From the Guidelines
No, SGLT2 inhibitors do not improve glucose control by reducing glucose secretion. Instead, these medications work by preventing glucose reabsorption in the kidneys, causing excess glucose to be excreted in the urine. SGLT2 inhibitors like empagliflozin (Jardiance), dapagliflozin (Farxiga), canagliflozin (Invokana), and ertugliflozin (Steglatro) block the sodium-glucose cotransporter 2 protein in the proximal tubule of the kidney. This protein normally reabsorbs about 90% of filtered glucose back into the bloodstream. By inhibiting this process, these medications promote glucosuria (glucose excretion in urine), effectively lowering blood glucose levels independent of insulin action. This mechanism is particularly valuable for patients with type 2 diabetes as it works regardless of beta-cell function or insulin resistance.
Key Benefits of SGLT2 Inhibitors
- Lower HbA1c by 0.5-1.0%
- Offer additional benefits including weight loss (typically 2-3 kg)
- Blood pressure reduction
- Cardiovascular and renal protection
- Common side effects include genital mycotic infections, urinary tract infections, and volume depletion, so adequate hydration is important while using these medications.
According to the most recent study 1, SGLT2 inhibitors should be used for minimizing progression of CKD, reduction in cardiovascular events, and reduction in hospitalizations for HF. The study also notes that the glycemic benefits of SGLT2 inhibitors are reduced at eGFR <45 mL/min per 1.73 m2.
Important Considerations
- Patients initiating SGLT2 inhibitors should be educated on potential adverse effects
- Clinicians should consider decreasing the diuretic dose and advising patients about symptoms of volume depletion and low blood pressure
- SGLT2 inhibitors may cause a modest reduction in eGFR that is hemodynamic in nature and reversible.
Overall, SGLT2 inhibitors are a valuable treatment option for patients with type 2 diabetes, offering benefits beyond glucose control, including cardiovascular and renal protection.
From the Research
Mechanism of SGLT2 Inhibitors
- SGLT2 inhibitors work by increasing urinary glucose excretion by suppressing glucose reabsorption at the proximal tubule in the kidney 2, 3.
- This mechanism of action is insulin-independent, which means that SGLT2 inhibitors can be used in patients with any degree of β-cell function or insulin sensitivity 3.
- By reducing glucose reabsorption in the kidney, SGLT2 inhibitors lower plasma glucose levels in people with diabetes 3.
Effect on Glucose Control
- SGLT2 inhibitors have been shown to significantly reduce glycated hemoglobin (HbA1c) by 0.6-0.8% (6-8 mmol/mol) without increasing the risk of hypoglycemia 2, 4.
- The improvement of glucose control is similar or slightly better compared to metformin, sulfonylureas, or sitagliptin, with the added benefit of significant reductions in body weight and blood pressure 4.
- SGLT2 inhibitors have also been shown to reduce glucotoxicity, improve beta-cell sensitivity to glucose, and increase tissue insulin sensitivity 4.
Reduction of Glucose Secretion
- SGLT2 inhibitors do not directly reduce glucose secretion, but rather increase urinary glucose excretion by reducing glucose reabsorption in the kidney 2, 3.
- The reduction of glucotoxicity and improvement of beta-cell sensitivity to glucose may indirectly reduce glucose secretion, but this is not a direct effect of SGLT2 inhibitors 4.
Clinical Implications
- SGLT2 inhibitors have been shown to improve cardiovascular and renal outcomes in patients with type 2 diabetes, especially in those with prior cardiovascular events, heart failure, or chronic kidney disease 2, 5.
- The use of SGLT2 inhibitors may also have potential benefits in reducing the risk of diabetic nephropathy, although more clinical research is needed to confirm this 5, 6.