Canagliflozin
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Haworth projection (bottom) | |
| Clinical data | |
|---|---|
| Pronunciation | KAN-ə-gli-FLOH-zin |
| Trade names | Invokana, Sulisent |
| AHFS/Drugs.com | invokana |
| Pregnancy category |
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| Routes of administration | By mouth (tablets) |
| ATC code | A10BX11 (WHO) |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 65% |
| Protein binding | 99% |
| Metabolism | Hepatic glucuronidation |
| Biological half-life | 11.8 (10–13) hours |
| Excretion | Fecal and 33% renal |
| Identifiers | |
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| Synonyms | JNJ-28431754; TA-7284; (1S)-1,5-anhydro-1-C-(3-{[5-(4-fluorophenyl)thiophen-2-yl]methyl]}-4-methylphenyl)-D-glucitol |
| CAS Number |
842133-18-0  |
| PubChem (CID) | 24812758 |
| IUPHAR/BPS | 4582 |
| DrugBank |
DB08907  |
| ChemSpider |
26333259 |
| UNII |
6S49DGR869 |
| ChEBI |
CHEBI:73274 |
| ChEMBL |
CHEMBL2103841 |
| ECHA InfoCard | 100.223.671 |
| Chemical and physical data | |
| Formula | C24H25FO5S |
| Molar mass | 444.52 g/mol |
| 3D model (Jmol) | Interactive image |
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Canagliflozin (INN,[1] trade name Invokana or Sulisent) is a drug of the gliflozin class or subtype 2 sodium-glucose transport (SGLT-2) inhibitors used for the treatment of type 2 diabetes.[2][3] It was developed by Mitsubishi Tanabe Pharma and is marketed under license by Janssen, a division of Johnson & Johnson.[4]
Medical use
Canagliflozin is an anti-diabetic drug used to improve glycemic control in people with type 2 diabetes. In extensive clinical trials, canagliflozin produced a consistent dose-dependent decrease in HbA1c levels of 0.77% to 1.16% when administered either as monotherapy, in combination with metformin, in combination with metformin and a sulfonylurea, in combination with metformin and pioglitazone, or in combination with insulin, from initial HbA1c levels of 7.8% to 8.1%. When added to metformin, canagliflozin 100 mg daily was shown to be non-inferior to both sitagliptin 100 mg daily and glimepiride in reducing HbA1c levels at one year, whilst canagliflozin 300 mg successfully demonstrated statistical superiority over both sitagliptin and glimiperide in decreasing HbA1c levels. Secondary efficacy endpoints of higher reductions in weight and blood pressure (versus sitagliptin and glimiperide) were also observed in studies. Canagliflozin produces beneficial effects on HDL cholesterol whilst increasing LDL cholesterol to produce no change in total cholesterol.[5][6]
Contraindications
Canaglifozin is contraindicated in:
- Type 1 diabetes
- Diabetic ketoacidosis
- Severe renal impairment (estimated glomerular filtration rate >30 mL/min/1.73 m2), end-stage renal disease
- Patients on dialysis[6]
Adverse effects
As with all SGLT-2 inhibitors, canagliflozin is associated with increased incidence of urinary tract infections, fungal infections of the genital area, thirst,[7] elevations in LDL cholesterol, increased urination and episodes of low blood pressure. There are concerns that it may also increase the risk of diabetic ketoacidosis.[8]
Possible cardiovascular problems are an ongoing issue with gliflozin drugs.[9] The pre-specified endpoint for cardiovascular safety in the canagliflozin clinical development program was "Major Cardiovascular Events Plus," defined as the occurrence of cardiovascular death, non-fatal myocardial infarctions, non-fatal strokes, 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, a United States Food and Drug Administration advisory committee expressed concern regarding the cardiovascular safety of canagliflozin. A greater number of cardiovascular events was observed during the first 30 days in study subjects who received canagliflozin (0.45%) compared those who received placebo (0.07%), suggesting an early period of increased cardiovascular risk. In addition, there was an increased risk of stroke in subjects who received canagliflozin. However, none of these effects were statistically significant. Additional cardiovascular safety data from another ongoing study are expected in 2015.[9]
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 ketone bodies. The FDA is continuing to investigate the issue, and cautions that patients should not stop taking canagliflozin without first talking to their doctor.[10]
