What are SGLT2 Inhibitors?
SGLT2 inhibitors are oral medications that block glucose reabsorption in the kidney's proximal tubule, causing the body to eliminate excess glucose through urine, thereby lowering blood sugar levels independently of insulin. 1
Mechanism of Action
SGLT2 (sodium-glucose cotransporter-2) is a protein in the proximal tubule of the kidney responsible for approximately 90% of urinary glucose reabsorption. 1 By inhibiting this transporter, SGLT2 inhibitors induce glucosuria (glucose in urine), which becomes more pronounced during hyperglycemia and diminishes as blood glucose normalizes. 1 This glucose-dependent mechanism means the risk of hypoglycemia is very low when used alone, though it increases when combined with insulin or insulin secretagogues like sulfonylureas. 2
The drugs work independently of β-cell function and insulin secretion, improving both insulin secretion by relieving glucotoxicity and enhancing peripheral insulin sensitivity. 2, 3
Available Medications
Currently approved SGLT2 inhibitors include: 2
- Dapagliflozin
- Empagliflozin
- Canagliflozin
- Ertugliflozin
- Sotagliflozin
These can be used as monotherapy or in combination with metformin. 2
Beyond Glucose Control: Pleiotropic Effects
SGLT2 inhibitors provide benefits that extend far beyond glucose lowering, including: 1
- Diuretic and natriuretic effects (promoting sodium and water excretion)
- Weight loss (typically 1.5-3.5 kg)
- Blood pressure reduction (systolic BP lowered by 3-5 mmHg)
- Reduced renal cortical hypoxia by decreasing the oxygen burden on proximal tubular cells 2
Cardiovascular and Renal Benefits
The landmark EMPA-REG OUTCOME and CANVAS trials demonstrated that SGLT2 inhibitors significantly reduce major adverse cardiovascular events (MACE) and heart failure hospitalizations in patients with type 2 diabetes and established cardiovascular disease. 1
Specifically, empagliflozin showed: 1
- 14% reduction in CV death, MI, or stroke (HR 0.86)
- 38% reduction in CV death (HR 0.62)
- 32% reduction in all-cause mortality (HR 0.68)
- 35% reduction in heart failure hospitalization (HR 0.65)
For chronic kidney disease, SGLT2 inhibitors reduce disease progression regardless of diabetes status. 2 In patients at very high CKD risk, they decrease all-cause mortality by 48 per 1000 and kidney failure by 58 per 1000. 4
Dosing and Renal Considerations
Important caveat: While SGLT2 inhibitors are less effective at lowering glucose when renal function is impaired (eGFR <45 mL/min/1.73 m²), their cardiovascular and renal protective benefits persist down to eGFR of 30 mL/min/1.73 m². 1
For empagliflozin: 1
- eGFR ≥45: No dose adjustment needed
- eGFR <45: Do not initiate; discontinue if persistently below 45
For canagliflozin: 1
- eGFR ≥60: No dose adjustment
- eGFR 45-59: Do not exceed 100 mg/day
Safety Profile
Common adverse effects include: 1, 5
- Mycotic genital infections (most common)
- Urinary tract infections (8% increased risk in T2DM) 6
- Intravascular volume contraction (particularly in elderly, those on diuretics, or with renal impairment)
Rare but serious adverse events: 1, 5
- Euglycemic ketoacidosis (in vulnerable patients)
- Increased bone fractures (canagliflozin)
- Amputation risk (canagliflozin and ertugliflozin specifically; not seen with empagliflozin or dapagliflozin)
- Acute kidney injury (rare; actually reduced by 22% in T2DM patients overall) 6
Clinical Indications
FDA-approved indications have expanded beyond glucose control: 1
- Improve glycemic control in adults with type 2 diabetes
- Reduce cardiovascular death in T2DM adults with established CVD (canagliflozin)
- Treat heart failure with reduced ejection fraction (expanding to preserved ejection fraction)
- Treat chronic kidney disease and reduce progression
Current guidelines recommend SGLT2 inhibitors as preferred first-line therapy in combination with metformin for most individuals with type 2 diabetes, particularly those with or at high risk for cardiovascular-kidney-metabolic complications. 7, 8