Euglycemic Diabetic Ketoacidosis Sometimes Seen with SGLT2 Inhibitors
Euglycemic DKA can be easily overlooked and cause big problems.
Diabetic ketoacidosis (DKA) in patients with presenting serum blood glucose <200 mg/dL isn’t common. More often, it’s seen in patients with type 1 diabetes in conjunction with starvation and acute illness.1
It’s difficult to determine an incidence of euglycemic DKA (euDKA) among all DKA cases in the literature, given the migration of the serum glucose cutoff from ≤300 mg/dL to ≤200 mg/dL. The best estimation based on an analysis of case reports suggests an incidence anywhere between 0.8% and 7.5%.1
However, the sodium-glucose cotransporter-2 (SGLT2) inhibitors canagliflozin, dapagliflozin, and empagliflozin can apparently induce this once-rare form of DKA.2,3
SGLT2 inhibitors are a class of oral hypoglycemic drugs indicated only for type 2 diabetes. Their novel mechanism of action prevents glucose reabsorption from the proximal renal tubules, resulting in increased glucosuria and decreasing plasma glucose.
SGLT2 inhibitors lower serum glucose and HBA1C levels, and even produce weight loss. However, the increased glucose concentration in the bladder is a terrific incubation environment for fungi and bacteria, so much so that the FDA stuck a post-marketing warning on the drug class for the increased risk of serious urinary tract infections and urosepsis, in addition to euglycemic DKA.
The proposed mechanism suggests that while SGLT2 inhibitors lower serum glucose, they also reduce insulin secretion from pancreatic beta cells in a negative feedback fashion. The lower serum insulin coupled with lower serum glucose consequently shifts energy metabolism to antilipolytic activity, and thus free fatty acid (FFA) oxidation and ketosis.
It’s been postulated that this SGLT2 inhibitor-induced insulin deficiency may promote fatty acid oxidation due to decreased production of malonyl-CoA, which would normally inhibit the transport of FFA into mitochondria via carnitine palmitoyltransferase I. Increased glucagon secretion is just the cherry on top.
Of the estimated 40,000 patients taking SGLT2 inhibitors, why do only a small proportion of them ever manifest euDKA? One possible mechanism involves alterations in the metabolism of these drugs through genetic mutations.
The normal metabolic pathway for SGLT inhibitors involves UGT1A9-producing inactive metabolites. However, known polymorphisms of UGT1A9 (potentially allele *3 and *22) may alter the expression of genes coding UGT1A9 and alter its metabolic activity.4-7
The end result is active drug accumulation leading to profound glucosuria, insulin secretion depression, and subsequently FFA oxidation. However, the clinical implications of this polymorphism aren’t known, and pharmacogenomic research rarely leads to cost-effective screening methods to prevent given adverse events.
In terms of management, patients with SGLT inhibitor-related euDKA should be treated the same as any other DKA patient. That is, if the entire treatment team understands the goals of treating DKA: correction of acidosis, not just normoglycemia.
Failure to start insulin with dextrose will cause the outlined mechanism to persist and potentially worsen the metabolic picture. That may mean starting an insulin drip at 0.1 unit/kg/hr with D10W on a patient with a blood glucose of 130 mg/dL.
These patients should be responsive to insulin/dextrose since the pathophysiology doesn’t involve exacerbated insulin resistance. However, there’s no evidence suggesting lower insulin doses should be substituted for conventional dosing for DKA.
When considering patients’ home diabetes regimen, they should no longer receive any SGLT2 inhibitors since the manifestation of euDKA should be considered a class effect.
1. Joseph F, et al.Starvation-induced True Diabetic Euglycemic Ketoacidosis in Severe Depression. J Gen Intern Med. 2009 Jan;24(1):129-131.
2. Ogawa W, et al. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. Journal of Diabetes Investigation. 2016:7(2)135-138.
3. Rosenstock J, et al. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015 Sep;38(9):1638-1642.
4. Kasichayanula S, et al. Clinical pharmacokinetics and pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2. Clinical Pharmacokinetics. 2014 Jan;53(1):17-27.
5. Jiao Z, et al. Population pharmacokinetic modelling for enterohepatic circulation of mycophenolic acid in healthy Chinese and the influence of polymorphisms in UGT1A9. Br J Clin Pharmacol. 2008 Jun;65(6):893-907.
6. Yamanaka H, et al. A novel polymorphism in the promoter region of human UGT1A9 gene (UGT1A9*22) and its effects on the transcriptional activity. Pharmacogenetics. 2004 May;14(5):329-332.
7. Pattanawongsa A, et al. Inhibition of human UDP-glucuronosyltransferase enzymes by canagliflozin and dapagliflozin: implications for drug-drug interactions. Drug Metab Dispos. 2015 Oct;43(10):1468-1476.