COVID-19 infections
In July 2020 AstraZeneca reported that Cambridge University Hospitals NHS Foundation Trust initiated a phase II/III TACTIC-E trial to evaluate the efficacy of combination of the dapagliflozin and ambrisentan be compared with the standard of care therapy in pre-ICu patients with COVID-2019 infections (EudraCT2020-002229-27; NCT04393246). The randomised, open-label trial intends to enrol approximately 1407 patients in the UK [8] [9] .
In June 2021, AstraZeneca completed the phase III Dare-19 trial that evaluated the efficacy and safety of dapagliflozin in addition to background local standard of care therapy, on the risk of all-cause death or disease progression and complications in adults who are hospitalised with COVID-19 at the time of trial enrolment (NCT04350593; D1690C00081; ESR-20-20653). Earlier in April 2021, AstraZeneca reported that the phase III DARE-19 trial did not achieve primary endpoint, in which 30 day treatment with dapagliflozin in addition of standard-of-care therapies did not showed statistically significant prevention of organ dysfunction, all-cause mortality and improvement in clinical recovery, preventing death from any cause. Safety profile of dapagliflozin in the trial was similar as reported in previous clinical trials. The trial was initiated in April 2020 and included COVID-19 patients with medical history of hypertension (HTN), atherosclerotic CV disease, heart failure with reduced or preserved ejection fraction, T2D or CKD Stage III to IV who received dapagliflozin for 30 days. The randomised, investigator-sponsored trial enrolled 1250 patients in the US, Brazil, Mexico, Canada, Argentina, India and the UK. In June 2021, safety and efficacy data from the trial was released [10] [11] [12] [13] .
Type 2 diabetes mellitus (T2DM), monotherapy, combination therapy
In January 2014, AstraZeneca and BMS announced that the US FDA approved Farxiga™ (dapagliflozin) as an adjunct to diet and exercise in patients with T2DM [4] [14] . AstraZeneca and BMS resubmitted their NDA for once-daily oral dapagliflozin in adults with T2DM to FDA in July 2013. In December 2013, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) recommended approval. The EMDAC voted 13-1 that the benefits outweigh identified risks and support marketing of the drug, and 10-4 that the data provided ample evidence on the acceptable cardiovascular risk of the drug relative to comparators [15] . The companies had previously received a Complete Response Letter from the FDA in January 2012 requesting additional clinical data to better assess the risk/benefit profile after the FDA's EMDAC recommended against approval, in July 2011. BMS and AstraZeneca had submitted the original NDA in December 2010, and this was accepted for review by the FDA in March 2011. The resubmitted NDA included data from new studies as well as long-term (4 years) follow-up data from previously submitted studies, increasing patient-years exposure to the drug by 50% over the initial submission [16] [17] [18] [19] [20] [21] [22] [23] . The companies plan to conduct a large, post-marketing, randomised cardiovascular outcomes study in patients with T2DM to provide data on the long-term safety profile of the drug and examine whether or not the drug may provide a cardioprotective effect [24] . In addition to this, phase III development is underway in patients with diabetes and cardiovascular disease and/or hypertension (see below).
In November 2018, the China NMPA approved dapagliflozin in combination metformin and with insulin, separately for the treatment of inadequately-controlled type-2 diabetes mellitus in China. The drug was launched for the treatment of type 2 diabetes mellitus in China in 2018 [25] . The China State Food and Drug Administration (CFDA) approved dapagliflozin for the treatment of type 2 diabetes mellitus, before April 2017 (AstraZeneca pipeline, April 2017). In January 2013, a regulatory submission for dapagliflozin for the treatment of T2DM was accepted for review by the China State Food and Drug Administration.
In February 2016, the EMA’ s Pharmacovigilance Risk Assessment Committee (PRAC) finalised a review of SGLT2 inhibitors including, dapagliflozin and made recommendations to minimise the risk of diabetic ketoacidosis. The committee recommended that if diabetic ketoacidosis is suspected or confirmed, treatment should be stopped immediately and should not be re-started unless another cause for the ketoacidosis is identified and resolved. The Committee for Medicinal Products for Human Use (CHMP) of the EMA confirmed the recommendations made by PRAC. The EMA recommended updating the product information of SGLT2 inhibitors, including dapagliflozin, to list diabetic ketoacidosis as a rare adverse reaction. Additionally, the EMA recommended temporarily stopping SGLT2 inhibitors in patients who are undergoing major surgery or are in hospital due to serious illness [26] [27] .
Dapagliflozin has been launched in Hungary, Brazil, Argentina, Phillipines, Indonesia, Belgium, Sweden for the treatment of type 2 diabetes mellitus.
Dapagliflozin has been launched in the UK, Denmark, Netherlands, Czech Republic, Austria, Poland and Portugal for the once-daily treatment of adult patients with T2DM, following approval from the EMA in this indication in November 2012. Dapagliflozin is indicated as an adjunct to diet and exercise in combination with other glucose-lowering treatments, including insulin, or as a monotherapy in metformin-intolerant patients. In June 2019, the CHMP of EMA adopted a positive opinion, recommending modification of existing authorisation of dapagliflozin, to include treatment in type 2 diabetes mellitus patients, as an adjunct to diet and exercise, as a monotherapy (when metformin is deemed inappropriate on account of intolerance) and as a combination therapy with other medicinal products [28] [29] . BMS and AstraZeneca had submitted the MAA in December 2010, which was validated by the EMA in January 2011 [23] . The Committee for Medicinal Products for Human Use (CHMP) of the EMA adopted a positive opinion for the approval of dapagliflozin, in April 2012. The positive opinion was based on data from 11 core phase III trials [30] .
In August 2019, the European Commission approved an update to include positive cardiovascular outcomes and renal data from the phase III DECLARE-TIMI 5 trial to the marketing authorisation of dapagliflozin. The trial achieved statistically significant reduction in the composite endpoint of hospitalisation for heart failure or cardiovascular deaths with fewer adverse events. Inclusion of these results in the label is under regulatory review in the US and China [31] . In October 2020, AstraZeneca announced that the NMPA approved an update to the label for dapagliflozin to include the positive CV outcomes and renal data from the DECLARE-TIMI 58 Phase III trial in adults with Type 2 diabetes mellitus in China [32] .
In November 2016, NICE issued final guidance recommending dapagliflozin for treating type-II diabetes mellitus in ‘triple therapy’. The guideline recommended dapagliflozin for use as a triple therapy regimen in combination with metformin and a sulfonylurea [33] . In May 2016, NICE issued final guidance recommending dapagliflozin as monotherapy for treating type-II diabetes mellitus in adults for whom metformin is contraindicated or not tolerated [34] . Earlier, in a final appraisal determination issued in late May 2013, the UK National Institute for Health and Care Excellence (NICE) had recommended the use of dapagliflozin in combination with metformin or in combination with insulin with or without other oral antidiabetic drugs as an option for treating T2DM [35] [36] [37] . In July 2019, NICE issued final guidance recommending dapagliflozin with insulin as an option for treating adults type-I diabetes mellitus, when insulin alone does not provide adequate glycemic control despite optimal insulin therapy. NICE will publish final guidance to the NHS in August 2019 [38] .
