Chemistry:Dapagliflozin

From HandWiki
Short description: Diabetes medication
Dapagliflozin
Dapagliflozin skeletal.svg
Haworth projection of dapagliflozin.svg
Dapagliflozin-from-xtal-Mercury-3D-bs.png
Clinical data
Pronunciation/ˌdæpəɡlɪˈfloʊzɪn/ DAP-ə-glif-LOH-zin
Trade namesForxiga, Farxiga, Edistride, others
Other namesBMS-512148; (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		By mouth (tablets)
Drug classSodium-glucose co-transporter 2 (SGLT2) inhibitor
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only [2]
  • EU: Rx-only [3][4]
  • In general: ℞ (Prescription only)
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%)[2]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC21H25ClO6
Molar mass408.88 g·mol−1
3D model (JSmol)

Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes.[2][3][5] It is also used to treat adults with heart failure and chronic kidney disease.[6][7][3]

Common side effects include hypoglycaemia (low blood sugar), urinary tract infections, genital infections, and volume depletion (reduced amount of water in the body).[8] Diabetic ketoacidosis is a common side effect in type 1 diabetic patients.[9] Serious but rare side effects include Fournier gangrene.[10] Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor and works by removing sugar from the body with the urine.[2]

It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. It is on the World Health Organization's List of Essential Medicines.[11] In 2021, it was the 187th-most commonly prescribed medication in the United States, with more than 2 million prescriptions.[12] Dapagliflozin is available as a 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 and to reduce the risk of hospitalization for heart failure among adults with type 2 diabetes and known cardiovascular disease or other cardiovascular risk factors (including high blood pressure, high cholesterol, and smokers). Dapagliflozin, in addition to other SGLT2-inhibitors, was shown to reduce the rate of decline in kidney function and kidney failure in non-diabetic and type 2 diabetic adults.[13][14] Dapagliflozin is also considered as an option for people that have type 2 diabetes mellitus and heart failure with reduced ejection fraction with a LVEF <40%.[15] It can be given regardless of current diabetes status, in addition to standard medical therapy. Recent studies have indicated that the use of dapagliflozin and other medications from the SGLT-2 inhibitor class, such as empagliflozin can reduce the risk of worsening HF or death and hospitalization from CVD.[15][16] All SGLT-2 inhibitors are useful to reduce the risk of hospitalization for heart failure in people with atherosclerotic cardiovascular disease, but a small number of meta-analyses and cohort studies have shown that dapagliflozin is superior to others such as empagliflozin.[17][18][19]

In addition, dapagliflozin is indicated for the treatment of adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.[6][7][3]

In the European Union it is indicated in adults:

  • For the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise:[3][20][21][22]
    • as monotherapy when metformin is considered inappropriate due to intolerance;[3][20][21][22]
    • in addition to other medicinal products for the treatment of type 2 diabetes;[3]
  • For the treatment of heart failure with reduced ejection fraction[3]

In November 2021, the European Medicines Agency (EMA) stated that dapagliflozin should no longer be used to treat type 1 diabetes.[5]

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 treatment of nondiabetic patients with chronic kidney disease (CKD).[23][24] 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 bodyweight of 1.5 kg.[25][26]

The DAPA-CKD trial (2017-2020) showed in a median treatment period of 2.4 years of patients 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 8 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.[13][26]

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 SGLT2 drug, including dapagliflozin, is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene.[27]

Dapagliflozin is also associated with hypotensive reactions. Concerns exist that it may increase the risk of diabetic ketoacidosis.[28] 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.[29] However, the DEPICT-1 and DEPICT-2 trials showed that dapagliflozin caused additional diabetic ketoacidosis events in the Type I diabetic patients that received dapagliflozin.[30]

