Dapagliflozin

Source: Wikipedia, the free encyclopedia.

Dapagliflozin
Haworth projection (bottom)
Clinical data
Pronunciation/ˌdæpəɡlɪˈfloʊzɪn/ DAP-ə-glif-LOH-zin
Trade namesForxiga, Farxiga, others
Other namesBMS-512148; (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol
AHFS/Drugs.comMonograph
MedlinePlusa614015
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classSodium-glucose co-transporter 2 (SGLT2) inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability78% (after 10 mg dose)
Protein binding~91%
MetabolismUGT1A9 (major), CYP (minor)
MetabolitesDapagliflozin 3-O-glucuronide (inactive)
Elimination half-life~12.9 hours
ExcretionUrine (75%), feces (21%)[6]
Identifiers
  • (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
JSmol)
  • Clc1ccc(cc1Cc2ccc(OCC)cc2)[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O
  • InChI=1S/C21H25ClO6/c1-2-27-15-6-3-12(4-7-15)9-14-10-13(5-8-16(14)22)21-20(26)19(25)18(24)17(11-23)28-21/h3-8,10,17-21,23-26H,2,9,11H2,1H3/t17-,18-,19+,20-,21+/m1/s1
  • Key:JVHXJTBJCFBINQ-ADAARDCZSA-N

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes.[6][7][9] It is also used to treat adults with heart failure and chronic kidney disease.[10][11][7] It reversibly inhibits sodium-glucose co-transporter 2 (SGLT-2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.[12]

Common side effects include

volume depletion (reduced amount of water in the body).[13] Diabetic ketoacidosis is a common side effect in people with type 1 diabetes.[14] Serious but rare side effects include Fournier gangrene.[15]

It was developed by

generic medication
.

Medical uses

Dapagliflozin is used along with diet, exercise, and usually with other glucose lowering medications, to improve glycaemic control in adults with type 2 diabetes. Dapagliflozin, in addition to other SGLT-2 inhibitors, was shown to reduce the rate of decline in kidney function and kidney failure in non-diabetic and type 2 diabetic adults.[19][20]

Dapagliflozin is also considered as an option for people with heart failure with reduced ejection fraction with a

atherosclerotic cardiovascular disease, but a small number of meta-analyses and cohort studies have shown that dapagliflozin is superior to others such as empagliflozin.[23][24][25]

In the European Union, dapagliflozin is indicated in adults:

In November 2021, the European Medicines Agency (EMA) stated that dapagliflozin should no longer be used to treat type 1 diabetes.[9]

Effects in nondiabetic chronic kidney disease

In 2021, the US Food and Drug Administration (FDA) and the EMA expanded the indications for dapagliflozin to include the treatment of people who have chronic kidney disease but don't have diabetes.[29][30] Clinical trials had shown the following effects of such a treatment.

The DIAMOND trial (2017-2019) showed in treatment periods of 6 weeks no improvement of excess proteins in the urine (proteinuria), a significant deterioration of the kidney's filtration rate (reversible within 6 weeks after dapagliflozin discontinuation), and a significant mean loss of body weight of 1.5 kg.[31][32]

The DAPA-CKD trial (2017-2020) showed in a median treatment period of 2.4 years of participants who had already been under ACE or ARB therapy that the events of a sustained decline of 50% in the kidney's filtration rate, kidney failure, or death occurred statistically around eight months later in the treatment group than in the placebo group. In the first 12-16 months of treatment, however, the kidney's filtration rate was worse in the treatment group than in the placebo group, being slightly less negative in the treatment group than in the placebo group only thereafter.[19][32]

Adverse effects

Since dapagliflozin leads to heavy glycosuria (sometimes up to about 70 grams per day), it can lead to rapid weight loss and tiredness. The glucose acts as an osmotic diuretic (this effect is the cause of polyuria in diabetes), which can lead to dehydration. The increased amount of glucose in the urine can also worsen the infections already associated with diabetes, particularly urinary tract infections and thrush (candidiasis). Rarely, use of an SGLT-2 drug, including dapagliflozin, is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene.[33]

Dapagliflozin is also associated with hypotensive reactions. Concerns exist that it may increase the risk of diabetic ketoacidosis.[34] A 2017 meta-analysis showed that SGLT-2 inhibitors such as dapagliflozin were not statistically correlated with an increase in diabetic ketoacidosis occurrence in Type II diabetic patients.[35] However, the DEPICT-1 and DEPICT-2 trials showed that dapagliflozin caused additional diabetic ketoacidosis events in the Type I diabetic patients who received dapagliflozin.[36] Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, fatigue, and trouble breathing.[37]

