What is the mechanism of SGLT2 (sodium-glucose linked transporter 2) inhibitors, including reduction of oxidative stress and mitochondrial dysfunction through activation of SIRT1 (sirtuin-1), and decreased activation of the Na+/H+ exchanger?

From the Guidelines

SGLT2 inhibitors work through multiple mechanisms to improve cardiovascular and renal outcomes, including reducing oxidative stress in mitochondria by activating SIRT1 and decreasing the activation of the sodium-hydrogen exchanger, as supported by recent studies such as 1 and 1.

Key Mechanisms of SGLT2 Inhibitors

• Inhibiting sodium-glucose cotransporter 2 in the proximal tubule of the kidney to prevent glucose reabsorption and promote urinary glucose excretion
• Reducing oxidative stress in mitochondria by activating SIRT1 (Sirtuin-1), a protein deacetylase that regulates cellular metabolism and stress responses
• Decreasing the activation of the sodium-hydrogen (Na+/H+) exchanger in both the kidney and heart to reduce intracellular sodium and calcium levels, improving cardiac energetics and preventing cardiomyocyte injury

Benefits of SGLT2 Inhibitors

• Improving cardiovascular and renal outcomes beyond their glucose-lowering properties
• Reducing major adverse cardiovascular events, including hospitalization for heart failure and cardiovascular death, as shown in studies such as 1 and 1
• Providing benefits in heart failure and chronic kidney disease even in non-diabetic patients, as supported by guidelines such as 1

Clinical Implications

• SGLT2 inhibitors are recommended as a key treatment approach to reduce cardiovascular disease and heart failure outcomes in people with diabetes, as stated in 1
• Patients on SGLT2 inhibitors should be closely monitored for potential risks, including severe genitourinary infections and diabetic ketoacidosis, as noted in 1

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

SGLT2 Inhibitors Mechanism

• The SGLT2 inhibitors work by increasing urinary glucose excretion, thereby improving glucose control 2, 3, 4, 5, 6
• They block glucose reabsorption by the kidneys to increase glucosuria 4
• The reduction of glucotoxicity improves beta-cell sensitivity to glucose and tissue insulin sensitivity 6

Effects on Oxidative Stress and Mitochondrial Function

• There is no direct evidence in the provided studies on the effect of SGLT2 inhibitors on oxidative stress and mitochondrial function, including the role of Sirtuina-1

Effects on NaH Exchanger Activation

• There is no direct evidence in the provided studies on the effect of SGLT2 inhibitors on the activation of NaH exchanger

Clinical Benefits

• SGLT2 inhibitors have been shown to improve glycemic control, reduce body weight, and decrease blood pressure 2, 3, 4, 5, 6
• They have also been shown to have cardiovascular benefits, including reducing the risk of composite cardiovascular events and cardiovascular deaths 3, 4, 6