Dapagliflozin can cause dehydration, serious urinary tract infections, and genital yeast infections.[6] Elderly people, people with kidney problems, those with low blood pressure, and people on diuretics should be assessed for their volume status and kidney function.[6] People with signs and symptoms of metabolic acidosis or ketoacidosis (acid buildup in the blood) should also be assessed.[6] Dapagliflozin can cause low blood sugar when combined with insulin.[6]

To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high levels of blood acids called ketones) after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines 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.[31]

Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.[31]

The glucose lowering effect of dapagliflozin starts to diminish in CKD patients with a reduced kidney function (eGFR <45mL/min), and may not be as effective for glycemic control. However, as recent 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 diabetic patients with CKD to prevent kidney function decline, further interventions may be needed for glycaemic control.[13][32]

Chemistry

The first synthesis of dapaglifloxin was disclosed in a patent filed by Bristol Myers Squibb in 2002.[33]

Dapaglifloxin synthesis.svg

The two main carbon-containing fragments are combined by the reaction of an aryl lithium with a trimethylsilyl-protected gluconolactone. The trimethylsilyl groups are then removed by treatment with methanesulfonic acid in methanol. This gives an intermediate with an unwanted methoxy group at the 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.[34]

Mechanism of action

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins (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.[35] 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.[36][37][38]

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.[39]

Selectivity

The IC50 for SGLT2 is less than one-thousandth of the IC50 for SGLT1 (1.1 versus 1390 nmol/L), so that the drug does not interfere with intestinal glucose absorption.[40]

Names

Dapagliflozin is the International nonproprietary name (INN),[41] and the United States Adopted Name (USAN).[42]

The fixed-dose combination product, dapagliflozin/metformin extended-release, is called Xigduo XR.[43][44][45]

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.[46] 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.[47][48]

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.[49] The combination drug was approved for use in the European Union in November 2019, and is sold under the brand name Qtrilmet.[50]

History

In 2012, the Committee for Medicinal Products for Human Use (CHMP) of the EMA issued a positive opinion on the drug.[3]

Dapagliflozin was found effective in several studies in participants with type 2.[3] The main measure of effectiveness was the level of glycated haemoglobin (HbA1c), which gives an indication of how well blood glucose is controlled.[3]

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.[3] 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.[3]

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.[3] Both combinations reduced HbA1c levels by 0.52% after 52 weeks.[3]

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.[3] The study indicated that dapagliflozin's effects were in line with those of other diabetes medicines that also work by blocking SGLT2.[3]

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.[3]

Dapagliflozin was approved for medical use in the European Union in November 2012.[3] It is marketed in a number of European countries.[51]

Dapagliflozin was approved for medical use in the United States in January 2014.[52][23]

In 2020, the U.S. 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.[6] 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.[6]

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.[53][54]

The safety and effectiveness of dapagliflozin were evaluated in a randomized, double-blind, placebo-controlled study of 4,744 participants.[6] The average age of participants was 66 years and more participants were male (77%) than female.[6] To determine the drug's effectiveness, investigators examined the occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart-failure visits.[6] Participants were randomly assigned to receive a once-daily dose of either 10 mg of dapagliflozin or a placebo (inactive treatment).[6] 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.[6]

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 failure or cardiovascular death in adults following a heart attack.[55]

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.[56]

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 CKD who are at risk of disease progression.[23] 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.[23]

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.[57][58]

Society and culture

Legal status

A generic version of dapagliflozin was approved by the US FDA in February 2022,[59] but cannot be sold until October 2025.[60][61] A generic version was approved in Canada in May 2023.[62]

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.[63] Dapagliflozin Viatris was approved for medical used in the European Union in March 2023.[4]

Research

A systematic review concluded that dapagliflozin reduced heart failure hospitalization, cardiovascular death, and all-cause mortality in patients with HFrEF (i.e., congestive heart failure) and diabetes.[64]

