Sodium-glucose infection triggered DKA in most of T2DM.

Sodium-glucose
co-transporter-2 inhibitors (SGLT2i) are the newest oral antihyperglycemic
medications to be approved in 2013 by the Food and Drug Administration (FDA)
for the treatment of patients with type 2 diabetes mellitus (T2DM).
SGLT2 inhibitors help in reduction in blood glucose without stimulating insulin
release.  It also help weight loss and
decrease blood pressure. Its use is rising and is being one of the favorites
among clinicians. In 2015, FDA released warning about Diabetes
Ketoacidosis  with normal glucose (EuDKA)
as potential side effect of SGLT2i. In this review we tried to investigate the
relationship between SGLT-2 inhibitor and EuDKA in patients with diabetes.

Numerous
databases were searched to identify appropriate primary literature. Search
terms included  SGLT2, sodium-glucose
cotransporter-2 inhibitor, diabetic ketoacidosis, ketoacidosis, metabolic
acidosis, and Euglycemic diabetes ketoacidosis. Primary literatures and case reports
were searched on Pubmed, Cochrane library and Google. Cases of DKA taking
SGLT-2 with blood sugar below 250mg/dl at presentation were only included.
Total of 26 cases were included for this review.  38% patient were T1DM and 61% were T2DM with
average blood glucose of 170.3 ± 43.3 mg/dl. 77% cases were taking
Canagliflozin. All cases had low pH and high Anion Gap during presentation.
Major precipitating factors for T2DM were reduction in insulin dose where
surgery and infection triggered DKA in most of T2DM. Most common symptoms were
vomiting. Nausea and abdomen pain. Diagnosis difficulties were present due to
non markedly elevated blood sugar with three cases of misdiagnosis and delayed
treatment.  Almost all cases were treated
at ICU as typical DKA and responded well to IV fluids and Insulin. No death was
reported among these cases.

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We
concluded that, in absence of good laboratory resources EuDka can be very
difficult to diagnose. Clinician should be well aware of this condition of  DKA with normal glucose level. Precipitating
factor and detailed medical and dietary history may help to identify patient
with higher risk of developing DKA while using SGLT2 inhibitors.

 

 

Introduction

 

There is a rising worldwide prevalence of diabetes which
is one of the most challenging health problems in the 21st century. Globally,
an estimated 422 million adults were living with diabetes in 2014, compared to
108 million in 1980 with  prevalence  rising from 4.7% to 8.5% in the adult
population.1 American Diabetes Association
(ADA) states that One in three American adults will have diabetes in the year
2050 if current trends continue and estimates a person diagnosed at age 50 dies
six years earlier than a person without diabetes. Latest survey showed that  India has the highest number of people
suffering from diabetes followed by China and then United States.2

The
optimal treatments for diabetic patients are effective blood glucose control,
blood pressure and lipids control , and to avert the serious complications
associated with sustained tissue exposure to excessively high glucose
concentrations. Prevention and control of diabetes with diet, weight control,
and physical activity has been difficult. Different drugs including insulin are
used to control the high blood sugar but 
many still fails to reach the goal despite dedicated efforts to achieve
glycemic control.

 A new drug SGLT-2 inhibitor was approved by
FDA in 2013 for treatment of diabetes and has been showing its efficacy ever
since. But there have been reports of some life threatening side effects
associated with this class of drug, one of which is ketoacidosis with or
without elevated glucose level. In march 2015, FDA warned  that SGLT2 inhibitors for diabetes may result
in a the serious condition of too much acid in the blood and suggested
considering labeling the drug with warning of DKA.3

 

Sodium Glucose Co-Transporter 2
inhibitor

 

Sodium-glucose co-transporter-2 inhibitors
(SGLT2i) are the newest oral antihyperglycemic medications to be approved by
the Food and Drug Administration (FDA) for the treatment of patients with type
2 diabetes mellitus (T2DM). SGLT2 inhibitors provide insulin-independent
glucose lowering by blocking glucose reabsorption in the proximal renal tubule
by inhibiting SGLT2.4 SGLT2 inhibitors help in reduction
in blood glucose without stimulating insulin release. It also has other
beneficial effects on blood pressure (BP) reduction and weight loss.5 EMPA-REG OUTCOME study has
demonstrated the positive cardiovascular outcomes of SGLT2 inhibitors.6

 Approximately 180g of glucose per day is
filtered by the kidneys.7 These glucose are reabsorbed by
Sodium-glucose co-trasporter proteins at proximal tublules of the kidney.There
are several types of SGLT proteins that are insulin independent and inhibiting
these proteins resulted in changes that 
improved carbohydrate metabolism which became an attractive concept for
the treatment of diabetes8. SGLT1 proteins are high
affinity, low capacity transporters of glucose which are found in the small
intestines and the proximal tubule of the kidneys where as SGLT2 proteins are
found in the proximal convoluted tubule of the kidneys. The SGLT1 proteins in
the proximal convoluted tubule of the kidneys are responsible for less than 10%
of filtered glucose reabsorption where as SGLT2 
protiens are responsible for roughly 90% of filtered glucose
reabsorption making it a genuine target for diabetes treatment. 5 Also, SGLT1 has more gastrointestinal
side effects like severe diarrhea due to involvement in small intestine.9

 

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