What are the potential effects induced by SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors?

Potential Effects Induced by SGLT2 Inhibitors

SGLT2 inhibitors induce multiple effects including cardiovascular and renal benefits, but also carry significant risks of genital mycotic infections, urinary tract infections, volume depletion, and rare but serious euglycemic diabetic ketoacidosis. 1

Beneficial Effects

Glycemic Control

• SGLT2 inhibitors reduce HbA1c levels by 0.5-1.0% by inhibiting renal tubular SGLT2 responsible for glucose reabsorption, promoting urinary glucose excretion 1
• They work through an insulin-independent mechanism, making them effective across various stages of type 2 diabetes 2

Cardiovascular Benefits

• SGLT2 inhibitors reduce the risk of major adverse cardiovascular events in patients with established cardiovascular disease 1
• They significantly reduce hospitalization rates for heart failure, regardless of diabetes status 1
• These cardiovascular benefits appear to be mediated through hemodynamic effects via osmotic diuresis and natriuresis rather than direct glucose-lowering effects 2

Renal Protection

• SGLT2 inhibitors slow the progression of chronic kidney disease 1
• They are strongly recommended for patients with type 2 diabetes, CKD, and an eGFR ≥20 ml/min per 1.73 m² 1
• They can be continued even if eGFR falls below 20 ml/min per 1.73 m², unless not tolerated or kidney replacement therapy is initiated 1
• SGLT2 inhibitors typically cause an initial reversible decline in eGFR of 3-5 mL/min/1.73 m² in the first 4 weeks, followed by stabilization and long-term renal protection 1

Other Metabolic Effects

• Weight loss of 1.5-3.5 kg due to caloric loss through glucosuria 1, 2
• Reduction in systolic blood pressure by 3-5 mmHg 1, 2
• Improvement in lipid profile and reduction in hyperuricemia 2

Adverse Effects

Genitourinary Infections

• Significantly increased risk of genital mycotic infections, especially in women (RR 3.30,95% CI 2.74 to 3.99) 3
• Higher rate of urinary tract infections compared to placebo, though the increase is less dramatic than for genital infections 1, 4
• Non-diabetic patients taking SGLT2 inhibitors also experience increased odds of genital infections (OR 3.01) and urinary tract infections (OR 1.33) 4

Volume Depletion and Electrolyte Disturbances

• Can cause clinically significant volume depletion through osmotic diuresis 1
• Particular caution needed in older adults who are frail or prone to orthostasis 1
• May cause hypotension, especially in patients already at risk for volume depletion 5, 6
• Can affect electrolyte balance, though they typically reduce risks of hyperkalemia without causing hypokalemia 1

Diabetic Ketoacidosis

• Risk of euglycemic diabetic ketoacidosis, a rare but potentially serious adverse event 1, 6
• Higher risk in patients with multimorbidity, particularly during infection, prolonged fasting, surgery, or critical illness 1
• Requires monitoring and temporary discontinuation during times of prolonged fasting, surgery, or critical medical illness 1, 6

Other Adverse Effects

• Potential increase in osteoporotic bone fractures, particularly concerning in older adults at high fracture risk 1
• May worsen symptoms of urinary incontinence due to increased urine volume 1
• Increased low-density lipoprotein cholesterol (LDL-C) levels 6
• Risk of acute kidney injury, particularly in settings of reduced oral intake or fluid losses 6

Special Considerations

Older Adults

• Similar or greater cardiovascular benefits in older adults compared to younger people 1
• Increased risk of volume depletion and orthostasis in frail elderly patients 1
• Consider minimizing use in older adults at high fracture risk 1

Renal Impairment

• Efficacy decreases with declining renal function 7
• Generally recommended for patients with eGFR ≥20 ml/min per 1.73 m² 1
• Renal function should be evaluated prior to initiation and monitored periodically thereafter 6

Drug Interactions

• Risk of hypoglycemia is increased when used with insulin or insulin secretagogues (e.g., sulfonylureas) 6, 8
• May require dose adjustment of concomitant medications like digoxin 8
• May decrease serum lithium concentrations when used concomitantly 8

Practical Management Considerations

• Implement hygienic counseling to reduce risk of genital mycotic and urinary tract infections 1
• Consider reducing diuretics for patients at risk for hypovolemia or hypotension 1
• Develop sick day protocols to reduce risk of euglycemic ketoacidosis 1, 6
• Withhold SGLT2 inhibitors during acute illness with nausea, vomiting, or diarrhea 5
• Stop SGLT2 inhibitors 3-4 days before scheduled surgery, including coronary artery bypass grafting 1