References

  1. ↑ "Dapagliflozin (Farxiga) Use During Pregnancy". 30 August 2018. https://www.drugs.com/pregnancy/dapagliflozin.html. 
  2. ↑ 2.0 2.1 2.2 2.3 "Farxiga- dapagliflozin tablet, film coated". DailyMed. National Institutes of Health, National Library of Medicine, U.S. Department of Health & Human Services. 3 February 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72ad22ae-efe6-4cd6-a302-98aaee423d69. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 3.17 3.18 "Forxiga EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/forxiga.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. ↑ 4.0 4.1 "Dapagliflozin Viatris EPAR". 4 April 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/dapagliflozin-viatris.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. ↑ 5.0 5.1 "Forxiga (dapagliflozin) 5mg should no longer be used for the treatment of Type 1 Diabetes Mellitus". 11 November 2021. https://www.ema.europa.eu/en/medicines/dhpc/forxiga-dapagliflozin-5mg-should-no-longer-be-used-treatment-type-1-diabetes-mellitus. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 "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. This article incorporates text from this source, which is in the public domain.
  7. ↑ 7.0 7.1 National Institute for Health and Care Excellence (24 February 2021). "Dapagliflozin for treating chronic heart failure with reduced ejection fraction.". NICE. https://www.nice.org.uk/guidance/TA679. 
  8. ↑ "Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events". Drug Safety 37 (10): 815–829. October 2014. doi:10.1007/s40264-014-0213-4. PMID 25096959. 
  9. ↑ "Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes: The DEPICT-1 52-Week Study". Diabetes Care 41 (12): 2552–2559. December 2018. doi:10.2337/dc18-1087. PMID 30352894. 
  10. ↑ "Fournier Gangrene Associated with Sodium-Glucose Cotransporter-2 Inhibitors: A Pharmacovigilance Study with Data from the U.S. FDA Adverse Event Reporting System". Journal of Diabetes Research 2020: 3695101. 2020. doi:10.1155/2020/3695101. PMID 32695827. 
  11. ↑ World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. 2021. WHO/MHP/HPS/EML/2021.02. 
  12. ↑ "The Top 300 of 2021". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  13. ↑ 13.0 13.1 13.2 "Dapagliflozin in Patients with Chronic Kidney Disease". The New England Journal of Medicine 383 (15): 1436–1446. October 2020. doi:10.1056/NEJMoa2024816. PMID 32970396. 
  14. ↑ "Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy". The New England Journal of Medicine 380 (24): 2295–2306. June 2019. doi:10.1056/NEJMoa1811744. PMID 30990260. 
  15. ↑ 15.0 15.1 "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction". The New England Journal of Medicine 381 (21): 1995–2008. November 2019. doi:10.1056/NEJMoa1911303. PMID 31535829. https://pure.rug.nl/ws/files/118672689/nejmoa1911303.pdf. 
  16. ↑ "Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure". The New England Journal of Medicine 383 (15): 1413–1424. October 2020. doi:10.1056/NEJMoa2022190. PMID 32865377. https://hal.univ-lorraine.fr/hal-03733888/file/nejmoa2022190.pdf. 
  17. ↑ "Comparative Efficacy of Dapagliflozin and Empagliflozin of a Fixed Dose in Heart Failure: A Network Meta-Analysis". Frontiers in Cardiovascular Medicine 9: 869272. 4 April 2022. doi:10.3389/fcvm.2022.869272. PMID 35445086. 
  18. ↑ "Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis". JAMA Cardiology 6 (2): 148–158. February 2021. doi:10.1001/jamacardio.2020.4511. PMID 33031522. 
  19. ↑ "SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials". Lancet 393 (10166): 31–39. January 2019. doi:10.1016/S0140-6736(18)32590-X. PMID 30424892. 
  20. ↑ 20.0 20.1 "Dapagliflozin's Effects on Glycemia and Cardiovascular Risk Factors in High-Risk Patients With Type 2 Diabetes: A 24-Week, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study With a 28-Week Extension". Diabetes Care 38 (7): 1218–1227. July 2015. doi:10.2337/dc14-0315. PMID 25852208. 
