American Association Of Clinical Endocrinologists and American College Of Endocrinology Position Statement on the Association of SGLT-2 Inhibitors and Diabetic Ketoacidosis

Yehuda Handelsman, MD, FACP, FNLA, FACE, Co-Chair; Robert R. Henry, MD, FACE, Co-Chair; Zachary T. Bloomgarden, MD, MACE; Sam Dagogo-Jack, MD, DM, FRCP, FACE; Ralph A. DeFronzo, MD, BMS, MS, BS; Daniel Einhorn, MD, FACP, FACE; Ele Ferrannini, MD; Vivian A. Fonseca, MD, FACE; Alan J. Garber, MD, PhD, FACE; George Grunberger, MD, FACP, FACE; Derek LeRoith, MD, PhD, FACE; Guillermo E. Umpierrez, MD, FACP, FACE; Matthew R. Weir, MD


Endocr Pract. 2016;22(6):753-762. 

In This Article

Which Pathophysiologic Factors Contribute to SGLT-2 Inhibitor–Associated DKA?

Ketones such as acetoacetate and β-hydroxybutyrate are acidic alternate fuel molecules produced in the liver through the oxidation of fatty acids when dietary carbohydrates are in short supply. Ketones can be metabolized for energy by cardiac and skeletal muscle, the intestine, kidney, and the brain when sufficient glucose is not readily available, and they are excreted in the urine and through the lungs as acetone. When ketone production exceeds clearance, ketoacidosis may occur.[21] DKA results from a combination of glucagon elevations, which promote a shift to fat metabolism, and insulin deficiency that may manifest as either an absolute insulin deficiency or a relative deficiency coupled with severe insulin resistance. Hyperglycemia occurs when the lack of insulin and increased glucagon stimulate glycogenolysis and gluconeogenesis in the liver, whereas insulin deficiency, insulin resistance exacerbated by lipolysis, and elevated counterregulatory hormones act in concert to reduce glucose utilization in peripheral tissues. Reduced insulin action coupled with increased glucagon and free fatty acid (FFA) levels promote β-oxidation and hepatic ketogenesis and possibly decreasing ketone utilization in other tissues.[8,22] External factors that can precipitate DKA include surgery, infections, sepsis, alcohol, severe injury, hypovolemia, pancreatitis, and severe metabolic stress–related conditions such as myocardial infarction or marathon running.[8,22,23]

Changes in diet, notably decreased carbohydrate intake, shifts metabolism to utilization of fat for energy, which promotes ketone production and may contribute to eventual development of DKA under stressful conditions. Very-low-carbohydrate and ketogenic diets (e.g., the Atkins diet) deprive the body of glucose, and the resulting ketosis may develop into ketoacidosis when conditions favor an excessive increase in counterregulatory hormones and the glucagon to insulin ratio,[7,19,24–26] such as during severe metabolic stress and (relative) insulin deficiency. Reduced carbohydrate intake was the common factor in a 1973 case series describing 37 T1D patients with "euglycemic" DKA.[9] Counterregulatory hormones, including catecholamines, cortisol, and growth hormone—which may be increased by severe stress such as hypovolemia or hypotension—also promote lipolysis and may increase ketone metabolism.[27–31] In the setting of insulin deficiency, elevated glucagon also stimulates ketogenesis through promotion of lipolysis in adipocytes and stimulation of β-oxidation of FFAs in the liver.[31] People with diabetes are typically already more prone to ketosis compared to healthy individuals, perhaps because they may have dopamine deficiency in the brain and central nervous system, which may unleash sympathetic control of glycolysis, lipolysis, neoglucogenesis, and ketogenesis.[32]

The kidney plays a central role in conservation of both glucose and ketones, particularly in the fasting state.[33,34] During starvation, renal re-absorption of ketones increases with blood concentrations, with no apparent excretion threshold, but renal utilization of ketone bodies is reduced.[34,35] By lowering the renal glucose excretion threshold, SGLT-2 inhibition may mimic starvation conditions and cause an increase in ketone production and renal re-absorption.[36–40] These findings suggest that ketonuria may be an insensitive biomarker for hyperketonemia and should not be used to diagnose DKA. Similarly, analyses have shown no correlation between plasma glucose and serum bicarbonate values in DKA, in general and specifically during SGLT-2 inhibitor use.[41,42]

Proposed causative factors for DKA with lower-than-anticipated glucose levels include partial treatment of DKA, fasting, carbohydrate avoidance, dehydration, alcohol intake, and persistent glycosuria.[7,11] "Euglycemic" DKA was first described as being associated with blood glucose values <300 mg/dL,[9] and later, a 2009 American Diabetes Association consensus on DKA defined it as glucose level <250 mg/dL.[8] However, although blood glucose <140 mg/dL (the postmeal upper limit of normal) has been occasionally reported, the vast majority of so-called euglycemic DKA involves glucose levels above the defined threshold. Therefore, AACE/ACE considers euglycemic DKA a misleading term and instead recommends use of "DKA with lower-than-anticipated glucose levels."