The Scottish Medicines Consortium has restricted the use of dapagliflozin as a combination therapy with metformin or insulin, when these alone with exercise and diet do not provide adequate glycaemic control [35] .
The EMA issued a decision on the modification of the Paediatric Investigation Plan (PIP) for dapagliflozin in September 2012. The PIP covers a tablet formulation of dapagliflozin for the treatment of T2DM in children and adolescents aged from 10 to < 18 years, with a waiver for those aged < 10 years. The PIP detailed several trials to be conducted by BMS and AstraZeneca, including a pharmacokinetics/pharmacodynamics trial assessing the ability of children to swallow tablets, oral carcinogenicity studies in mice and rats, and two clinical efficacy trials of the drug. The PIP is expected to be completed by September 2017.
AstraZeneca launched Forxiga® (dapagliflozin) as monotherapy and adjunctive therapy in India in February 2015. The approval was granted earlier in February 2015 [39] [DCGI website, April 2016].
Dapagliflozin (5mg and 10mg tablets) was launched in Japan in May 2014 as a once-daily oral treatment for T2DM [40] . The product received approval in Japan in March 2014 [41] . The regulatory filing was accepted for review in March 2013 by Japan's Ministry of Health, Labor and Welfare [42]
AstraZeneca launched Forxiga® (dapagliflozin) in Greece in April 2015. The product is also available in the Canada, Cyprus, Hong Kong, Ireland, Israel, Malaysia, Singapore, Thailand, UAE, Ukraine, Chile, Russia and Kuwait.
In June 2015, Health Canada initiated a safety review for dapagliflozin and the risk of ketoacidosis [43] . The American Association of Clinical Endocrinologists also announced plans to examine the issue of diabetic ketoacidosis among patients treated with SGLT2 inhibitors, in June 2015 [44] . In December 2014, Health Canada approved Forxiga® (dapagliflozin) to be used in combination with diet and exercise in patients with T2DM [45] . Previously, in January 2011, Health Canada issued a Notice of Noncompliance, regarding the marketing application for dapagliflozin [46] . The candidate was also launched in Switzerland after approval in August 2014 [47] .
The TGA in Australia approved dapagliflozin on 5 October 2012 and has since been launched in this country. It is indicated as a monotherapy in patients who are intolerant to metformin, as an initial combination therapy with metformin, and as an add-on therapy to either metformin, a sulfonylurea, or insulin. Dapagliflozin was rejected from being listed on the Australian Pharmaceutical Benefits Schedule in March 2012.
In September 2013, AstraZeneca reported that dapagliflozin has been approved in Brazil for the treatment of type 2 diabetes mellitus [48] . The drug regulatory agency had previously rejected the marketing application for dapagliflozin in October 2011, after it was filed in February 2011.
AstraZeneca planned a phase IV study to evaluate the effects of dapagliflozin plus metformin regimen, on the quality of life, obesity-specific quality of life and treatment satisfaction in patients with type-2 diabetes mellitus, in the real world clinical practice (FLORA; NCT02719132). Approximately 820 subjects were to be enrolled in Russia. The trial was however, withdrawn prior to enrolment [49] .
AstraZeneca completed enrolment in a post-marketing safety study of dapagliflozin in approximately 3 000 Japanese patients, aged 65 years and older, with type 2 diabetes mellitus (NCT02200627) [50] .
Owing to business decision, AstraZeneca, in September 2020, terminated a phase III trial that was designed to evaluate the safety and efficacy of dapagliflozin in patients with type 2 diabetes mellitus and inadequate glycemic control on metformin and saxagliptin (DS Navigation) (D1683C00008; NCT03608358). Earlier, in March 2020, AstraZeneca had temporarily halted the recruitment in a phase III trial, to streamline resources and re-evaluate study overall timeline. This double-blind, randomised trial was initiated in February 2019 and recruited 41 patients in Thailand and Vietnam China [51] .
In October 2017, AstraZeneca initiated a phase III trial to evaluate the efficacy and safety of the drugs dapagliflozin and saxagliptin [see Adis Insight Drug profile 800016588] in patients with type 2 diabetes who are aged 10 to below 18 years old and are currently taking metformin, insulin, or both drugs (D1680C00019; EudraCT2015-005042-66; NCT03199053; P059/2016). The double-blind, parallel, prospective, randomised trial is enrolling approximately 243 patients in the US, Poland, Finland, Australia, Brazil, Canada, Chile, Colombia, India, Italy, South Korea, Malaysia, Mexico, New Zealand, Philippines, Romania, Russia, Taiwan, Thailand, Turkey, Ukraine, in the UK and will be extending to Israel. In china trial was withdrawn prior to initiation [52] .
In December 2017, AstraZeneca completed a phase III trial that investigated the efficacy and safety of simultaneous administration of dapagliflozin and exenatide once-weekly suspension [see Adis Insight Drug profile 800022798] compared with dapagliflozin alone and exenatide alone in patients with type 2 diabetes mellitus who have inadequate glycaemic control on metformin (EuraCT2014-003503-29; NCT02229396; DURATION-8; D5553C00003). The randomised, double-blind, 28-week study was to be followed by 24-week extension study. The trial was initiated in September 2014 and enrolled 695 patients in the US, Hungary, Poland, Romania, Slovakia and South Africa. In September 2017, results from the trial were released at the 53rd Annual Meeting of the European Association for the Study of Diabetes (EASD-2017) [53] [54] .
Top-line data from the phase III DERIVE trial showed that the study met the primary endpoint in patients with type 2 diabetes and stage 3A chronic kidney disease (D1690C00024; P310-2014; EudraCT2015-000804-24; NCT02413398) [55] . AstraZeneca completed the trial in November 2017, which was initiated in August 2015. The trial evaluated the glycaemic efficacy and renal safety of dapagliflozin in patients with Type 2 diabetes and moderate renal impairment. Evaluation of the mean change from baseline in HbA1c between dapagliflozin and placebo was the primary endpoint of the trial. The randomised, double-blind, parallel-group assignment, placebo-controlled trial enrolled 323 patients in the US, Spain, Sweden, Poland, the Czech Republic, Bulgaria, Canada, Italy [56] . In February 2018, AstraZeneca reported top-line data from the phase III DERIVE trial [57] . The company plans to submit this DERIVE study results to the US FDA, to be added to the breadth of data already contained within the existing dapagliflozin (FARXIGA) prescribing information. In March 2018, the company presented safety and efficacy data at the The 100th Annual Meeting of the Endocrine Society (AMES-2018) [58] [55] . In November 2018, the European Commission approved an update of the European Study of Product Characteristics (SmPC) , based on the DERIVE trial. The updates to the SmPC included a change to allow the use of dapagliflozin by patients with type-2 diabetes mellitus and renal impairment down to and including, CKD stage 3A. The update removes the restriction for dapagliflozin to CKD, stages 2 and above [25] .
In April 2020, AstraZeneca completed a phase III trial that assessed the efficacy and safety of dapagliflozin 10mg tablet in patients with type 2 diabetes mellitus (D1690C00017; EudraCT2015-005041-31; NCT02725593). The randomised, double-blind, parallel, placebo-controlled trial was initiated in June 2016, and enrolled 72 patients (aged 10 - 24 years)in the US, Hungary, Israel, Mexico, Russia, the UK and Romania [59] .