  21. ↑ 21.0 21.1 "Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial". Diabetes Care 33 (10): 2217–2224. October 2010. doi:10.2337/dc10-0612. PMID 20566676. 
  22. ↑ 22.0 22.1 "Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials". The Lancet. Diabetes & Endocrinology 10 (1): 24–34. January 2022. doi:10.1016/S2213-8587(21)00295-3. PMID 34856173. https://eprints.gla.ac.uk/261109/3/261109Suppl%28Figure%201%29.pdf. 
  23. ↑ 23.0 23.1 23.2 23.3 "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. This article incorporates text from this source, which is in the public domain.
  24. ↑ "Forxiga EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/forxiga.  Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  25. ↑ "Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial". The Lancet. Diabetes & Endocrinology 8 (7): 582–593. July 2020. doi:10.1016/S2213-8587(20)30162-5. PMID 32559474. https://pure.rug.nl/ws/files/147208221/Effects_of_the_SGLT2_inhibitor_dapagliflozin_on_proteinuria_in_non_diabetic_patients_with_chronic_kidney_disease_DIAMOND_a_randomised_double_blind_crossover_trial.pdf. 
  26. ↑ 26.0 26.1 "Prescribing SGLT2 Inhibitors in Patients With CKD: Expanding Indications and Practical Considerations". Kidney International Reports 7 (7): 1463–1476. July 2022. doi:10.1016/j.ekir.2022.04.094. PMID 35812300. 
  27. ↑ "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. https://www.fda.gov/drugs/drug-safety-and-availability/fda-warns-about-rare-occurrences-serious-infection-genital-area-sglt2-inhibitors-diabetes.  This article incorporates text from this source, which is in the public domain.
  28. ↑ "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. https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm446994.htm.  This article incorporates text from this source, which is in the public domain.
  29. ↑ "Effects of SGLT-2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials". Diabetes Research and Clinical Practice 130: 53–60. August 2017. doi:10.1016/j.diabres.2017.04.017. PMID 28570924. 
  30. ↑ "Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies". Diabetes, Obesity & Metabolism 23 (2): 549–560. February 2021. doi:10.1111/dom.14248. PMID 33145944. 
  31. ↑ 31.0 31.1 "FDA revises labels of SGLT2 inhibitors for diabetes to include warning". 19 March 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious.  This article incorporates text from this source, which is in the public domain.
  32. ↑ "Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control". Kidney International 85 (4): 962–971. April 2014. doi:10.1038/ki.2013.356. PMID 24067431. 
  33. ↑ Ellsworth B, Washburn WN, Sher PM, Wu G, Meng W, "C-aryl glucoside SGLT2 inhibitors and method", US patent 6515117B2, published 2003-02-04, assigned to AstraZeneca
  34. ↑ "An overview of the synthetic routes to essential oral anti-diabetes drugs". Tetrahedron 96: 132378. 2021. doi:10.1016/j.tet.2021.132378. 
  35. ↑ "Molecule of the Month: Clarivate". Prous Science. November 2007. http://www.prous.com/molecules/default.asp?ID=165. 
  36. ↑ "Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial". Lancet 375 (9733): 2223–2233. June 2010. doi:10.1016/S0140-6736(10)60407-2. PMID 20609968. 
  37. ↑ "Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial". BMC Medicine 11 (1): 43. February 2013. doi:10.1186/1741-7015-11-43. PMID 23425012. 
  38. ↑ "Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial". International Journal of Clinical Practice 66 (5): 446–456. May 2012. doi:10.1111/j.1742-1241.2012.02911.x. PMID 22413962. 
  39. ↑ "The effects of sodium-glucose cotransporter 2 inhibitors on left ventricular function: current evidence and future directions". ESC Heart Failure 6 (5): 927–935. October 2019. doi:10.1002/ehf2.12505. PMID 31400090. 
