In 2022 and 2023, two sodium-glucose cotransporter 2 inhibitors (SGLT2i) – Bexacat™ (bexagliflozin) and Senvelgo™ (velagliflozin) – were FDA-approved for treatment of newly diagnosed cats with diabetes mellitus (DM) that have never been treated with insulin in the U.S. Euglycemic diabetic ketoacidosis (eDKA) is an emerging condition in veterinary medicine that was not observed until the introduction of SGLT2i into clinical use. Although euglycemic diabetic ketoacidosis was first described in people as a rare complication of pregnancy and fasting in 1973, it was not until after 2013, when SGLT2i was approved for treating people with Type 2 DM, that many physicians became aware of this syndrome. These medications, designed to manage feline DM by promoting glucose excretion in the urine, can lead to ketoacidosis without significant hyperglycemia, making diagnosis challenging. As SGLT2i gain popularity in veterinary medicine, cases of eDKA will occur, highlighting the need for increased awareness and careful monitoring in cats with DM receiving these drugs.
Euglycemic diabetic ketoacidosis (DKA) occurs in approximately 5% to 7% of cats receiving SGLT2 inhibitors, with the majority being eDKA. Most cases of eDKA or DKA occur within the first 5 to 14 days but can occur at any time during treatment.
DKA due to insulin deficiency and excessive glucagon activity. In other species, proposed mechanisms by which SGLT2 inhibitors alter the insulin-to-glucagon ratio include the loss of paracrine insulin inhibition during euglycemia, leading to increased endogenous glucose production (EGP), heightened glucagon secretion, reduced glucose utilization by tissues, insulin deficiency, and elevated plasma cortisol and catecholamines. In cats treated with SGLT2i, the pathogenesis of eDKA is undetermined; however, avoidance requires adequate endogenous insulin secretion by the cat. There are no commercial diagnostic tests to assess if a cat can produce enough insulin to prevent DKA.
In the velagliflozin study, previous insulin treatment was identified as a risk factor, with these cats experiencing a higher incidence of DKA/eDKA compared to insulin-naïve cats (18% vs. 5%, respectively). Additional reported risk factors included an initial triglyceride concentration exceeding 500 mg/dL, a tenfold increase in serum triglycerides at any point during treatment, and significant weight loss—≥5% within the first 2 to 3 days or ≥8% within the first two weeks.
Cats that develop concurrent illnesses, have poor glycemic control or treatment response, or show progressive elevation or lack of initial decrease in beta-hydroxybutyrate (BHB) concentrations may also be at greater risk.
In people with diabetes on SGLT2i, fasting, surgery, ketogenic diets, concurrent illness and Type 1 diabetes are additional risk factors. The recommendation is to discontinue SGLT2i 72 to 96 hours before surgery in people on SGLT2i.9 During the perioperative and postoperative time periods, insulin and
dextrose support may be necessary. SGLT2i administration in people should also be discontinued with fasting (often associated with acute illness) or ketogenic diets. Although we do not know if these recommendations are beneficial in cats on SGLT2i, it may be prudent to discontinue SGLT2i at least 48 hours prior to surgery or anesthetic procedure, during which time and post operatively, insulin and dextrose administration may be necessary. Bouts of prolonged anorexia or hyporexia may also increase the risk of DKA/eDKA in SGLT2i-treated cats. If feeding a low-carbohydrate diet is a risk factor in cats it is unknown.
Cats on SGLT2i with eDKA/DKA most frequently exhibit lethargy, hyporexia or anorexia, vomiting and dehydration. Any cat with DM on SGLT2i displaying these signs should be promptly evaluated for DKA or eDKA. When concurrent illnesses are present, cats may exhibit additional clinical signs. Some cases of eDKA/DKA in SGLT2i-treated cats have been associated with pancreatitis or hepatic lipidosis.
The American Diabetes Association defines eDKA as “the presence of high anion-gap metabolic acidosis and increased plasma ketones in the presence of blood glucose levels below 250 mg/dL.” We have adopted this definition, and in cats, documentation of acidosis, elevated plasma or urine ketones and euglycemia (BG 250 mg/dL) is sufficient for diagnosis. BHB is the predominant ketone body in DKA and rises earlier than acetoacetate and acetone in blood, allowing earlier detection of ketosis compared to urine acetoacetic acid testing via dipstick.
Portable ketone meters are easily accessible to veterinarians and can accurately and quickly measure BHB levels for immediate diagnosis and intervention of cases with eDKA/DKA. In human patients with Type 1 diabetes, blood BHB testing has been associated with reduced emergency assessments, shorter hospital stays, faster recovery from DKA and lower healthcare costs compared to urine acetoacetate testing.10 In “unwell” cats, SGLT2i should be discontinued and insulin therapy initiated if BHB exceeds 2.4 mmol/L with acidemia, while monitoring those with BHB levels of 1 to 2.4 mmol/L for potential progression to eDKA/DKA. Urine ketone monitoring can also be effective in managing these cats. Regardless of insulin or SGLT2i therapy, cats with eDKA/ DKA should be evaluated for concurrent diseases.
Therapy for eDKA is the same as therapy for hyperglycemic DKA, including fluids, electrolyte supplementation and insulin—even in the face of euglycemia. The SGLT2i should be discontinued. Insulin infusion should be administered at the rate for hyperglycemic DKA and not lower. People with eDKA require insulin CRI for shorter duration, but higher glucose and insulin rates are needed to resolve ketoacidosis. Intravenous dextrose supplementation is critical to avoid iatrogenic hypoglycemia. Nutritional support should be initiated early, with feeding tubes if necessary.
