SGLT-2 Inhibitors

Introduction and Uses

• Canagliflozin (first SGLT-2 inhibitor) approved in 2013), dapagliflozin, and empagliflozin are approved for adult and pediatric patients aged 10 years and older.
• Ertugliflozin and bexagliflozin are only approved for adults.
• All are recommended as adjuncts to diet and exercise for improving glycemic control in adults with T2DM.
• In patients with HF with a reduced EF, SGLT-2 inhibitors have been shown to reduce cardiovascular mortality and hospitalizations significantly. Empagliflozin is also approved for the treatment of HF with a preserved EF.
• Sotagliflozin (FDA approval 2023), the first dual SGLT-1 and SGLT-2 inhibitor, is FDA-approved specifically for the treatment of patients with HF, without an indication for glycemic control.¹

Mechanism of Action and Pharmacodynamics

• These agents block the SGLT-2 in the proximal convoluted tubuleleading to increased urinary glucose and sodium excretion.
• Urinary glucose excretion reduces serum glucose levels via an insulin-independent mechanism, thereby reducing the risk of hypoglycemia.
• Urinary sodium excretion (natriuresis) triggers other intrarenal mechanisms
  • Afferent arteriole vasoconstriction leads to reduced glomerular filtration pressures, hyperfiltration, and albuminuria.²

Pharmacokinetics

Systemic Effects and Clinical Uses

Renal

• Natriuresis leads to afferent arteriole vasoconstriction, which reduces glomerular filtration pressure, induces hyperfiltration, and causes albuminuria, thereby exerting nephroprotective effects in diabetic nephropathy and potentially offering benefits in CKD.
• Diuresis reduces activation of the renin-angiotensin-aldosterone system (RAAS).
  Endocrine
• Reduced glucose reabsorption in the kidneys improves glycemic control via an insulin-independent pathway without increasing hypoglycemic events.

Hepatic

• SGLT-2 inhibitors reduce glucose uptake, insulin resistance, gluconeogenesis, lipid accumulation, and cellular apoptosis in the liver.
• Patients with T2DM and metabolic-dysfunction-associated liver disease on SGLT-2 inhibitors have a lower risk of major adverse liver events and liver-related death relative to patients on other oral medications for T2DM.⁴

Cardiovascular

• The mechanisms of diuresis and decreased RAAS activation reduce plasma volume (preload), blood pressure (afterload), and cardiac wall tension.^5,6
• The EMPEROR trials showed that, independent of EF (useful in both HF with reduced EF, as well as with preserved EF), empagliflozin reduces HF hospitalizations and deaths.^7,8
• Canagliflozin induces endothelium-independent vasorelaxation in arterioles from human visceral adipose tissue.⁹

Perioperative Considerations

eDKA

• The primary concern perioperatively is the risk for eDKA in patients taking these medications.

• Because surgery inherently elicits a physiological stress response and surgical patients present in a fasted state, surgical patients on SGLT-2 inhibitors are at an elevated risk of eDKA.¹⁰
• The presence of infection will further increase this risk, as will critical illness and/or a prolonged postoperative fast.
• While eDKA is easily treatable, it is often unrecognized. A high suspicion for eDKA is necessary to diagnose this rare but serious complication, which, if untreated, can lead to respiratory failure, coma, and death.¹¹

Current Recommendations

The United States FDA issued a statement saying patients undergoing surgery who continue these medications have worse outcomes and longer hospital stays. Current guidelines recommend holding the -flozins for at least 3 days (4 days for ertugliflozin).¹¹

• Patients taking SGLT-2 inhibitors only for HF are at a lower risk of eDKA than patients with T2DM. However, the current recommendation for cessation does not differentiate by indication
• Patients undergoing low-risk, short-duration, outpatient surgery are at a lower risk for eDKA than those undergoing major surgery.
• eDKA can occur preoperatively, intraoperatively, or postoperatively.
• During prolonged surgery, eDKA should be considered intraoperatively in patients with metabolic acidosis on SGLT-2 inhibitors as outpatients.
• In patients without an appropriate hold on SGLT-2 inhibitors, an appropriate postoperative plan to monitor for eDKA should include regular blood gas screening. An identified anion gap metabolic acidosis should trigger the measurement of serum ketones and, if positive, the diagnosis of eDKA.
• The treatment of eDKA is correction of the dehydrated state and administration of insulin with glucose-containing fluids, with serial measurement of ketones and blood gases to monitor treatment.