How does a medication induce glycosuria?

From the Guidelines

Medications that induce glycosuria, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors, work by inhibiting glucose reabsorption in the kidneys, causing glucose to be excreted in urine regardless of blood glucose levels. The most direct way to induce glycosuria is through SGLT2 inhibitors like empagliflozin (Jardiance), dapagliflozin (Farxiga), and canagliflozin (Invokana) 1. These medications are typically dosed once daily (empagliflozin 10-25mg, dapagliflozin 5-10mg, canagliflozin 100-300mg) and are used to treat type 2 diabetes. Alternatively, medications that significantly raise blood glucose levels above the renal threshold (approximately 180-200 mg/dL) can indirectly cause glycosuria, including corticosteroids like prednisone, certain antipsychotics, and some immunosuppressants 1. Patients taking SGLT2 inhibitors should be monitored for urinary tract infections, genital mycotic infections, and volume depletion, as these are common side effects resulting from the increased glucose in the urine and the osmotic diuresis it produces 1. Some key points to consider when using SGLT2 inhibitors include:

• They can be used in patients with chronic kidney disease (CKD) and have been shown to reduce the risk of CKD progression and cardiovascular events 1.
• They can be used in combination with other antihyperglycemic medications, such as metformin, to achieve individualized glycemic targets 1.
• They have been shown to have beneficial effects on weight loss, blood pressure reduction, and cardiovascular risk reduction 1.
• They may cause a modest reduction in eGFR, but this is generally reversible and not a reason to discontinue therapy 1.
• They should be used with caution in patients at risk for hypovolemia, such as those taking diuretics, and patients should be educated on potential adverse effects, including modest volume contraction, blood pressure reduction, and weight loss 1.

From the FDA Drug Label

12.1 Mechanism of Action Canagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor. It works by inhibiting SGLT2 in the proximal renal tubules, which reduces glucose reabsorption and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion.

The medication canagliflozin induces glycosuria by inhibiting the SGLT2 in the kidneys, which leads to a reduction in glucose reabsorption and an increase in urinary glucose excretion 2.

• The main mechanism is the inhibition of SGLT2 in the proximal renal tubules.
• This results in a decrease in glucose reabsorption and a lowering of the renal threshold for glucose.
• The end result is an increase in glucose excretion in the urine.

From the Research

Mechanism of Glycosuria Induction

• Farsi, or more specifically, Sodium-glucose cotransporter 2 (SGLT2) inhibitors, induce glycosuria by blocking glucose reabsorption in the proximal convoluted tubules of the kidneys, resulting in increased glucose excretion in the urine 3, 4, 5.
• This mechanism is insulin-independent and not limited by the degree of insulin resistance or beta-cell dysfunction, making it a unique approach to controlling type 2 diabetes 5.
• SGLT2 inhibitors, such as canagliflozin, dapagliflozin, and empagliflozin, have been shown to reduce the renal glucose threshold and increase urinary glucose excretion, leading to improved glycemic control and weight loss 3, 4, 6.

Effects on Glucose Excretion

• Canagliflozin, a potent SGLT2 inhibitor, has been shown to dose-dependently reduce the calculated renal threshold for glucose excretion and increase urinary glucose excretion in healthy subjects 6.
• In patients with type 2 diabetes, SGLT2 inhibitors have been shown to increase glycosuria, leading to improved glycemic control and weight loss, without increasing the risk of hypoglycemia 3, 4, 5.

Clinical Implications

• SGLT2 inhibitors have been approved for use as monotherapy or in combination with other anti-hyperglycemic agents, including insulin, to improve glycemic control in patients with type 2 diabetes 3, 4.
• The use of SGLT2 inhibitors has been associated with additional benefits, including weight loss, improved blood pressure control, and reduced cardiovascular risk 4, 5, 7.
• However, SGLT2 inhibitors may also increase the risk of genital mycotic infections and urinary tract infections, and caution is recommended in fragile elderly patients and patients with chronic kidney disease 4.