Dapagliflozin - AstraZeneca

At a glance

Originator Bristol-Myers Squibb
Developer AstraZeneca; AstraZeneca KK; Bayer; Bristol-Myers Squibb; Novo Nordisk Foundation; Ono Pharmaceutical; University Medical Center Groningen; Uppsala University
Class Antihyperglycaemics; Benzhydryl compounds; Chlorobenzenes; Glucosides; Heart failure therapies; Obesity therapies; Pyrans; Small molecules; Urologics
Mechanism of Action Sodium-glucose transporter 2 inhibitors

Orphan Drug Status

Orphan designation is assigned by a regulatory body to encourage companies to develop drugs for rare diseases.

No
New Molecular Entity Yes

Highest Development Phases

Marketed Cardiovascular disorders; Chronic heart failure; Type 1 diabetes mellitus; Type 2 diabetes mellitus
Phase III COVID 2019 infections; Heart failure; Renal failure
Phase II Kidney disorders; Obesity; Prediabetic state

Most Recent Events

19 Nov 2020 AstraZeneca expects regulatory decision for Chronic heart failure (In the elderly, In adults) in Japan (PO) in Q4 2020
19 Nov 2020 AstraZeneca expects regulatory decision for Chronic heart failure (In the elderly, In adults) in China (PO) in the first half of 2021
05 Nov 2020 Launched for Chronic heart failure (In the elderly, In adults) in Norway, Liechtenstein, Iceland, European Union (PO)

Development Overview

Introduction

Dapagliflozin is an oral, once-daily, sodium glucose co-transporter type 2 (SGLT2) inhibitor, being developed by Bristol-Myers Squibb (BMS) and its licensee AstraZeneca, for the treatment of type-2, type-1 diabetes mellitus and COVID-19 infections. However, AstraZeneca subsequently acquired all rights to the drug from Bristol-Myers Squibb. SGLT2 is a low affinity, high-capacity transporter located in the brush-border membrane of the early segment of the proximal tubule of the kidney. The transporter is responsible for 90% of the glucose reabsorbed by the kidneys. SGLT2 inhibitors maintain blood glucose levels by regulating the re-absorption of filtered glucose. Dapagliflozin has been launched worldwide for type-2 and type-1 diabetes mellitus. The drug is also available in the US, 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. Dapaglifozin is launched in India for the treatment of heart failure associated with ejection fraction (HFrEF). The drug has been launched in multiple countries. It is approved in European Union and Liechtenstein for type-1 and type-2 diabetes mellitus. The drug is approved in the US and European Union for chronic heart failure. The drug is under regulatory review in the Japan, China for chronic heart failure. Clinical development for chronic heart failure and renal failure is ongoing in multiple countries worldwide. Clinical development for COVID-19 infections is undergoing in the US, Brazil and in the Europe.

Regulatory submissions were also made for dapagliflozin for the treatment of type-2 diabetes mellitus in South Africa. However, no recent reports of development have been identified. As at May 2017, development of the dapagliflozin oral solution was discontinued as the same was not listed on the company pipeline. The oral solution of dapagliflozin was in phase I development for T2DM (AstraZeneca pipeline, April 2017). As at November 2017, no recent reports of development were identified for phase I development in Type II diabetes mellitus in Mexico.

Phase III trials of dapagliflozin in combination with metformin and other oral antihyperglycaemics have also been conducted. BMS and AstraZeneca have subsequently developed a fixed-dose combination of these therapies [see AdisInsight drug profiles 800027878 and 800038479].

Edistride, comprising dapagliflozin propanediol monohydrate has also been developed by AstraZeneca as monotherapy and as add-on combination therapy for the treatment of adults with type-2 diabetes mellitus. The candidate is approved in the EU as an informed consent application under the Article 10(c) of Directive 2001/83/EC.

AstraZeneca acquired the global rights for dapagliflozin from BMS in February 2014^[1].

Company Agreements

Marketing agreement

In March 2016, AstraZeneca India and Sun Pharma entered into a distribution agreement for dapagliflozin. Under the terms of agreement, Sun Pharma will market and distribute dapagliflozin under the brand name Oxra^®, while AstraZeneca India will market dapagliflozin under the brand name Forxiga^® and retain the intellectual property rights to dapagliflozin^[2].

In February 2014, AstraZeneca acquired global rights for development, manufacture and commercialisation of dapagliflozin. Earlier, in December 2013, Bristol-Myers Squibb entered into an agreement with AstraZeneca. Under the terms of the agreement, AstraZeneca acquired the intellectual property and global rights to BMS's diabetes portfolio, including dapagliflozin. AstraZeneca paid BMS $US2.7 billion on completion of the acquisition. The company has also agreed to pay up to $US1.4 billion to BMS in regulatory, launch and sales-related payments and various royalty payments till 2025, of which $US600 million relates to the approval of dapagliflozin in the US. Additionally, AstraZeneca announced that, it may make payments up to $US225 million on transfer of certain company assets^[3]^[1]^[4].

In January 2007, BMS and AstraZeneca entered into a worldwide collaboration agreement to develop and commercialise dapagliflozin and saxagliptin. Any additional sodium glucose co-transporter type 2 (SGLT2) inhibiting or dipeptidyl peptidase IV (DPP IV) inhibiting compounds to arise in development could be added to the collaboration. Under the terms of the agreement, AstraZeneca paid BMS an upfront payment of $US100 million, and will also make additional milestone payments of up to $US650 million for the two compounds, and possible sales milestones of up to $US300 million per product. Both companies will jointly develop the clinical and marketing strategy of the compounds. AstraZeneca also agreed to fund the majority of development costs from 2007 through 2009. BMS will manufacture both compounds and book sales. The agreement initially excluded all activities in Japan. However, the collaboration was expanded in December 2008 to include development and commercialisation of dapagliflozin in Japan^[5]^[6].

In December 2013, AstraZeneca obtained from BMS the exclusive rights to commercialise dapagliflozin in Japan. AstraZeneca K.K. simultaneously entered into an agreement with Ono Pharmaceutical to co-promote dapagliflozin in Japan. Under the terms of the agreement, Ono will make an upfront payment, as well as launch and sales-related milestone payments, which will be shared by BMS and AstraZeneca. BMS and AstraZeneca will supply the product, and Ono will be responsible for distribution^[7].

Key Development Milestones

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 April 2020, AstraZeneca and Saint Luke’s Mid America Heart Institute initiated a phase III DARE-19 trial to evaluate 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). The trial includes medical history of hypertension (HTN), atherosclerotic CV disease, heart failure with reduced or preserved ejection fraction, T2D or CKD Stage III to IV. The randomised, investigator-sponsored trial intends to enrol approximately 900 patients in the US, Brazil and other European countries^[10]^[11].

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]^[12]. 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^[13]. 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^[14]^[15]^[16]^[17]^[18]^[19]^[20]^[21]. 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^[22]. 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^[23]. 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^[24]^[25].

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^[26]^[27]. BMS and AstraZeneca had submitted the MAA in December 2010, which was validated by the EMA in January 2011^[21]. 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^[28].

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^[29]. 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^[30].

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^[31]. 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^[32]. 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^[33]^[34]^[35]. 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^[36].

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^[33].

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^[37][DCGI website, April 2016].

Dapagliflozin (5mg and 10mg tablets) was launched in Japan in May 2014 as a once-daily oral treatment for T2DM^[38]. The product received approval in Japan in March 2014^[39]. The regulatory filing was accepted for review in March 2013 by Japan's Ministry of Health, Labor and Welfare^[40]

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^[41]. 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^[42]. In December 2014, Health Canada approved Forxiga^® (dapagliflozin) to be used in combination with diet and exercise in patients with T2DM^[43]. Previously, in January 2011, Health Canada issued a Notice of Noncompliance, regarding the marketing application for dapagliflozin^[44]. The candidate was also launched in Switzerland after approval in August 2014^[45].

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^[46]. 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^[47].

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)^[48].

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^[49].

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^[50].

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)^[51]^[52].

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)^[53]. 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^[54]. In February 2018, AstraZeneca reported top-line data from the phase III DERIVE trial^[55]. 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)^[56]^[53]. 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^[23].

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^[57].

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^[58]. In June 2018, efficacy results from the trial were released by AstraZeneca^[59]. Updated efficacy data from the trial were presented at the 54th Annual Meeting of the European Association for the Study of Diabetes (EASD-2018)^[60].

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^[61].

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^[62].

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^[63].

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^[64].

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^[65]. 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)^[66], as well as patients inadequately controlled by insulin and one or two oral antidiabetics (NCT00357370)^[67]^[68]. Phase I and II trials have been completed to determine the effects of dapagliflozin on insulin resistance and insulin secretion (NCT00831779)^[69], efficacy and safety in Japanese patients (NCT00972244)^[70], safety and efficacy of dapagliflozin in treatment-naïve patients who had inadequate glycaemic control on diet and exercise (NCT00263276)^[71], pharmacokinetics and pharmacodynamics (NCT00162305)^[72], (NCT01165268)^[73], (NCT01072578)^[74], (NCT00538174)^[75], as well as potential drug interaction with rifampicin (NCT01068756)^[76], and glimepiride (NCT00562250)^[77]. One phase I pharmacokinetic study was initiated in the US, but terminated for an undisclosed reason (NCT00726505)^[78].

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)^[79].

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)^[80], a 52-week trial with a 156-week extension period in 814 patients (NCT00660907)^[81]^[82]^[83], a 1 093-patient trial to compare combination therapy with the drugs as monotherapy (NCT00859898)^[84]^[85], 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)^[86]^[87]^[88], and a 600-patient study with the combination used as initial therapy (NCT00643851)^[89]^[85].

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^[90].

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^[91].

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^[92].

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)^[93]. 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)^[94], a 597-patient study in combination with glimepiride (NCT00680745)^[95]^[96]^[97]^[98], a 833-patient trial in combination with sitagliptin with or without metformin (NCT00984867)^[99], and a 972-patient study in combination with thiazolidinedione therapy (NCT00683878)^[100].

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^[46]. 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^[101].

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^[102]. Results reported in June 2015 showed that the trial met its primary endpoint^[103].

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^[104].

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^[105].

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^[106].

A phase II DIET trial, conducted by AstraZeneca and Ono Pharmaceutical, is examining the hypoglycemic action of dapagliflozin and its effects on body composition and dietary intake during weight loss in 60 Japanese patients with type 2 diabetes mellitus (UMIN000019192)^[107].

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^[108].

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^[109].

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^[110].

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^[111].

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]^[112].

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]^[113]

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^[114].

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^[115]. The randomised, double-blind, placebo-controlled trial was initiated in April 2013 and enrolled 17190 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. 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 80^th Annual Scientific Sessions of the American Diabetes Association (ADA-2020). In September 2020, data was presented at the 56^th Annual Meeting of the European Association for the Study of Diabetes (EASD-2020)^[116]^[117]^[118]^[119]^[120]^[121]^[122]^[13]^[123]^[124]^[125]^[126].

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^[127].

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^[128].

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^[129]. 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^[130].

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^[131].

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^[132].

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)^[133]^[134].

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^[135]. 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)^[136].

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)^[137].

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^[138]. 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^[139]^[140]^[141].

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^[140].

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^[142]^[143].

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^[144].

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 79^th 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^[145]^[146].

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 55^th Annual Meeting of the European Association for the Study of Diabetes (EASD-2019) ^[147]^[55]^[148].

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^[55]^[149].

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^[150]^[151].

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^[152].

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 78^th Annual Scientific Sessions of the American Diabetes Association (ADA-2018)^[153]^[154].

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^[155].

Chronic heart failure and renal failure

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^[156]^[157].

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^[158]. 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]^[159]. In fourth quarter of 2019, the European Medicines Agency accepted a regulatory filing for dapagliflozin for chronic heart failure in European Union^[160].

In fourth quarter of 2019, AstraZeneca filed a regulatory submission for dapagliflozin for chronic heart failure in China^[160].

In fourth quarter of 2019, AstraZeneca filed a regulatory submission for dapagliflozin for chronic heart failure in Japan^[160].