  40. ↑ "Dapagliflozin". Neue Arzneimittel. 2008–2009. 
  41. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names: List 59". World Health Organization. 2008. p. 50. https://www.who.int/medicines/publications/druginformation/innlists/RL59.pdf. 
  42. ↑ "Statement on a Nonproprietary Name Adopted by the USAN Council". American Medical Association. http://www.ama-assn.org/ama1/pub/upload/mm/365/dapagliflozin.pdf. 
  43. ↑ "US FDA Approves Once-Daily Xigduo XR Tablets for Adults with Type 2 Diabetes". AstraZeneca. 30 October 2014. https://www.astrazeneca.com/media-centre/press-releases/2014/us-fda-approved-xigduo-type-2-diabetes-patients-30102014.html. 
  44. ↑ "Drug Approval Package: Xigduo XR (dapagliflozin and metformin HCl) Extended-Release Tablets". 7 April 2015. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/205649Orig1s000TOC.cfm. 
  45. ↑ "Xigduo XR- dapagliflozin and metformin hydrochloride tablet, film coated, extended release". 3 February 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ac8a0f7b-9f69-4495-abbc-3a47cd75a859. 
  46. ↑ "Qtern EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/qtern. 
  47. ↑ "Drug Approval Package: Qtern (dapagliflozin and saxagliptin)". 10 October 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209091Orig1s000TOC.cfm. 
  48. ↑ "Qtern- dapagliflozin and saxagliptin tablet, film coated". 24 January 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=423c489c-085b-4320-b892-7868ebd6dc6b. 
  49. ↑ "Drug Approval Package: Qternmet XR". 27 January 2020. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/210874Orig1s000TOC.cfm. 
  50. ↑ "Qtrilmet EPAR". 16 September 2019. https://www.ema.europa.eu/en/medicines/human/EPAR/qtrilmet. 
  51. ↑ "Forxiga". 4 May 2020. https://www.drugs.com/international/forxiga.html. 
  52. ↑ "Drug Approval Package: Farxiga (dapagliflozin) Tablets NDA #202293". 24 December 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/202293Orig1s000TOC.cfm. 
  53. ↑ "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction". The New England Journal of Medicine 381 (21): 1995–2008. November 2019. doi:10.1056/NEJMoa1911303. PMID 31535829. 
  54. ↑ "Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus". Circulation 139 (22): 2528–2536. May 2019. doi:10.1161/CIRCULATIONAHA.119.040130. PMID 30882238. 
  55. ↑ "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.
  56. ↑ "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.
  57. ↑ "Forxiga approved in EU for chronic heart failure". https://www.europeanpharmaceuticalreview.com/news/179288/forxiga-approved-in-eu-for-chronic-heart-failure/. 
  58. ↑ "Dapagliflozin Gets Expanded Heart Failure Indication in Europe". https://www.medscape.com/viewarticle/988034. 
  59. ↑ "Drugs@FDA: Dapagliflozin". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211582. 
  60. ↑ "Patent Blocks Zydus After Landmark US Approval For Dapagliflozin". 24 February 2022. https://generics.pharmaintelligence.informa.com/GB151678/Patent-Blocks-Zydus-After-Landmark-US-Approval-For-Dapagliflozin. 
  61. ↑ "Dapagliflozin – USA". 15 October 2021. https://www.pharmaipcircle.com/uncategorized/dapagliflozin-usa/. 
  62. ↑ "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.
  63. ↑ "Dapagliflozin Viatris: Pending EC decision". 26 January 2023. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/dapagliflozin-viatris.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  64. ↑ "The Effects of Dapagliflozin in Patients With Heart Failure Complicated With Type 2 Diabetes: A Meta-Analysis of Placebo-Controlled Randomized Trials". Frontiers in Clinical Diabetes and Healthcare 2: 703937. 30 June 2021. doi:10.3389/fcdhc.2021.703937. PMID 36994345. 



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