What do Health Canada and the FDA (Food and Drug Administration) say about the risk of Diabetic Ketoacidosis (DKA) with Invokana (Canagliflozin), a SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitor, in a patient with type 2 diabetes experiencing reduced oral intake, stomach ache, nausea, and undergoing surgery with NPO (Nil Per Os) status?

FDA and Health Canada Warnings on DKA Risk with Invokana in Surgical/NPO Settings

Both the FDA and Health Canada (through aligned international guidelines) mandate that Invokana (canagliflozin) must be withheld at least 3 days before surgery, and the drug carries explicit warnings about life-threatening diabetic ketoacidosis (DKA) risk in patients with reduced oral intake, gastrointestinal symptoms (nausea, stomach pain), and NPO status. 1

FDA-Mandated Warnings and Dosing Instructions

The FDA label for Invokana contains a black-box-level warning specifically addressing your clinical scenario:

Precipitating Conditions for DKA

The FDA explicitly identifies the following as precipitating factors for ketoacidosis with Invokana 1:

• Reduced caloric intake (directly applicable to your patient's reduced oral intake)
• Surgery (your patient is undergoing a procedure)
• Volume depletion (risk with NPO status)
• Acute febrile illness (may accompany nausea and stomach pain)
• Nausea and vomiting (your patient's presenting symptoms)

Mandatory Preoperative Discontinuation

The FDA label provides explicit dosing instructions 1:

• Withhold Invokana at least 3 days prior to surgery or procedures associated with prolonged fasting
• Resume only when the patient is clinically stable and has resumed oral intake
• This recommendation is based on the drug's pharmacokinetics, as urinary glucose excretion persists for 3 days after discontinuation 1

Critical FDA Warning on Euglycemic DKA

The FDA emphasizes a particularly dangerous aspect of SGLT2 inhibitor-associated DKA 1:

• Blood glucose levels may be below those typically expected for DKA (less than 250 mg/dL)
• Ketoacidosis can present with normal or near-normal glucose levels
• Clinicians must assess for ketoacidosis regardless of presenting blood glucose levels in patients with signs/symptoms of severe metabolic acidosis
• Signs include: nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath

Prolonged Drug Effects

The FDA warns that ketoacidosis and glucosuria may persist longer than expected 1:

• Postmarketing reports document ketoacidosis/glucosuria lasting greater than 6 days and some up to 2 weeks after SGLT2 inhibitor discontinuation
• This means even if the drug was stopped 3 days ago, DKA risk persists

International Guideline Consensus (Aligned with Health Canada Approach)

American College of Cardiology/American Heart Association 2024 Guidelines

The most recent high-level guidelines recommend 2:

• Discontinue SGLT2 inhibitors 3-4 days before elective surgery
• Specifically: canagliflozin ≥3 days before scheduled surgery
• This timing is based on preventing euglycemic DKA, which has higher incidence in emergency surgery (1.1%) versus elective surgery (0.17%) 2

UK Multidisciplinary Consensus 2025

While UK guidelines suggest a less conservative approach (withholding the day before and day of surgery), they acknowledge 3:

• Postoperative ketoacidosis can occur even when patients have withheld SGLT2 inhibitors for >72 hours
• The risk is a continuum rather than having a defined threshold
• Critical mitigation strategies include: ensuring patients remain well hydrated, avoiding long starvation periods, and adequate glucose and ketone monitoring

Specific Management in Your Clinical Scenario

Immediate Actions Required

Given your patient has reduced oral intake, stomach ache, nausea, and is NPO for surgery 1:

1. Assess for DKA immediately - Check ketones (blood or urine) and arterial blood gas, regardless of blood glucose level 1

2. If ketoacidosis is suspected 1:

   • Discontinue Invokana immediately
   • Promptly evaluate and treat ketoacidosis if confirmed
   • Monitor for resolution before considering restarting

3. Ketone monitoring - The FDA recommends considering ketone monitoring in at-risk patients, which your patient clearly is 1

Perioperative Risk Mitigation

If surgery must proceed 3, 2:

• Ensure adequate hydration
• Avoid prolonged fasting periods
• Consider glucose-containing intravenous fluids in settings of unavoidable prolonged fasting to mitigate ketone generation
• Monitor glucose AND ketone levels throughout the perioperative period

When to Resume Invokana

The FDA is explicit 1:

• Resume only when the patient is clinically stable AND has resumed oral intake
• For hospitalized patients, consider restarting only once eating and drinking normally and capillary ketones are <0.6 mmol/L 3
• Typically 24-48 hours after surgery 3

Critical Pitfalls to Avoid

The Euglycemic DKA Trap

The most dangerous pitfall is assuming the patient doesn't have DKA because glucose is normal 2, 1:

• SGLT2 inhibitors alter the insulin/glucagon ratio, promoting ketogenesis despite normal glucose levels
• Your patient's nausea and stomach pain could be early DKA symptoms, not just surgical stress
• Always check ketones, not just glucose, in symptomatic patients on SGLT2 inhibitors

Prolonged Drug Effects

Even if Invokana was stopped 3 days ago, your patient remains at risk 1, 4:

• Case reports document DKA occurring 7-11 days after last dose 4, 5
• One case series showed DKA developing 54-151 hours after last dose in cardiac surgery patients 5
• Persistent glucosuria and ketonuria can occur for up to 2 weeks 1

Patient Education Mandate

The FDA requires that all patients be educated on 1:

• Signs and symptoms of ketoacidosis
• Instructions to discontinue Invokana and seek immediate medical attention if symptoms occur
• This should have been provided at pre-operative assessment 3

Special Consideration: Emergency vs. Elective Surgery

If this is emergency surgery 2:

• Risk of perioperative ketoacidosis is 6.5-fold higher (1.1% vs 0.17%)
• Even more aggressive monitoring and mitigation strategies are required
• Consider glucose-containing IV fluids prophylactically

The combination of reduced oral intake, gastrointestinal symptoms, NPO status, and recent/current Invokana use creates a perfect storm for euglycemic DKA that both regulatory agencies explicitly warn against 1, 2.