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]^[161].

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)^[162].

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^[163].

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^[164].

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^[165]^[166].

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^[165]^[167].

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^[168].

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^[169].

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 4 744 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^[170]^[171]. 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^[172]^[173]^[174]^[175]. In June 2020, The efficacy results from the trial in prevention of diabetes were presented at 80^th American Diabetes Association (ADA-2020)^[176]. 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)^[177].

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^[178]^[179]^[180]^[181]^[182]. In August 2020, updated safety and efficacy results from the trial were released by the AstraZeneca^[183]

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^[184]

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^[185].

Other investigator-sponsored trials

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 intended to enrol approximately 13 patients in Germany^[186].

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^[187].

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 55^th Annual Meeting of the European Association for the Study of Diabetes (ESAD-2019)^[188]^[189].

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^[190].

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^[191].

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)^[192]^[193]. Results from the trial were presented at the 80th Annual Scientific Sessions of the American Diabetes Association (ADA-2020)^[194]^[195].

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^[196].

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^[197]^[198].

Patent Information

qBMS owns a patent covering the composition of matter of dapagliflozin which has an expiry date of October 2020 in the US and May 2023 in the EU.

Drug Properties & Chemical Synopsis

Route of administration PO
Formulation Liquid, Tablet, unspecified
Class Antihyperglycaemics, Benzhydryl compounds, Chlorobenzenes, Glucosides, Heart failure therapies, Obesity therapies, Pyrans, Small molecules, Urologics
Target Sodium-glucose transporter 2
Mechanism of Action Sodium-glucose transporter 2 inhibitors
WHO ATC code
A10B-X09 (Dapagliflozin)

C01 (Cardiac Therapy)

G04B (Urologicals)

J05 (Antivirals for Systemic Use)
EPhMRA code
A10X (Other Drugs Used in Diabetes)

A8 (Antiobesity Preparations, Excluding Dietetics)

C1 (Cardiac Therapy)

J5 (Antivirals for Systemic Use)
Chemical name (2S,3R,4R,5S,6R)-2-[4-Chloro-3-(4-ehoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
Molecular formula C21 H25 Cl O6
SMILES C1C(=CC(=C(C=1)Cl)CC1C=CC(=CC=1)OCC)C1C(C(C(C(O1)CO)O)O)O
Chemical Structure

Download PNG Download MOL file
CAS Registry Number 461432-26-8
Related CAS Registry Number 960404-48-2(Dapagliflozin propanediol)

Indication	Biomarker Function	Biomarker Name	Number of Trials
cardiovascular disorders	Outcome Measure	BNP	1
carotid artery diseases	Outcome Measure	VCAM-1 TNF-alpha Nitric Oxide Leptin IL6 IL2 ICAM-1 Endothelin 1 CRP Adiponectin 8 more biomarker names Show less	1 1 1 1 1 1 1 1 1 1
Chronic heart failure	Exclusion	BNP A1C	1 1
Chronic heart failure	Inclusion	BNP A1C	2 2
Chronic heart failure	Outcome Measure	BNP A1C	3 2
Chronic heart failure	Safety	A1C	1
coronary artery disease	not specified	P-selectin IL6 CRP 1 more biomarker names Show less	1 1 1
coronary artery disease	Exclusion	A1C	1
coronary artery disease	Inclusion	A1C	1
coronary artery disease	Outcome Measure	VCAM-1 TNF-alpha Nitric Oxide MMP9 MCP1 Leptin IL8 IL6 IL2 IL17 IL10 IL1 beta IL1 alpha ICAM-1 Endothelin 1 CRP BNP Adiponectin A1C 17 more biomarker names Show less	1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 1
diabetes mellitus	Inclusion	A1C	1
diabetes mellitus	Outcome Measure	A1C	1
diabetic nephropathies	Exclusion	C-peptide A1C	1 1
diabetic nephropathies	Inclusion	A1C	1
diabetic nephropathies	Outcome Measure	VCAM-1 RBP4 Endothelin 1 C-peptide Aldosterone A1C 4 more biomarker names Show less	1 1 1 1 1 1
diabetic retinopathy	Outcome Measure	A1C	1
heart failure	Outcome Measure	BNP	1
hypercholesterolaemia	not specified	L-Leucine Apo B	1 1
hypercholesterolaemia	Exclusion	Insulin	1
hypercholesterolaemia	Inclusion	A1C	1
hypercholesterolaemia	Outcome Measure	Insulin	1
hypertension	Outcome Measure	Uric acid Creatinine A1C 1 more biomarker names Show less	1 1 1
hypertension in diabetes	not specified	Angiotensinogen	1
hypertension in diabetes	Inclusion	A1C	2
hypertension in diabetes	Outcome Measure	Uric acid Purine CKM CKB A1C 3 more biomarker names Show less	2 1 1 1 2
hypertension in diabetes	Safety	CKM	1
hyperuricaemia	Exclusion	A1C	1
hyperuricaemia	Outcome Measure	Uric acid Cystatin C A1C 1 more biomarker names Show less	1 1 1
left ventricular hypertrophy	Inclusion	A1C	1
left ventricular hypertrophy	Outcome Measure	Uric acid Insulin BNP A1C 2 more biomarker names Show less	1 1 1 1
metabolic syndrome	Outcome Measure	Uric acid Insulin Creatinine 1 more biomarker names Show less	1 1 1
obesity	not specified	Testosterone	1
obesity	Exclusion	Creatinine A1C	1 1
obesity	Inclusion	A1C	2
obesity	Outcome Measure	Leptin Insulin Hydrocortisone Ghrelin Creatinine C-peptide Bilirubin A1C 6 more biomarker names Show less	1 1 1 1 1 1 1 2
overweight	Exclusion	Creatinine	1
overweight	Outcome Measure	Creatinine	1
prediabetic state	Inclusion	A1C	1
prediabetic state	Outcome Measure	Uric acid Insulin Creatinine A1C 2 more biomarker names Show less	2 1 2 1
proteinuria	Exclusion	C-peptide A1C	1 1
proteinuria	Inclusion	ACE A1C	1 2
proteinuria	Outcome Measure	VCAM-1 RBP4 Endothelin 1 C-peptide Aldosterone ACE A1C 5 more biomarker names Show less	1 1 1 1 1 1 2
renal failure	Inclusion	A1C	1
renal failure	Outcome Measure	A1C	1
type 1 diabetes mellitus	not specified	lipase E, hormone sensitive type Hydrocortisone C-peptide 1 more biomarker names Show less	1 1 2
type 1 diabetes mellitus	Outcome Measure	Ketone bodies IL6 GLP-1 CRP Acetoacetic acid A1C 3-Hydroxybutyric acid 5 more biomarker names Show less	2 1 1 1 1 5 2
type 1 diabetes mellitus	Exclusion	GLP-1	1
type 1 diabetes mellitus	Inclusion	A1C	5
type 1 diabetes mellitus	Safety	Ketone bodies	1
type 2 diabetes mellitus	not specified	Visfatin Uric acid TNF-alpha TLR4 Thyroid stimulating hormone, beta T cell receptor gamma variable 9 Resistin Renin PAI-1 P-selectin oviductal glycoprotein 1 NFkB microRNA 29b-1 microRNA 27b microRNA 210 microRNA 130a Leptin L-Leucine JNK1 IL8 IL6 IL1 beta CRP cholesteryl ester transfer protein Apo B Angiotensinogen Alkaline phosphatase Adiponectin acyl-CoA synthetase bubblegum family member 1 A1C 28 more biomarker names Show less	1 1 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 3 1 1 1 1 2 3 1 1 2
type 2 diabetes mellitus	Outcome Measure	VCAM-1 Uric acid TNF-alpha Taurine suppressor of cytokine signaling 3 Retinoyl b-glucuronide RBP4 Purine PTH Paraoxonase 1 oviductal glycoprotein 1 Osteocalcin Nitric Oxide NGAL NFkB MMP9 meningioma expressed antigen 5 (hyaluronidase) MCP1 lipoprotein lipase Leptin L-Valine L-Threonine L-Leucine KIM-1 Ketone bodies Insulin IL8 IL6 IL2 IL17 IL10 IL1 beta IL1 alpha IK cytokine, down-regulator of HLA II IFN-gamma ICAM-1 Hydrocortisone Ghrelin Endothelin 1 dipeptidyl-peptidase 4 Dimethylamine Deoxypyridinoline Cyclic GMP CTx CRP Creatinine Creatine CKM CKB C-peptide BNP Bilirubin Betaine B2M apolipoprotein C-II apolipoprotein A-II ApoE Apo C-III Apo B Apo A-1 Alpha-D-Glucose Aldosterone Adiponectin A1C 4-Aminohippuric acid 3-Hydroxybutyric acid 64 more biomarker names Show less	2 7 2 1 1 1 1 4 1 1 1 1 1 1 1 1 1 1 1 2 1 1 1 1 1 6 1 2 1 1 1 1 1 1 1 1 1 1 2 2 1 1 1 1 3 4 1 2 2 4 4 2 1 1 1 1 1 1 2 2 2 1 5 71 1 1
type 2 diabetes mellitus	Exclusion	Insulin dipeptidyl-peptidase 4 Creatinine C-peptide Bilirubin A1C 4 more biomarker names Show less	3 1 2 1 1 6
type 2 diabetes mellitus	Inclusion	Insulin IFN-gamma A1C 1 more biomarker names Show less	1 1 57
type 2 diabetes mellitus	Safety	PTH Osteocalcin Deoxypyridinoline CKM A1C 3 more biomarker names Show less	1 1 1 2 1

Drug Name	Biomarker Name	Biomarker Function
Dapagliflozin - AstraZeneca		3-Hydroxybutyric acid	Outcome Measure
	4-Aminohippuric acid	Outcome Measure
	A1C	Exclusion, Inclusion, Outcome Measure, Safety
	ACE	Inclusion, Outcome Measure
	Acetoacetic acid	Outcome Measure
	acyl-CoA synthetase bubblegum family member 1	not specified
	Adiponectin	Outcome Measure
	Alkaline phosphatase	not specified
	Alpha-D-Glucose	Outcome Measure
	Angiotensinogen	not specified
	Apo A-1	Outcome Measure
	Apo B	Outcome Measure
	Apo C-III	Outcome Measure
	ApoE	Outcome Measure
	apolipoprotein A-II	Outcome Measure
	apolipoprotein C-II	Outcome Measure
	B-cell linker	not specified
	B2M	Outcome Measure
	Betaine	Outcome Measure
	Bilirubin	Exclusion, Outcome Measure
	BNP	Exclusion, Inclusion, Outcome Measure
	C-peptide	Outcome Measure
	cholesteryl ester transfer protein	not specified
	CKB	Outcome Measure
	CKM	Outcome Measure, Safety
	Creatine	Outcome Measure
	Creatinine	Exclusion, Outcome Measure
	CRP	Outcome Measure
	CTx	Outcome Measure
	Cyclic GMP	Outcome Measure
	Cystatin C	Outcome Measure
	Deoxypyridinoline	Outcome Measure, Safety
	Dimethylamine	Outcome Measure
	dipeptidyl-peptidase 4	Outcome Measure
	Endothelin 1	Outcome Measure
	epithelial mitogen	not specified
	gamma-glutamyltransferase light chain 1	Outcome Measure
	Ghrelin	Outcome Measure
	GIP	Outcome Measure
	GLP-1	Exclusion, Outcome Measure
	growth hormone 1	Outcome Measure
	Hydrocortisone	Outcome Measure
	ICAM-1	Outcome Measure
	IFN-gamma	Inclusion, Outcome Measure
	IK cytokine, down-regulator of HLA II	Outcome Measure
	IL1 alpha	Outcome Measure
	IL1 beta	Outcome Measure
	IL10	Outcome Measure
	IL17	Outcome Measure
	IL2	Outcome Measure
	IL6	Outcome Measure
	IL8	Outcome Measure
	Insulin	Exclusion, Inclusion, Outcome Measure
	JNK1	not specified
	Ketone bodies	Outcome Measure, Safety
	KIM-1	Outcome Measure
	L-Leucine	Outcome Measure
	L-Threonine	Outcome Measure
	L-Valine	Outcome Measure
	Leptin	Outcome Measure
	lipase E, hormone sensitive type	not specified
	lipoprotein lipase	Outcome Measure
	MCP1	Outcome Measure
	meningioma expressed antigen 5 (hyaluronidase)	Outcome Measure
	microRNA 130a	not specified
	microRNA 210	not specified
	microRNA 27b	not specified
	microRNA 29b-1	not specified
	MMP9	Outcome Measure
	NFkB	Outcome Measure
	NGAL	Outcome Measure
	Nitric Oxide	Outcome Measure
	Norepinephrine	Outcome Measure
	Osteocalcin	Outcome Measure, Safety
	oviductal glycoprotein 1	Outcome Measure
	P-selectin	not specified
	PAI-1	not specified
	Paraoxonase 1	Outcome Measure
	PTH	Outcome Measure, Safety
	Purine	Outcome Measure
	Renin	not specified
	Resistin	not specified
	Retinoyl b-glucuronide	Outcome Measure
	sex hormone-binding globulin	Outcome Measure
	suppressor of cytokine signaling 3	Outcome Measure
	T cell receptor gamma variable 9	not specified
	Taurine	Outcome Measure
	Testosterone	not specified
	Thyroid stimulating hormone, beta	Outcome Measure
	Thyroxine	Outcome Measure
	TLR4	not specified
	TNF-alpha	Outcome Measure
	Troponin T, cardiac	Outcome Measure
	Uric acid	Outcome Measure
	VCAM-1	Outcome Measure
	Visfatin	not specified

