Canagliflozin

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Canagliflozin
250px
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 names Invokana, Sulisent
AHFS/Drugs.com entry
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability 65%
Protein binding 99%
Metabolism Hepatic glucuronidation
Biological half-life 11.8 (10–13) hours
Excretion Fecal and 33% renal
Identifiers
CAS Number 842133-18-0 YesY
ATC code A10BX11 (WHO)
PubChem CID: 24812758
IUPHAR/BPS 4582
DrugBank DB08907 YesY
ChemSpider 26333259 N
UNII 6S49DGR869 N
ChEBI CHEBI:73274 N
ChEMBL CHEMBL2103841 N
Synonyms JNJ-28431754; TA-7284; (1S)-1,5-anhydro-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol
Chemical data
Formula C24H25FO5S
Molecular mass 444.52 g/mol
  • Cc1ccc(cc1Cc2ccc(s2)c3ccc(cc3)F)[C@H]4[C@@H]([C@H]([C@@H]([C@H](O4)CO)O)O)O
  • InChI=1S/C24H25FO5S/c1-13-2-3-15(24-23(29)22(28)21(27)19(12-26)30-24)10-16(13)11-18-8-9-20(31-18)14-4-6-17(25)7-5-14/h2-10,19,21-24,26-29H,11-12H2,1H3/t19-,21-,22+,23-,24+/m1/s1 N
  • Key:XTNGUQKDFGDXSJ-ZXGKGEBGSA-N N
 NYesY (what is this?)  (verify)

Canagliflozin (INN, trade name Invokana or Sulisent) is a drug of the gliflozin class, used 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]

Medical use

Canagliflozin is an antidiabetic drug used to improve glycemic control in people with type 2 diabetes. In extensive clinical trials, canagliflozin produced a consistent dose-dependent reduction in HbA1c of 0.77% to 1.16% when administered as monotherapy, combination with metformin, combination with metformin and a sulfonylurea, combination with metformin and pioglitazone, and in combination with insulin from a baselines of 7.8% to 8.1%, in combination with metformin, or in combination with metformin and a sulfonylurea. When added to metformin, canagliflozin 100 mg was shown to be non-inferior to both sitagliptin 100 mg and glimepiride in reductions on HbA1c at one year, whilst canagliflozin 300 mg successfully demonstrated statistical superiority over both sitagliptin and glimiperide in HbA1c reductions. Secondary efficacy endpoint of superior body weight reduction and blood pressure reduction (versus sitagliptin and glimiperide)) were observed as well. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.[4][5]

Contraindications

Canagliflozin has proven to be clinically effective in people with moderate renal failure and treatment can be continued in patients with renal impairment.

Adverse effects

As is common with all SGLT-2 inhibitors, Canagliflozin is associated with increased urinary tract infections, fungal infections of the genital area, increased thirst,[6] elevations in LDL cholesterol, increased urination and episodes of low blood pressure. There are concerns it may also increase the risk of diabetic ketoacidosis.[7]

Possible cardiovascular problems are an issue of discussion with this drug class.[8] 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 people in the placebo group (20.5%) than in the canagliflozin treated group (18.9%).

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 people (0.45%) relative to placebo treated people (0.07%), suggesting an early period of enhanced cardiovascular risk. In addition, there was an increased risk of stroke in canagliflozin treated people. However none of these effects were seen as statistically significant. Additional cardiovascular safety data from the ongoing CANVAS trial is expected in 2015.[8]

On May 15, 2015, the FDA issued a warning that certain SGLT2 diabetes drugs, including canagliflozin, may lead to ketoacidosis, a condition where the body produces higher levels of blood acid. The FDA is continuing to investigate the issue, and cautions that patients should not stop taking canagliflozin without first talking to their doctor.[9]

On September 10, 2015, the FDA issued a Drug Safety Communication strengthening the label for canagliflozin to address risks for bone fracture and decreased bone density. A label warning for bone fractures was already included in the Adverse Reactions section, however the agency made the addition to the Warnings and Precautions section to reflect new data from a placebo study. They advised health care professionals should consider fracture risk factors before prescribing the drug and patients should disclose any bone fracture risk factors to their doctors. However, patients should not stop taking the medication without first talking to their doctor.[10]

Interactions

The drug may increase the risk of dehydration in combination with diuretic drugs.

Because it increases renal excretion of glucose, treatment with canagliflozin 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.[11]

Mechanism of action

Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport protein (SGLT2), which is responsible for at least 90% of the renal glucose reabsorption (SGLT1 being responsible for the remaining 10%). Blocking this transporter causes up to 119 grams of blood glucose per day to be eliminated through the urine,[12] corresponding to 476 kilocalories. Additional water is eliminated by osmotic diuresis, resulting in a lowering of blood pressure.

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.[13]

History

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.[14]

In March 2013, canagliflozin became the first SGLT2 inhibitor to be approved in the United States.[15]

References

  1. ↑ New J&J diabetes drug effective in mid-stage study, Jun 26, 2010
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ http://www.investor.jnj.com/releasedetail.cfm?releaseid=710584
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ 8.0 8.1 Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Prous Science: Molecule of the Month November 2007
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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