In November 2017, Bristol-Myers Squibb and AstraZeneca completed a phase IIIb trial that evaluated the efficacy and safety of saxagliptin with dapagliflozin [see Adis Insight Drug profile 800016588], in addition to metformin, with or without sulfonylurea, when compared with insulin glargine in patients with type 2 diabetes mellitus, over a treatment period of 52 weeks (CV181-369; EudraCT2015-001702-33; NCT02551874). Mean change from baseline in Hemoglobin A1c (HbA1c) in a time frame of 24 weeks was to be evaluated as primary outcome measure. The randomised, open-label, active-controlled, parallel-group trial was initiated in October 2015 and enrolled 651 patients in the US, Czech Republic, Denmark, Hungary, Mexico, Poland, Romania, South Africa, Spain, and Sweden [60] . In June 2018, efficacy results from the trial were released by AstraZeneca [61] . Updated efficacy data from the trial were presented at the 54th Annual Meeting of the European Association for the Study of Diabetes (EASD-2018) [62] .
In June 2017, AstraZeneca completed a phase III trial that evaluated the safety and efficacy of saxagliptin 5mg co-administered with dapagliflozin 5mg, as compared with saxaglipgtin 5mg or dapagliflozin 5mg, in patients who are inadequately controlled on ≥ 1500 mg/day of metformin monotherapy (D1683C00005; EudraCT2015-005406-11; NCT02681094). The randomised, double-blind, placebo-controlled trial was initiated in February 2016, and enrolled 906 patients in the US, Canada, Germany, the Czech Republic, Mexico and Russia [63] .
AstraZeneca plans to initiate a phase III trial, with a 28-week safety extension period, to assess the safety and efficacy of dapagliflozin (5mg and 10mg) and saxagliptin (2.5mg and 5mg) [see Adis Insight Drug profile 800016588] in paediatric patients (aged 10 to 18 years) with type 2 diabetes mellitus (UKCRN31254). The double-blind, parallel-group, randomised, placebo-controlled trial will enrol patients in the UK [64] .
AstraZeneca, in April 2018, completed a phase II/III trial which assessed the effect of dapagliflozin with and without saxagliptin, and also evaluated the effect of dapagliflozin and saxagliptin on HbA1C in patients with type 2 diabetes mellitus, albuminuria and renal impairment (CKD) (NCT02547935; D1690C00023). The randomised, double-blind trial initiated in September 2015 enrolled 459 patients in the US, Australia, Canada, Japan, South Korea, Mexico, South Africa, Spain and Taiwan [65] .
In March 2012, AstraZeneca and BMS completed a 24-week phase III trial that evaluated the efficacy and safety of dapagliflozin monotherapy (NCT01294423). This randomised, double-blind, placebo-controlled study involved 261 Japanese patients with inadequately controlled T2DM [66] .
In mid-2012, BMS and AstraZeneca completed a phase III study of dapagliflozin in Asian patients with T2DM and inadequate glycaemic control with diet and exercise (NCT01095653). The double-blind, placebo-controlled, parallel group trial evaluated the safety and efficacy of dapagliflozin monotherapy in approximately 1 179 patients in China, India, South Korea and Taiwan. Patients were randomised to receive oral dapagliflozin 5 or 10mg or placebo, once-daily, for 24 weeks. Patients also had the option to receive metformin on an as-needed basis for rescue based upon protocol specific criteria [67] . As of March 2015, no recent reports of development have been identified in Taiwan for dapagliflozin as monotherapy for T2DM.
Several phase III studies have been completed examining the effect of dapagliflozin monotherapy in varying patient groups or study outcomes. This include treatment-naïve patients with T2DM not well controlled with diet and exercise or existing medication (NCT00528372) [68] , as well as patients inadequately controlled by insulin and one or two oral antidiabetics (NCT00357370) [69] [70] . Phase I and II trials have been completed to determine the effects of dapagliflozin on insulin resistance and insulin secretion (NCT00831779) [71] , efficacy and safety in Japanese patients (NCT00972244) [72] , safety and efficacy of dapagliflozin in treatment-naïve patients who had inadequate glycaemic control on diet and exercise (NCT00263276) [73] , pharmacokinetics and pharmacodynamics (NCT00162305) [74] , (NCT01165268) [75] , (NCT01072578) [76] , (NCT00538174) [77] , as well as potential drug interaction with rifampicin (NCT01068756) [78] , and glimepiride (NCT00562250) [79] . One phase I pharmacokinetic study was initiated in the US, but terminated for an undisclosed reason (NCT00726505) [80] .
Bristol-Myers Squibb completed a phase III trial investigating the efficacy and effects of dapagliflozin on endothelial and microvascular function of the retinal circulation in patients with type 2 diabetes mellitus. The primary endpoint was the retinal capillary flow. The trial was conducted in Germany and enrolled 62 patients (EudraCT2013-004169-14) [81] .
A number of phase III trials have examined the antidiabetic efficacy of dapagliflozin in combination with metformin/extended-release metformin in patients with T2DM. Completed trials include a 392-patient study (NCT01217892) [82] , a 52-week trial with a 156-week extension period in 814 patients (NCT00660907) [83] [84] [85] , a 1 093-patient trial to compare combination therapy with the drugs as monotherapy (NCT00859898) [86] [87] , a 915-patient trial that examined efficacy over 24 weeks. The study also included an extension phase for a total duration of two years (NCT00528879) [88] [89] [90] , and a 600-patient study with the combination used as initial therapy (NCT00643851) [91] [87] .
One phase III trial (EudraCT2008-004916-12) of dapagliflozin plus metformin versus sitagliptin plus metformin was initiated in March 2009 at sites in Austria, Czech Republic and the UK. However, the trial was terminated in May 2009 [92] .
A phase III study of dapagliflozin in combination with metformin has been completed in Asian patients with T2DM who have inadequate glycaemic control on metformin alone (MB102-055; NCT01095666). The double-blind, placebo-controlled trial enrolled 445 patients in China, India and South Korea [93] .
January 2016, Bristol-Myers Squibb completed a phase III trial in March 2014 that assessed the efficacy and safety of dapagliflozin as add-on therapy to insulin in Asian patients with type 2 diabetes, with inadequate glycaemic control on insulin (MB102-137; NCT02096705). The randomised, double-blinded, 24-week trial was initiated in March 2014 and enrolled 477 patients in China, South Korea and Singapore [94] .
AstraZeneca and BMS have completed an open label 52-week phase III trial in 700 Japanese patients with inadequately controlled T2DM, which evaluated the safety and efficacy of dapagliflozin alone or in combination with antihyperglycaemics (NCT01294436) [95] . A regulatory filing has been made for approval of dapagliflozin, as an add-on to sitagliptin, in the EU. A filing in the EU has also been made for the agent as an add-on to insulin and metformin.
AstraZeneca and BMS conducted a number of phase III trials examining dapagliflozin in combination with other antidiabetic drugs, including 1 240-patient study in combination with insulin (NCT00673231) [96] , a 597-patient study in combination with glimepiride (NCT00680745) [97] [98] [99] [100] , a 833-patient trial in combination with sitagliptin with or without metformin (NCT00984867) [101] , and a 972-patient study in combination with thiazolidinedione therapy (NCT00683878) [102] .
