Dapagliflozin

Structural formula
General
Non-proprietary name	Dapagliflozin
other names	(2 S , 3 R , 4 R , 5 S , 6 R ) -2- {4-chloro-3 - [(4-ethoxyphenyl) methyl] phenyl} -6- (hydroxymethyl) oxane-3,4,5- triplet (2 S , 3 R , 4 R , 5 S , 6 R ) -2- [4-chloro-3- (4-ethoxybenzyl) phenyl] -6- (hydroxymethyl) tetrahydro-2 H -pyran-3,4, 5-triplet
Molecular formula	C 21 H 25 ClO 6
External identifiers / databases
CAS number 461432-26-8 EC number 639-683-0 ECHA InfoCard 100.167.331 PubChem 9887712 ChemSpider 8063384 DrugBank DB06292 Wikidata Q409898
Drug information
Drug class	Antidiabetic drug
Mechanism of action	SGLT-2 inhibitor
properties
Molar mass	408,87 g · mol -1
safety instructions
GHS labeling of hazardous substances danger H and P phrases H: 302-319-360-362-372 P: ?
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Dapagliflozin is an orally administered antidiabetic drug for the treatment of type 2 diabetes . Dapagliflozin was developed by the US pharmaceutical company Bristol-Myers Squibb in partnership with the Swedish-British pharmaceutical company AstraZeneca .

Mechanism of action

Dapagliflozin is a selective SGLT-2 inhibitor ( sodium dependent glucose transporter ). SGLT2 is a protein that resorbs sodium and glucose from the primary urine in the proximal tubule of the kidney and is therefore responsible for most of the glucose resorption in the kidney. The inhibition of SGLT2 causes an increased excretion of glucose in the urine in the presence of hyperglycaemia , and this glucosuria supports weight loss to a small extent. In contrast to its predecessors in the group of SGLT-2 inhibitors , the O -glycosides, dapagliflozin is stable towards β- glycosidases and thus has a longer plasma half-life .

In previous studies, patients treated with dapagliflozin had significantly more infections of the genital area than placebo and - with a weaker effect - of the urinary tract. The number of malignant bladder and breast tumors in the studies was not significantly increased. The cause of these diseases is the subject of intensive follow-up in phase IV.

Approval and Marketing

Dapagliflozin was approved by the European Medicines Agency (EMA) in 2012 under the trade name Forxiga , followed in 2014 by the combination preparation of dapagliflozin and metformin under the trade name Xigduo .

In the USA, the Food and Drug Administration (FDA) initially refused approval for dapagliflozin in 2012 due to safety concerns. Further studies should clarify whether the drug can cause bladder cancer , breast cancer, or liver damage. After data from more recent studies and applications allowed a corresponding assessment, it was approved for the US market in January 2014. There the preparation is sold under the trade name Farxiga .

According to the current product information, dapagliflozin is approved in the EU for use in adult type 2 diabetes patients for monotherapy if diet and exercise alone do not adequately control blood sugar in patients for whom the use of metformin is considered unsuitable due to intolerance or in combination with other blood sugar lowering medicines, including insulin, when these, together with diet and exercise, do not adequately control blood sugar.

Early benefit assessment

In Germany, since 2011, newly approved drugs with new active ingredients must be subjected to an " early benefit assessment " by the Federal Joint Committee (G-BA) in accordance with Section 35a SGB ​​V if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. The dossier evaluations, on the basis of which the G-BA makes its decisions, are created by the Institute for Quality and Efficiency in Health Care (IQWiG) .

The G-BA resolutions of the first four early benefit assessments (2013 to 2018) were repealed.

In 2019, dapagliflozin was re-evaluated for the treatment of adults with insufficiently controlled type 2 diabetes mellitus in addition to diet and exercise (as monotherapy, if metformin is considered unsuitable due to intolerance, or in addition to other drugs). According to the G-BA decision, the active ingredient has no additional benefit compared to the respective appropriate comparator therapy in five of eight patient groups. For certain patients at high cardiovascular risk who receive further medication to treat cardiovascular risk factors, however, there is a hint of a minor added benefit.

The combination with metformin was also reassessed in 2019 based on new scientific findings. According to the G-BA, an additional benefit has not been proven for patients without a high cardiovascular risk. In contrast, there is a hint of a minor additional benefit for patients at high cardiovascular risk who receive further medication to treat cardiovascular risk factors.

In addition, an early benefit assessment for dapagliflozin for the treatment of type 1 diabetes was carried out in 2019 following an extension of the approval. According to the G-BA decision, there are dapagliflozin for the treatment of adults with inadequately controlled type 1 diabetes and a BMI of at least 27 kg / m², whose blood sugar is not adequately controlled despite optimal insulin therapy, compared to the appropriate comparator therapy (human insulin or insulin analogues) a hint of a minor added benefit.

refund

Germany

In Germany, Forxiga has been in use since November 2012 according to the approval. After a temporary withdrawal from the German market in December 2013, the drug was put on the market again in February 2014 following an agreement on the price with the National Association of Statutory Health Insurance Funds.

