Title: Management of SGLT2i in Patients with Diabetes Preparing for Surgery
Author: Vivian Tran, PharmD Candidate 2024, University of Rhode Island School of Pharmacy
Reviewer: Courtney Cameron, PharmD, BCACP
Background
The management of diabetes is often complex, involving a combination of lifestyle changes, pharmacologic therapy, and even surgical interventions. Sodium-glucose cotransporter-2 (SGLT2) inhibitors are recommended for patients with type 2 diabetes and established ASCVD or multiple risk factors for ASCVD. These agents have also shown efficacy and mortality benefit in patients with heart failure and chronic kidney failure regardless of diabetic status.1 With such a large range of indications, they have become an increasingly common medication class for patients with a variety of conditions.
The perioperative management of SGLT2 inhibitors in patients preparing for surgery is guided by guidelines and the clinical judgment of the provider. Standard procedure involves holding SGLT2 inhibitors prior to surgery.2 The Food and Drug Administration (FDA) approved safety label changes for all SGLT2 inhibitors in 2015 to warn about the increased risk of developing euglycemic ketoacidosis (EDKA) with SGLT2 inhibitors.3 Subsequently, after several care reports, another warning was released in 2020 to hold SGLT2 inhibitors prior to major surgery. The recommendation from the FDA is that canagliflozin, dapagliflozin, and empagliflozin be discontinued 3 days before scheduled surgery, while ertugliflozin be discontinued 4 days before. The SGLT2 inhibitor may be restarted once the patient’s oral intake is back to baseline.4
As part of their mechanism of action, SGLT2 inhibitors can also help to promote weight loss through osmotic diuresis.4 If further weight loss is indicated, such as for a patient with a BMI over 35.0 kg/m2 (or over 32.5 kg/m2 in Asian Americans) who did not achieve optimal glycemic control, metabolic surgery is an effective option that can also reduce cardiovascular risk.5 Metabolic surgery, also known as bariatric surgery, includes procedures such as a gastric bypass and sleeve. The risk of developing EDKA post-procedure is already higher for patients due to the stress of surgery, but the risk of developing EDKA from metabolic surgeries as opposed to other procedures may be even higher due to special dietary requirements prior to
surgery.6
What is euglycemic diabetic ketoacidosis?
EDKA is a complication that is associated with both type 1 and type 2 diabetes mellitus.4,7 It is characterized by severe metabolic acidosis (arterial pH <7.3 and serum bicarbonate <18 mEq/L), ketosis, and euglycemia (blood glucose <250 mg/dl). Shortly after SGLT2 inhibitors were introduced to the market, the FDA issued a warning about an increased risk of developing EDKA based on incidents identified through the adverse event reporting system.3,8 EDKA is often under-diagnosed because symptoms of hyperglycemia, including polyuria and polydipsia, are absent and serum glucose levels may only be mildly elevated, which can lead to life-threatening situations.
The pathophysiology of EDKA primarily involves a deficiency in carbohydrates.7 This results in decreased serum insulin levels and an excess in counter-regulatory hormones such as glucagon. The increased glucagon/insulin ratio leads to lipolysis as an alternative for energy, which releases free fatty acids and promotes ketoacidosis.4,7 A similar condition can be observed with patients that go on ketogenic diets, though the risk of developing EDKA on a keto diet is beyond the scope of this discussion.9
Risk factors for EDKA include fasting, pregnancy, alcohol use disorder, surgical procedures, and infection, as well as other conditions that would result in a deficit in carbohydrate intake.8 While glucose levels may not be hugely abnormal, patients with EDKA may present with nausea, vomiting, abdominal pain, loss of appetite, and shortness of breath.7 In severe cases, patients may even present with Kussmaul respiration, a deep and rapid breathing that is indicative of severe metabolic acidosis.4
Why is there an increased risk in continuing SGLT2i perioperatively?
It is unclear how SGLT2 inhibitors directly cause EDKA, but several factors of their mechanism may contribute to why there is an increased risk in developing EDKA in surgery patients. They primarily work by blocking renal cotransporters in the kidneys, which decreases the amount of glucose that is reabsorbed into the kidneys.2 The glucose is instead excreted out of the body through the urine. SGLT2 inhibitors may also directly stimulate glucagon production. In order to maintain glucose levels, glucagon stimulates glucose production in the liver and promotes the release of free fatty acids from adipose tissue to be used for energy instead. The risk associated with continuing SGLT2 inhibitors throughout surgery is due to the requirement to fast prior to a major procedure, which can decrease glucose levels and contribute to the imbalance between insulin and glucagon.4
Out of the major surgeries, there is an increased risk of developing EDKA when a patient on an SGLT2 inhibitor goes through metabolic surgery because standard procedure involves the patient being put on an all-liquid diet that is low in carbohydrates two weeks prior to surgery.5 This leaves the patient in an even more extreme fasting state with decreased serum glucose levels, presenting as euglycemia. Insulin levels are decreased due to the low levels of glucose. Because SGLT2 inhibitors stimulate glucagon production and insulin is decreased due to the liquid diet pre-surgery, the increased ratio between insulin and counterregulatory hormones ultimately leads to a greater degree of lipolysis and ketoacidosis.7
What data exists to support SGLT2i-associated EDKA?
