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\begin{document}

\title{Euglycemic DKA (euDKA) as a presentation of COVID19}



\author[1]{Bhagwan Dass}%
\author[2]{Andrew Beck}%
\author[2]{Cody Holmes}%
\author[2]{Glenville Morton}%
\affil[1]{University of Florida}%
\affil[2]{Eglin Air Force Base}%


\vspace{-1em}



  
  \date{May 04, 2024}


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\selectlanguage{english}
\begin{abstract}
Euglycemic DKA (euDKA) is a serious side effect associated with SGLT2
inhibitors. We present a case euDKA in a patient on an SGLT-2 inhibitor
likely precipitated by COVID-19 infection. We suspect that COVID-19 led
to euDKA. We pose the question of whether these medications should be
discontinued proactively.%
\end{abstract}%



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\textbf{Keywords:~}

COVID-19, diabetic ketoacidosis, euglycemia, diabetes mellitus,
diabetes, diabetes type 2, type I diabetes mellitus

\textbf{Key Clinical Message:}

COVID-19 in the setting of SGLT2 inhibitor use may precipitate
euglycemic DKA separate from known acute viral illness and dehydration
precipitants. There should be consideration of proactive discontinuation
of these medications in these patients.

\textbf{Introduction} :

Diabetic ketoacidosis (DKA) is a medical emergency characterized by
hyperglycemia, metabolic acidosis, and ketosis. EuDKA differs from
typical DKA in that it often presents with serious metabolic acidosis
but only mild to moderate glucose elevation (\textless{}200
mg/dl)\textsuperscript{1}. Known precipitants for euDKA include severe
acute illness, dehydration, extreme physical activity, surgery, low
carbohydrate intake, fasting, excessive alcohol intake, and SGLT2
inhibitors\textsuperscript{2}.

Diabetes is associated with an increased risk of severe COVID-19 with
both higher morbidity and mortality rates in patients with diabetes
mellitus\textsuperscript{3,4}. SARS-CoV-2 utilizes the ACE-2 receptor
for viral entry, which is expressed in several organs, and may have
diabetogenic effects beyond the well-recognized stress response
associated with severe illness. The virus may cause alterations of
glucose metabolism at the tissue level directly and indirectly that
could complicate existing diabetes\textsuperscript{5}. COVID-19 may
alter the pathophysiology of preexisting diabetes~or worsen it with
associated complications such as ketoacidosis.

\textbf{Case Presentation} :

A 59 year-old female with history of documented type 2 diabetes on
empagliflozin, sitagliptin, and metformin presented with 9 days of
progressively worsening shortness of breath, low grade fevers, and
fatigue. She was seen two days prior in the emergency department and had
an elevated glucose of 198, normal CO2 of 22 (normal 20-31) on basic
metabolic panel and was found to have bilateral infiltrates on chest
x-ray. She was diagnosed with community acquired pneumonia and
discharged on doxycycline. On representation to the ED less than 48
hours later, she presented with tachypnea, tachycardia, and was found to
have a profound metabolic acidosis with significant respiratory
compensation with an associated non-gap acidosis as seen on her initial
ABG (pH of 6.94, PaCO2 of 13, PaO2 of 99 and a HCO3 of 3). On serum
analysis her lactate was 0.9, her glucose 154, confirmed bicarb of
\textless{}10, serum osmolality of 346, an elevated anion gap of 30,
beta-hydroxybutyrate of 95. Her urinalysis showed 3+ glucose and 2+
ketones. She had a negative UDS and salicylate levels were normal. She
was found to have a positive COVID-19 test and was admitted for
Euglycemic DKA (euDKA). She was started on an insulin drip and IV fluid
and had resolution over the next 2 days. After resolution of DKA the
patient was continued on her Sitagliptin and Metformin, but
Empagliflozin was discontinued given the association of SGLT2 inhibitors
with euDKA. She was also started on 20 units of insulin glargine nightly
which was continued upon discharge.

\textbf{Discussion} :

We performed a literature search of PubMed using a combination of the
words ``euglycemic diabetic ketoacidosis,'' ``COVID-19'' with ``SGLT2
inhibitors.'' To our knowledge this is the first case report in the
literature that documents DKA with normal glucose levels in the setting
of COVID-19 and SGLT2 inhibitor use in type 2 Diabetes (there is a case
report in type 1).

Diabetic ketoacidosis (DKA) is a medical emergency characterized by
hyperglycemia (blood sugar \textgreater{}250 mg/dl), metabolic acidosis
(arterial pH \textless{}7.3 and serum bicarbonate \textless{}18 mEq/L),
and ketosis -- Euglycemic DKA includes blood glucose levels \textless{}
200 mg/dl, arterial pH \textless{} 7.3, anion gap
\textgreater{} 12 mEq/L, HCO3- \textless{} 15 mEq/L and the presence of
ketones in blood and urine\textsuperscript{1}. EuDKA was first described
as a discrete entity by Munro et al. in 1973\textsuperscript{6}. EuDKA
differs from typical DKA in that it often presents with serious
metabolic acidosis but only mild to moderate glucose and anion gap
elevation. Diagnosis should be confirmed with the direct measurement of
the beta-hydroxybutyrate level in blood and arterial blood
pH\textsuperscript{7}. Known precipitants for euDKA include severe acute
illness, dehydration, extreme physical activity, surgery, low
carbohydrate intake, fasting, excessive alcohol intake, and SGLT2
inhibitors\textsuperscript{2}.

