Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors

It is possible that SGLT2 inhibitors trigger euglycemic diabetic ketoacidosis in some patients. Possible mechanism of euglycemic DKA induced by SGLT2 inhibitors is illustrated. Diabetic ketoacidosis (DKA) is a serious acute complication of diabetes mellitus that occasionally can become life threatening. It is induced as a result of a profound deficiency of insulin action in the body, often developing in individuals with poorly controlled type 1 diabetes or in those with type 2 diabetes who are subject to external stress such as infection, injury, or surgery. Although DKA is typically associated with marked hyperglycemia and resultant dehydration, it can occur with only a moderate increase in blood glucose (BG) levels or, in rare instances, in the setting of normal glucose concentrations. This latter, uncommon form of DKA, known as euglycemic or normoglycemic DKA, was originally defined as DKA with a BG level of 300 mg/dL in five cases, and not determined in 14 cases (Table 1). In addition, the U.S. Food and Drug Administration recently made known in a safety announcement that 20 cases of DKA, ketoacidosis, or ketosis associated with SGLT2 inhibitors had been reported from March 2013 (date of approval of the first drug in this class) through 6 June 2014 and that ‘glucose levels were only mildly elevated at less than 200 mg/dL in some reports' (http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm). Given the limited amount of information available to date, it is difficult to judge precisely whether the reported cases of DKA were directly triggered by SGLT2 inhibitors or were induced independently of these drugs, with the SGLT2 inhibitors simply reducing the BG levels during the events. However, a possible mechanism by which SGLT2 inhibitors might trigger euglycemic DKA is presented in Figure 1. SGLT2 inhibitors lower BG levels by increasing urinary glucose excretion, which in turn reduces insulin secretion from pancreatic β-cells. The decline in circulating insulin levels results in a lowering of the antilipolytic activity of insulin and consequent stimulation of the production of free fatty acids, which are converted to ketone bodies by β-oxidation in the liver. Moreover, insulin stimulates the activity of acetyl-CoA carboxylase, which produces malonyl-CoA, a potent inhibitor of carnitine palmitoyltransferase–I (CPT-I). Given that CPT-I promotes the transport of fatty acids into mitochondria and hence increases the rate of β-oxidation, the decrease in the circulating level of insulin promotes the production of ketone bodies through activation of CPT-I. In addition, evidence suggests that the administration of SGLT2 inhibitors stimulates the secretion of glucagon4, which might be either a secondary effect mediated by the decrease in insulin secretion or a direct effect of SGLT2 inhibitors on pancreatic α-cells.4 Given that glucagon inhibits acetyl-CoA carboxylase and thereby increases CPT-I activity in the liver, the up-regulation of glucagon secretion also likely contributes to the overproduction of ketone bodies. Obviously, not all individuals who take SGLT2 inhibitors are at high risk for euglycemic DKA. Eleven episodes reported by Peters et al.1 developed in patients with type 1 diabetes, and the two cases reported by Hine et al.2 were in patients with organic pancreatic insufficiency. The postmarketing reports of the Japanese drug manufacturers do not feature any cases in individuals with type 1 diabetes but include one case in a patient with pancreatic cancer (Table 1). Given that administration of SGLT2 inhibitors can further reduce the circulating level of insulin in individuals with impaired insulin secretion, caution is warranted in dispensing these drugs for such patients. The case reported by Hayami et al.3 occurred in a patient who followed a low-carbohydrate diet, which also reduces circulating insulin levels and triggers a ketogenic metabolic state. The postmarketing reports of the Japanese drug manufacturers include two cases of DKA associated with carbohydrate restriction (one being that described by Hayami et al.3) and one case associated with long-term (3 days) starvation (Table 1). The withdrawal of insulin or insulin secretagogues at the onset of treatment with an SGLT2 inhibitor, which occurred in one case described by Hine et al.2 and in the case reported by Hayami et al.3, also appears to be a risk factor for the development of euglycemic DKA. In the postmarketing reports, insulin treatment was terminated in four cases (likely at the instruction of health care providers in three cases and based on the patient's own judgment as a result of appetite loss in one case) and insulin secretagogues were withdrawn (on the instruction of health care providers) in three cases (including the case described by Hayami et al.3) before the development of the events. The relative frequencies of DKA in individuals taking SGLT2 inhibitors in Japan and in other countries are unknown. However, evidence suggests that individuals with type 2 diabetes in East Asia, including Japan, tend to be leaner and their disease to be more largely attributable to β-cell insufficiency5. It is thus possible that more caution is warranted in the administration of SGLT2 inhibitors to patients with such characteristics—and, in particular, to those with a long history of diabetes, given that β-cell function in type 2 diabetes is thought to decline with time. The postmarketing reports of the Japanese drug manufacturers do not include information on insulin secretory capacity for most cases, and body mass index is available for only 12 cases (25 kg/m2 in seven cases) (Table 1). A point worth emphasizing is that euglycemic DKA might easily be missed based on only clinical signs, given that it is not necessarily associated with typical manifestations of DKA such as dehydration induced by marked hyperglycemia. Severe metabolic acidosis alone has the potential to become a life-threatening condition, however. Further insight into the metabolic and humoral effects of SGLT2 inhibitors as well as more detailed clinical information on related DKA cases should help to provide a more solid basis for the safe, appropriate, and broad application of this new class of drugs. We thank Takeshi Ohara, Yushi Hirota, and Genzo Iguchi for discussion and suggestions. W.O. and K.S. have received lecture fees from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, MSD, Novartis, Ono Pharmaceutical, Sanofi, and Taisho Toyama Pharmaceutical. W.O. has received research support from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Kowa Pharmaceutical, Mitsubishi Tanabe Pharma, MSD, Novartis, Ono Pharmaceutical, and Taisho Toyama Pharmaceutical, and K.S. has received research support from Astellas, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, and Ono Pharmaceutical.