The FDA published the warning in 2015 about a potential increased risk of diabetic ketoacidosis associated with the use of SGLT2 inhibitors based on twenty case reports.4 Within the next few years, multiple large trials like DECLARE–TIMI 58 and CREDENCE would show an increased probability of DKA with SGLT2 inhibitors as compared to placebo.10,11 DECLARE-TIMI investigated the cardiovascular safety profile of dapagliflozin and found that diabetic ketoacidosis was more common with dapagliflozin than with placebo (0.3% vs. 0.1%, P=0.02).10 CREDENCE investigated the renal outcomes of canagliflozin and also found that rates of diabetic ketoacidosis were overall low but higher in the canagliflozin group than in the placebo group (2.2 vs. 0.2 per 1000 patient-years).11 Presented below are two case reports of patients developing EDKA specifically after undergoing a major procedure.12,13
Case Report #1:
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Situation
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60-year-old man referred to hospital for coronary artery bypass graft (CABG) surgery following cardiac catheterization ○ Upon arrival to hospital: asymptomatic, vital signs WNL
○ Relevant laboratory values:
■ Serum glucose of 157 mg/dL
■ Bicarbonate of 24 mmol/L
■ Anion gap of 12 mmol/L
■ Urinalysis revealed glucosuria of >1000
■ Ketonuria of 15 mg/dL
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Day 3: patient underwent CABG
○ Within a few hours after surgery:
■ Elevated metabolic acidosis with an arterial pH of
7.23
■ Reduced bicarbonate level of 15 mmol/L
■ Elevated anion gap of 25 mmol/L
■ Serum glucose level normal at 138 mg/dL
■ β-hydroxybutyric acid level elevated at 6.52 mmol/L
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Background
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Medical history significant for coronary artery disease, hypercholesterolemia, and type 2 DM diagnosed 15 years previously
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Medication list: glimepiride (2 mg twice daily), metformin (1000 mg twice daily), subcutaneous semaglutide (0.25 mg weekly), and empagliflozin (10 mg orally daily)
○ Semaglutide and empagliflozin started 1 year prior, but were not on medication list provided by patient on admission
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Assessment
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Further investigation revealed that the patient had been on
Invokana (canagliflozin) for many years and was switched to
Jardiance (empagliflozin) about 1 year prior to admission
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Last dose of Jardiance was the morning of hospital admission, about 48 hours before the CABG surgery
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Diagnosis of EDKA made based off of:
○ Arterial pH <7.3
○ Bicarbonate <18 mEq/L
○ Elevated β-hydroxybutyric acid level (measures ketones)
○ Glucose level <250 mg/dL
○ History of SGLT2 use
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Recommendation
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Patient started on intravenous insulin drip with an infusion of 5% dextrose in water, as well as transient 24-hour intravenous norepinephrine for hypotension
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Ketoacidosis resolved in two days, after which patient transitioned
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to subQ insulin with adequate glycemic control
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Patient educated about need to discontinue SGLT2 inhibitors at least 3 days before any procedure requiring prolonged fasting
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Case Report #2:
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Situation
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51-year-old female presented one day after laparoscopic-assisted sleeve gastrectomy with lethargy and cold extremities
○ On examination: afebrile, tachycardiac with pulse of 130, hypertensive with systolic pressure of 200, strong pedal
pulses bilaterally with cool extremities ○ Relevant laboratory values:
■ Elevated metabolic acidosis with an arterial pH of
7.21
■ Reduced bicarbonate level of 8 mmol/L, 4 mmol/L upon repeat hours later
■ Elevated anion gap of 37 mmol/L
■ Serum glucose level ranging from 150 to 180 mg/dL
■ Urine analysis positive for ketonuria and glucosuria
■ Blood urea nitrogen (BUN) increased to 22 mg/dL
■ Creatinine increased to 22 mg/dL
■ Potassium of 2.6 mmol/L
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Background
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Medical history significant for type 2 DM, hypertension, hypercholesterolemia, gastroesophageal reflux disease, and morbid obesity
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Medication list: insulin aspart, insulin glargine, metformin, and canagliflozin, unspecified GLP-1 agonist
○ To prepare for surgery, canagliflozin was discontinued two days prior
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Patient reported a diet consisting of three protein shakes per day for three weeks prior to surgery
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Assessment
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Elevated BUN and creatinine indicative of acute kidney injury (AKI)
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Diagnosis of EDKA made based off of:
○ Arterial pH <7.3
○ Bicarbonate <18 mEq/L
○ Glucose level <250 mg/dL
○ History of SGLT2 use
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Recommendation
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Patient started on intravenous insulin drip with an infusion of 5% dextrose in water following initial fluid resuscitation with lactated ringers
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Hypokalemia treated with oral and IV potassium chloride
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Insulin drip discontinued after patient stabilized, at which time insulin detemir and solid food consumption started
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Day 4: transferred out of ICU
○ Metformin and GLP-1 agonists held until evaluation in outpatient office for follow-up
○ SGLT inhibitors added to allergy list with life-threatening
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side effect of EDKA
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When should SGLT2 inhibitors be restarted post-surgery?