Dapagliflozin can cause dehydration, serious urinary tract infections, and genital yeast infections.[10] Elderly people and people with kidney dysfunction, low blood pressure, or who are on diuretic medications should have their volume status and kidney function assessed.[10] Individuals with signs and symptoms of metabolic acidosis or ketoacidosis should also be assessed.[10] Dapagliflozin can cause low blood sugar when combined with insulin.[10]

To lessen the risk of developing ketoacidosis after surgery, the FDA has approved changes to the prescribing information for SGLT-2 inhibitors to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery.[37]

The glucose lowering effect of dapagliflozin starts to diminish in people with chronic kidney disease with a reduced kidney function (eGFR <45mL/min), and may not be as effective for glycemic control. However, studies have demonstrated a renoprotective effect in reducing kidney function decline, dapagliflozin can still be used to reduce kidney function decline regardless of diabetes status. Therefore, while dapagliflozin can be used in people with diabetes and chronic kidney disease to prevent kidney function decline, further interventions may be needed for glycemic control.[19][38]

Chemistry

The first synthesis of dapaglifloxin was disclosed in a patent filed by Bristol Myers Squibb in 2002.[39]

The two main carbon-containing fragments are combined by the reaction of an

anomeric centre, which is removed by reaction with triethylsilane in the presence of boron trifluoride etherate. This route, as well as others developed for the manufacture of the drug, have been reviewed.[40]

Mechanism of action

Dapagliflozin inhibits subtype 2 of the

SGLT2), which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine.[41] In combination with metformin, dapagliflozin at standard treatment dose of 10 mg daily lowered HbA1c by 0.54-0.84% when compared to metformin monotherapy in patients with inadequately controlled type 2 diabetes and normal renal function.[42][43][44]

Its protective effects in heart failure is attributed primarily to haemodynamic effects, where SGLT2 inhibitors potently reduce intravascular volume through osmotic diuresis and natriuresis. This consequently may lead to a reduction in preload and afterload, thereby alleviating cardiac workload and improving left ventricular function.[45]

Selectivity

The

SGLT1 (1.1 versus 1390 nmol/L), so that the drug does not interfere with intestinal glucose absorption.[46]

Names

Dapagliflozin is the International nonproprietary name (INN),[47] and the United States Adopted Name (USAN).[48]

The fixed-dose combination product, dapagliflozin/metformin extended-release, is called Xigduo XR.[49][50][51]

In July 2016, the fixed-dose combination of saxagliptin and dapagliflozin was approved for medical use in the European Union and is sold under the brand name Qtern.[52] The combination drug was approved for medical use in the United States in February 2017, where it also is sold under the brand name Qtern.[53][54]

In May 2019, the fixed-dose combination of dapagliflozin, saxagliptin, and metformin hydrochloride as extended-release tablets was approved in the United States to improve glycemic control in adults with type 2 diabetes when used in combination with diet and exercise. The FDA granted the approval of Qternmet XR to AstraZeneca.[55] The combination drug was approved for use in the European Union in November 2019, and is sold under the brand name Qtrilmet.[56]

History

In 2012, the Committee for Medicinal Products for Human Use (CHMP) of the EMA issued a positive opinion on the drug.[7]

Dapagliflozin was found effective in several studies in participants with type 2.

glycated haemoglobin (HbA1c), which gives an indication of how well blood glucose is controlled.[7]

In two studies involving 840 participants with type 2 diabetes, dapagliflozin when used alone decreased HbA1c levels by 0.66% more than placebo (a dummy treatment) after 24 weeks.[7] In four other studies involving 2,370 participants, adding dapagliflozin to other diabetes medicines decreased HbA1c levels by 0.54–0.68% more than adding placebo after 24 weeks.[7]

In a study involving 814 participants with type 2 diabetes, dapagliflozin used in combination with metformin was at least as effective as a sulphonylurea (another type of diabetes medicines) used with metformin.[7] Both combinations reduced HbA1c levels by 0.52% after 52 weeks.[7]

A long-term study, involving over 17,000 participants with type 2 diabetes, looked at the effects of dapagliflozin on cardiovascular (heart and circulation) disease.[7] The study indicated that dapagliflozin's effects were in line with those of other diabetes medicines that also work by blocking SGLT2.[7]

