Discussion
Herein, we described a case of EDKA induced by SGLT2i while on a
very-low-carbohydrate diet. Since islet-associated autoantibodies were
negative and insulin secretory capacity was preserved, this case was
diagnosed as T2DM with EDKA.
DKA is an acute life-threatening complication in patients with T1DM and
T2DM, with diagnostic criteria including a high anion gap metabolic
acidosis (pH <7.3 and serum bicarbonate <15 mmol/L),
ketone bodies in the blood and/or urine, and hyperglycemia
(>250 mg/dL) [9]. On the contrary, EDKA was first
reported by Munro et al. in 1973 as a rare DKA condition that develops
in T1DM [5]. Despite the lack of unified diagnostic criteria, EDKA
is a subgroup of DKA without a concurrent rise in blood glucose levels
<200–250 mg/dL [10]; since the start of using SGLT2i for
the treatment of diabetes, reports of EDKA associated with SGLT2i have
increased [11]. An analysis of the Food and Drug Administration’s
adverse event reporting system described a sevenfold increased risk of
developing DKA due to SGLT2i, and around two-thirds of the reported DKA
cases were in euglycemia [12]. Multiple factors are assumed to be
involved in the association between SGLT2i and EDKA. SGLT2i decreases
blood glucose levels via increased urinary glucose excretion, which is
considered to result in a relative reduction in insulin secretion,
leading to a lower insulin/glucagon ratio, which enhances lipolysis, and
free fatty acids are metabolized in the liver to produce ketone bodies.
SGLT2i is also supposed to decrease ketone excretion by the kidneys, and
a combination of these factors is responsible for the elevated blood
ketones and ketoacidosis. Other factors that have been implicated in the
development of EDKA include starvation, acute infection, pregnancy,
low-carbohydrate diet, dehydration, insulin depletion, and vigorous
exercise [13].
The consensus report issued by the ADA defines a very-low-carbohydrate
diet as reducing carbohydrate intake to <26% of the total
calories, and a carbohydrate intake of 20–50 g/day. This report
indicates that low- and very-low-carbohydrate diets are viable
approaches for select patients with T2DM who are not meeting glycemic
targets or in whom reducing antiglycemic medications is a priority
[8]. However, a very-low-carbohydrate diet may cause nutritional
ketosis; thus, further studies are needed to determine its effectiveness
in preventing long-term complications. The patient had been on a
very-low-carbohydrate diet with a carbohydrate intake of 20–40 g/day
for approximately 5 years, which likely led to a chronic increase in
ketone bodies in the blood. The addition of an SGLT2i in such a chronic
hyperketonic state may lead to EDKA in a very short period of 3 days.
The treatment of EDKA generally follows the usual form of DKA treatment,
which requires intravenous administration of rapid-acting insulin and
large volumes of infusions. However, early glucose replacement may be
also necessary to prevent hypoglycemia. On the contrary, there was a
case report of a patient with SGLT2i-induced EDKA who required insulin
administration only for the first 3 h of treatment and could be treated
only with a glucose-containing infusion [14]. Since EDKA is
primarily due to an absolute lack of available glucose and increased
urinary glucose excretion by SGLT2i, whereas DKA is primarily due to
significant insulin deficiency, cases of EDKA with preserved insulin
secretory capacity may not require continuous insulin administration and
may be treatable only by the cessation of SGLT2i and appropriate glucose
replacement. However, even though the patient had preserved insulin
secretory capacity, glucose administration markedly elevated the blood
glucose level, requiring continuous administration of high-dose insulin;
further case studies are needed to determine the treatment strategy for
EDKA. The STICH protocol has been proposed for the treatment of DKA
complicated by T1DM on SGLT2i, which consists of (1) the discontinuation
of SGLT2i, (2) bolus insulin administration, (3) 30-g carbohydrate
intake, and (4) fluid intake [15]. A treatment strategy comparable
to this protocol may be appropriate for EDKA in T2DM, but this is also
an issue for future consideration.