frequent and severe exacerbations, and reduced response
to several asthma medications. Preliminary data suggest that
people with obesity are at increased risk of severe COVID‑19.
However, as data on metabolic parameters in patients with
COVID‑19 are scarce, increased reporting is needed to improve
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Saha and Mukherjee: COVID-19, hypertension and diabetes
the understanding of COVID‑19 and the care of affected
patients. For better estimating the risk of complications in
patients with COVID‑19, in addition to evaluation of standard
hospital parameters, the measurement of anthropometrics and
metabolic parameters is crucial. These parameters include
body mass index, waist and hip circumferences, and levels of
glucose and insulin.[29,30]
Chronic Obstructive Pulmonary Disease
COVID‑19 is an acute respiratory disease that can lead to
respiratory failure and death. Previous epidemics of novel
coronavirus diseases, such as SARS and Middle East
respiratory syndrome, were associated with similar clinical
features and outcomes. One might anticipate that patients
with chronic respiratory diseases, particularly COPD and
asthma, would be at increased risk of SARS‑CoV‑2 infection
and more severe presentations of COVID‑19. However, it
is striking that both diseases appear to be under‑represented
in the comorbidities reported for patients with COVID‑19,
compared with the global burden of disease estimates of the
prevalence of these conditions. The lower reported prevalence
of asthma and COPD in patients diagnosed with COVID‑19
might be due to one or a number of factors like underdiagnosis
and varied immune response elicited by the chronic disease
itself. However, this theory is not supported by the finding that
among those with COVID‑19 who have COPD as comorbidity,
mortality is increased, as would otherwise be expected.[31]
Another possibility is that the therapies used by patients with
chronic respiratory diseases can reduce the risk of infection or
of developing symptoms leading to diagnosis. In vitro studies
have shown inhaled corticosteroids alone or in combination
with bronchodilators suppressing coronavirus replication and
cytokine production. A case series in Japan[32] demonstrated
improvement seen in three patients with COVID‑19 requiring
oxygen, but not ventilatory support, after being given inhaled
ciclesonide; however, no control group was used and it is
not known whether these patients would have improved
spontaneously. More robust evidence can embark on the
same.[33]
Renal Failure
Emerging evidence suggests the possibility of a direct
cytopathic effect of SARS‑CoV‑2. ACE2 and members of
the serine protease family, essential for viral uptake by host
cells, are highly expressed on podocytes and tubule epithelial
cells. Reports of albuminuria and hematuria along with viral
RNA isolation from the urine further support potential viral
tropism for the kidney.[34] Cytokine release syndrome (CRS),
also termed “cytokine storm,” can occur in various conditions
including sepsis, hemophagocytic syndrome, and chimeric
antigen receptor (CAR) T‑cell therapy. The occurrence of
CRS in COVID‑19 has also been documented. In patients with
CRS, AKI might occur as a result of intrarenal inflammation,
increased vascular permeability, volume depletion, and
Journal of the Practice of Cardiovascular Sciences ¦ Volume 7 ¦ Issue 2 ¦ May-August 2021
cardiomyopathy, which can lead to type 1 cardiorenal
syndrome. Pro‑inflammatory IL‑6 is considered to be the most
important causative cytokine in CRS. Among patients with
COVID‑19, the plasma concentration of IL‑6 is increased
in those with ARDS. Tocilizumab, an anti‑IL‑6 monoclonal
antibody, is widely used to treat CRS in patients who have
undergone CAR T‑cell therapy and is thus being used now
as an empiric approach in patients with severe COVID‑19.
However, extracorporeal membrane oxygenation, invasive
mechanical ventilation, and continuous kidney replacement
therapy can also contribute to cytokine generation and have
been proposed beneficial in critically ill COVID‑19 patients as
cytokine removal could prevent CRS‑induced organ damage.[35]
Cancer
Liang et al. in a prospective cohort of 1571 patients with
COVID‑19 reported 18 of them having a prior history of
cancer had a higher incidence of severe events. However, it did
not establish a definitive increase in incidence of COVID‑19
infection.[36]
Conclusion
Studies as of now have postulated that laboratory‑confirmed
cases of COVID‑19 with one or more comorbidities have
yielded poorer clinical outcomes than those without. With
older age and male sex being a significant clinical predictor
of COVID‑19, the most prevalent comorbidities were
hypertension, followed by diabetes. Studies have probed the
association and found hypertensive, diabetic, and renal patients
at greater risk of COVID‑19. Increased incidence has been
observed in obese individuals in intensive care. However,
considering the dynamic behavior of the virus, more research
findings can test the hypothesis and embark on the definitive
mechanism underlying the same. A thorough assessment of
comorbidities may help establish risk stratification of patients
with COVID‑19 upon hospital admission.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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