Indication	Qualifier	Patient Segment	Phase	Countries	Route / Formulation	Developers	Event Date
COVID 2019 infections	with cardiometabolic disease (hypertension, type 2 diabetes, atherosclerotic cardiovascular disease, heart failure, and/or kidney disease)	-	Phase III	Brazil, Europe, USA	PO / Tablet	AstraZeneca	27 Aug 2020
COVID 2019 infections	in combination with ambrisentan	Combination therapy	Phase II/III	United Kingdom	PO / Tablet	AstraZeneca	03 Jul 2020
Cardiovascular disorders	to reduce the risk of hospitalisation for heart failure in adults with type 2 diabetes mellitus and established cardiovascular disease or multiple cardiovascular risk factors	-	Marketed	USA	PO / unspecified	AstraZeneca	19 Oct 2019
Chronic heart failure	with reduced ejection fraction (HFrEF)	In adults, In the elderly	Marketed	European Union, Iceland, India, Liechtenstein, Norway	PO / Tablet	AstraZeneca	05 Nov 2020
Chronic heart failure	In patients with reduced ejection fraction with and without type 2 diabetesno	In adults, In the elderly	Registered	USA	PO / Tablet	AstraZeneca	06 May 2020
Chronic heart failure	-	In adults, In the elderly	Preregistration	China, Japan	PO / Tablet	AstraZeneca	31 Dec 2019
Chronic heart failure	-	-	Phase III	United Kingdom	unspecified / unspecified	AstraZeneca	12 Sep 2016
Chronic heart failure	-	In adults, In the elderly	Phase III	Argentina, Brazil, Canada, Denmark, Russia, Slovakia, South Africa, South Korea, Sweden, Taiwan, Vietnam	PO / Tablet	AstraZeneca	09 Apr 2019
Heart failure	With Preserved Ejection Fraction	-	Phase III	Bulgaria, Italy, Slovakia, South Africa	PO / Tablet	AstraZeneca	04 Apr 2019
Heart failure	in patients with type 2 diabetes	In the elderly, Prevention	Clinical Phase Unknown	Australia	PO / Tablet	AstraZeneca	01 Mar 2020
Kidney disorders	-	-	Phase II	Netherlands	PO / Tablet	AstraZeneca, University Medical Center Groningen	12 Nov 2017
Obesity	-	-	Phase II	Denmark	PO / unspecified	AstraZeneca, Novo Nordisk Foundation, Bayer	15 Jul 2019
Obesity	in combination with exenatide	Combination therapy	Phase II	Sweden	PO / unspecified	AstraZeneca, Uppsala University	01 Dec 2014
Prediabetic state	-	-	Phase II	Denmark	PO / Tablet	AstraZeneca, Novo Nordisk Foundation, Bayer	01 Feb 2016
Renal failure	chronic kidney disease	-	Phase III	Argentina, Brazil, Canada, China, Denmark, Germany, Hungary, India, Japan, Mexico, Peru, Philippines, Poland, Russia, South Korea, Spain, Sweden, USA (fast track), Ukraine, United Kingdom, Vietnam	PO / unspecified	AstraZeneca	22 Feb 2017
Type 1 diabetes mellitus	-	Adjunctive treatment	Marketed	Austria, Croatia, Czech Republic, Denmark, Finland, Iceland, Japan, Netherlands, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, United Kingdom	PO / Tablet	AstraZeneca	28 Mar 2019
Type 1 diabetes mellitus	-	Adjunctive treatment	Registered	European Union, Liechtenstein	PO / Tablet	AstraZeneca	27 Mar 2019
Type 1 diabetes mellitus	-	Adjunctive treatment	Preregistration	USA	PO / Tablet	AstraZeneca	01 Feb 2019
Type 1 diabetes mellitus	-	-	Phase III	Argentina, Australia, Canada, Chile, Israel, Japan, Mexico	PO / Tablet	AstraZeneca	08 Jul 2015
Type 1 diabetes mellitus	-	Adjunctive treatment	Phase I	Germany	PO / Tablet	AstraZeneca	09 Feb 2017
Type 2 diabetes mellitus	-	-	Marketed	Singapore, United Arab Emirates	PO / Tablet	Bristol-Myers Squibb	11 May 2017
Type 2 diabetes mellitus	Add on to antihyperglycaemics, including insulin; In metformin-intolerant patients Add on to antihyperglycaemics, including insulin; in metformin-intolerant patients Add on to antihyperglycaemics, including insulin; In metformin-intoelrant patients Add on to antihyperglycaemics, including insulin In combination with metformin, or as an add-on therapy to either metformin, a sulfonylurea, or insulin; In metformin-intolerant patients	Combination therapy, Monotherapy	Marketed	Australia, Austria, Croatia, Czech Republic, Denmark, Finland, Germany, Iceland, Netherlands, New Zealand, Norway, Poland, Portugal, Slovakia, Slovenia, Spain, United Kingdom	PO / Tablet	AstraZeneca	11 May 2017
Type 2 diabetes mellitus	-	-	Marketed	Argentina, Belgium, Brazil, Canada, Chile, China, Cyprus, Greece, Hong Kong, Hungary, Indonesia, Ireland, Israel, Kuwait, Malaysia, Mexico, Philippines, Russia, South Korea, Sweden, Switzerland, Thailand, USA, Ukraine	PO / Tablet	AstraZeneca	04 Nov 2020
Type 2 diabetes mellitus	-	In adults, Monotherapy	Marketed	India	PO / Tablet	AstraZeneca	25 Feb 2016
Type 2 diabetes mellitus	-	-	Marketed	Japan	PO / Tablet	AstraZeneca, Ono Pharmaceutical	23 May 2014
Type 2 diabetes mellitus	-	Adjunctive treatment, In adults	Marketed	India	PO / Tablet	AstraZeneca	25 Feb 2016
Type 2 diabetes mellitus	Add on to antihyperglycaemics, including insulin; In metformin-intoelrant patients - Centralised Procedure for marketing approval	Combination therapy, Monotherapy	Registered	European Union, Liechtenstein	PO / Tablet	AstraZeneca	27 Mar 2019
Type 2 diabetes mellitus	Add-on to insulin or metformin	Combination therapy	Registered	China	PO / Tablet	AstraZeneca	01 Nov 2018
Type 2 diabetes mellitus	-	-	Registered	Argentina, Brazil	PO / Tablet	AstraZeneca	22 Nov 2013
Type 2 diabetes mellitus	on diet and exercise and metformin	Adjunctive treatment, In adolescents, In children	Phase III	Argentina, Australia, Brazil, Canada, Chile, Colombia, Finland, India, Israel, Italy, Malaysia, Mexico, New Zealand, Philippines, Poland, Romania, Russia, South Korea, Taiwan, Thailand, Turkey, USA, Ukraine, United Kingdom	PO / Tablet	AstraZeneca	11 Oct 2017
Type 2 diabetes mellitus	-	Adjunctive treatment	Phase III	China, Thailand, Vietnam	PO / Tablet	AstraZeneca	10 Mar 2020
Type 2 diabetes mellitus	as add-on to insulin in Asian patients	Combination therapy	Phase III	South Korea	PO / Tablet	Bristol-Myers Squibb	01 Mar 2014
Type 2 diabetes mellitus	-	Adjunctive treatment, Combination therapy	Phase III	Canada, Czech Republic, Denmark, Germany, Hungary, Mexico, Poland, Romania, Russia, South Africa, Spain, Sweden, USA	PO / Tablet	AstraZeneca, Bristol-Myers Squibb	01 Feb 2016
Type 2 diabetes mellitus	-	Combination therapy	Phase III	Philippines, Puerto Rico, Taiwan	PO / Tablet	AstraZeneca	22 Apr 2009
Type 2 diabetes mellitus	-	In adolescents, In adults, In children	Phase III	Hungary, Israel, Mexico, Romania, Russia, USA, United Kingdom	PO / Tablet	AstraZeneca	06 Feb 2017
Type 2 diabetes mellitus	-	Monotherapy	Phase III	Philippines, Puerto Rico	PO / Tablet	AstraZeneca	22 Apr 2009
Type 2 diabetes mellitus	-	-	Phase II/III	Israel	PO / Tablet	AstraZeneca	26 Jul 2007
Type 2 diabetes mellitus	-	Adjunctive treatment	Phase II	Japan	PO / Tablet	AstraZeneca KK, Ono Pharmaceutical	01 Oct 2015
Type 2 diabetes mellitus	-	-	No development reported (Preregistration)	South Africa	PO / Tablet	AstraZeneca	10 May 2017
Type 2 diabetes mellitus	-	Monotherapy	No development reported (III)	Taiwan	PO / Tablet	AstraZeneca	18 Mar 2015
Type 2 diabetes mellitus	-	Combination therapy	No development reported (III)	Peru	PO / Tablet	AstraZeneca	18 Mar 2015
Type 2 diabetes mellitus	-	In adolescents, In children	No development reported (I)	Mexico	PO / Tablet	AstraZeneca	04 Nov 2017
Type 2 diabetes mellitus	-	In volunteers	Discontinued (I)	USA	PO / Liquid	AstraZeneca	10 May 2017

Type	Region	Indication
Fast Track	USA	Renal failure
BTT	USA	Renal failure

Scientific Summary

Adverse Events Frequent: Genitourinary disorders
Occasional: Arthralgia; Back pain; Constipation; Cough; Diarrhoea; Dizziness; Dyslipidaemias; Dyspepsia; Fatigue; Headache; Hypertension; Hypoglycaemia; Influenza virus infections; Nasopharyngitis; Nausea; Respiratory tract infections

Pharmacokinetics

Phase I

In a multiple dose escalation (2.5-100 mg) trial in 40 healthy volunteers, dapagliflozin exposure (AUC) increased dose-proportionally. An accumulation index of approximately 1.25 was observed with repeat daily dosing. The mean daily amount of glucose eliminated in the urine was similar after the first dose and after 14 days. Cumulative 24 hour urine glucose excretion after 2.5 and 10mg dapagliflozin was approximately 50% and 70% of that excreted after doses ≥ 20 mg, respectively^[224].

In a single dose escalation (2.5-500mg) trial in 64 healthy volunteers, the C_max increased slightly less after an overnight fast compared with that after a high-fat breakfast. In the fasted state, the AUC_inf increased slightly more than proportionally with the dapagliflozin dose. After a high-fat breakfast, the median T_max was delayed by 2.5 hours, geometric mean C_max was 39% lower, and AUC_inf was 7% lower^[223].