There are no clear guidelines about the timeframe in which an SGLT2 inhibitor should be restarted post-surgery. The postoperative period, especially in the first couple of weeks, is where the patient is most at risk of adverse events since they are still recovering and not yet back at baseline. Caution should be exhibited especially for metabolic surgery, where patients are at a higher risk of SGLT2-associated ketoacidosis due to rapid weight loss and the low-carbohydrate diet prescribed prior to surgery. Careful monitoring of acid-base and ketone status should be done perioperatively and postoperatively for all surgeries until the patient is stable. The FDA states that SGLT2 inhibitors may be re-introduced once the patient’s oral intake and volume status are back to normal.3 If the patient develops EDKA or had it in the past, it may also be an option to discontinue the drug permanently due to the increased risk of developing EDKA again.13
Conclusion
Due to the growing popularity of SGLT2 inhibitors for patients, it is becoming more important for providers to know how to manage them when patients are due to undergo a major surgery. Most guidelines suggest that SGLT2 inhibitors be discontinued at least 3 to 4 days prior, with careful monitoring of ketones and glucose throughout and after the procedure. It is up to the provider’s discretion when the SGLT2 inhibitor may be restarted, and individual patient factors such as diet, volume status, and laboratory tests should be considered in that decision.
References
1. Chan JCH, Chan MCY. SGLT2 Inhibitors: The Next Blockbuster Multifaceted Drug?
Medicina. 2023;59(2):388. doi:https://doi.org/10.3390/medicina59020388
2. Preoperative Cessation of SGLT2i. American College of Cardiology. https://www.acc.org/latest-in-cardiology/articles/2022/10/07/17/21/preoperative-cessation -of-sglt2i#:~:text=When%20working%20for%20 patients%20being
3. FDA: Suspend SGLT2 inhibitors before surgery. www.healio.com. https://www.healio.com/news/endocrinology/20200317/fda-suspend-sglt2-inhibitors-befo re-surgery
4. Milder DA, Milder TY, Kam PCA. Sodium-glucose co-transporter type-2 inhibitors: pharmacology and peri-operative considerations. Anaesthesia. 2018;73(8):1008-1018. doi:https://doi.org/10.1111/anae.14251
5. Bariatric Surgery Guidelines and Recommendations. American Society for Metabolic and
Bariatric Surgery. Published June 6, 2012.
https://asmbs.org/resources/bariatric-surgery-guidelines-and-recommendations
6. Legner L. Diet before and after weight-loss surgery. OSF HealthCare Blog. Published
August 30, 2021. https://www.osfhealthcare.org/blog/bariatric-surgery-diet/
7. Nasa P, Chaudhary S, Shrivastava PK, Singh A. Euglycemic diabetic ketoacidosis: A missed diagnosis. World Journal of Diabetes. 2021;12(5):514-523. doi:https://doi.org/10.4239/wjd.v12.i5.514
8. Varthya S, Dutta S, Kumar T, Singh S, Ambwani S, Charan J. Euglycemic diabetic ketoacidosis associated with SGLT2 inhibitors: A systematic review and quantitative analysis. Journal of Family Medicine and Primary Care. 2022;11(3):927. doi:https://doi.org/10.4103/jfmpc.jfmpc_644_21
9. Blanco JC, Khatri A, Kifayat A, Cho R, Aronow WS. Starvation Ketoacidosis due to the Ketogenic Diet and Prolonged Fasting – A Possibly Dangerous Diet Trend. American Journal of Case Reports. 2019;20:1728-1731. doi:https://doi.org/10.12659/ajcr.917226
10. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 2019;380(4):347-357. doi:https://doi.org/10.1056/NEJMoa1812389
11. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine. 2019;380(24):2295-2306. doi:https://doi.org/10.1056/nejmoa1811744
12. Osafehinti DA, Okoli OJ, Karam JG. A Case of SGLT2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis Following Coronary Artery Bypass Surgery. AACE Clinical Case Reports. 2021;7(1):20-22. doi:https://doi.org/10.1016/j.aace.2020.11.014
13. Kapila V, Topf J. Sodium-Glucose Co-transporter 2 Inhibitor-Associated Euglycemic Diabetic Ketoacidosis After Bariatric Surgery: A Case and Literature Review. Cureus. Published online August 11, 2021. doi:https://doi.org/10.7759/cureus.17093