Canagliflozin

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Canagliflozin
300px
Systematic (IUPAC) name
(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Clinical data
Trade namesInvokana
AHFS/Drugs.comentry
Pregnancy cat.C (US)
Legal status-only (US)
RoutesOral
Pharmacokinetic data
Bioavailability65%
Protein binding99%
MetabolismHepatic glucuronidation
Half-life11.8 (10–13) hours
ExcretionFecal and 33% renal
Identifiers
CAS number842133-18-0 YesY
ATC codeA10BX11
PubChemCID 24812758
ChemSpider26333259 N
UNII6S49DGR869 N
ChEBICHEBI:73274 N
SynonymsJNJ-24831754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
FormulaC24H25FO5S 
Mol. mass444.52 g/mol
 N (what is this?)  (verify)
 
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Canagliflozin
300px
Systematic (IUPAC) name
(2S,3R,4R,5S,6R)-2-{3-[5-[4-Fluoro-phenyl)-thiophen-2-ylmethyl]-4-methyl-phenyl}-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol
Clinical data
Trade namesInvokana
AHFS/Drugs.comentry
Pregnancy cat.C (US)
Legal status-only (US)
RoutesOral
Pharmacokinetic data
Bioavailability65%
Protein binding99%
MetabolismHepatic glucuronidation
Half-life11.8 (10–13) hours
ExcretionFecal and 33% renal
Identifiers
CAS number842133-18-0 YesY
ATC codeA10BX11
PubChemCID 24812758
ChemSpider26333259 N
UNII6S49DGR869 N
ChEBICHEBI:73274 N
SynonymsJNJ-24831754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
FormulaC24H25FO5S 
Mol. mass444.52 g/mol
 N (what is this?)  (verify)

Canagliflozin (INN, trade name Invokana) is a drug for the treatment of type 2 diabetes.[1][2] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.[3]

In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States.[4]

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.[5]

Medical Use[edit]

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.[6][7]

Mechanism of action[edit]

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,[8] 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.[9]

This mechanism is associated with a low risk of hypoglycaemia (too low blood glucose) compared to other antidiabetic drugs such as sulfonylurea derivatives and insulin.[9]

Contraindications[edit]

Canagliflozin is less effective in patients with moderate renal failure and probably ineffective in severe renal failure and type 1 diabetes.[10][9]

Adverse effects[edit]

Canagliflozin increased (generally mild) urinary tract infections, genital mycotic infections, thirst,[10] 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.[citation needed] 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.[11]

Interactions[edit]

The drug may increase the risk of dehydration in combination with diuretic drugs, especially in elderly people.[10]

References[edit]

  1. ^ New J&J diabetes drug effective in mid-stage study, Jun 26, 2010
  2. ^ Edward C. Chao (2011). "Canagliflozin". Drugs of the Future 36 (5): 351–357. doi:10.1358/dof.2011.36.5.1590789. 
  3. ^ http://www.investor.jnj.com/releasedetail.cfm?releaseid=710584
  4. ^ "U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin". Reuters. Mar 29, 2013. "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." 
  5. ^ "EMEA-001030-PIP01-10". EMA European Medicines Agency. Retrieved May 6, 2013. 
  6. ^ "www.accessdata.fda.gov". 
  7. ^ "www.accessdata.fda.gov". 
  8. ^ Prous Science: Molecule of the Month November 2007
  9. ^ a b c A. Klement (20 January 2014). "Tubuläre Senkung des Blutzuckers bei Diabetes mellitus: Invokana". Österreichische Apothekerzeitung (in German) (2/2014): 20f. 
  10. ^ a b c Haberfeld, H (ed.). Austria-Codex (in German) (2013/14, supplement 01/14 ed.). Vienna: Österreichischer Apothekerverlag. 
  11. ^ [1]