In a phase I trial, addition of dapagliflozin to insulin resulted in dose-proportional increase in C_max and AUC_τ. The randomised 1:1:1, single-blind, 3-arm, parallel trial 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^[153]^[154].

Adverse Events

Treatment with dapagliflozin was safe and generally well tolerated in patients (n=815) with type 1 diabetes mellitus, in the phase III DEPICT 2 trial. Adverse events (AEs), serious AEs and hypoglycaemic episodes were similar among the three treatment groups in the trial. Total events of adjudicated definite diabetic ketoacidosis were similar in the long-term and short-term periods, with more events in the dapagliflozin treated groups (5mg, 4.3%; 10mg, 3.7%) versus placebo (0.4%), over 52 weeks. Most diabetic ketoacidosis events were mild or moderate, with the primary cause being missed insulin doses or pump failure^[147]^[148].

Pooled analysis

A pre-specified meta-analysis of data from 14 phase IIb/III trials showed that dapagliflozin was not associated with an increased cardiovascular (CV) risk, but rather tended to decrease the CV risk in adult patients with type 2 diabetes mellitus (n=6228). This analysis compared dapagliflozin (2.5, 5 or 10mg; n=4287) with control (placebo or active comparator; n=1941), both with or without add-on/combination antidiabetic medications. The primary outcome was a composite of time to first event of CV death, myocardial infarction (MI), stroke or hospitalisation for unstable angina. A total of 78 primary outcome events occurred across all the studies. Dapagliflozin was associated with a lower stratified primary outcome event rate (patients with events/1000 patient years) compared with controls (11.3 vs. 16.6; hazard ratio [HR]=0.67; 98% CI 0.38, 1.18). Analysis of the secondary outcome (primary outcome plus unplanned coronary revascularisation and hospitalisation for heart failure; HR=0.632; 95% CI 0.416, 0.959) and an analysis of a composite of CV death, MI, and stroke (HR=0.596; 95% CI 0.357, 0.996) also favoured dapagliflozin. Results from the subanalysis by dapagliflozin dose were similar to overall results, and results from the 4-month safety update confirmed the findings from the initial analysis. Results from the meta-analysis were presented at the American Heart Association (AHA) Scientific Sessions in November 2011^[22]^[44].

Analysis of data pooled from 12 randomised, placebo-controlled trials ranging from 12 to 24 weeks treatment duration showed that the incidence of signs, symptoms and events suggestive of urinary tract infection (UTI) and the diagnoses of UTI were higher with dapagliflozin 5mg and 10mg than with placebo. These results suggested that the increased renal excretion of glucose with dapagliflozin treatment is correlated to the increase in the signs and symptoms and diagnoses of UTI^[205].

Data from a phase III pooled analysis showed that the adverse events occurred more frequently in patients with the lowest eGFR in both the dapagliflozin and placebo groups. Atleast one AE was reported in patients treated with dapagliflozin with varying degrees of renal function (eGFR =45 to <60; eGFR =60 to <90; eGFR =90 mL/min/1.73m²) 68.3%, 58.3%, and 59.4% respectively^[201].

Data from a pooled analysis of phase IIb/III trial showed that the adverse events were similar between the dapaliflozin and placebo groups, including adverse events of renal impairment/failure (3.7% vs. 6.7%); hypotension/volume reduction (2.8% vs. 1.7%), and potassium =6 mEq/L (1.9% vs. 7.6%)^[201].

Type 2 diabetes mellitus

Phase III

The phase III DECLARE-TIMI 58 trial confirmed the well-established safety profile for dapagliflozin, meeting the primary safety endpoint of non-inferiority versus placebo. No increase in the composite of MACE, defined as CV death, heart attack (myocardial infarction), or stroke was observed in the trial. Occurrences of amputations (1.4% versus 1.3%), fractures (5.3% versus 5.1%), bladder cancer (0.3% versus 0.5%) or Fournier’s gangrene (1 case versus 5 cases) were same across both the arms. The respective incidences of diabetic ketoacidosis (0.3% versus 0.1%) and genital infections (0.9% versus 0.1%) were rare. Serious adverse events were reported to be less frequent with dapagliflozin versus placebo in patients age ≥ 65 as well as <65. Hypoglycaemia events were less frequent in the dapagliflozin group compared to placebo, with the effect consistent in all ages including the elderly and very elderly. Fractures and events associated with volume depletion were observed in dapagliflozin and placebo group, with similar rates at all age groups. Diabetic ketoacidosis was rare, but more events were observed in the dapagliflozin treatment group, at all ages. Genital infections reported in dapagliflozin arm lead to discontinuation was reported to be more common versus placebo, irrespective of age. The trial enrolled more than 17 000 patients^[124]^[115]^[123].

Headache, urinary tract infection, influenza and genital infections were the most common adverse events (≥ 5%) in a phase III trial of dapagliflozin in 320 adult patients with type 2 diabetes who were uncontrolled on saxagliptin plus metformin. The 24-week study included an open-label lead-in period in which patients on metformin were given open-label saxagliptin 5mg and metformin for 16 weeks, while patients on metformin and any DPP-4 inhibitor were given open-label saxagliptin 5mg and metformin for 8 weeks. After the open-label period, patients with inadequate glycaemic control were randomised to placebo or dapagliflozin 10mg in addition to open-label saxagliptin and metformin. A similarity of adverse events were noted across treatment arms. The rate of hypoglycaemia was 1.3% in the dapagliflozin combination arm and 0.0% in the placebo arm^[103].

The overall rates of adverse events, including hypoglycaemia, were similar between the three groups of patients treated with dapagliflozin and saxagliptin, alone or in combination, during a phase III trial. Most adverse events were reported as mild to moderate in intensity. The trial included 534 patients (aged ≥ 18 years) with T2DM who experienced inadequate glycaemic control on metformin extended release (≥1500mg per day). Patients were randomised at a 1 : 1 : 1 ratio to receive the combination of saxagliptin 5mg and dapagliflozin 10mg plus metformin, saxagliptin and metformin plus placebo, or dapagliflozin and metformin plus placebo, for 24 weeks^[202].

In a phase III trial, the percentage of patients with type 2 diabetes mellitus who experienced ≥ 1 adverse event was similar across the dapagliflozin 10mg and placebo arms (48.6% and 51.4%, respectively). More patients in the dapagliflozin arm reported mild or moderate renal adverse events (1.8%), hypoglycaemia (12.8%) and genital infection (5.5%), compared with placebo (0%, 3.7% and 0%, respectively). This randomised, double-blind trial enrolled 216 patients with type 2 diabetes mellitus whose disease was inadequately controlled on background therapy with metformin and sulfonylurea^[46].

Dapagliflozin 10mg was not associated with a significant change from baseline in placebo-adjusted seated SBP at 24 weeks in a phase III trial in 477 patients with type 2 diabetes. 18.8% of patients receiving dapagliflozin discontinued treatment due to a lack of efficacy compared with 41.5% of patients in the placebo group. At least one adverse event over the 48-week (24-week plus 24-week extension period) treatment was observed in 66.2% of patients in the dapagliflozin group compared with 61.1% of patients in the placebo group. The most frequently reported adverse events (in ≥4% of the trial participants) included nasopharyngitis, back pain, urinary tract infection, pharyngitis, arthralgia and headache. At least one serious adverse event was reported in 6.7% of patients in the dapagliflozin group compared with 8.0% in the placebo group. 9.3% of patients in the dapagliflozin group and 0.4% of patients in the placebo group were diagnosed with genital infections; urinary tract infections were observed in 5.8% and 3.5% of patients in the dapagliflozin and placebo groups, respectively^[203].

Administration of dapagliflozin and metformin resulted in similar frequencies of adverse events and study discontinuations compared with an active control, glipizide (sulfonylurea) plus metformin, in patients with inadequately-controlled type 2 diabetes on metformin monotherapy. Overall, 78.3% of dapagliflozin plus metformin and 77.9% of glipizide plus metformin treated patients experienced adverse events after 52 weeks. Similar proportions of patients in each group had serious adverse events; 8.6% for dapagliflozin plus metformin and 11.3% for glipizide plus metformin. The adverse events that occurred most frequently, in both treatment groups, were nasopharyngitis, hypertension, and influenza. Dapagliflozin plus metformin resulted in a comparatively higher incidence of urinary tract and genital infections than with glipizide plus metformin, although these were mild-to-moderate in severity. However, one case of UTI in each treatment group resulted in discontinuation. The proportion of discontinuations in the dapagliflozin and glipizide treatment groups were 9.1% and 5.9%, respectively. The 814 patients in this trial were randomised to receive either dapagliflozin plus metformin (n = 406) or glipizide plus metformin (n = 408) for a 52-week treatment period. On a baseline of metformin (≥1500 mg/day), respective doses of dapagliflozin and glipizide started at 2.5mg and 5mg per day, and were up-titrated to ≤10mg and ≤20mg per day over the first 18 weeks as was needed. Overall, doses of dapagliflozin and glipizide at 52 weeks were 10 and 20mg, respectively^[83]. Patients completing this 52-week protocol were entered into a 156-week extension. Results at 104 weeks have been reported, demonstrating lower rates of hypoglycaemia with dapagliflozin + metformin than with glipizide + metformin (4.2% vs 45.8% of patients). No major hypoglycaemic events were observed in the dapagliflozin arm; three were reported in the glipizide arm. Compared with glipizide, dapagliflozin was associated with greater risk of genital infections in both men (8.0% vs 0.4%) and women (23.3% vs 5.9%). Most of these patients only experienced one infection (60% in the dapagliflozin group; 83.3% in the glipizide group). Rates of events suggestive of UTI were similar between the dapagliflozin and glipizide groups (13.5% vs 9.1%, respectively). Most events occurred in the first year, were of mild to moderate severity, and were responsive to standard treatment. Three cases of genital infections in the first year led to discontinuation in the dapagliflozin treatment group. One case of UTI in the dapagliflozin group and one case in the glipizide group led to discontinuation, respectively, in the first year. No discontinuations due to genital infections or urinary tract infections occurred in the second year. No kidney infections were reported in the dapagliflozin group, whereas in the glipizide group, two patients reported pyelonephritis and one patient reported pyelonephritis followed by pyelocystitis. There was no clinically relevant change in renal function during the 104 weeks^[82].

The addition of dapagliflozin (2.5, 5 or 10 mg/day) to glimepiride produced a similar overall rate of adverse events (AEs), compared with placebo, in patients with type 2 diabetes mellitus in a phase III study. Over 48 weeks of treatment, the proportion of patients experiencing at least one AE was 58%, 61% and 59%, in the dapagliflozin 2.5, 5 and 10 mg/day groups, respectively, compared with 56% for placebo. The most common AEs (at least 3% in any group) included back pain, nasopharyngitis, upper respiratory tract infection, bronchitis, cough, urinary tract infection (UTI), dyslipidaemia, hypertension, arthralgia, diarrhoea and dyspepsia. The frequency of genital tract infections was higher in the dapagliflozin groups compared with placebo (5%, 6% and 9% vs 1%, respectively), as was the incidence of hypoglycaemic events (10%, 10% and 11% vs 7%). The incidence of events suggestive of UTIs was similar across treatment groups; no kidney infections were reported. Serious AEs occurred in 10%, 11% and 9% of dapagliflozin 2.5, 5 and 10 mg/day recipients, respectively, compared with 9% of placebo recipients. Discontinations due to AEs occurred in 3% of patients across all treatment groups. This was a 24-week multicenter, randomised, double-blind placebo-controlled trial with a 24-week extension^[96]^[97]^[98].

In a phase III study, dapagliflozin, as add-on to insulin, was generally well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control with insulin therapy. However, UTIs and genital infections occurred more commonly in patients who received dapagliflozin than placebo (8% vs 4% of patients and 7% vs 2% of patients, respectively)^[210]^[209].