In two studies involving 1,648 participants with type 1 diabetes whose blood sugar was not controlled well enough on insulin alone, adding dapagliflozin 5 mg decreased HbA1c levels after 24 hours by 0.37% and by 0.42% more than adding placebo.[7]

Dapagliflozin was approved for medical use in the European Union in November 2012.[7] It is marketed in a number of European countries.[57]

Dapagliflozin was approved for medical use in the United States in January 2014.[58][29]

In 2020, the US FDA expanded the indications for dapagliflozin to include treatment for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.[10] It is the first in this particular drug class, sodium-glucose co-transporter 2 inhibitors, to be approved to treat adults with New York Heart Association's functional class II-IV heart failure with reduced ejection fraction.[10]

The results of the DAPA-HF and DECLARE-TIMI 58 clinical trials demonstrated the efficacy of dapagliflozin compared to placebo in improving survival in adults with heart failure with reduced ejection fraction by 17%. They both showed a reduction in the number of hospitalizations from worsening heart failure, cardiovascular death and all-cause mortality.[59][60]

The safety and effectiveness of dapagliflozin were evaluated in a randomized, double-blind, placebo-controlled study of 4,744 participants.[10] The average age of participants was 66 years and more participants were male (77%) than female.[10] To determine the drug's effectiveness, investigators examined the occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart-failure visits.[10] Participants were randomly assigned to receive a once-daily dose of either 10 mg of dapagliflozin or a placebo (inactive treatment).[10] After about 18 months, people who received dapagliflozin had fewer cardiovascular deaths, hospitalizations for heart failure, and urgent heart-failure visits than those receiving the placebo.[10]

In July 2020, the FDA granted AstraZeneca a Fast Track Designation in the US for the development of dapagliflozin to reduce the risk of hospitalization for

heart attack.[61]

In August 2020, detailed results from the Phase III DAPA-CKD trial reportedly showed that dapagliflozin on top of standard of care reduced the composite measure of worsening of renal function or risk of cardiovascular or renal death by 39% compared to placebo (p<0.0001) in patients with chronic kidney disease stages 2–4 and elevated urinary albumin excretion. The results were consistent in patients both with and without type 2 diabetes.[62]

In April 2021, the FDA expanded the indications for dapagliflozin to include reducing the risk of kidney function decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression.[29] The efficacy of dapagliflozin to improve kidney outcomes and reduce cardiovascular death in people with chronic kidney disease was evaluated in a multicenter, double-blind study of 4,304 participants.[29]

In February 2023, the EU approved dapagliflozin for extended use to cover heart failure patients across the full spectrum of left ventricular ejection fraction (LVEF), including those with mildly reduced and preserved ejection fraction.[63][64]

Society and culture

Legal status

A

generic version of dapagliflozin was approved by the US FDA in February 2022,[65] but cannot be sold until October 2025.[66][67] A generic version was approved in Canada in May 2023.[68]

In January 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for a generic version of Forxiga, which has been authorized in the EU since November 2012.[69] Dapagliflozin Viatris was approved for medical used in the European Union in March 2023.[8]

Research

A systematic review concluded that dapagliflozin reduced heart failure hospitalization, cardiovascular death, and all-cause mortality in people with HFrEF (i.e., congestive heart failure) and diabetes.[70]

