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.