Any concurrent disease, whether it contributed to the onset of DKA/eDKA or not, should be actively managed. Impaired renal or liver function can extend the therapeutic effects and delay the clearance of SGLT2i, causing some cats to remain euglycemic and glucosuric for more than 24 hours after discontinuation. After the cat is eating and ketoacidosis is resolved, it should be transitioned to insulin therapy.
If we can take a lesson from our human physician counterparts and their initial experience with SGLT2i, educating our clients, ourselves and our staff is paramount in preventing serious complications like eDKA. Physicians have developed SGLT2i patient risk mitigation strategies. Patients prescribed SGLT2i are trained on symptoms and causes of eDKA, how to monitor ketones, how to recognize eDKA and immediate interventions that should be taken. Patients are provided with treatment protocols to follow such as the STOP DKA protocol—if Symptomatic, stop SGLT2i, Test ketones and glucose every 2 to 4 hours, Oral ingestion of fluid and carbohydrates and Protocol with instructions for supplemental insulin and carbohydrates—or the STICH protocol—Stop SGLT2i, Insulin administration, Carbohydrate consumption and Hydration to follow.12,13 An acronym for management of eDKA in cats is SIIN— Stop SGLT2i, Intravenous fluids, dextrose and electrolytes, Insulin therapy and Nutritional support.
Spending the time educating our clients and providing them with clear instructions on what signs to watch for and when to seek veterinary care will hopefully help decrease the risk of complications like eDKA. Choosing good candidates for SGLT2i through appropriate screening is equally important. If delayed recognition or inappropriate treatment occurs, cats can succumb to eDKA. Notably, mortality rates were similar between diabetic cats treated with velagliflozin (7%) and those receiving Caninsulin (8%).3 Prognosis can improve with early detection and prompt treatment. Monitoring of body weight, clinical signs, BHB or urine ketones, and glycemic control is crucial for identifying eDKA/DKA early and preventing progression to severe DKA.
References
- Hadd MJ, Bienhoff SE, Little SE, Geller S, Ogne- Stevenson J, Dupree TJ, et al. Safety and effectiveness of the sodium-glucose cotransporter inhibitor bexagliflozin in cats newly diagnosed with diabetes mellitus. J Vet Intern Med. 2023 May 6;
- Behrend EN, Ward CR, Chukwu V, Cook AK, Kroh C, Lathan P, et al. Velagliflozin, a once-daily, liquid, oral SGLT2 inhibitor, is effective as a stand-alone therapy for feline diabetes mellitus: the SENSATION study. J Am Vet Med Assoc. 2024 Aug 14;1–11.
- Niessen SJM, Kooistra HS, Forcada Y, Bjørnvad CR, Albrecht B, Roessner F, et al. Efficacy and safety of once daily oral administration of sodium-glucose cotransporter-2 inhibitor velagliflozin compared with twice daily insulin injection in diabetic cats. J Vet Intern Med. 2024;38(4):2099–119.
- Perry RJ, Rabin-Court A, Song JD, Cardone RL, Wang Y, Kibbey RG, et al. Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats. Nat Commun. 2019 Feb 1;10(1):548.
- Chae H, Augustin R, Gatineau E, Mayoux E, Bensellam M, Antoine N, et al. SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans. Mol Metab. 2020 Dec; 42:101071.
- Pedersen MG, Ahlstedt I, El Hachmane MF, Göpel SO. Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells. Sci Rep. 2016 Aug 18;6:31214.
- Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015 May;21(5):512–7.
- Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014 Feb;124(2):499–508.
- Diabetes care in the hospital: Standards of medical care in diabetes-2021. Diabetes Care. 2021 Jan 1;44:S211– 20.
- Klocker AA, Phelan H, Twigg SM, Craig ME. Blood β-hydroxybutyrate vs. urine acetoacetate testing for the prevention and management of ketoacidosis in Type 1 diabetes: a systematic review. Diabet Med. 2013 Jul;30(7):818–24.
- Albert SG, Shrestha E, Wood EM. Euglycemic diabetic ketoacidosis: The paradox of delayed correction of acidosis. Diabetes Metab Syndr. 2023 Sep;17(9):102848.
- Goldenberg RM, Gilbert JD, Hramiak IM, Woo VC, Zinman B. Sodium-glucose co-transporter inhibitors, their role in type 1 diabetes treatment and a risk mitigation strategy for preventing diabetic ketoacidosis: The STOP DKA Protocol. Vol. 21, Diabetes, Obesity and Metabolism. Blackwell Publishing Ltd; 2019. p. 2192–202.
- Garg SK, Peters AL, Buse JB, Danne T. Strategy for Mitigating DKA Risk in Patients with Type 1 Diabetes on Adjunctive Treatment with SGLT Inhibitors: A STICH Protocol. Vol. 20, Diabetes Technology and Therapeutics. Mary Ann Liebert Inc.; 2018. p. 572–5.
JOCELYN MOTT | DVM, MS, DACVIM (LAIM)
Dr. Jocelyn Mott graduated from Western College of Veterinary Medicine in Saskatoon, SK, Canada. After graduation, she completed an internship at Oklahoma State University and a small animal internal medicine residency at the University of Wisconsin-Madison. Dr. Mott is board certified by the ACVIM in small animal internal medicine and fellow accredited by ACVIM in feline and canine diabetes. Dr. Mott is currently an associate professor of small animal internal medicine at the University of Florida.