References

  1. ^ "Dapagliflozin (Farxiga) Use During Pregnancy". Drugs.com. 30 August 2018. Archived from the original on 17 April 2021. Retrieved 5 May 2020.
  2. ^ "Forxiga dapagliflozin (as propanediol monohydrate) 10 mg film-coated tablet blister pack (180147)". Therapeutic Goods Administration (TGA). 27 May 2022. Retrieved 20 April 2024.
  3. ^ "AusPAR: Dapagliflozin". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 20 April 2024.
  4. ^ "AusPAR: Dapagliflozin (as propanediol monohydrate)". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 20 April 2024.
  5. ^ "Product monograph brand safety updates". Health Canada. 7 July 2016. Retrieved 1 April 2024.
  6. ^ a b c "Farxiga- dapagliflozin tablet, film coated". DailyMed. National Institutes of Health, National Library of Medicine, U.S. Department of Health & Human Services. 3 February 2020. Archived from the original on 30 October 2020. Retrieved 5 May 2020.
  7. ^ a b c d e f g h i j k l m n o p q r "Forxiga EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 17 February 2020. Retrieved 17 February 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. ^ a b "Dapagliflozin Viatris EPAR". European Medicines Agency. 4 April 2023. Retrieved 17 June 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  9. ^ a b "Forxiga (dapagliflozin) 5mg should no longer be used for the treatment of Type 1 Diabetes Mellitus". European Medicines Agency (EMA). 11 November 2021. Archived from the original on 11 November 2021. Retrieved 11 November 2021.
  10. ^ a b c d e f g h i j k l "FDA approves new treatment for a type of heart failure". U.S. Food and Drug Administration (FDA) (Press release). 5 May 2020. Archived from the original on 6 May 2020. Retrieved 5 May 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  11. ^ National Institute for Health and Care Excellence (24 February 2021). "Dapagliflozin for treating chronic heart failure with reduced ejection fraction". NICE Technology Appraisal Auidance [TA679]. NICE. Archived from the original on 9 May 2021. Retrieved 9 May 2021.
  12. ^ "BNF: Dapagliflozin". NICE. Retrieved 2 February 2024.
  13. S2CID 24064402
    .
  14. S2CID 53027785.{{cite journal}}: CS1 maint: overridden setting (link
    )
  15. PMID 32695827
    .
  16. hdl:10665/345533
    . WHO/MHP/HPS/EML/2021.02.
  17. ^ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  18. ^ "Dapagliflozin - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  19. ^
    S2CID 221887260.{{cite journal}}: CS1 maint: overridden setting (link
    )
  20. S2CID 117730201.{{cite journal}}: CS1 maint: overridden setting (link
    )
  21. ^
    S2CID 202687033.{{cite journal}}: CS1 maint: overridden setting (link
    )
  22. S2CID 221383070.{{cite journal}}: CS1 maint: overridden setting (link
    )
  23. PMID 35445086
    .
  24. PMID 33031522.{{cite journal}}: CS1 maint: overridden setting (link
    )
  25. S2CID 53277899.{{cite journal}}: CS1 maint: overridden setting (link
    )
  26. ^
    PMID 25852208
    .
  27. ^
    PMID 20566676
    .
  28. ^
    S2CID 244737266.{{cite journal}}: CS1 maint: overridden setting (link
    )
  29. ^ a b c d "FDA Approves Treatment for Chronic Kidney Disease". U.S. Food and Drug Administration (FDA) (Press release). 30 April 2021. Archived from the original on 30 April 2021. Retrieved 30 April 2021. Public Domain This article incorporates text from this source, which is in the public domain.
  30. ^ "Forxiga EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 17 February 2020. Retrieved 17 February 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  31. S2CID 219948034.{{cite journal}}: CS1 maint: overridden setting (link
    )
  32. ^
    PMID 35812300
    .
  33. ^ "FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes". U.S. Food and Drug Administration (FDA). 9 February 2019. Archived from the original on 13 December 2019. Retrieved 16 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  34. ^ "SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood". U.S. Food and Drug Administration (FDA). 15 May 2015. Archived from the original on 27 October 2016. Retrieved 15 November 2016. Public Domain This article incorporates text from this source, which is in the public domain.
  35. PMID 28570924
    .
  36. PMID 33145944.{{cite journal}}: CS1 maint: overridden setting (link
    )
  37. ^ a b "FDA revises labels of SGLT2 inhibitors for diabetes to include warning". U.S. Food and Drug Administration. 19 March 2020. Archived from the original on 7 June 2020. Retrieved 6 June 2020. Public Domain This article incorporates text from this source, which is in the public domain.
  38. PMID 24067431
