What is the risk of starvation ketosis with Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

Risk of Starvation Ketosis with SGLT2 Inhibitors

SGLT2 inhibitors significantly increase the risk of ketoacidosis during periods of starvation, fasting, or reduced carbohydrate intake, with specific risk factors including very-low-carbohydrate diets, prolonged fasting, dehydration, and excessive alcohol intake requiring careful patient education and monitoring. 1

Incidence Rates by Patient Population

Type 2 Diabetes

• DKA is uncommon in type 2 diabetes patients on SGLT2 inhibitors, occurring at 0.6-4.9 events per 1,000 person-years 1
• In hospitalized type 2 diabetes patients receiving SGLT2 inhibitors, ketone levels >3 mmol/L occurred in only 2.8% of patients after the first dose 2
• Biochemical ketoacidosis occurred in 0.7% of hospitalized patients after receiving their first SGLT2 inhibitor dose 2

Type 1 Diabetes (High-Risk Population)

• SGLT2 inhibitor-associated DKA occurs in approximately 4% of people with type 1 diabetes 1
• The risk is 5-17 times higher compared to type 1 diabetes patients not treated with SGLT2 inhibitors 1
• SGLT2 inhibitors are not FDA-approved for type 1 diabetes 1

Non-Diabetic Patients

• Non-diabetic patients taking SGLT2 inhibitors for heart failure remain at risk for euglycemic ketoacidosis because they may lack sufficient insulin to prevent significant ketosis 3, 4
• Literature review identified six cases of euglycemic ketoacidosis in non-diabetic patients on SGLT2 inhibitors for heart failure, with five out of six cases involving decreased oral intake 5

Mechanism of Ketosis Induction

SGLT2 inhibitors promote ketosis through multiple interconnected pathways 1:

• Altered insulin-glucagon ratio with decreased insulin secretion and relative increase in glucagon, creating a hormonal environment favoring ketogenesis 3
• Increased lipolysis and ketone production driven by elevated glucagon levels 1
• Decreased renal clearance of ketones (β-hydroxybutyrate and acetoacetate) 1
• These mechanisms persist even with normal glucose levels, explaining the euglycemic presentation 3

Specific Risk Factors for Starvation Ketosis

Dietary and Fasting States

• Very-low-carbohydrate diets significantly increase DKA risk 1
• The first reported case of SGLT2 inhibitor-induced ketoacidosis involved a patient on a strict low-carbohydrate diet with relatively low glucose (191 mg/dL) but severe ketoacidosis 6
• Prolonged fasting periods are a major precipitant 1
• Reduced oral intake due to acute illness 7, 5

Perioperative Risk

• Emergency surgery carries higher ketoacidosis incidence (1.1%) versus elective surgery (0.17%) 3, 4
• Prolonged fasting associated with major surgical procedures triggers stronger stress responses 3
• Among hospitalized patients with ketones >3 mmol/L post-SGLT2 inhibitor, 11 out of 12 had ketosis in the setting of procedure/surgery, sepsis, reduced oral intake, or critical illness 2

Other Precipitants

• Dehydration 1
• Excessive alcohol consumption 1, 7
• Insulin pump malfunctions or significant insulin dose reductions 1
• Female gender 7
• Intercurrent illness 7

Atypical Presentation: Euglycemic Ketoacidosis

Up to one-third of SGLT2 inhibitor-treated patients who develop DKA present with glucose levels <200 mg/dL (11.1 mmol/L) 1, and in one study 71% presented with glucose levels ≤250 mg/dL (13.9 mmol/L) 1. This euglycemic presentation creates diagnostic challenges and delays recognition 3.

The diagnostic criteria for euglycemic DKA include 3:

• Blood glucose <250 mg/dL despite metabolic acidosis
• pH <7.3
• Elevated ketones
• High anion gap metabolic acidosis
• Decreased serum bicarbonate (<18 mEq/L)

Prevention Strategies

Patient Education

• Educate all at-risk individuals about signs and symptoms of DKA 1
• Provide written sick-day rules instructing patients to withhold SGLT2 inhibitors during intercurrent illness 3, 7
• Prescribe accurate tools for ketone measurement (β-hydroxybutyrate monitoring) 1

Perioperative Management

• Discontinue SGLT2 inhibitors 3-4 days before elective surgery (canagliflozin, dapagliflozin, empagliflozin ≥3 days; ertugliflozin ≥4 days) 3, 4, 8
• The effects of SGLT2 inhibitors persist beyond plasma half-life, with clinical effects continuing 3-4 days after discontinuation 3
• Maintain adequate hydration and avoid prolonged fasting periods 3, 4
• Consider glucose-containing IV fluids during unavoidable prolonged fasting to mitigate ketone generation 3, 4

Restarting After Surgery or Illness

• SGLT2 inhibitors should only be restarted once the patient is eating and drinking normally (usually 24-48 hours post-surgery) 3, 8
• Check capillary ketones before restarting, with target level <0.6 mmol/L 3, 8
• Do not initiate SGLT2 inhibitors in patients on very low energy/liver reduction diets, as these diets already induce ketosis 3

Absolute Contraindications

Individuals who have experienced DKA should not be treated with SGLT2 inhibition 1. This represents an absolute contraindication regardless of the potential cardiovascular or renal benefits.

Clinical Pitfalls to Avoid

• Do not assume normal glucose levels exclude ketoacidosis in SGLT2 inhibitor users—always check ketones when patients present with nausea, vomiting, or abdominal pain 3, 4
• Do not continue SGLT2 inhibitors during periods of illness, fasting, or reduced oral intake 7, 5
• Do not restart SGLT2 inhibitors immediately postoperatively without confirming adequate oral intake and normal ketone levels 3, 8
• Recognize that non-diabetic patients on SGLT2 inhibitors for heart failure face similar ketoacidosis risks as diabetic patients during starvation states 3, 4, 5