Dapagliflozin, as adjunctive therapy to metformin, was generally well tolerated in a 24-week randomised phase III trial in patients with T2DM who were inadequately controlled with metformin alone. The rates of adverse events overall were 89%, 95% and 98% in patients who received dapagliflozin 2.5mg, 5mg or 10mg, respectively, compared with 88% in those who received placebo. Specifically, the incidence of UTIs was not significantly different between the dapagliflozin 2.5, 5 and 10mg groups and the placebo group (4.4, 7.3% and 8.1% vs 8.0%, respectively). Rates of genital infections were higher in the dapagliflozin 2.5, 5 and 10mg arms than the placebo arm (8.0%, 13.1% and 8.9% vs 5.1%, respectively), but these events were mild or moderate in severity and did not result in treatment discontinuation. Dapagliflozin was not associated with any clinically significant electrolyte level increases, or changes in renal function. Dapagliflozin decreased blood pressure to a greater extent than placebo (systolic BP −3.1 to −5.9 vs −0.3 mmHg and diastolic BP −2.1 to −2.7 vs −0.4 mmHg); although there were no cases of hypotension. Hypoglycaemic events occurred with a similar frequency in the dapagliflozin 2.5, 5 and 10mg and groups (2.2%, 3.6% and 3.7% vs 2.9% of patients, respectively), but did not lead to study withdrawal^[87]. Following the original 24-week protocol, patients were eligible to enter a 78-week extension resulting in a total of 102 weeks of dapagliflozin treatment. A total of 81-82% of all patients experienced at least one adverse event over the full 102 week period. Compared with placebo, dapagliflozin 2.5, 5, and 10 mg/day were all associated with a greater rate of events suggestive of genital infections (11.7%, 14.6%, and 12.6% vs 5.1% of patients, respectively). Rates of events suggestive of UTIs higher with dapagliflozin 10 mg/day relative to all other treatment groups (13.3% vs 8.0-8.8% of patients). Other adverse events, including hypoglycaemia, renal impairment/failure, were balanced across all treatment groups. One case of transitional cell bladder cancer was reported in the dapagliflozin 5 mg treatment group; none were reported in the placebo, dapagliflozin 2.5 mg or dapagliflozin 10 mg treatment groups. One case of breast cancer was reported in dapagliflozin 10 mg treatment group; none were reported in the placebo, dapagliflozin 2.5 mg or 5 mg groups^[207]^[208].

Oral once-daily dapagliflozin 5mg + metformin was generally well tolerated in previously untreated type 2 diabetic patients with inadequate glycaemic control. A total of 598 received 24-weeks of either dapagliflozin 5mg + metformin, dapagliflozin 5mg alone, or metformin alone in this randomised, double-blind, phase III, multinational trial. Overall rates of discontinuation due to adverse events were lower with the combination than with dapagliflozin or metformin alone (1.0% vs 2.5% and 3.0%, respectively). Diarrhoea and nausea were the most commonly observed adverse events across all treatment groups. Events suggestive of genital infection were higher with dapagliflozin-containing treatments than with metformin alone (6.7% and 6.9% vs 2.0%) but not UTIs which were observed at similar frequencies across all treatments (7.7% and 7.9% vs 7.5%). No major events of hypoglycaemia were observed; however, minor hypoglycaemia was observed more frequently in the combination arm than for dapagliflozin 5mg alone, or metformin alone (2.6% vs 0% and 0%). These findings were also observed with dapagliflozin 10mg in another identically designed 24-week, phase III, randomised, double-blind, multinational trial conducted in 638 patients. Discontinuation rates due adverse events were 1.9% for dapagliflozin + metformin, 4.1% for dapagliflozin alone, and 3.8% metformin alone. Events suggestive of genital infections and UTIs were higher with dapagliflozin + metformin (8.5% and 7.6%, respectively) and dapagliflozin alone (12.8% and 11.0%) compared with metformin alone (2.4% and 4.3%). Minor hypoglycaemia was observed in 3.3%, 0.9%, and 2.9% of patients in the dapagliflozin + metformin, dapagliflozin alone, and metformin alone treatment groups, respectively^[85].

Dapagliflozin (5 and 10 mg/day) + pioglitazone was as well tolerated as pioglitazone alone in patients with type 2 diabetes mellitus inadequately controlled on pioglitazone alone. Treatment discontinuation was low and the incidence was similar between dapagliflozin and placebo recipients. The proportion of patients reporting at least one adverse was similar between treatment groups. No episodes of major hypoglycaemia were reported. Over 48 weeks, one patient on placebo, and three patients receiving dapagliflozin 5 mg/day experienced hypoglycaemia; no hypoglycaemia was reported in dapagliflozin 10 mg/day recipients. This randomized, double-blind, placbo-controlled phase III trial enrolled 420 patients with type 2 diabetes mellitus inadequately controlled with thiazolidinedione (pioglitazone) therapy^[206].

In a phase III trial, once-weekly exenatide in combination with once-daily dapagliflozin was well tolerated with no unexpected adverse events (AEs). AEs occurring in ≥ 5% of patients were diarrhoea, headache, injection site nodule, nausea, upper respiratory tract in- fection, and urinary tract infection. Serious AEs occurred in 4.8%, 5.2%, and 5.2%, respectively. Minor hypoglycaemia occurred in 1.3%, 0%, and 0.4% patients^[51]^[52].

Results of the randomised, double-blind, placebo-controlled, phase III DERIVE trial in 321 patients with type 2 diabetes and stage 3A chronic kidney disease demonstrated that the adverse events (AEs) occurred in 41.9% of patients with dapagliflozin (DAPA) and 47.8% with placebo (PBO), overall. AEs related to study treatment by the investigators were reported in 10.6% of patients with dapagliflozin and 6.2% with placebo, and included urinary tract infection and pollakiuria. No AEs of bone fracture or amputation were reported. Patients in the DAPA and PBO arms had similar frequencies of urinary tract infection (2.5 vs 3.7%), genital infection (1.9 vs 1.2%), and hypoglycaemia (12.5 vs 13.7%)^[56]^[53]. Interim results showed that dapagliflozin was well tolerated without any adverse events or safety issues. Hypoglycaemia, diabetic ketoacidosis, and fractures were not experienced by any patient in the trial^[55]^[54].

Phase II/III

Adverse events were reported at similar rates across the dapagliflozin treatment arms and the placebo group, in a 12-week trial in 71 patients with type 2 diabetes. Patients were randomised to dapagliflozin 10mg, dapagliflozin 20mg or placebo, in addition to insulin and one or two anti-diabetes medications (metformin and/or pioglitazone or rosiglitazone). The numbers of patients experiencing ≥1 adverse event for dapagliflozin 10mg, dapagliflozin 20mg and placebo, were 18/24, 16/24 and 15/23, respectively. The most commonly reported (≥5% overall) adverse events for dapagliflozin 10mg, 20mg and placebo were: urinary frequency, back pain, nasopharyngitis, nausea, headache, and upper respiratory tract infection. One UTI and 5 genital tract infections occurred in the dapagliflozin 20mg group, and one genital tract infection occurred in the placebo group. The number of reported hypoglycaemic events was 7 for dapagliflozin 10mg, 6 for dapagliflozin 20mg, and 3 for placebo. There was no occurrence of major hypoglycaemia^[68]^[214].

Phase II

The tolerability of dapagliflozin was examined in a 12-week, phase IIb trial in 389 treatment-naive patients with T2DM. Patients were randomised to receive either 2.5, 5, 10, 20 or 50mg of dapagliflozin, metformin 750mg (titrated up to 1 500mg) or placebo, once-daily. The most common adverse events in dapagliflozin recipients were UTI, nausea, dizziness, headache, fatigue, back pain and nasopharyngitis. Hypoglycaemia was reported at a frequency similar to that for metformin, but there were no documented glucose levels of ≤ 50 mg/dL. There were no clinically meaningful changes in serum sodium, potassium, calcium or creatine, or urinary calcium noted. Serum uric acid declined by 1.0 mg/dL with all dapagliflozin doses tested^[221].

In the phase II EFFECT II trial, the safety profile of dapagliflozin was comparable to that observed in previous studies. All adverse events were mild or moderate in intensity. Two patients experienced a severe adverse event, which were assessed as unlikely to be caused by dapagliflozin. The trial enrolled 223 patients with type 2 diabetes mellitus^[133]^[134].

A phase IIa study showed no serious adverse events or treatment discontinuations due to adverse events following treatment with dapagliflozin and metformin in patients with T2DM. This 14-day, randomised study involved 47 patients who received dapagliflozin 5, 25, 100mg or placebo, once-daily. Metformin therapy was continued in patients who were receiving already receiving treatment upon entry into the study. Adverse events occurred with similar frequency in subjects receiving dapagliflozin or placebo. The most frequently reported adverse events were constipation, nausea and diarrhoea^[225].

Polyuria and pollakiuria were reported by 1.4% of subjects in the dapagliflozin groups (2.5, 5, 10, 20 and 50mg), in a phase II study including 389 treatment-naive patients with type 2 diabetes. There were no reports of nocturia^[220].

Phase I

Dapagliflozin up to 150mg did not prolong the QTc in 50 healthy male volunteers^[217].

In a multiple dose escalation (2.5-100 mg) trial in 40 healthy volunteers, 24 adverse events occurred in 16 subjects, 36.7% in the dapagliflozin group and 50% in the placebo group. All events were mild-to-moderate in intensity and the most common was rash, which occurred in five subjects. Dapagliflozin had no apparent effect on renal safety markers or the QTc interval^[224].

In a single dose escalation trial (2.5-500 mg) in 64 healthy volunteers, 22 adverse events occurred in 14 subjects, 21% in the dapagliflozin group and 25% in the placebo group. These were mild-to-moderate in intensity. A total of 38 subjects experienced 49 laboratory abnormalities, including 11 haematologic, seven blood chemistry variations, and 31 cases of elevated urinary glucose^[223].

Type 1 diabetes mellitus

Phase III

In the phase III DEPICT 1 and DEPICT 2 trials in patients with type 1 diabetes, dapagliflozin showed the safety profile, which was similar to the known safety profile in patients with type 2 diabetes. Adverse events that leads to treatment discontinuation, at week 24, with 5mg cohort, 10mg cohort and placebo cohort was observed in 23 (4.2), 20 (3.5) and 20 (3.8) patients, respectively. Whereas adverse events that leads to treatment discontinuation, at week 52, with 5mg cohort, 10mg cohort and placebo cohort was observed in 35 (6.4), 30 (5.3), and 27 (5.1) patients, respectively. Serious adverse events that leads to treatment discontinuation, at week 24, with 5mg cohort, 10mg cohort and placebo cohort was observed in 15 (2.7), 7 (1.2) and 6 (1.1) patients, respectively. Whereas serious adverse events that leads to treatment discontinuation, at week 52 was observed in 22 (4.0), 13 (2.3) and 9 (1.7) patients, after treatment with 5 mg DAPA, 10 mg DAPA and placebo, respectively. SAE of hypoglycemia was observed in 6 (1.1), 2 (0.4) and 2 (0.4) patients in 5 mg DAPA cohort, 10 mg DAPA cohort and placebo cohort, respectively, at week 24. SAE of hypoglycemia was observed in 8 (1.5), 5 (0.9) and 5 (0.9) patients in 5 mg DAPA cohort, 10 mg DAPA cohort and placebo cohort, respectively, at week 52. Three patients from 5 mg DAPA cohort and one patient from placebo cohort discontinued the treatment because of hypoglycemia, at week 24. Whereas three patients from 5mg DAPA cohort and one patient from 10 mg DAPA cohort and two patients from placebo cohort discontinued the treatment because of hypoglycemia. Higher incidences of diabetic ketoacidosis were seen in patients with type 1 diabetes, compared with type 2 diabetic patients. Diabetic ketoacidosis incidences in dapagliflozin group versus, placebo across the studies were 4.0% and 3.4% versus, 1.9% for 52 weeks in DEPICT-1, and 2.6% and 2.2% versus, 0% for 24 weeks in DEPICT-2^[146]^[59]^[55]^[149]^[148].