A phase III study was completed in August 2013, which evaluated the safety and efficacy of dapagliflozin in patients with type 2 diabetes mellitus who have inadequate glycaemic control on a background combination of metformin and sulfonylurea (NCT01392677). Positive results from the randomised, double-blind, placebo-controlled trial were released in September 2013 [48] . The trial was conducted by AstraZeneca and BMS, and a total of 311 patients were enrolled in Canada, Czech Republic, Germany, Poland, Slovakia and Spain [103] .
In February 2015, Bristol-Myers Squibb and AstraZeneca completed a phase III trial that assessed the safety and efficacy of adding dapagliflozin to saxagliptin plus immediate-release metformin in patients with T2DM who did not achieve adequate glycaemic control with saxagliptin plus metformin alone (NCT01646320; EudraCT2011-006324-20). The randomised, double-blind, placebo-controlled, parallel-group trial, which enrolled 320 patients in the US, Czech Republic, Poland, Puerto Rico, Romania, Russia, Mexico and the UK, was initiated in September 2012 [104] . Results reported in June 2015 showed that the trial met its primary endpoint [105] .
AstraZeneca and BMS completed a phase III trial in January 2014 which investigated the efficacy and tolerability of dapagliflozin and saxagliptin, administered alone or in combination, as an adjunct to metformin in patients with T2DM inadequately controlled by metformin (NCT01606007). The trial enrolled 536 patients in the US, Canada, South Korea, Mexico, Poland, Puerto Rico, Romania and South Africa. Positive results were reported in May 2014 [106] .
A phase III trial recruited 182 patients with T2DM from several countries in the EU to investigate the potential for dapagliflozin to assist with weight-loss (NCT00855166). When added to metformin + sitagliptin, dapagliflozin significantly reduced bodyweight compared with placebo. The trial also demonstrated that dapagliflozin significantly affected fat mass and waist circumference [107] .
In September 2019, AstraZeneca completed a phase III trial that evaluated the efficacy and safety of saxagliptin co-administered with dapagliflozin in combination with metformin compared to glimepiride in combination with metformin, in adult patients with type 2 diabetes who have inadequate glycaemic control on metformin therapy alone (CV181-365; NCT02419612). The randomised, double blind trial was initiated in August 2015, and enrolled 444 patients in the US, Czech Republic Germany, Hungary, Mexico, Poland, Romania, Russia, Sweden, United Kingdom [108] . In November 2020, long-term efficacy results from the trial on liver fat and adipose tissue volumes of patients were presented at 70th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2020) [109] .
In November 2017, Tokushima University Graduate School, in collaboration with AstraZeneca, completed the phase II DBOT clinical trial to evaluate whether add-on of dapagliflozin on basal insulin therapy improves mean daily blood glucose levels, measured by CGM, in patients with type II diabetes mellitus (UMIN000019457; R000022501). The trial was initiated in March 2016, and enrolled 30 patients in Japan [110] .
In October 2018, AstraZeneca and Ono Pharmaceutical completed phase II DIET trial which evaluated the hypoglycemic action of dapagliflozin and its effects on body composition and dietary intake during weight loss in Japanese patients with type 2 diabetes mellitus (UMIN000019192; R000021828). The open label trial initiated in October 2015 and enrolled 60 participants in Japan [111] .
In November 2018, AstraZeneca KK and Ono Pharmaceutical completed the phase II DEFENCE trial which evaluate the positive effects of dapagliflozin on body weight, blood pressure, lipid metabolism, glycemic levels and endothelial function in type-2 diabetes patients with moderately inadequate glycaemic control (R000021695; UMIN000018754). Patients enrolled was administered dapagliflozin 5mg once per day in addition to other medications or metformin dose from 750mg up to 1500mg during the 16 week period. The randomised, open label trial, initiated in October 2015 enrolled 80 patients in Japan [112] .
In September 2014, Bristol-Myers Squibb and AstraZeneca completed a phase I trial that investigated the pharmacokinetics and pharmacodynamics of single doses of dapagliflozin in children and adolescents, aged 10-17 years, with T2DM (NCT01525238; EudraCT2011-005225-40). The randomised, open-label trial enrolled 53 patients in in the US and Mexico [113] .
In November 2012, Bristol-Myers Squibb, in collaboration with AstraZeneca, completed a phase I drug interaction trial that evaluated the pharmacokinetics of saxagliptin 5mg and dapagliflozin 10mg when these drugs are co-administered under fasting condition, in healthy volunteers (NCT01662999). The randomised, open-label, crossover trial enrolled 42 volunteers in the US [114] .
In April 2019, AstraZeneca, Kyushu University and ONO Pharmaceutical terminated a clinical trial that investigated a combination therapy of dapaglifozin coupled with intensive physical exercises, for the prevention of muscle mass reduction in patients with type 2 diabetes (R000022897; UMIN000020263). The open label, randomized trial, which was initiated in June 2016, enrolled 146 patients in Japan [115] .
Type 2 diabetes mellitus; high cardiovascular risk
BMS and AstraZeneca are also examining the effects of dapagliflozin in patients with cardiovascular conditions (such as hypertension or cardiovascular disease) in a number of studies worldwide.
In October 2019, the US FDA approved dapagliflozin to reduce the risk of hospitalisation for heart failure (hHF) in adults with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors and, was subsequently launched. The approval is based on results from DECLARE-TIMI 58 trial [see below] [116] .
In October 2020, AstraZeneca reported that the China’s National Medical Products Administration (NMPA) updated the label for dapagliflozin for inclusion of data from the DECLARE-TIMI 58 phase III trial [see below] [117]
In April 2020, AstraZeneca in collaboration with Vanderbilt University Medical Center to initiate a phase III trial to test the decongesting effects ofdapagliflozin in patients with type 2 diabetes admitted with an acute decompensation of chronic heart failure (NCT04298229; 200017). The randomized, open-label trial intends to enrol 240 patients in the US [118] .
In September 2018, AstraZeneca, in collaboration with BMS, met its primary endpoint of non-inferiority for major adverse cardiovascular events (MACE) in a completed phase III DECLARE-TIMI 58 trial that investigated the impact of adding dapagliflozin to standard of care therapy on cardiovascular events in patients with T2DM (NCT01730534; EudraCT2013-000239-28; CTRI2014-08-004872; JapicCTI142473; P207-2012; D1693C00001; UKCRN14920; DRN2246; P207-2012). Treatment with dapagliflozin significantly reduced the composite endpoint of hospitalisation for heart failure (hHF) or cardiovascular death. Additionally, fewer MACE events were observed with the treatment arm. Data from the trial confirmed the safety profile of dapagliflozin. Additional results from the trial were released in November 2018 [119] . The randomised, double-blind, placebo-controlled trial was initiated in April 2013 and enrolled 17 190 patients in the US, Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, China, Czech Republic, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Japan, South Korea, Mexico, Netherlands, Philippines, Poland, Romania, Russia, Slovakia, South Africa, Spain, Sweden, Taiwan, Thailand, Turkey, Ukraine, the UK and Vietnam [120] . This study data will support the regulatory filings in China, the US and EU for the use of dapagliflozin in patients with T2DM and high-risk for cardiovascular disease. In June 2020, updated efficacy results from the trial were presented at the 80th Annual Scientific Sessions of the American Diabetes Association (ADA-2020). In September 2020, data was presented at the 56th Annual Meeting of the European Association for the Study of Diabetes (EASD-2020). In November 2020, updated data of the trial was presented at the American Heart Association Scientific Sessions (AHA-2020). In June 2021, the company presented the results at the 81st Annual Scientific Sessions of the American Diabetes Association (ADA-2021) [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [15] [131] [132] [133] .