The increased risk of euDKA associated with SGLT2 inhibitors is well
known. In 2015, the FDA released safety warnings about the risk of euDKA
associated with SGLT2 inhibitors\textsuperscript{8}. The development of
euDKA with SGLT2 inhibitors is thought to involve decreased insulin
production and increase in secretion of glucagon. Increase in glucagon
levels is multifactorial including both direct and indirect mechanisms.
It is increased directly via effects on SGLT2 expressed in the
glucagon-secreting alpha pancreatic cells. SGLT2 inhibitors also
increase glucose excretion leading to relative lower levels of insulin
and low ratio of insulin to glucagon. The relative lack of insulin
stimulates the production of free fatty acids and ketone bodies and a
shift from glucose to fat metabolism causing
ketoacidosis\textsuperscript{9}.

Ketone production may be further stimulated in the setting of SGLT2
inhibitors by the lowering of glucose reabsorption in the proximal
tubules increasing glycosuria and possibly simulating starvation
conditions\textsuperscript{10}. Ketones can be excreted in the urine as
sodium salts and are essentially the equivalent to the loss of
bicarbonate causing metabolic acidosis\textsuperscript{11}.

In addition to SGLT2 inhibitors, the COVID-19 virus itself may be
directly linked to the development of euDKA. Studies have shown that
COVID-19 utilizes the ACE-2 receptor, which is expressed on human
pancreatic beta cells, to gain entry to and infect human cells. Once
inside the cell, an immune response is triggered which leads to the
production of cytokines and chemokines resulting directly in cell
death\textsuperscript{12}. A similar effect was seen in the similar
SARS-CoV-1 coronavirus in which the virus also utilized the ACE2
receptor in the islet cells of the pancreas to gain entry leading to
direct cellular destruction precipitating acute diabetes in a subset of
patients\textsuperscript{5}. Acute infection with COVID-19 could lead to
further decrease in insulin production, and predisposition to euDKA. Low
pH in DKA also favors the entry and replication of the SARS-CoV-2, and
development of DKA makes the disease course of COVID-19
worse\textsuperscript{13}.

In this case the development of euDKA was likely multifactorial in the
setting of COVID-19 infection and SGLT2 inhibitor use and it is likely
that COVID-19 was an inciting factor for euDKA. Our patient who was on
metformin and empagliflozin prior to COVID-19 infection ended up being
discharged on insulin most likely due to combination of COVID-19 illness
and impaired beta cell function in setting of SARS-CoV-2 Infection.

Physicians need to acquaint themselves with euDKA to promptly recognize
and treat this medical emergency. This is particularly imperative in
this pandemic of COVID-19 and wide-spread use of SGLT2 inhibitors given
their proven cardiovascular and renal benefits. We believe the risk of
SGLT2-inhibitor-associated euDKA can be reduced or prevented by
the~discontinuation of these medications during acute illness with
COVID-19

As the majority of COVID-19 patients with type 2 diabetes are managed as
an outpatient with home quarantine, one possible option is to stop SGLT2
inhibitors or reduce their dose.

As research is evolving there could be a potential role for dipeptidyl
peptidase 4 (DPP4)-inhibitors. DPP4-inhibitors might interfere with and
modify viral binding and hypothetically reduce virulence.
DPP4-inhibitors modulate inflammation and exert anti-fibrotic activity.
These properties may be of potential use for halting progression to the
hyper inflammatory state associated with severe
COVID-19\textsuperscript{14}. This interaction deserves further
investigation and possibly DPP4-inhibitor trial during active COVID-19
infection.

\textbf{References:}

\begin{enumerate}
\tightlist
\item
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\item
  Goldenberg, Ronald M et al. ``SGLT2 Inhibitor-associated Diabetic
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\item
  Roncon, Loris et al. ``Diabetic patients with COVID-19 infection are
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\item
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\item
  Yang, Jin-Kui et al. ``Binding of SARS coronavirus to its receptor
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\item
  Munro, J F et al. ``Euglycaemic diabetic ketoacidosis.''~\emph{British
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\item
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\item
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\item
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\item
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\item
  Yang et al., 2020, Cell Stem Cell 27, 125--136 July 2, 2020 \selectlanguage{ngerman}ª 2020
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\end{enumerate}

\textbf{Consent} : Informed consent was obtained from patient for the
study.

\textbf{Author contributions :}

BD, AB, CH wrote manuscript, revised and approved manuscript, MG, AB, CH
involved in patient management, revised manuscript, approved manuscript

\textbf{Conflict of interest --}

The authors declare that they have no conflicts of interest.\selectlanguage{english}
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