GLIFOZIN 100

Indications

• Type 2 diabetes mellitus as monotherapy (if metformin is inappropriate)
• Type 2 diabetes mellitus in combination with insulin or other antidiabetic drugs (if existing treatment fails to achieve adequate glycemic control)

Dosage

Adults: 100 mg once daily; may increase to 300 mg once daily if tolerated, dose to be taken preferably before breakfast.

Mechanism of action

Canagliflozin inhibits the sodium-glucose co-transporter 2 (SGLT2) located in the proximal renal tubules. This inhibition decreases the reabsorption of filtered glucose, lowering the renal threshold for glucose (RTG) and resulting in increased glucose excretion in the urine. This process helps to lower blood glucose levels and improve overall glycemic control.

Pharmacodynamics

The pharmacodynamic effect of canagliflozin is characterized by a dose-dependent increase in urinary glucose excretion and a decrease in the renal threshold for glucose. By enhancing glucose elimination via urine, canagliflozin lowers blood glucose concentrations and contributes to improved glycemic control, which is particularly beneficial for patients with type 2 diabetes. Additionally, the drug may positively impact cardiovascular health by reducing hyperglycemic-induced vascular damage.

Pharmacokinetics

Canagliflozin is absorbed after oral administration, with peak plasma concentrations occurring within 1 to 2 hours. It has a bioavailability of approximately 65% and is primarily metabolized by the liver through glucuronidation. The elimination half-life is around 10 to 13 hours, allowing for once-daily dosing. Canagliflozin is excreted mainly through urine, and caution is advised in patients with renal impairment as this may affect drug clearance.

Contra-indications

• Diabetic ketoacidosis

Adverse effects

• Increased risk of lower-limb amputation (mainly toes)
• Diabetic ketoacidosis
• Fournier's gangrene (necrotising fasciitis of the genitalia or perineum)
• Skin ulceration
• Osteomyelitis
• Gangrene

Interactions

• Antiepileptics (carbamazepine, phenobarbital, phenytoin, primidone): Unknown (decreases exposure)
• NNRTIs: Unknown (decreases exposure)
• St. John's Wort: Unknown (decreases exposure)

Precautions

• Monitor for signs and symptoms of diabetic ketoacidosis, especially if blood glucose levels are near normal
• Ensure adequate hydration to prevent volume depletion
• Preventive foot care is important for all patients with diabetes
• Monitor patients with risk factors for amputation carefully

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Consult relevant guidelines for more information.

Breast-feeding

It is not known whether canagliflozin is excreted in human milk. Caution should be exercised when administering to a nursing mother.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Tablets: 100 mg, 300 mg

Mechanism of action

The sodium-glucose co-transporter2 (SGLT2), is found in the proximal tubules of the kidney, and reabsorbs filtered glucose from the renal tubular lumen. Canagliflozin inhibits the SGLT2 co-transporter. This inhibition leads to lower reabsorption of filtered glucose into the body and decreases the renal threshold for glucose (RTG), leading to increased glucose excretion in the urine. Sodium-glucose co-transporter 2 (SGLT2), expressed in the proximal renal tubules, is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. Canagliflozin is an inhibitor of SGLT2. By inhibiting SGLT2, canagliflozin reduces reabsorption of filtered glucose and lowers the renal threshold for glucose (RTG), and thereby increases urinary glucose excretion (UGE).

Pharmacodynamics

This drug increases urinary glucose excretion and decreases the renal threshold for glucose (RTG) in a dose-dependent manner. The renal threshold is defined as the lowest level of blood glucose associated with the appearance of detectable glucose in the urine. The end result of canagliflozin administration is increased urinary excretion of glucose and less renal absorption of glucose, decreasing glucose concentration in the blood and improving glycemic control. **A note on type 2 diabetes and cardiovascular disease** The risk of cardiovascular events in diabetes type 2 is increased due to the damaging effects of diabetes on blood vessels and nerves in the cardiovascular system. In particular, there is a tendency for hyperglycemia to create pro-atherogenic (plaque forming) lesions in blood vessels, leading to various fatal and non-fatal events including stroke and myocardial infarction. Long-term glycemic control has been proven to be effective in the prevention of cardiovascular events such as myocardial infarction and stroke in patients with type 2 diabetes.