BMS and AstraZeneca have completed a phase III trial which compared the efficacy of dapagliflozin in patients with T2DM and uncontrolled hypertension (NCT01137474). The randomised, double-blind study enrolled 2 996 patients in Canada, South America, the EU, India, Russia, and the USA. The primary endpoint was the change from baseline in seated systolic blood pressure and glycosylated haemoglobin. This was assessed at 12 weeks [134] .
In February 2013, BMS completed a phase III trial in 810 patients with T2DM and hypertension inadequately controlled with two or more classes of antihypertensive medications (NCT01195662). The primary endpoint was the change from baseline in seated systolic blood pressure which was assessed after 12 weeks. Patients were enrolled in Australia, Canada, South America, the EU, India, Russia, and the USA [135] .
In December 2012, AstraZeneca in collaboration with BMS, completed a phase III trial, Study 18, which evaluated the changes in haemoglobin, body weight and blood pressure in 922 patients with T2DM, cardiovascular disease and hypertension (D1690C00018; NCT01031680). Patients were randomised to receive dapagliflozin or placebo for 24 weeks, plus a 80-week extension period [136] . The companies completed another similar trial, Study 19, in December 2012, in 964 patients with T2DM and cardiovascular disease which explored the effects of dapagliflozin on haemoglobin, body weight and blood pressure (D1690C00019; NCT01042977). Initiated in March 2010, recruitment of participants was completed in December of that year [137] .
In March 2020, AstraZeneca initiated the clinical trial LEAVE-DM determining the effect of dapagliflozin on preventing heart failure in patients with type 2 diabetes (ACTRN12619001393145; HREC324-19Alfred2019; U1111-1236-7496). The randomised, placebo-controlled trial intends to enrol approximately 400 participants in Australia [138] .
In March 2019, AstraZeneca and Ono Pharmaceutical completed a clinical trial that evaluated the cardioprotective efficacy of dapagliflozin by comparing it with conventional anti diabetic agents in type 2 diabetic patients with hypertension(UMIN000023834; R000027461). The open-label prospective randomized controlled trial was initiated in September 2016 and enrolled 78 patients in Japan [139] .
Type 2 diabetes mellitus; non-alcoholic fatty liver disease
AstraZeneca completed the phase II EFFECT II trial in December 2015, that assessed the effects of dapagliflozin and omega-3 carboxylic acids on the liver fat content in patients with type 2 diabetes mellitus (D5883C00004; EudraCT2014-003638-26; NCT02279407). The primary endpoint of the study was the change of percent of liver fat content from baseline at week 12 of the study measured by MRI. The randomised, placebo-controlled, double-blind study initiated in January 2015, enrolled 223 patients in Sweden. In November 2016, results from the trial were reported at the 67th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD-2016) [140] [141] .
Type 2 diabetes mellitus; renal impairment
BMS completed a phase II/III randomised, double-blind, placebo-controlled, parallel group study that determined the safety, pharmacokinetics and pharmacodynamics of dapagliflozin in approximately 631 patients with T2DM and moderate renal impairment (NCT00663260). The study was conducted in the US, Australia, Canada, India, the EU, Latin America and Singapore [142] . In November 2010, AstraZeneca and BMS completed a phase II trial that evaluated the effects of dapagliflozin on kidney function (as assessed by glomerular filtration rate) in 75 patients with T2DM (NCT00976495) [143] .
Type 2 diabetes mellitus (oral solution)
As at May 2017, development of the dapagliflozin oral solution was discontinued as the same was not listed on the company pipeline (AstraZeneca pipeline, April 2017). In June 2010, BMS and AstraZeneca completed a phase I trial that assessed the pharmacodynamics, pharmacokinetics, safety and tolerability of dapagliflozin oral solution. The trial enrolled 30 healthy volunteers in the US (NCT01135446) [144] .
Type 1 diabetes mellitus
In March 2019, the European Commission (EC) approved dapagliflozin as an oral adjunct treatment for adult patients with type 1 diabetes [145] . The Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion and recommended dapagliflozin for approval in, February 2019. Marketing Authorisation Variation for the drug was accepted by the EMA in March 2018. The positive opinion and the submission acceptance was based on phase III data from the DEPICT clinical programme which demonstrated significant and clinically relevant reductions from baseline in HbA1c, weight and total daily insulin dose at 24 and 52 weeks, compared to placebo, at both 5mg and 10mg doses [146] [147] [148] .
In July 2019, the US FDA issued a complete response letter regarding AstraZeneca's sNDA for dapagliflozin as an adjunct treatment to insulin to improve glycaemic control in adult patients with type-1 diabetes, when insulin alone does not provide adequate glycaemic control. The sNDA was undergoing regulatory since February 2019 [147] .
In March 2019, the Japanese Ministry of Health, Labour and Welfare (MHLW) approved dapagliflozin (Forxiga) as an oral adjunct treatment to insulin in adults with type 1 diabetes. Earlier, in May 2018, AstraZeneca submitted a supplemental New Drug Application (sNDA) to Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) for the use of the drug. The submission was based on the phase III DEPICT (Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes) trial (see below) in type 1 diabetes mellitus [149] [150] .
In June 2017, AstraZeneca completed a long-term phase III trial (Part B) that assessed the safety, efficacy, pharmacokinetics and pharmacodynamics of dapagliflozin (5mg and 10mg) tablet as an oral adjunct to insulin in patients with T1DM (aged 18 to 75 years), with inadequate glycaemic control on insulin defined as HbA1c ≥ 7.5% and ≤ 10.5% at screening visit (D1695C00001; NCT02582814; JapicCTI163162). The randomised 1:1, open-label, 2-arm, parallel-group, placebo-controlled trial was initiated in October 2015 and enrolled 170 patients in Japan [151] .
In June 2019, results from a clinical trial involving patients from the phase III DEPICT-1 and DEPICT-2 trials [see below], in type 1 diabetes mellitus were presented at the 79th Annual Scientific Sessions of the American Diabetes Association (ADA-2019). These were patients in whom, dapagliflozin treatment was discontinued owing to adverse events and patient withdrawal of consent. At this time, pooled safety data from the two trials were also presented [152] [153] .
In April 2018, AstraZeneca, in collaboration with Bristol-Myers Squibb, completed the phase III DEPICT 2 trial, which evaluated the efficacy and safety of dapagliflozin in patients with type 1 diabetes mellitus (EudraCT2014-004599-49; NCT02460978). The randomised, double blind trial was initiated in June 2015, and enrolled 815 patients in the US, Argentina, Belgium, Canada, Chile, Germany, Japan, Netherlands, Poland, Russia, Sweden, Switzerland, and the UK. As per top-line results from the trial both 5mg and 10mg dose of dapagliflozin led to significant and clinically relevant reductions in HbA1c, weight and total daily insulin dosing, compared with placebo. In September 2019, data was presented at the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD-2019) [154] [57] [155] .