Phase II:

Treatment with dapagliflozin was generally well tolerated in 70 adult patients with type 1 diabetes mellitus who were on stable insulin in a phase IIa trial. In this double-blind trial, patients were randomised to receive dapagliflozin (1-10mg), or placebo once daily for 14 days. Adverse events included urinary tract infections, genital infections and hypoglycemia, and were unrelated to treatment. There was one major case of hypoglycaemia in the dapagliflozin 10mg group, and one serious adverse event of gastroparesis in the dapagliflozin 5mg group. Both adverse events resulted in treatment discontinuation^[150].

Phase I

In a phase I trial, adverse events and other laboratory findings were in line with the known dapagliflozin safety profile. No increase in hypoglycaemia or diabetic ketoacidosis were reported. The randomised 1:1:1, single-blind, 3-arm, parallel trial 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^[153]^[154].

Chronic heart failure:

Phase III:

Data from the phase III DAPA-HF trial indicated that the safety profile of dapagliflozin was consistent with the established safety profile of the drug. Data demonstrated that proportion of patients with volume depletion (7.5% vs 6.8%) and renal adverse events (6.5% vs 7.2%) in the treatment group were comparable with the placebo group. Major hypoglycemic events (0.2% vs 0.2%) were rare in both treatment groups. No apparent effect of age on the occurrence of adverse events or treatment discontinuation of dapagliflozin versus placebo was observed. Patients with HFrEF and taking a mineralocorticoid receptor antagonists (MRA) who were randomized to dapagliflozin had half the incidence of moderate/severe hyperkalaemia, compared with those randomized to placebo. Mild hyperkalaemia and moderate/severe hyperkalaemia occurred in 182 (11.1%) and 23 (1.4%) patients treated with dapagliflozin as compared to 204 (12.6%) and 40 (2.4%) of patients given placebo. A hazard ratio (HR) of 0.86 (0.70-1.05) for mild hyperkalaemia and 0.50 (0.29, 0.85) for moderate/severe hyperkalaemia, comparing dapagliflozin to placebo was observed^[177]^[172]^[174]^[171].

Results from phase III DAPA-CKD trial demonstrated fewer serious adverse events compared to placebo (29.5% versus 33.9%, respectively). None of the patients receiving dapagliflozin reported diabetic ketoacidosis compared to two patients receiving placebo^[183]^[181].

Pharmacodynamics

Summary

Phase I

In a multiple dose escalation (2.5-100mg) trial in 40 healthy volunteers, there were no apparent differences between dapagliflozin and placebo in urinary excretion of magnesium, amino acids, calcium, chloride, oxalate, potassium, phosphate, sodium, uric acid, NAG, and β2-MG^[224].

In a phase I trial, mean (SD) changes in 24h urinary glucose excretion (UGE) from baseline (BL) to Day 7 were 96.55 (30.08), 101.28 (20.13) and -6.16 (30.34) g/24h for dapagliflozin 5mg, 10mg, and placebo, respectively, consistent with previous dapagliflozin experience but with attenuated dose-response. From BL to Day 7, mean (SE) changes in total daily insulin dose were larger than expected; -36.86 (3.32), -39.13 (2.68) and -4.97 (5.28)% for dapagliflozin 5mg, 10mg and placebo, respectively. This reduction may be the cause for the attenuated glycaemic response affecting UGE (explored in a separate abstract). From BL to Day 7, mean (SD) changes in 7-point SMBG values were -1.99 (23.58), -5.68 (40.36) and 6.54 (52.69) mg/dL for dapagliflozin 5mg, 10mg and placebo, respectively. The randomised 1:1:1, single-blind, 3-arm, parallel trial 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^[153]^[154].

Pre-diabetic state:

In a phase II PRE-ED trial, after 13 weeks of treatment and 26 weeks of follow-up, analysis for secondary endpoint of changes in plasma levels showed 17% had elevated ALT levels, 3% elevated AST levels, and 6% elevated GGT levels. There were small within-group changes in GGT in the active groups after 6, 13 or 26 weeks, but it did not differ from the control group (P≥0.09 for all comparisons)^[195]^[193].

Preclinical

Dapagliflozin reduced the loss of pancreatic function in the high fat fed female ZDF rats with established hyperglycemia. The compound reduced further progression of hyperglycaemia and reduced the requirement for insulin to control blood glucose thus preserving beta cell function^[229].

Similarly in a model of rapid beta cell loss in male ZDF rats, dapagliflozin 1 mg/kg once daily for 5 weeks prevented the development of diabetes, did not increase body weigh and preserved beta cell function in a rodent model of type 2 diabetes^[212].

Data from the study evaluating the effect of dapagliflozin on pancreatic islet morphology in obese female ZDF rats showed that after once daily dose of 1 mg/kg for up to 34 days, the beta cell mass in the lean, obese vehicle and dapagliflozin obese groups were 0.68%, 1.15% and 1.49 of total cell count, respectively. Dapagliflozin also markedly improved islet morphology assessment by 2.3-fold (p < 0.05) compared with obese vehicle control group. The insulin staining intensity of islets after dapagliflozin was elevated 2.2-fold (p < 0.05) compared with obese vehicle-treated animals to the extent that there were no detectable differences between dapagliflozin and lean animal control groups^[213].

In diabetic rats, dapagliflozin acutely induced renal glucose excretion at doses ranging from 0.01-1.0 mg/kg of body weight without inducing hypoglycaemia. Additionally, as early as two hours after a single oral dose, there was a significant reduction in plasma glucose levels in diabetic rats treated with dapagliflozin, at doses of 0.1 and 1.0 mg/kg, compared with untreated diabetic rats^[225].

Treatment with dapagliflozin for 25 days reduced body weight in non-diabetic, diet induced obese rats. Significant weight loss was observed with all doses (0.5–5 mg/kg) which was a function of reduced adiposity. Dapagliflozin increased urine glucose concentration, total urine glucose and urine volume. There was also an observed increase in water and food consumption^[222].

In db/db mice and high fat diet-induced obese (DIO) mice, acute and chronic treatment with dapagliflozin resulted in complete normalisation of ambient and fasted glucose levels, without causing hypoglycemia. Chronic treatment with dapagliflozin increased insulin content in islets. Acute and chronic treatment of normoglycemic DIO mice did not significantly affect glucose levels, in contrast to db/db mice. Furthermore, the total body weight did not change in dapagliflozin-treated DIO mice despite a significant increase in food and water intake^[216].

In preclinical studies of dapaglifozin with ob/ob^-/- mice, there was a trend for reduced fractional area change (FAC) with time in the untreated group (mean±SD 52.9±4.0, 49.9±5.2, 49.9±6.2, p=0.0651), an increased FAC in 1.5mg/kg group (51.0±5.5, 52.3±5.1, 61.2±7.3, p<0.0001), and in 4mg/kg group (52.0±7.2, 56.9±8.0, 57.4±5.0, p=0.0173). Coronary flow velocity reserve (CFVR) was unchanged in the untreated group over time (mean±SD 3.05±1.37, 3.08±1.16, 3.22±1.35, p=ns), improved in 1.5mg/kg (2.45±0.58, 3.31±0.98, 3.88±1.44, p=0.0006) and in 4mg/kg (3.09±1.03, 4.06±1.25, 4.24±1.06, p=0.035). HbA1c was significantly reduced in treatment groups over time (mean±SEM 1.5mg/kg, 53.0±2.7, 43.0±1.6, 41.2±1.5, p<0.0001, and 4mg/kg, 51.4±3.0, 41.1±1.4, 39.7±1.9, p<0.0001). No detectable difference was observed, in the untreated group for HbA1c (51.3±1.9, 60.2±3.6, 54.1±5.1). Urine glucose/creatinine ratio was significantly increased in the treated groups, and there was no significant change in the untreated group^[155].

Therapeutic Trials

Pooled analysis:

Data from a phase III pooled analysis showed that dapagliflozin reduced body weight and systolic blood pressure regardless of baseline estimated glomerular filtration rate (eGFR), when compared to placebo. Additionally, dapagliflozin reduced urine albumin to creatinine ratio (UACR) in patients with a baseline UACR =30 mg/g when compared to placebo, including in patients with mild renal impairment (eGFR =60 to <90 mL/min/1.73m²). Further, the results showed a difference of -0.27%, -0.47% and -0.57% in A1C, -2.1, -1.8 and -2.3 kilograms in body weight, -4.3, -2.6 and -3.4 mmHg in systolic blood pressure and -38.3%, -23.3% and -16.1% in UACR with dapagliflozin compared to placebo for patients with the lowest to highest eGFR, respectively.The pooled data is from 11 phase III trial in more than 4,400 patients (n=2,226 and 2,178 for dapagliflozin and placebo groups, respectively)with type 2 diabetes with varying degrees of renal function as measured by eGFR (eGFR =45 to <60; eGFR =60 to <90; eGFR =90 mL/min/1.73m²) over 24 weeks^[201].

Data from a IIb/III pooled analysis demonstrated that, dapagliflozin, when co-administered with potassium-sparing agents, resulted in lower A1C, body weight and systolic blood pressure, with no evidence of increase in serum potassium. Further, the results showed a difference of -0.39% in A1C, -2.2 kg in body weight, -5.2 mmHg in systolic blood pressure, -3.2 mL/min/1.73m² in eGFR, and -0.12 mEq/L in serum potassium with dapagliflozin compared to placebo. Potassium levels =6 mEq/L during follow up were observed in two patients versus nine patients for the dapagliflozin and placebo groups, respectively. The pooled analysis was in 14 phase IIb/III clinical trials in more than 200 patients with type 2 diabetes treated with potassium-sparing agents (n=108 and 119 for dapagliflozin and placebo groups, respectively) of up to 24 weeks^[201].