Austria

In Austria, a reimbursement of preparations containing dapagliflozin is possible for patients with type II diabetes. The current version of the “Reimbursement Code” of the Main Association of Austrian Social Insurance Institutions defines the exact conditions for reimbursement.

Others

Forxiga was named " Most Innovative Product" in 2015 by PharmaBarometer magazine .

The randomized DAPA HF study on 4477 test subjects showed that 10 mg dapagliflozin per day in adults could "very effectively and well tolerated" alleviate heart failure .

Trade names

Monopreparations

Forxiga (EU, CH), Farxiga (USA)

Combination preparation

with metformin : Xigduo (EU, CH)

literature

• European public assessment report (EPAR) for Forxiga dapagliflozin (PDF; 123 kB) European Medicines Agency, EMA / 280091/2012. Summary, last updated October 2012.
• James F. List, Vincent Woo, Enrique Morales, Weihua Tang, Fred T. Fiedorek: Sodium-Glucose Cotransport Inhibition with Dapagliflozin in Type 2 Diabetes. Diabetes Care 32 (4) 2009, pp. 650-657. doi: 10.2337 / dc08-1863
• P. Cole, M. Vincente, R. Castaner: Dapagliflozin. In: Drugs of the Future . 33 (9) 2008, p. 745.
• Ramona Steri, Manfred Schubert-Zsilavecz: News in the therapy of diabetes mellitus, new drug classes in the pipeline. In: Pharmacy in our time . 39 (2) 2010, pp. 142-147.

Web links

Public Assessment Report (EPAR) of the European Medicines Agency (EMA) for: Dapagliflozin

Individual evidence

1. ↑ There is not yet a harmonized classification for this substance . A labeling of (1S) -1,5-anhydro-1-C- [4-chloro-3 - [(4-ethoxyphenyl) methyl] phenyl] -D-glucitol in the Classification and Labeling is shown, which is derived from a self-classification by the distributor Inventory of the European Chemicals Agency (ECHA), accessed on January 14, 2020.
2. ↑ New Medicines (PDF; 141 kB) Information from the Medicines Commission of the German Medical Association, as of February 28, 2013.
3. ↑ Type 2 diabetes: First SGLT-2 inhibitor approved. Pharmaceutical newspaper online November 16, 2012.
4. ↑ astrazeneca.com: XIGDUO (dapagliflozin and metformin hydrochloride) approved in the European Union for type 2 diabetes
5. ^ The New York Times: FDA Delays Approval of New Diabetes Drug , Jan. 19, 2012.
6. ↑ drugs.com: FDA Advisory Committee Recommends the Investigational SGLT2 Inhibitor Dapagliflozin for Treatment of Type 2 Diabetes in Adults
7. ↑ drugs.com: Farxiga
8. ↑ A19-53 Dapagliflozin (type 2 diabetes mellitus) - Benefit assessment according to Section 35a Social Code Book V; Accessed March 27, 2020.
9. ↑ A19-92 Dapagliflozin (diabetes mellitus type 2) - addendum to commission A19-53; Accessed March 27, 2020.
10. ↑ Benefit assessment procedure for the active ingredient dapagliflozin (renewed benefit assessment § 14: Diabetes mellitus type 2); Accessed March 27, 2020.
11. ↑ A19-52 Dapagliflozin / metformin (type 2 diabetes mellitus) - benefit assessment according to Section 35a Social Code Book V; Accessed March 27, 2020.
12. ↑ A19-93 Dapagliflozin / metformin (type 2 diabetes mellitus) - addendum to commission A19-52; Accessed March 27, 2020.
13. ↑ Medicinal Products Directive / Annex XII: Dapagliflozin / Metformin (reassessment based on new scientific findings: Diabetes mellitus type 2); Accessed March 27, 2020.
14. ↑ A19-37 Dapagliflozin (type 1 diabetes mellitus) - Benefit assessment according to Section 35a Social Code Book V; Accessed March 27, 2020.
15. ↑ A19-79 Dapagliflozin (diabetes mellitus type 1) - addendum to commission A19-37; Accessed March 27, 2020.
16. ↑ Sucker-Szet, Kerstin: Reimbursement amount agreed - Forxiga returns to the market, February 26, 2014 in: 'Deutsche Apotheker Zeitung'
17. ↑ Reimbursement Code - EKO 1/2019 of the Main Association of Austrian Social Insurance Institutions, as of January 1, 2019.
18. ↑ Forxiga is “the most innovative product” of 2015 from general practitioners, practitioners and internists , accessed on April 25, 2017.
19. ↑ Prof. Dr. Michael Böhm: Antidiabetic proves to be a highly effective heart failure drug, German Society for Cardiology - Heart and Circulatory Research eV ( pdf ), accessed on September 5, 2019.

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