    .
  39. ^ US patent 6515117B2, Ellsworth B, Washburn WN, Sher PM, Wu G, Meng W, "C-aryl glucoside SGLT2 inhibitors and method", published 2003-02-04, assigned to AstraZeneca 
  40. doi:10.1016/j.tet.2021.132378
    .
  41. ^ "Molecule of the Month: Clarivate". Prous Science. November 2007. Archived from the original on 5 November 2007.
  42. S2CID 9168659
    .
  43. S2CID 16429125
    .
  44. S2CID 9934488
    .
  45. PMID 31400090
    .
  46. ^ Schubert-Zsilavecz M, Wurglics M (2008–2009). "Dapagliflozin". Neue Arzneimittel.
  47. ^ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 59" (PDF). World Health Organization. 2008. p. 50. Archived (PDF) from the original on 18 May 2016. Retrieved 15 November 2016.
  48. ^ "Statement on a Nonproprietary Name Adopted by the USAN Council" (PDF). American Medical Association. Archived from the original (PDF) on 7 February 2012. Retrieved 15 November 2016.
  49. ^ "US FDA Approves Once-Daily Xigduo XR Tablets for Adults with Type 2 Diabetes". AstraZeneca. 30 October 2014. Archived from the original on 16 November 2016. Retrieved 15 November 2016.
  50. ^ "Drug Approval Package: Xigduo XR (dapagliflozin and metformin HCl) Extended-Release Tablets". U.S. Food and Drug Administration (FDA). 7 April 2015. Archived from the original on 20 February 2020. Retrieved 5 May 2020.
  51. ^ "Xigduo XR- dapagliflozin and metformin hydrochloride tablet, film coated, extended release". DailyMed. 3 February 2020. Archived from the original on 2 March 2021. Retrieved 5 May 2020.
  52. ^ "Qtern EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 14 July 2020. Retrieved 7 May 2020.
  53. ^ "Drug Approval Package: Qtern (dapagliflozin and saxagliptin)". U.S. Food and Drug Administration (FDA). 10 October 2018. Archived from the original on 14 July 2020. Retrieved 8 May 2020.
  54. ^ "Qtern- dapagliflozin and saxagliptin tablet, film coated". DailyMed. 24 January 2020. Archived from the original on 14 July 2020. Retrieved 17 February 2020.
  55. ^ "Drug Approval Package: Qternmet XR". U.S. Food and Drug Administration (FDA). 27 January 2020. Archived from the original on 17 February 2020. Retrieved 17 February 2020.
  56. ^ "Qtrilmet EPAR". European Medicines Agency (EMA). 16 September 2019. Archived from the original on 29 December 2019. Retrieved 30 March 2020.
  57. ^ "Forxiga". Drugs.com. 4 May 2020. Archived from the original on 28 August 2021. Retrieved 5 May 2020.
  58. ^ "Drug Approval Package: Farxiga (dapagliflozin) Tablets NDA #202293". U.S. Food and Drug Administration (FDA). 24 December 1999. Archived from the original on 19 September 2020. Retrieved 5 May 2020.
  59. S2CID 202687033.{{cite journal}}: CS1 maint: overridden setting (link
    )
  60. S2CID 81977866.{{cite journal}}: CS1 maint: overridden setting (link
    )
  61. ^ "FARXIGA Granted Fast Track Designation in the US for Heart Failure Following Acute Myocardial Infarction Leveraging an Innovative Registry-Based Trial Design" (Press release). AstraZeneca. 16 July 2020. Archived from the original on 20 July 2020. Retrieved 20 July 2020 – via Business Wire.
  62. ^ "FARXIGA Demonstrated Unprecedented Reduction in the Risk of Kidney Failure and Cardiovascular or Renal Death in Patients with Chronic Kidney Disease in the Phase III DAPA-CKD Trial" (Press release). AstraZeneca. 30 August 2020. Archived from the original on 31 August 2020. Retrieved 4 September 2020 – via Business Wire.
  63. ^ "Forxiga approved in EU for chronic heart failure". European Pharmaceutical Review. Retrieved 9 February 2023.
  64. ^ "Dapagliflozin Gets Expanded Heart Failure Indication in Europe". Medscape. Retrieved 9 February 2023.
  65. ^ "Drugs@FDA: Dapagliflozin". U.S. Food and Drug Administration (FDA). Archived from the original on 25 March 2022. Retrieved 25 March 2022.
  66. ^ Rudge D (24 February 2022). "Patent Blocks Zydus After Landmark US Approval For Dapagliflozin". Archived from the original on 10 June 2022. Retrieved 8 June 2022.
  67. ^ "Dapagliflozin – USA". 15 October 2021. Archived from the original on 10 June 2022. Retrieved 8 June 2022.
  68. ^ "JAMP Pharma Group receives Health Canada approval for PrJAMP Dapagliflozin, a new generic alternative for the treatment of type 2 diabetes" (Press release). JAMP Pharma. 16 May 2023. Retrieved 17 June 2023 – via Newswire.
  69. ^ "Dapagliflozin Viatris: Pending EC decision". European Medicines Agency. 26 January 2023. Archived from the original on 27 January 2023. Retrieved 29 January 2023. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  70. PMID 36994345
    .
Retrieved from "https://en.wikipedia.org/w/index.php?title=Dapagliflozin&oldid=1219839251"