What are Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors?

What are SGLT2 Inhibitors?

SGLT2 inhibitors are oral medications that block the sodium-glucose cotransporter-2 protein in the kidney's proximal tubule, preventing glucose reabsorption and causing the body to excrete excess glucose in the urine. 1

Mechanism of Action

SGLT2 is the predominant transporter responsible for reabsorbing approximately 90% of filtered glucose from the kidney back into the bloodstream. 1 By inhibiting this transporter, SGLT2 inhibitors:

• Reduce renal glucose reabsorption and lower the renal threshold for glucose, thereby increasing urinary glucose excretion 1
• Cause glucosuria (glucose in urine), which leads to caloric loss and modest weight reduction 2
• Produce an osmotic diuresis that increases urine volume by approximately 341 mL on Day 1 and 135 mL by Day 5 of treatment 1
• Work through an insulin-independent mechanism, improving β-cell function by reducing glucotoxicity rather than stimulating insulin release 2

Available SGLT2 Inhibitors

The FDA-approved SGLT2 inhibitors include empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin. 2 These agents are highly selective for SGLT2 over SGLT1, distinguishing them from dual SGLT1/SGLT2 inhibitors like sotagliflozin. 3

Clinical Applications Beyond Diabetes

Cardiovascular and Renal Protection

SGLT2 inhibitors provide cardiovascular and kidney benefits that are out of proportion to their glucose-lowering effects and persist even when glycemic efficacy is lost at lower kidney function. 3

The BMJ guideline provides strong evidence that SGLT2 inhibitors:

• Reduce all-cause mortality, cardiovascular death, hospitalization for heart failure, kidney failure, non-fatal myocardial infarction, and non-fatal stroke in patients with chronic kidney disease 4
• Should be used in all adults with CKD regardless of diabetes status, with particularly strong recommendations for high and very high-risk patients 5
• Can be initiated if eGFR ≥20 mL/min/1.73 m² and continued even if eGFR falls below 20 mL/min/1.73 m² until dialysis initiation 5

Risk-Stratified Recommendations

The BMJ guideline stratifies recommendations based on CKD risk: 4

• Very high-risk patients (eGFR <30 mL/min/1.73 m² with albuminuria ≥200 mg/g): Strong recommendation to initiate SGLT2 inhibitors 4, 5
• High-risk patients (eGFR 30-44 mL/min/1.73 m² with albuminuria ≥200 mg/g): Strong recommendation to initiate SGLT2 inhibitors 4, 5
• Moderate and low-risk patients: Weak recommendation in favor of SGLT2 inhibitors 4

Glucose-Lowering Efficacy vs. Cardiorenal Benefits

A critical distinction exists between the glucose-lowering efficacy and cardiorenal protective effects of SGLT2 inhibitors. 3

Glucose-Lowering Effects by eGFR:

• eGFR ≥45 mL/min/1.73 m²: Full glucose-lowering efficacy expected 3
• eGFR 30-45 mL/min/1.73 m²: Substantially reduced glucose-lowering efficacy 3, 1
• eGFR <30 mL/min/1.73 m²: Minimal to no glucose-lowering effect 3

Cardiorenal Protection:

Cardiovascular and kidney benefits persist across all eGFR categories down to 20 mL/min/1.73 m², even when glycemic efficacy is lost. 3 This is why SGLT2 inhibitors should not be discontinued solely because glucose-lowering efficacy has declined. 3

Physiological Effects

Beyond glucose excretion, SGLT2 inhibitors produce several pleiotropic effects: 6

• Revert tubuloglomerular feedback and reduce intraglomerular pressure, central to nephroprotective effects 6
• Reduce tubular energy and oxygen demand, likely decreasing kidney hypoxia 6
• Improve blood pressure through negative sodium and water balance, with systolic BP reduction of 3-5 mm Hg 7, 6
• Shift metabolism toward gluconeogenesis and ketogenesis, thought to be protective for heart and kidneys 6
• Reduce hepcidin levels, improving erythropoiesis and anemia 6

Dosing and Practical Considerations

A fixed dose of 10 mg daily for dapagliflozin or empagliflozin is recommended for cardiovascular/renal protection, with no titration required. 5

Expected eGFR Changes:

An initial, reversible decrease in eGFR of 3-5 mL/min/1.73 m² is expected within the first 1-4 weeks and is NOT a reason to discontinue therapy. 5 This is followed by long-term kidney protection with slower eGFR decline. 5

Administration:

SGLT2 inhibitors may be administered with or without food, as food has no clinically relevant effect on pharmacokinetics. 1

Safety Profile and Adverse Effects

Common adverse effects include: 2, 8

• Genital mycotic infections (most common) 2, 8
• Urinary tract infections 2, 8
• Euglycemic diabetic ketoacidosis (rare but serious) 5, 2
• Volume depletion and hypotension, particularly in frail older adults 7, 2
• Increased urination, most pronounced when blood glucose is elevated 7

Absolute Contraindications:

• Polycystic kidney disease 5
• Patients requiring immunosuppressive therapy for kidney disease 5
• Kidney transplant recipients (limited data, increased infection risk) 5

Common Pitfalls to Avoid

• Do not withhold SGLT2 inhibitors in non-diabetic CKD patients, as benefits are equivalent regardless of diabetes status 5
• Do not discontinue SGLT2 inhibitors when eGFR falls below 45 mL/min/1.73 m², as cardiovascular and renal benefits persist at lower eGFR levels 5, 3
• Do not discontinue therapy due to the initial reversible eGFR dip 5, 3
• Do not discontinue solely because glucose-lowering efficacy has declined 3
• Use cautiously in older adults prone to orthostasis or urinary incontinence 7

Combination Therapy

SGLT2 inhibitors should be used alongside RAS inhibitors (ACEi or ARB) for enhanced kidney protection. 5 For patients with persistent albuminuria despite SGLT2 inhibitor and RAS inhibitor therapy, nonsteroidal mineralocorticoid receptor antagonists can be added. 5