Type

2 diabetes mellitus
Phase III
Updated results from the phase III DECLARE-TIMI 58 trial, demonstrated that higher risk of cardiovascular death (CVD) or hospitalization for heart failure in placebo arm was associated with increase in BMI. Dapagliflozin reduced the composite of CVD and hospitalization for heart failure (CVD/HHF) versus placebo, regardless of baseline glucose lowering agents (GLA), though the effect appeared to be particularly large in the small group of patients with baseline use of GLP-1 receptor agonist (GLP-1 RA). The overall HR for major adverse cardiovascular events (MACE; CVD, myocardial infarction, ischemic stroke) was 0.93 (95% CI 0.84-1.03) with dapagliflozin versus placebo, with no interaction by non-insulin GLA, yet a tendency toward greater benefit with dapagliflozin versus placebo was observed in baseline insulin users. The renal specific outcome (sustained decrease of ≥40% in eGFR to <60 ml/min/1.73m², new end stage renal disease, or renal death) was overall reduced with DAPA vs. PBO (HR 0.53, 95% CI 0.43-0.66) with no interaction by baseline GLA (p interaction >0.05). The mean change in body weight and HbA1c between treatment groups did not differ across the BMI categories. Relative risk of reduction in outcome of interest in patients treated with dapagliflozin were similar across the BMI categories. The absolute risk of reduction in HHF were reported tobe greater in patients with higher BMI (p=0.01). Reduction of intracellular Ca²⁺ overload of -47,6% was reported with dapagliflozin versus treatment with anticancer drugs (p<0,001). The lipid peroxidation phenomena reported mean reduction of 35-43 % compared to anticancer drugs (p<0,001). Cardiomyocytes exposed to dapagliflozin during anticancer drugs reported a reduced expression of pro-inflammatory cytokines involved in cardiotoxicity (- 37,3 % for Interleukin-1β; -39,5 for Interleukin 8; -41,3 % for Interleukin 6; p<0,001 for all). Also reduction in p65-NF-κB activation (- 36,5% vs cells treated only to anticancer drugs) and inhibition of 27,8 % the expression of NLRP3 inflammasome was reported. Earlier results from 17 160 showed that, 30.3% patients had albuminuria (UACR 30-300: n=4029; UACR >300: n=1169) and 7.4% had an eGFR <60 ml/min/1.73m². Accordingly, 10958 (63.9%) patients had no manifestation of CKD, 31.3% had either an eGFR <60 ml/min/1.73m² or albuminuria, and 3.2% patients had both manifestations. Patients with more abnormal markers had higher event rates for CV death/HHF (KM event rates at 4 years of 3.9%, 8.3%, 17.4%) and MACE (7.5%, 11.7%, and 18.9%) for no, 1, or 2 markers of CKD, respectively. The relative risk reductions for CV death/HHF and MACE were consistent across the subgroups (both P-interaction >0.29), and numerically greatest (42%) in patients with reduced eGFR and albuminuria. Absolute risk difference increased substantially in patients with greater kidney damage (absolute risk difference of CV death/HHF: -0.5%, -1.0%, and -8.3%, respectively; P-INT for ARD 0.002). Dapagliflozin reported reduction in sustained decrease of 40% or more in estimated GFR to less than 60 ml/min/1.73m ²2 , new end-stage renal disease, or death from renal or cardiovascular causes. Incidence rates of all outcomes were reported to be higher in the older versus younger patients. Earlier, sub-analysis demonstrated a 47% reduction of composite kidney function decline, end-stage renal disease or death compared to placebo (1.5% vs. 2.6%; HR 0.53 [95% CI 0.43-0.66], p<0.0001). Dapagliflozin reduced the progression of kidney disease or renal death in patients with type 2 diabetes. The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (11[0.1%] vs. 27 [0.3%]; HR 0.41 [95% CI 0.20-0.82]; p=0.012). Dapagliflozin significantly reduced the incidence of end-stage renal stage compared to the placebo (0.1% vs 0.3%, respectively). Acute kidney injury occurred in 1.5% and 2.0% in the dapagliflozin and placebo arms, respectively. Patients treated with the dapagliflozin experienced fewer clinically important renal outcomes. Dapagliflozin reduced the relative risk of a cardio-renal composite of kidney function decline, ESRD, or renal or cardiovascular (CV) death by 24% compared to placebo (4.3% vs. 5.6%; HR 0.76 [95% CI 0.67-0.87]) and improved renal function as measured by changes in UACR (improved from micro- to normo-albuminuria [HR 1.35, 95% CI {1.24, 1.47}], improved from macro- to micro- or normo-albuminuria [HR 1.55, 95% CI {1.34, 1.8}], and decreased deterioration from normo- to micro- or macro-albuminuria [HR 0.84, 95% CI {0.79, 0.89}]). Dapagliflozin attenuated the eGFR decline in patients with type II diabetes and in subgroups based on baseline eGFR, urine albumin-to-creatinine ratio (UACR), use of ACEi/ARB and diuretics. Fewer patients experienced an eGFR decline of 30% (HR 0.68 [95% CI 0.58, 0.79], p < 0.002), 40% (HR 0.54 [95% CI 0.43, 0.67], p < 0.002), or 50% (HR 0.57 [95% CI 0.40, 0.81], p < 0.002) to eGFR <60 ml/min/1.73m² with FARXIGA versus placebo. In cox and negative binomial regression models analysis, the risk of incident atrial fibrillation (AF) and atrial flutter (AFL) was reduced by 19% (264 versus 325 events; hazard ratio 0.81, 95% CI 0.68 to 0.95, P = 0.009) in dapagliflozin treated patients. Also, presence of known atherosclerotic cardiovascular disease (ASCVD), multiple risk factors (MRF) or history of heart failure did not affect effect of dapagliflozin on AF/AFL reduction. Reduced the total number of AF/AFL events were also reduced post treatment with dapagliflozin (337 versus 432; rate ratio 0.77, 95% CI 0.64 to 0.92, P=0.005). Dapagliflozin significantly reduced the risk of hospitalisation for heart failure (hHF) or CV death composite against placebo by 17% (4.9% versus 5.8%; HR = 0.83, 95% CI: 0.73, 0.95, p = 0.005). The reduction in hHF or CV death was consistent. Fewer major adverse cardiovascular events (MACE) were observed with dapagliflozin for the other primary efficacy endpoint, however this did not reach statistical significance (8.8% for dapagliflozin versus 9.4% for placebo; HR = 0.93, 95% CI 0.84, 1.03, p = 0.17). Dapagliflozin and placebo arm shows primary composite renal outcome (PCRO) in 370 (4.3%) versus 480 (5.6%) patients corresponding to event rates per 1 000 patient-years (ER) of 10.8 and 14.1 [HR 0.76 (0.67, 0.87) p<0.001]. ]. The ER of the secondary composite renal outcome was 3.7 and 7.0 in the dapagliflozin and placebo arms [HR 0.53 (0.43 to 0.66)], respectively. These differences were due to decrease in the sustained 40% eGFR decline to < 60 ml/min/1.73m²: 120 (1.4%) vs. 221 (2.6%) in the dapagliflozin and placebo arms [HR 0.54 (0.43, 0.67) p<0.001]. Directional uniformity for a lower rate of ESRD in the dapagliflozin 6 (<0.1%) and placebo arms 19 (0.2%) [HR 0.31 (0.13, 0.79) p=0.013] were observed. Acute kidney injury was less common in the dapagliflozin arm (1.5%) in comparison with placebo arm (2.0%) (p=0.002). The HR (95% CI) for HHF was 0.64 (0.46-0.88) and for the renal specific outcome was 0.51 (0.37-0.69) with dapagliflozin versus placebo in the overall MRF group and was consistent across subgroups. At 48 months, patients, randomised to dapagliflozin versus placebo, had lower HbA1c (7.8 ±1.2 vs. 8.0±1.4%), weight (86.8±19.7 versus 88.4±20.4 kg), systolic blood pressure (132.8±14.6 versus 135.1±15.0 mmHg), and urinary albumin creati- nine ratio (92.9±437.5 versus 130.0±483.8 mg/gr), and had higher eGFR (77.7 ±16.8 vs. 76.8±17.3 mL/min/1.73m 2) p<0.05 for difference in change from baseline for dapagliflozin versus placebo for all parameters. The MRF population in the study experienced significant reduction with dapagliflozin versus placebo in HHF and in the renal specific outcome regardless of age, BMI, diabetes duration, HbA1c, eGFR, history of HF or number of additional risk factors. Metabolic outcomes improved as well^[116]^[126]^[228]^[173]^[120]^[121]^[124]^[125]^[117]^[118]^[119]^[115]^[123].

In a clinical study assessing changes in HbA1c, weight and insulin dose after discontinuation of dapagliflozin in the phase III DEPICT-1 and DEPICT-2 trials, in 91 evaluable patients, annualised changes in HbA1c and weight were +0.99% (95% CI: 0.39, 1.59) and +3.75Kg (1.65, 5.86), respectively. Mean insulin dose two weeks post-discontinuation exceeded that observed two weeks before discontinuation (5mg: +4.0 IU, 10mg: +4.4 IU). These values were in stark contrast to those observed with HbA1c, weight and insulin dose reductions associated with dapagliflozin treatment. Treatment discontinuation significantly augmented HbA1c and weight, and insulin doses also saw an upswing post-discontinuation^[145]^[149]^[148].

The primary endpoint, change in HbA1c levels from baseline at week 24, was met in a phase III trial of dapagliflozin in 320 adult patients with type 2 diabetes who were uncontrolled on saxagliptin plus metformin. The 24-week study included an open-label lead-in period in which patients on metformin were given open-label saxagliptin 5mg and metformin for 16 weeks, while patients on metformin and any DPP-4 inhibitor were given open-label saxagliptin 5mg and metformin for 8 weeks. After the open-label period, patients with inadequate glycaemic control were randomised to placebo or dapagliflozin 10mg in addition to open-label saxagliptin and metformin. Significantly greater mean reductions in HbA1c levels at week 24 were achieved in patients who received the dapagliflozin combination versus those who received placebo + saxagliptin + metformin (–0.82% vs -0.10%, respectively; p<0.0001). In secondary endpoints, the dapagliflozin arm showed a significantly greater adjusted mean reduction from baseline in 2-hour postprandial glucose (-74 mg/dL vs -38 mg/dL, respectively; p<0.0001)¹ and fasting plasma glucose versus the placebo arm (-33 mg/dL vs -5 mg/dL, respectively; p<0.0001).In addition, more patients in the dapagliflozin arm achieved a HbA1c level of <7% compared with patients in the placebo arm at week 24 (38% vs 12%, respectively, p<0.0001). A greater reduction in weight (mean -1.9 kg vs -0.4 kg, respectively; p<0.0001) were seen in the dapagliflozin arm than those in the placebo arm^[103].

Patients with type-2 diabetes mellitus (T2DM) who were treated with dapagliflozin/saxagliptin plus metformin during a phase III trial achieved statistically significant greater reductions in HbA1c at 24 weeks compared with patients who were treated with either of the individual drugs plus metformin alone. At 24 weeks, an adjusted mean change from baseline HbA1c of -1.47% was observed in the dapagliflozin/saxagliptin group compared with -0.88% in the saxagliptin group and 1.20% in the dapagliflozin group. Additionally, a larger proportion patients in the dapagliflozin/saxagliptin group (41%) achieved HbA1c levels of less than 7% compared with patients in the saxagliptin (18%) and dapagliflozin (22%) groups. Glycaemic control was associated with reductions in body weight. The dapagliflozin/saxagliptin combination group achieved a significantly greater adjusted mean reduction from baseline in two hour postprandial glucose levels versus the saxagliptin group, but not the dapagliflozin group. The adjusted mean reduction in fasting plasma glucose was greater in the dapagliflozin/saxagliptin combination group (-38 mg/dL) than the saxagliptin group (-14 mg/dL), but similar to the dapagliflozin grou (-32 mg/dL). The trial included 534 patients (aged ≥ 18 years) with T2DM who experienced inadequate glycaemic control on metformin extended release (≥1500mg per day). Patients were randomised at a 1 : 1 : 1 ratio to receive the combination of saxagliptin 5mg and dapagliflozin 10mg plus metformin, saxagliptin and metformin plus placebo, or dapagliflozin and metformin plus placebo, for 24 weeks^[202].

In a phase III trial, treatment with dapagliflozin 10mg significantly reduced glycosylated haemoglobin (HbA1c) levels from baseline to week 24, compared with placebo, in patients with type 2 diabetes mellitus (-0.86% and -0.17%, respectively; p < 0.0001). Significant reductions in secondary end-point measures, including HbA1c < 7.0%, fasting plasma glucose, total body weight and systolic blood pressure, were also observed in the dapagliflozin group, compared with the placebo group. This randomised, double-blind trial enrolled 216 patients with type 2 diabetes mellitus whose disease was inadequately controlled on background therapy with metformin and sulfonylurea^[46].

Dapagliflozin 10mg significantly reduced glycosylated haemoglobin levels (HbA1c) levels from baseline compared with placebo at 24 weeks when added to sitagliptin therapy (with or without metformin) in a phase III trial in 477 patients with type 2 diabetes. These results were maintained during the 24-week extension period. Similar trend was observed for dapagliflozin on reductions in total body weight and fasting blood glucose levels at 24 weeks and over 48 weeks. Dapagliflozin therapy added to sitagliptin with or without metformin reduced HbA1c by 0.48% from baseline compared with placebo (p < 0.0001, Last Observation Carried Forward [LOCF]) at week 24. Dapagliflozin added to sitagliptin 100mg alone reduced HbA1c by 0.56% compared with placebo (p < 0.0001, LOCF) and by 0.40% when added to sitagliptin plus metformin (p < 0.0001, LOCF)^[203].

