Mechanism of Action of SGLT2 Inhibitors
SGLT2 inhibitors selectively block the sodium-glucose co-transporter-2 proteins located in the S1 and S2 segments of the proximal convoluted tubule, preventing approximately 90% of filtered glucose from being reabsorbed and causing it to be excreted in the urine instead. 1
Primary Renal Mechanism
SGLT2 proteins are expressed predominantly in the early proximal tubule of the kidney, where they normally reabsorb the majority of filtered glucose (approximately 90%) back into the bloodstream 1, 2
By inhibiting SGLT2, these medications block glucose reabsorption and increase urinary glucose excretion (glucosuria), which lowers blood glucose levels independently of insulin secretion or β-cell function 3, 4
The renal threshold for glucose is approximately 180 mg/dL—when blood glucose exceeds this level, SGLT2 activity becomes saturated and glucosuria appears 3, 4
Sodium is co-transported with glucose, so SGLT2 inhibition also increases sodium excretion, which triggers multiple downstream effects 2, 5
Selectivity Profile Among Available Agents
Dapagliflozin, empagliflozin, and ertugliflozin exhibit the highest selectivity for SGLT2 over SGLT1, distinguishing them from canagliflozin (which has appreciable SGLT1 inhibition affecting intestinal glucose absorption) and sotagliflozin (a dual SGLT1/SGLT2 inhibitor) 1
During SGLT2 inhibition, SGLT1 in the downstream proximal tubule reabsorbs 40-50% of the remaining filtered glucose, which explains why complete glucosuria does not occur 6
Hemodynamic and Renal Protective Mechanisms
Increased sodium delivery to the distal tubule reverses tubuloglomerular feedback, reducing intraglomerular pressure and providing nephroprotection 2, 5
SGLT2 inhibition reduces oxygen consumption and ATP demand by proximal tubular cells, alleviating renal cortical hypoxia that occurs in diabetes when these cells work harder to reabsorb excess glucose 3, 1
The resulting reduction in glomerular hyperfiltration acutely lowers GFR but preserves long-term kidney function by reducing cortical oxygen demand and preventing progressive damage 5
Metabolic and Systemic Effects
Caloric loss from glucosuria (approximately 200-300 kcal/day) promotes weight loss of 1.5-3.5 kg and increases insulin sensitivity 4, 7
Metabolism shifts toward gluconeogenesis and ketogenesis, which may provide cardioprotective and nephroprotective effects, though this also explains the rare risk of euglycemic ketoacidosis 2, 8
SGLT2 inhibition is uricosuric, lowering serum urate levels through mechanisms related to functional co-regulation with other proximal tubule transporters 5
Osmotic diuresis and sodium excretion reduce plasma volume, increasing hematocrit and improving oxygen delivery to tissues, which contributes to cardiovascular benefits 2, 5
Cardiovascular Mechanisms
Blood pressure decreases by 3-5 mmHg systolic through negative sodium and water balance, and possibly through inhibition of the sympathetic nervous system 4, 2
Reduction in plasma volume and improved cardiac preload contribute to decreased heart failure hospitalizations 7, 2
The cardiovascular and renal benefits persist even when glucose-lowering efficacy is lost at lower eGFR levels, indicating mechanisms independent of glycemic control 1
Central Nervous System Expression
- SGLT2 is expressed at low levels in brain regions including the cerebellum, hippocampus, and frontal cortex, where it may contribute to potential neuroprotective effects, though clinical evidence remains limited 1, 7
Clinical Implications of the Mechanism
SGLT2 inhibitors work independently of insulin, allowing use at any stage of diabetes and conferring low intrinsic hypoglycemia risk when used alone or with metformin 3, 4
Glucose-lowering efficacy progressively declines as eGFR falls below 45 mL/min/1.73 m², with substantially reduced glycemic effects below 30 mL/min/1.73 m², though cardiorenal benefits persist 1
The insulin-sparing effect and reduction in glucotoxicity improve β-cell function and peripheral insulin sensitivity over time 3