Main Mechanism of SGLT2 Receptor Antagonists
SGLT2 inhibitors work by blocking the sodium-glucose cotransporter 2 protein in the S1 and S2 segments of the proximal convoluted tubule of the kidney, which prevents approximately 90% of filtered glucose from being reabsorbed back into the bloodstream, thereby increasing urinary glucose excretion and lowering blood glucose levels through an insulin-independent mechanism. 1, 2
Primary Renal Mechanism
SGLT2 is predominantly expressed in the proximal renal tubules where it is responsible for the majority of renal glucose reabsorption from the tubular lumen. 1, 3
By inhibiting SGLT2, these drugs reduce the renal threshold for glucose (RTG) from approximately 240 mg/dL down to 70-90 mg/dL, which triggers glucosuria (urinary glucose excretion) of approximately 100 grams per day. 1, 4
This mechanism is completely insulin-independent, meaning it works regardless of pancreatic beta-cell function or insulin resistance status. 5, 6
Secondary Sodium and Hemodynamic Effects
SGLT2 inhibitors increase the delivery of sodium to the distal tubule by blocking SGLT2-dependent coupled glucose and sodium reabsorption in the proximal tubule. 1, 7
This increased distal sodium delivery activates tubuloglomerular feedback, which reduces intraglomerular pressure and corrects glomerular hyperfiltration—a key mechanism underlying the renal protective effects. 1, 7
The natriuretic effect produces a mild osmotic diuresis that contributes to systolic blood pressure reductions of 3-5 mm Hg and modest weight loss through net caloric loss. 8, 4
Selectivity Profiles Among SGLT2 Inhibitors
Dapagliflozin, empagliflozin, and ertugliflozin are the most selective inhibitors for SGLT2 over SGLT1. 3, 2
Canagliflozin has greater SGLT1 inhibitory activity (Ki for SGLT1 = 770.5 nM vs. SGLT2 = 4.0 nM), which allows it to also inhibit intestinal glucose absorption from the luminal side when present at sufficient concentrations in the gut. 3, 9
Despite this difference, all SGLT2 inhibitors share the same fundamental mechanism of blocking renal glucose reabsorption. 10, 8
Clinical Implications of the Mechanism
The glucose-lowering efficacy is dependent on both renal function (eGFR) and the filtered glucose load (plasma glucose × GFR). 2
Efficacy progressively declines as eGFR falls below 45 mL/min/1.73 m², with substantially reduced glycemic effects when eGFR drops below 30 mL/min/1.73 m². 2
However, the cardiovascular and renal protective benefits persist even when glucose-lowering efficacy is lost, suggesting pleiotropic mechanisms beyond glycemic control. 2, 10
The insulin-independent mechanism results in a low intrinsic risk of hypoglycemia when used alone or with metformin, though risk increases when combined with insulin or sulfonylureas. 5, 6
Additional Mechanisms Beyond Glucose Excretion
SGLT2 inhibitors also inhibit the sodium:proton exchanger in the proximal tubule, contributing to their natriuretic and blood pressure-lowering effects. 7
The drugs may generate additional pleiotropic effects through mechanisms not yet completely identified, including potential neuroprotective properties related to SGLT2 expression in the central nervous system (cerebellum, hippocampus, frontal cortex). 3, 2
Canagliflozin can delay intestinal glucose absorption and reduce postprandial glucose through its SGLT1 inhibitory activity in the small intestine. 1, 9
Common Pitfalls to Avoid
Do not discontinue SGLT2 inhibitors solely because glucose-lowering efficacy has declined with reduced eGFR—the cardiorenal benefits persist and are the primary reason to continue therapy in advanced CKD. 2
Recognize that the increased urination and glucosuria are most pronounced when blood glucose is elevated and diminish as glucose normalizes, typically approaching baseline within 3 days after discontinuation. 8, 1
Be aware that volume depletion risk is increased due to the osmotic diuretic effect, particularly in frail older adults or those on concurrent diuretics. 8