AstraZeneca reported top-line results from the 52-week, phase III DEPICT 1 trial in patients with type 1 diabetes. Both, the 5mg and 10mg dose of dapagliflozin led to significant and clinically relevant reductions in HbA1c, weight and total daily insulin dosing, compared with placebo (UKCRN17609; NCT02268214; MB102-229; EudraCT2013-004674-97; D1695C00006; DRN3281; MB102-229; U1111-1160-6249; DRKS00009951). The trial was completed in August 2017, and was initiated by BMS in collaboration with AstraZeneca in November 2014. The trial was designed to determine the safety and efficacy of dapagliflozin added to insulin in patients with type 1 diabetes mellitus. The primary endpoint of the study was an adjusted mean change of Hemoglobin A1C from baseline at week 24 of the study. This randomised, placebo-controlled, double-blind study enrolled 833 patients in the US, the UK, Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hungary, Italy, Israel, Mexico, Romania, Sweden and Spain [57] [156] .
BMS and AstraZeneca have completed a phase II trial in the USA, which assessed the safety, pharmacokinetics and pharmacodynamics of dapagliflozin as an add-on to insulin therapy in 171 patients with type 1 diabetes mellitus (NCT01498185). Results were reported in July 2013 [157] [158] .
In December 2017, Kinderkrankenhaus auf der Bult, in collaboration with, AstraZeneca completed a phase I trial that evaluated the safety and efficacy of dapagliflozin as an add-on to day and night closed-loop control in patients with type 1 diabetes mellitus (ESR15-11453; NCT02987738). The randomised, cross-over trial was initiated in February 2017, and enrolled 30 patients in Germany [159] .
In June 2016, AstraZeneca completed a long-term phase I trial (Part A), which assessed the safety, efficacy, pharmacokinetics and pharmacodynamics of dapagliflozin (5mg and 10mg) tablet plus insulin in patients with T1DM (aged 18 to 65 years), with inadequate glycaemic control on insulin defined as HbA1c ≥ 7.0% and ≤ 10.0% at screening visit (D1695C00001sub; NCT02582840). The randomised 1:1:1, single-blind, 3-arm, parallel-group, placebo-controlled trial was initiated in October 2015 and enrolled 42 patients in Japan. In June 2018, data supporting adjunctive therapy of dapagliflozin with insulin in T1DM patients were presented at the 78th Annual Scientific Sessions of the American Diabetes Association (ADA-2018) [160] [161] .
Results from a preclinical study of dapagliflozin were presented at the 90th Annual Scientific Sessions of the American Heart Association (AHA/ASA-2017) in November 2017. The results showed that, in addition to an improved metabolic profile, improved coronary flow velocity reserve (CFVR) and contractile function in the treated groups were observed, indicating that micro-vascular dysfunction is ameliorated following SGLT2 inhibition [162] .
Chronic heart failure and renal failure
In August 2021, AstraZeneca announced that the Ministry of Health, Labour and Welfare (MHLW) approved dapagliflozin (Forxiga®) for the treatment of chronic kidney disease (CKD) in adults with and without type-2 diabetes (T2D). The decision is based on positive results from the DAPA-CKD Phase III trial. The decision follows the Priority Review designation granted by the MHLW earlier this year [163]
In August 2021, AstraZeneca announced that the European Medicines Agency (EMA) approved dapagliflozin (Forxiga®) for the treatment of chronic renal disease in adults with and without type-2 diabetes (T2D). The decision is based on the data obtained from a phase III DAPA-CKD trial. Earlier, Committee for Medicinal Products for Human Use of EMA had given the recommendation for approval [164] .
In April 2021, dapagliflozin (Farxiga®) was launched in the US, subsequent to the US FDA approval of the dapagliflozin oral tablets to reduce the risk of kidney function decline, kidney failure, cardiovascular death and hospitalization for heart failure in adults with renal failure (chronic kidney disease), who are at risk of disease progression [165] . In May 2020, the US FDA approved dapagliflozin (FARXIGA®) to reduce the risk of cardiovascular (CV) death or the worsening of heart failure (HF) in adults with heart failure with reduced ejection fraction (HFrEF) with and without type 2 diabetes (T2D). The supplemental New Drug Application (sNDA) was acceped and granted Priority Review, in In January 2020, by the US FDA. The Prescription Drug User Fee Act date, for this supplemental application scheduled for the second quarter of 2020. The sNDA was submitted on the basis of results from the landmark Phase III DAPA-HF trial [166] [167] .
In January 2021, AstraZeneca reported that dapagliflozin (FARXIGA ) has been granted Priority Review by the US FDA for the treatment of new or worsening chronic kidney disease (CKD) in adults with and without type 2 diabetes (T2D). The acceptance of the regulatory submission by the US FDA and the granting of priority review was based on clinical evidence from the DAPA-CKD phase III trial (see below). The Prescription Drug User Fee Action date, will be during the second quarter of 2021 [168] .
In November 2020, European Commission approved dapagliflozin (Forxiga®) for the treatment of chronic heart failure with reduced ejection fraction (HFrEF) in patients with and without type-2 diabetes [169] . In October 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended dapagliflozin (FARXIGA®) for approval for the treatment of heart failure. This recommendation is based on results of DAPA-HF trial [see below] [170] . In fourth quarter of 2019, the European Medicines Agency accepted a regulatory filing for dapagliflozin for chronic heart failure in European Union [171] .
In February 2021, China’s National Medical Products Administration (NMPA) approved dapagliflozin to reduce the risk of cardiovascular (CV) death and hospitalisation for heart failure (hHF) in adults with heart failure (NYHA class II-IV) with reduced ejection fraction (HFrEF). In fourth quarter of 2019, AstraZeneca filed a regulatory submission for dapagliflozin for chronic heart failure in China [172] [171] .
In November 2020, Japanese Ministry of Health, Labour and Welfare (MHLW) approved dapagliflozin (5mg and 10mg tablets) for the treatment of chronic heart failure who are receiving standard of care in the Japan. This approval was based on positive results of DAPA-HF trial. The product was launched subsequently [173] [174] . In fourth quarter of 2019, AstraZeneca filed a regulatory submission for dapagliflozin for chronic heart failure in Japan [171] .
In July 2020, Astra Zeneca reported that dapagliflozin (Forxiga®) was approved via accelerated approval, for the treatment of patients with heart failure with reduced ejection fraction (HFrEF). The approval was based on favourable results from the phase III DAPA-HF trial [see below] [175] .
In October 2020, the US FDA granted Breakthrough therapy designation to dapagliflozin (FARXIGA) for patients with chronic kidney disease (CKD), with and without type 2 diabetes (T2D) [176] .
In September 2019, the US FDA granted fast track designation to dapagliflozin (FARXIGA) to reduce the risk of cardiovascular death or the worsening of heart failure in adults with heart failure with reduced ejection fraction or preserved ejection fraction. The fast track designation is based on results fromtwo phase III trials, DAPA-HF and DELIVER (see below), which investigated the role of dapagliflozin in patients with heart failure with reduced ejection fraction and preserved ejection fraction respectively [177] .
