From the Guidelines
Sodium-Glucose Linked Transporter 2 Inhibitors (SGLT2i) work by blocking the reabsorption of glucose in the proximal renal tubule, increasing glucose elimination and reducing hyperglycemia.
Mechanism of Action
- SGLT2 proteins are expressed in the proximal convoluted tubule of the kidneys, where they play a key role in glucose homeostasis 1.
- SGLT2 inhibitors block the resorption of glucose by the proximal renal tubules, increasing glucose elimination and reducing hyperglycemia 1.
- This effect is more pronounced in the setting of hyperglycemia, where significant amounts of glucose are filtered into the urine 1.
- Beyond their effect on blood glucose, SGLT2 inhibitors also cause diuretic and natriuretic effects, weight loss, and lowering of systolic blood pressure 1.
Key Benefits
- SGLT2 inhibitors provide insulin-independent glucose lowering, making them a useful treatment option for patients with type 2 diabetes 1.
- They also provide modest weight loss and blood pressure reduction, which can be beneficial for patients with cardiovascular risk factors 1.
- SGLT2 inhibitors have been shown to reduce the risk of major adverse cardiovascular events (MACE) and hospitalization for heart failure (HF) in patients with type 2 diabetes and high cardiovascular risk 1.
From the Research
Mechanism of Action
The mechanism of Sodium-Glucose Linked Transporter 2 Inhibitors (SGLT2i) involves the inhibition of renal glucose reabsorption by blocking the SGLT2 cotransporters in the proximal tubules, causing glucosuria 2. This leads to a reduction in glycemia and lowers HbA1c by approximately 1.0% 2.
Key Effects
Some key effects of SGLT2i include:
- Reduction in intraglomerular pressure, which contributes to the nephroprotective effects of SGLT2i 2
- Caloric loss, which reduces weight, increases insulin sensitivity, and improves lipid metabolism 2
- Metabolic shifts towards gluconeogenesis and ketogenesis, thought to be protective for the heart and kidneys 2, 3
- Reduction in tubular cell glucotoxicity through reduced mitochondrial dysfunction and inflammation 2
- Improvement in blood pressure through a negative sodium and water balance and possibly by inhibiting the sympathetic nervous system 2, 4
Cardiovascular and Renal Benefits
SGLT2i have been shown to have significant benefits in renal and cardiovascular protection, including:
- Reduction in cardiovascular events such as heart failure 4, 3
- Renal protection, including reduced glomerular hyperfiltration and albuminuria 3, 5
- Improved cardiovascular function, potentially due to reduced volume retention and blood pressure, and preserved heart function 5
Additional Mechanisms
Other possible mechanisms of SGLT2i include: