II. Epidemiology: SGLT2 Inhibitor Associated Ketosis

  1. Initially 73 reported cases in 2 years for patients on SGLT2 Inhibitors with Serum Glucose <250 mg/dl
  2. Subsequently 2500 cases with patients on SGLT2 Inhibitors reported to FDA
    1. Fadini (2017) Diebetologia 60(8): 1385-9 [PubMed]

III. Mechanism: SGLT2 Inhibitor Associated Ketosis

  1. Sodium-Glucose Co-Transporter-2 Inhibitor (SGLT2 Inhibitor) are Oral Hypoglycemic agents in Type II Diabetes
  2. SGLT2 Inhibitors block Glucose reabsorption in the Kidneys, with Glucose excreted in the urine
  3. Results in lower Blood Sugars, results in decreased Insulin release
  4. May result in increased Fatty Acid breakdown and Ketone production due to Hypoglycemia
    1. SGLT2 Inhibitor may also directly increase Fatty Acid breakdown and Ketone production

IV. Risk Factors: SGLT2 Inhibitor Associated Ketosis

  1. Type 1 Diabetes Mellitus (avoid SGLT2 Inhibitors in type I DM)
  2. Fasting (see Starvation Ketoacidosis)
  3. Very Low Carbohydrate Diet (e.g. Ketogenic Diet)
  4. Acute Infection
  5. Surgery
  6. Increased risk with renal Impairment (as well as Dehydration, acute illness)
    1. Avoid Farxiga (Dapagliflozin) if GFR <60 ml/min
    2. Avoid Invokana (Canagliflozin) and Jardiance (Empagliflozin) if GFR <45 ml/min

V. Symptoms

  1. Onset as early as first 2 weeks of starting an SGLT2 Inhibitors
  2. Nausea and Vomiting
  3. Fatigue
  4. Malaise
  5. Dyspnea

VI. Signs

  1. Dehydration
  2. Tachypnea
  3. Sinus Tachycardia
  4. Confusion
  5. Fruit scented breath

VII. Labs

  1. Metabolic Acidosis with Anion Gap
    1. Decreased serum bicarbonate <18 mEq/L
    2. Increased Anion Gap >15
  2. Serum Ketones increased (but Urine Ketones often normal)
    1. Serum Beta-Hydroxybutyrate >3.8 mmol/l
  3. Serum Glucose paradoxically normal or <250 mg/dl

IX. Management: SGLT2 Inhibitor Associated Ketosis

  1. Similar management as with Diabetic Ketoacidosis Management
  2. Potassium Replacement if <3.5 meq/dl before Insulin initiated
  3. Initiate fluid bolus
  4. Start D5 or D10 infusion
  5. Start Insulin 0.1 units/kg/h infusion (do not give Insulin bolus)
    1. Confirm normal Potassium (>3.5 meq/dl) before initiating Insulin

X. Prevention

  1. Hold SGLT2 Inhibitor before sustained exertional activity (e.g. marathon run)
  2. Hold SGLT2 Inhibitors when significant acute medical stressors are present (e.g. hospital admission)
    1. Practice Diabetes Sick Day Management
    2. Hold SGLT2 Inhibitor for significant Vomiting or Diarrhea
    3. Hold SGLT2 Inhibitor starting 3-4 days before surgery
    4. May restart SGLT2 Inhibitor when tolerating oral food and fluids

XII. References

  1. (2023) Presc Lett 30(12): 69
  2. Swaminathan and Hayes in Herbert (2019) EM:Rap 19(6): 12
  3. Long and Lentz (2021) EM:Rap 21(8): 15-6

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