In August 2019, US FDA granted fast track designation to dapagliflozin for the treatment of renal failure and prevent cardiovascular (CV) and renal death in patients with chronic kidney disease [178] .
In February 2021, AstraZeneca discontinued the phase III DETERMINE-preserved trial that evaluated the effect of dapagliflozin on exercise capacity, in heart failure patients with preserved ejection fraction (HFpEF), due to strategic reasons. In July 2020, AstraZeneca completed a phase III DETERMINE-preserved trial that evaluated the effect of dapagliflozin on exercise capacity, in heart failure patients with preserved ejection fraction (HFpEF) (NCT03877224; D169EC00001; EudraCT2018-003441-42). The randomized, double blind, placebo-controlled trial was initiated in April 2019 and enrolled 504 patients in the US, Argentina, Bulgaria, Canada, South Korea, Brazil, Denmark, Italy, Japan, Slovakia, South Africa and Sweden (AstraZeneca's pipeline, February 2021) [179] [180] .
In February 2021, AstraZeneca discontinued the phase III DETERMINE-preserved trial that evaluated the effect of dapagliflozin on exercise capacity, in heart failure patients with preserved ejection fraction (HFpEF), due to strategic reasons. In April 2019, AstraZeneca initiated, and enrolled the first patient in the phase III DETERMINE-reduced trial, to evaluate the effect of dapagliflozin on exercise capacity, in heart failure patients with reduced ejection fraction (HFrEF) (NCT03877237; D169EC00002; EudraCT2018-003442-16). The randomized, double blind, placebo-controlled trial was completed in March 2020 and enrolled 4744 patients in the US, Canada, Denmark, South Korea, Brazil, Japan, Slovakia, South Africa and Sweden. Change from baseline in 6-minute walking distance (6MWD) at week 16 will be assessed as the primary endpoint in the trial. The DETERMINE trial is a part of the extensive DapaCare clinical programme for dapagliflozin, which is designed to generate data across a spectrum of patients with CV risk factors, established CV disease and varying stages of renal disease, both with and without T2D [179] [181] .
AstraZeneca, in September 2016, announced a programme comprising of two phase IIIb outcome studies, to evaluate dapagliflozin in the management of chronic heart failure and renal failure, in patients with or without type-2 diabetes mellitus. The company also reported the initiation of mechanistic studies, to provide further rationale for the cardiovascular and renal protective effects of SGLT-2 inhibitors [182] .
In August 2018, AstraZeneca initiated the phase III DELIVER trial to evaluate the effect of dapagliflozin 10mg versus placebo, given once daily in addition to background regional standard of care therapy, including treatments to control co-morbidities, in reducing the composite of CV death or heart failure events (EudraCT2018-000802-46; NCT03619213; D169CC00001) . The double-blind, randomised, placebo-controlled trial is enrolling approximately 4 700 participants in Hungary, the US, Canada, Argentina, Belgium, Brazil, Bulgaria, China, Czech Republic, France, Japan, Mexico, Netherlands, Peru, Poland, Romania, Russia, Saudi Arabia, Spain, Taiwan, Vietnam [183] .
In July 2019, AstraZeneca completed the DAPA-HF (Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure), phase III clinical trial which evaluated the efficacy of dapagliflozin, on the incidence of worsening of heart failure or cardiovascular death, in patients with chronic heart failure with reduced ejection fraction (D1699C00001; JapicCTI173524; Eudra2016-003897-41; CTRI2017-08-009207; NCT03036124). Evaluation of the time to the first occurrence of cardiovascular death, hospitalisation for heart failure, an urgent heart failure visit, is the defined primary endpoints of the study. The randomised, double blind, parallel assignment, placebo controlled trial initiated in January 2017, enrolled 4744 patients in Argentina, Brazil, Denmark, the US, the UK, Canada, China, Bulgaria, Czechia (Czech Republic), India, Japan, Netherlands, Poland, Russia, Slovakia, Sweden, Taiwan, Germany, Hungary and Vietnam [184] [185] . In August 2019, AstraZeneca announced that the trial met its primary endpoint, showed statistically-significant and clinically-meaningful reduction of cardiovascular death or the worsening of heart failure (defined as hospitalisation or an urgent heart failure visit), compared with placebo. The safety profile was consistent in the trial. In September 2019, data from the trial was presentated at the ESC Congress 2019: Annual Congress of the European Society of Cardiology (ESC-Card-2019) and sub-analysis from the trial was reported in November 2019. In November 2019, post hoc efficacy and safety analysis data from the trial was released by AstraZeneca [186] [187] [188] [189] . In June 2020, The efficacy results from the trial in prevention of diabetes were presented at 80th American Diabetes Association (ADA-2020) [190] . In August 2020, safety results from the trial were presented at the ESC Congress 2020 - Annual Congress of the European Society of Cardiology (ESC-Card-2020) [191] . In November 2020, efficacy results from the trial were presented at American Heart Association Scientific Sessions 2020 (AHA-2020) [192]
In July 2020, AstraZeneca reported that the phase III Dapa-CKD trial met its primary and secondary endpoints, showing statistically significant and clinically meaningful effect of dapagliflozin on worsening of renal function or risk of death in CKD patients with and without type-2 diabetes (T2D) (D169AC00001; EudraCT2016-003896-24; NCT03036150; JapicCTI183962). The double-blind, randomised trial was completed in June 2020. The trial was initiated in February 2017 and enrolled 4 304 patients in the US, Canada, Denmark, South Korea, Poland, Russia, Spain, Sweden, Germany, Hungary, Ukraine, Brazil, Argentina, Vietnam, Peru, Philippines, China, India, Japan Mexico, and the UK. The primary endpoint of a composite of worsening of renal function or risk of death was defined as a composite endpoint of 50% sustained decline in estimated glomerular filtration rate (eGFR), onset of end stage kidney disease (ESKD) or cardiovascular (CV) or renal death, in patients with chronic kidney disease. The safety profile was consistent with the well-established safety profile of the drug. Earlier, in March 2020, the company announced that the study was being stopped early following a recommendation from an independent Data Monitoring Committee (DMC) based on its determination of overwhelming efficacy. The decision was made following a routine assessment of efficacy and safety which showed benefits earlier than originally anticipated [193] [194] [195] [196] [197] . In August 2020, updated safety and efficacy results from the trial were released by the AstraZeneca [198] . In June 2021, the company presented updated safety and efficacy data from the trial at the 81st Annual Scientific Sessions of the American Diabetes Association (ADA-2021) [199] .
In January 2021, AstraZeneca initiated a phase II MIRACLE trial to evaluate the efficacy, safety and tolerability of AZD 9977 and dapagliflozin alone and as combination treatment in patients with heart failure and chronic kidney disease (NCT04595370; EudraCT2020-003126-23 ; D6402C00001). The randomised, double-blind, placebo-controlled trial intends to enrol 540 patients in the US and Hungary and expected to expand in Belgium, Bulgaria, Canada, Czech Republic, Denmark, Germany, Italy, Japan, Lithuania, Poland, Spain, Thialand, Ukraine [200] .