On September 10, 2015, the FDA issued a drug safety communication for canagliflozin to address risks for bone fracture and decreased bone density. A label warning for fractures was already included in the Adverse Reactions section; however, the FDA made the addition to the Warnings and Precautions section to reflect new information from a placebo study. They advised health care professionals should consider fracture risk factors before prescribing canagliflozin, and patients should disclose any bone fracture risk factors to their doctors, but that patients should not stop taking the medication without first talking to their doctor.[11]
On December 4, 2015, the FDA issued another safety communication for SGLT2 inhibitors, indicating that it would require new warnings to be added to the canagliflozin label about elevated blood acid levels and urinary tract infections.[12]
A June 29, 2016 report on the ongoing cardiovascular outcomes trial for canagliflozin (CANVAS) revealed interim findings of new safety concerns including heightened risk of bone fracture that was found to increase with the duration of treatment.[13]
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. Therefore, canagliflozin can interfere with the use of serum 1,5-anhydroglucitol (assay trade name, GlycoMark) as a measure of postprandial glucose levels.[14]
Mechanism of action
Canagliflozin is an inhibitor of subtype 2 sodium-glucose transport proteins (SGLT2), which is responsible for at least 90% of 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,[15] 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 types of anti-diabetic drugs such as sulfonylurea derivatives and insulin.[16]
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.[17]
Canagliflozin was approved by the FDA on March 29, 2013, and became the first SGLT2 inhibitor in the United States.[18][19]
References
- ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 64" (PDF). World Health Organization. 2010. p. 263. Retrieved 14 November 2016.
- ↑ New J&J diabetes drug effective in mid-stage study, Jun 26, 2010
- ↑ Edward C. Chao (2011). "Canagliflozin". Drugs of the Future. 36 (5): 351–357. doi:10.1358/dof.2011.36.5.1590789.
- ↑ http://www.investor.jnj.com/releasedetail.cfm?releaseid=710584
- ↑ "Summary Review" (PDF). fda.gov. March 29, 2013. Retrieved 2014-07-09.
- 1 2 "Invokana (canagliflozin) Tablets, for Oral Use. Full Prescribing Information" (PDF). Janssen Pharmaceuticals, Inc. Retrieved 14 November 2016.
- ↑ Haberfeld, H (ed.). Austria-Codex (in German) (2013/14, supplement 01/14 ed.). Vienna: Österreichischer Apothekerverlag.
- ↑ FDA (2015-05-15). "SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood". Retrieved 19 May 2015.
- 1 2 Tucker, Miriam (10 January 2013). "FDA Advisory Panel Supports Diabetes Drug Canagliflozin". Medscape Family Medicine. Retrieved 3 August 2015.
Safety discussions by the panel circled back repeatedly to the cardiovascular risk data
- ↑ Research, Center for Drug Evaluation and. "Drug Safety and Availability - FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood". www.fda.gov. Retrieved 2016-06-07.
- ↑ "FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density". FDA. U.S. Food & Drug Administration. Retrieved 10 September 2015.
- ↑ "SGLT2 Inhibitors: Drug Safety Communication - Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections". FDA. Food and Drug Administration. Retrieved 11 March 2016.
- ↑ Schroeder, C. "New Report Warns of Increasing SGLT2 & Invokana Risks". DrugNews. Pro Media One. Retrieved 8 August 2016.
- ↑ Balis, Dainius A; Tong, Cindy; Meininger, Gary (July 2014). "Effect of canagliflozin, a sodium–glucose cotransporter 2 inhibitor, on measurement of serum 1,5-anhydroglucitol". J Diabetes. 6 (4): 378–380. doi:10.1111/1753-0407.12116.
- ↑ Prous Science: Molecule of the Month November 2007
- ↑ A. Klement (20 January 2014). "Tubuläre Senkung des Blutzuckers bei Diabetes mellitus: Invokana". Österreichische Apothekerzeitung (in German) (2/2014): 20f.
- ↑ "EMEA-001030-PIP01-10". EMA European Medicines Agency. Retrieved May 6, 2013.
- ↑ "Canagliflozin". www.fda.gov. United States Food and Drug Administration. Retrieved 23 March 2016.
- ↑ "U.S. FDA approves Johnson & Johnson diabetes drug, canagliflozin". Reuters. March 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.