|Systematic (IUPAC) name|
|Half-life||11.8 (10–13) hours|
|Excretion||Fecal and 33% renal|
|Synonyms||JNJ-24831754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol|
|Mol. mass||444.52 g/mol|
|(what is this?)|
Canagliflozin (INN, trade name Invokana) is a drug for the treatment of type 2 diabetes. It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.
Canagliflozin is an antidiabetic drug used to improve glycemic control in patients with type 2 diabetes. In clinical trials, canagliflozin produced a dose-dependent reduction in HbA1c of 0.6 to 0.9 greater than that obtained with placebo when administered as monotherapy, in combination with metformin, or in combination with metformin and a sulfonylurea. Modest effects on the secondary efficacy endpoint of decreased body weight (0.3% to 3.3% greater than placebo) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol and systolic blood pressure, but these effects are offset by increased LDL cholesterol.
History of approvals
On July 4, 2011, the European Medicines Agency approved a paediatric investigation plan and granted both a deferral and a waiver for canagliflozin (EMEA-001030-PIP01-10) in accordance with EC Regulation No.1901/2006 of the European Parliament and of the Council.
Mechanism of action
Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the glucose reabsorption in the kidney (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes about 50 to 80 grams of blood glucose per day to be eliminated through the urine, corresponding to 200–300 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure. Two thirds of the resulting weight loss are caused by the body using up fat tissue to replace the lost glucose, and the rest is mostly water.
Canagliflozin increased (generally mild) urinary tract infections, genital mycotic infections, thirst, LDL cholesterol, and was associated with increased urination and episodes of hypotension.
Cardiovascular problems have been noted with this class of drugs along with canagliflozin. The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was Major Cardiovascular Events Plus (MACE-Plus), defined as the occurrence of any of the following events: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina leading to hospitalization. This endpoint occurred in more patients in the placebo group (20.5%) than in the canagliflozin treated group (18.9%), but the difference was not statistically significant.
Nonetheless, an FDA advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days of treatment in canagliflozin treated patients (0.45%) relative to placebo treated patients (0.07%), suggesting an early period of enhanced cardiovascular risk. In addition, there was an increased risk of stroke in canagliflozin treated patients. Neither of these effects was statistically significant. Additional cardiovascular safety data from the ongoing CANVAS trial is expected in 2015.
Because it increases renal excretion of glucose, treatment with canagliflozin and other SGLT2 inhibitors prevents renal reabsorption of 1,5-anhydroglucitol, leading to artifactual decreases in serum 1,5-anhydroglucitol; it can therefore interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose excursions.
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U.S. health regulators have approved a new diabetes drug from Johnson & Johnson, making it the first in its class to be approved in the United States.
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