In December 2020, Nagoya Graduate School of Medicine terminated AstraZeneca funded clinical trial that evaluated effects of dapagliflozin on stabilizing coronary atherosclerotic plaques using IB-IVUS imaging study (UMIN000027422; R000031182). The trial was initiated in May 2017 and intended to enroll 100 patients in Japan [201] .
Heart failure following acute myocardial infraction
(MI): In July 2020, AstraZeneca granted Fast Track Designation in the US for the development of dapagliflozin to reduce the risk of hospitalization for heart failure (hHF) or cardiovascular (CV) death in adults following an acute myocardial infarction (MI) or heart attack. The designation is based on the phase III DAPA-MI trial that will explore the efficacy and safety of FARXIGA in this patient population. In addition to Fast Track Designation, the FDA recently granted Special Protocol Assessment (SPA) agreement to the DAPA-MI trial [202]
In August 2020, AstraZeneca, in collaboration with Uppsala University, initiated a phase III DAPA-MI trial to evaluate the effect of dapagliflozin versus placebo, given once daily in addition to standard of care therapies for the prevention of hospitalisation for heart failure or cardiovascular (CV) death in patients with myocardial infarction and without diabetes (D169DC00001; EudraCT2020-000664-31; NCT04564742). This event-driven, registry-based randomised controlled, double-blind study is enrolling approximately 6 400 patients in Sweden and will extend to sites in the United Kingdom [203] .
Obesity
In March 2016, Uppsala University, in collaboration with AstraZeneca, completed a phase II trial investigated the efficts of dapagliflozin, in combination with exenatide, on body weight in non-diabetic obese subjects (NCT02313220). The randomised, double-blind trial was initiated in December 2014 and enrolled 50 patients in Sweden [204] .
Other investigator-sponsored trials
In September 2021, Postgraduate Institute of Medical Education and Research initiated a phase II trial to evaluate the efficacy and safety of dapagliflozin in cirrhotic patients with recurrent ascites (NCT05014594). The randomized, double-blind, parallel trial is expected to enroll 44 patients in India.
Owing to the delay in the patient enrolment, in March 2020, University Medical Center Hamburg-Eppendorf and AstraZeneca terminated a phase III trial that evaluated the potential synergistic effect of dapagliflozin plus exenatide [see Adis insight drug profile800022798] once-weekly, in combination with high-dose intensive insulin therapy, in obese insulin-resistant patients with type II diabetes mellitus and inadequate glycaemic control (ESR16-12160UKE-DapEx001; UKE-DapEx001; EudraCT2016-003738-25; NCT03419624). Evaluation of the change in HbA1c level is the defined primary endpoint of the trial. The randomised, double-blind, placebo-controlled trial was initiated in February 2018 and enrolled approximately 13 patients in Germany [205] .
In March 2019, the Japan Society for Patient Reported Outcome (PRO) and Saitama Medical University completed a phase II trial which evaluated the efficacy of dapagliflozin versus sitagliptin, for preventing of cardiovascular risk factors in patients with type II diabetes mellitus patients (UMIN000029640; R000033859). Primary endpoint of the trial was 24-hour Holter electrocardiogram, frequency of arrhythmia, and its symptom. The Randomised, open label trial that was initiated in November 2017 enrolled 40 patients in Japan [206] .
In March 2019, Toho University Omori Medical Center and the Japan Society for Patient Reported Outcome (PRO) in collaboration with AstraZeneca completed the DIVERSITY-CVR trial which evaluated the efficacy of dapagliflozin versus sitagliptin, for preventing of cardiovascular risk factors in patients with type II diabetes mellitus patients (R000032081; UMIN000028014). The open label trial that was initiated in July 2017 enrolled 340 patients in Japan. In the trial no severe adverse events were reported in both the groups. In September 2019, results from the trial were presented at the 55th Annual Meeting of the European Association for the Study of Diabetes (ESAD-2019) [207] [208] .
In April 2016, the Seoul National University Hospital in collaboration with AstraZeneca completed a phase II trial which investigated the effect of dapagliflozin on the incretin sensitivity of the pancreatic beta cell (NCT02420392). The trial enrolled 30 patients with type II diabetes in South Korea [209] .
In June 2014, the King's College London and the Guy's and St. Thomas NHS Foundation Trust initiated a phase III trial to study the protective effect on renal disease in patients with type 2 diabetes and diabetic nephropathies (DEER; EudraCT2013-004042-42). The trial compares the combination effect of dapagliflozin and ramipril on reduction in microalbuminuria compared with ramipril alone. The randomised, open-label trial is intended to enrol 40 patients in the UK [210] .
In October 2018, Steno Diabetes Center, Copenhagen in collaboration with the Novo Nordic Foundation, Rigshospitalet, AstraZeneca and Bayer completed the phase II PRE-D trial in patients with pre-diabetic state and obesity. The trial is designed to compare the short-term (3 months) effectiveness of dapagliflozin, metformin and physical activity on glucose variability, body composition, and cardiometabolic risk factors in overweight or obese individuals with pre-diabetes (EudraCT2015-001552-30; NCT02695810). The trial enrolled 120 patients in Denmark. In the trial, statistically significant differences were not observed in any of the glucagon measures in patients with prediabetes, when treated with dapagliflozin, metformin or exercise from baseline to 13 or 26 weeks. The trial was initiated in February 2016. In June 2019, efficacy data from the trial were presented at the 79th Annual Scientific Sessions of the American Diabetes Association (ADA-2019) [211] [212] . Results from the trial were presented at the 80th Annual Scientific Sessions of the American Diabetes Association (ADA-2020) [213] [214] .
In November 2017, AstraZeneca in collaboration with University Medical Center Groningen initiated the phase II DIAMOND trial to test the hypothesis that dapagliflozin lowers proteinuria in patients with non-diabetic chronic kidney disease (NCT03190694; EudraCT2017-001090-16; 2017003001). The crossover, double-blind, prospective, randomised trial is enrolling approximately 53 patients in the Netherlands and may extend to Canada and Malaysia [215] .
In February 2021, Jiangsu Hansoh Pharmaceutical completed a phase I trial which evaluated bioequivalence of two formulations of dapagliflozin 10 mg tablets in healthy volunteers under fasting conditions.(NCT04880993;2020-4925).The trial also evaluated the safety and tolerability of the treatment.The primary endpoint of the trial was peak plasma concentration (Cmax) of dapagliflozin in plasma after administration of the test and the reference products. The randomized, open-label, cross-over, prospective, single-dose trial was initiated in December 2020 and enrolled 30 healthy volunteers in Canada [216]
Labelling information
In November 2019, AstraZeneca reported that the US FDA has updated label of dapagliflozin (Farxiga) with use to reduce the risk of hospitalisation for heart failure (hHF) in adults with type 2 diabetes mellitus and established cardiovascular diseases (CVD) or multiple cardiovascular (CV) risk factors. In May 2015, the FDA issued a Safety Communication, warning against the risk of diabetic ketoacidosis caused by all SGLT2 inhibitors. The warning was issued following the agency received reports of 20 patients suffering from the condition after taking the medications [217] [218] .
