How to manage adverse effects associated with Sodium-Glucose Linked Transporter 1 (SGLT-1) inhibitors?

Managing Adverse Effects of SGLT-1 Inhibitors

SGLT-1 inhibitors primarily cause gastrointestinal adverse effects (particularly diarrhea), increase the risk of euglycemic diabetic ketoacidosis, and can interfere with oral correction of hypoglycemia. 1

Primary Adverse Effects

Gastrointestinal Effects

• Diarrhea is the most common adverse effect of SGLT-1 inhibition, occurring because unabsorbed glucose remains in the intestinal lumen, creating an osmotic effect. 1, 2
• The dual SGLT1/SGLT2 inhibitor sotagliflozin demonstrated diarrhea rates of 6.1% versus 3.4% with placebo. 3
• This occurs because SGLT-1 is the primary transporter for glucose absorption in the gastrointestinal tract, and its inhibition blocks intestinal glucose uptake. 4, 5

Volume Depletion

• SGLT-1 inhibition can lead to volume depletion through both gastrointestinal fluid losses (from diarrhea) and the combined diuretic effect when SGLT-2 is also inhibited. 1
• Maintain adequate hydration during therapy, particularly when initiating treatment or during intercurrent illness. 6, 7

Serious Adverse Effects

Euglycemic Diabetic Ketoacidosis (DKA)

• SGLT-1 inhibition (particularly in dual SGLT1/SGLT2 inhibitors) increases the risk of euglycemic DKA, presenting with blood glucose <250 mg/dL despite metabolic acidosis (pH <7.3) and elevated ketones. 6, 1
• The mechanism involves altered insulin-glucagon ratio, decreased insulin secretion, and relative increase in glucagon, creating a hormonal environment promoting ketogenesis despite normal glucose levels. 6
• Sotagliflozin showed increased severe hypoglycemia rates (1.5% vs. 0.3% with placebo) and DKA risk (RR 3.11; 95% CI, 2.11-4.58) in meta-analyses. 3, 8

Prevention strategies for euglycemic DKA:

• Discontinue SGLT inhibitors 3-4 days before elective surgery (canagliflozin, dapagliflozin, empagliflozin ≥3 days; ertugliflozin ≥4 days). 6, 7
• Avoid prolonged fasting periods and ensure adequate hydration. 6, 7
• Educate patients on DKA triggers: insulin dose reductions, low caloric/fluid intake, intercurrent illness, alcohol consumption. 6, 4
• Monitor for symptoms even with normal glucose: malaise, nausea, vomiting, abdominal pain. 6, 7
• Consider glucose-containing IV fluids during unavoidable prolonged fasting. 6, 7

Hypoglycemia Management Interference

• SGLT-1 inhibition blocks intestinal glucose absorption, which interferes with oral correction of hypoglycemia using carbohydrates. 1
• This is a critical safety concern requiring patient education on alternative hypoglycemia management strategies.
• Patients must understand that oral glucose may not effectively treat hypoglycemia while on SGLT-1 inhibitors. 1

Metabolic and Hormonal Effects

Incretin Hormone Alterations

• SGLT-1 inhibition reduces glucose-dependent insulinotropic peptide (GIP) secretion, indicating downregulation of K cell secretion. 2
• Conversely, GLP-1 and peptide YY (PYY) secretion are enhanced by SGLT-1 inhibition in humans. 2
• These hormonal changes may contribute to both therapeutic effects and adverse event profiles. 2

Risk Stratification

Higher risk patients requiring closer monitoring:

• Type 1 diabetes patients (baseline DKA risk already elevated). 4, 8
• Patients undergoing surgery, especially emergency procedures (1.1% ketoacidosis incidence vs. 0.17% for elective surgery). 6
• Patients with reduced kidney function (though dual inhibitors may maintain efficacy). 4
• Non-diabetic patients taking SGLT inhibitors for heart failure (insufficient insulin to prevent ketosis). 6

Monitoring Requirements

• Monitor blood glucose and ketone levels regularly, particularly during illness, fasting, or perioperative periods. 6, 7
• Check capillary ketones before restarting SGLT inhibitors post-surgery (should be <0.6 mmol/L). 6
• Assess hydration status and electrolytes, especially during gastrointestinal symptoms. 6, 7
• Monitor for genital mycotic infections (increased risk with SGLT-2 component). 3, 8

Perioperative Management

• Withhold SGLT inhibitors 3-4 days before scheduled surgery per American College of Cardiology/American Heart Association guidelines. 6, 7
• UK guidelines suggest a less conservative approach (omit day before and day of procedure), but American guidelines are more cautious. 6
• Restart only when patient is eating and drinking normally (usually 24-48 hours post-surgery) and ketones are <0.6 mmol/L. 6
• Provide written sick-day rules at discharge. 6

Common Pitfalls to Avoid

• Do not initiate SGLT inhibitors in patients on very low energy diets, as this already induces ketosis and combination could cause significant ketoacidosis. 6
• Do not restart SGLT inhibitors too early post-operatively before normal oral intake is established. 6
• Do not rely on oral glucose alone for hypoglycemia correction in patients on SGLT-1 inhibitors. 1
• Do not ignore normal glucose levels when assessing for DKA—euglycemic DKA is the characteristic presentation. 6