At 52 weeks, dapagliflozin added to metformin therapy was non-inferior to an active comparator (glipizide plus metformin therapy) at reducing HbA1c levels (HbA1c), in a phase III trial of 814 patients with poorly-controlled type 2 diabetes mellitus. An identical reduction in HbA1c of -0.52% from baseline was detected in both dapagliflozin and glipizide groups. Additionally, significant reductions of total body weight and hypoglycaemic events resulted from the dapagliflozin plus metformin combination, compared with the glipizide plus metformin combination. The proportion of patients who achieved a reduction in body weight of ≥ 5% from baseline was 33.3% in the dapagliflozin and 2.5% in the glipizide groups. The number of patients who experienced hypoglycaemic events was 3.5% for dapagliflozin plus metformin, compared with 40.8% for glipizide plus metformin. The 52-week study randomised patients with inadequately-controlled diabetes (on metformin therapy alone) to receive either dapagliflozin (n = 406, starting at 2.5 mg/day) or glipizide (n = 408, starting at 5 mg/day) on a baseline of metformin (≥ 1500 mg/day). Up-titration of dapagliflozin and glipizide (≤ 10 and ≤ 20 mg/day, respectively) occurred as needed for the first 18 weeks. The respective doses of dapagliflozin and glipizide after 52 weeks were 10 and 20 mg/day^[83]. Patients completing this 52-week protocol were entered into a 156-week extension. Results from weeks 52-104 indicated that dapagliflozin + metformin was associated with long-term antihyperglycaemic benefits. Change from baseline to 104 weeks in HbA1c was -0.32% for dapagliflozin + metformin and -0.14% for glipizide + metformin. The weight reduction with dapagliflozin + metformin at 52 weeks and the weight gain with glipizide + metformin at 52 weeks were both sustained at 104 weeks (-3.70kg vs. +1.36kg, respectively)^[82].

The addition of dapagliflozin (2.5, 5 and 10 mg/day) to glimepiride maintained HbA1c reductions over 48 weeks in patients with type 2 diabetes mellitus in a phase III study. These three dapagliflozin dosage groups were compared with placebo (-0.37%; 95% CI 0.60, 0.14; -0.53%; 95% CI 0.75, 0.30; and -0.70%; 95% CI 0.92, 0.47, respectively; primary endpoint). Reductions in fasting plasma glucose levels (-1.07 mmol/L; 95% CI 1.59, 0.55; -1.06 mmol/L; 95% CI 1.57, 0.54; and -1.74 mmol/L; 95% CI 2.24, 1.24, respectively), 2h post-prandial glucose (-0.88 mmol/L; 95% CI 2.00, 0.24; -1.38 mmol/L; 95% CI 2.49, 0.27; and -1.20 mmol/L; 95% CI 2.26, 0.14, respectively) and total body weight (-0.59kg; 95% CI 1.46, 0.28; -0.76kg; 95% CI -1.63, 0.11; and -1.64kg; 95% CI 2.48, -0.79, respectively) were also maintained over 48 weeks. At 24 weeks, significantly more 5 and 10 mg/day dapagliflozin recipients achieved an HbA1c level < 7% compared with placebo (30% and 32% vs 13%, respectively). Dapagliflozin also reduced seated systolic (-4.7, -4.0, -5.0 vs -1.2 mmHg) and diastolic (-1.1, -1.7, -2.8 vs -1.4 mmHg) BP. This was a 24-week multicenter, randomised, double-blind, placebo-controlled trial with a 24-week extension^[96]^[97]^[98].

In a phase III trial, dapagliflozin, as add-on to insulin, significantly reduced HbA1c, compared with placebo, in patients who have inadequate glycaemic control with insulin with or without oral anti-diabetic agents [primary endpoint]. Dapagliflozin also reduced bodyweight, insulin dose and fasting plasma glucose^[210]^[209].

A phase III randomised trial met its primary endpoint of significant reductions in HbA1c levels with 24 weeks of treatment with dapagliflozin in addition to metformin, compared with placebo and metformin, in patients with type 2 diabetes mellitus who were inadequately controlled with metformin alone (n = 546). Patients received either dapagliflozin 2.5mg, 5mg, 10mg, or placebo, in addition to metformin at a dosage of at least 1500 mg/day. At 24 weeks, the mean changes from baseline in HbA1c levels were significantly greater in the dapagliflozin 2.5, 5 and 10mg groups (−0.67%, −0.70% and −0.84%, respectively) than in the placebo group (−0.30%). Mean reductions in fasting plasma glucose (FPG) were also significantly greater in the dapagliflozin groups (−17.8, −21.5 and −23.5 mg/dL, respectively) than in the placebo group (−6.0 mg/dL). The proportion of patients who achieved an HbA1c level of <7% at 24 weeks was significantly greater in the dapagliflozin 5 and 10mg arms, compared with the placebo arm (37.5% and 40.6% vs 25.9%), but the difference between dapagliflozin 2.5mg and placebo was not significant for this endpoint. Significantly greater decreases in body weight were observed in all three dapagliflozin groups, compared with the placebo group^[87]^[215]. Following the original 24-week protocol, patients were eligible to enter a 78-week extension resulting in a total of 102 weeks of dapagliflozin treatment. At 102 weeks, dapagliflozin (2.5 mg/day), dapagliflozin (5 mg/day) and dapagliflozin (10 mg/day) were associated with greater reductions from baseline in the proportion of glycosylated haemoglobin, compared with placebo (-0.48%, -0.58% and -0.78%, respectively, vs +0.02%) in type 2 diabetics with inadequate glucaemic control on metformin alone^[207]^[208].

Sustained increases in urinary glucose excretion were observed in dapagliflozin-treated patients with type-2 diabetes enrolled in a phase III trial (n = 389). A higher proportion of patients in each of the dapagliflozin groups experienced a 5% reduction in bodyweight compared with placebo. There were small dose-related increases in 24 hour urine volume observed in the dapagliflozin groups (from 107 to 470mL in the 2.5 and 50 mg/day groups) compared with reduction of 112 and 96mL in the placebo and metformin groups, respectively. Dapagliflozin had no apparent effect on appetite, as assessed using a Visual Analogue Scale^[218].

Dapagliflozin, at doses of 2.5, 5, 10, 20 and 50 mg/day, improved glycaemic control in treatment-naive patients with type 2 diabetes mellitus enrolled in a phase III trial (n = 389). All doses of dapagliflozin were associated with significantly greater reductions in the proportion of glycosylated haemoglobin than placebo at 12 weeks; the four highest doses also resulted in significantly greater reductions than placebo in fasting plasma glucose, and postprandial glucose measures reduced to a greater extent with dapagliflozin than placebo^[219].

Dapagliflozin at 5mg and 10mg doses once daily significantly reduced HbA1c levels, the primary endpoint in a phase III study in 485 treatment-naïve patients with type 2 diabetes who are not well controlled with diet and exercise, or who have been on medication for at least 24 weeks following diagnosis of type 2 diabetes. The relevant reductions in HbA1c level were -0.77% and -0.89% in dapagliflozin cohorts compared with placebo of -0.23%. Patients receiving dapagliflozin had significant reductions in fasting plasma glucose at week 24 compared with baseline (-24.1 mg/dL and -28.8 mg/dL for dapagliflozin doses vs -4.1 mg/dL for placebo). 41%, 44% and 51% of patients with dapagliflozin 2.5mg, 5mg and 10mg achieved target HbA1c levels of < 7% compared with 32% in placebo group. At week 24, the decrease in mean total body weight was greater with all dapagliflozin doses versus placebo. Dapagliflozin is equally efficacious with morning or evening dosing^[227]^[211].

HbA1c was reduced from baseline to a greater extent with oral once-daily dapagliflozin 5mg + metformin than with either dapagliflozin 5mg or metformin alone (primary endpoint; -2.05% vs -1.19% and -1.35%, respectively; both p < 0.001) in previously untreated type 2 diabetic patients with inadequate glycaemic control. Favourable improvements in fasting plasma glucose (FPG), bodyweight reduction, and the proportion of patients achieving a therapeutic glycaemic response of HbA1c < 7% was observed in all groups. Improvement in these parameters was greatest with the combination. A total of 598 patients received treatment in this 24-week, phase III, randomised, double-blind, multinational trial. These findings were also observed with dapagliflozin 10mg in another identically designed 24-week, phase III, randomised, double-blind, multinational trial conducted in 638 patients. HbA1c was reduced from baseline to a greater extent with dapagliflozin 10mg + metformin than either dapagliflozin 10mg or metformin alone (-1.98% vs -1.45% and -1.44%; both p < 0.001). Improvements in FPG, bodyweight reduction, and glycaemic response rates were observed in all groups with the greatest benefits observed in the combination arm. This trial also demonstrated that monotherapy with dapagliflozin 10mg was non-inferior to metformin alone for the reduction in HbA1c (-0.01%; 95% CI -0.22, 0.20) and superiority in reducing FPG (difference in adjusted means -11.6 mg/dL; 95% CI -18.6, -4.6; p = 0.0012) and weight at 24 weeks (difference in adjusted mean -1.37kg; 95% CI -2.03, -0.71; p < 0.002)^[85].

Dapagliflozin was effective in patients with type 2 diabetes mellitus also receiving pioglitazone. Dapagliflozin (5 and 10 mg/day) + pioglitazone, compared with pioglitazone alone, was associated with a significant reduction in the proportion of HbA1c from baseline to week-24 (-0.82% and -0.97% vs -0.42%, respectively; p < 0.001). This randomised, double-blind, placbo-controlled phase III trial enrolled 420 patients with type 2 diabetes mellitus inadequately controlled with thiazolidinedione (pioglitazone) therapy^[206].

In a phase III trial, at week 52, greater reductions in HbA1c, FPG, 2-h PPG, body weight and systolic blood pressure were observed with once-weekly exenatide plus once-daily dapagliflozin versus exenatide plus placebo or dapagliflozin plus placebo. Compared with week 28, reductions in HbA1c in all treatment groups and treatment differences were maintained at week 52^[51]^[52]

Results of the randomised, double-blind, placebo-controlled, phase III DERIVE trial in 321 patients with type 2 diabetes and stage 3A chronic kidney disease met its primary and secondary efficacy endpoints. Dapagliflozin 10 mg significantly decreased mean HbA1C (-0.37%) versus placebo (-0.03%) from baseline to week 24 (difference -0.34%, p < 0.001). Dapagliflozin 10 mg significantly reduced mean body weight (-3.17 kg), when compared with placebo (-1.92 kg) from baseline to week 24 (difference -1.25 kg, p < 0.001). Dapagliflozin 10 mg significantly reduced mean fasting plasma glucose (-21.46 mg/dL) versus placebo (-4.87 mg/dL) from baselines to week 24 (difference -16.6 mg/dL, p = 0.001). Dapagliflozin 10 mg significantly reduced mean systolic blood pressure (-4.8 mm Hg) versus placebo (-1.7 mm Hg) from baseline to week 24 (difference -3.1 mm Hg, p < 0.05). DAPA also significantly reduced BW (difference vs PBO [95% CI]: −1.43% [−2.15, −0.69], p<0.001); FPG (difference vs PBO [95% CI]: −16.59 mg/dL [−26.73, −6.46], p=0.001) and SBP (difference vs PBO [95% CI]: −3.1 mmHg [−6.3, 0.0], p<0.05). DAPA was associated with decreases from BL in eGFR compared with PBO after 4 weeks (difference vs PBO [95% CI]: −4.87 mL/min/1.73m² [−6.69, −3.05]), 12 weeks (−4.71 mL/min/1.73m² [−6.94, −2.49]), and 24 weeks (−2.60 mL/min/1.73m² [−5.03, −0.16]), but returned to baseline at week 27 (difference vs PBO [95% CI]: 0.61 mL/min/1.73m² [−1.59, 2.81]). Mean eGFR was decreased at 24 weeks with dapagliflozin (-3.23 mL/min/1.73m²) when compared with placebo (-0.63 mL/min/1.73m²) (difference [95% CI]: -2.60 mL/min/1.73m² [−5.03 vs −0.16])^[56]^[53]. Treatment with dapagliflozin for 24-weeks resulted into clinically relevant and statistically significant improvements in glycaemic control in patients with type 2 diabetes and stage 3A chronic kidney disease^[55]^[54].

A 24-week non-inferiority phase IIIb study conducted in 643 patients with type 2 diabetes mellitus, dapagliflozin 10 mg and saxagliptin 5mg plus metformin, met primary endpoint. Treatment showed reductions in HbA1c (-1.7% versus, -1.5%, BL~9.0%, P = 0.118), reduction in body weight (-1.5 kg versus, 2.1 kg, BL~89 kg, P < 0.001), reduction in mean 24-hour glucose at week two (-48.5 mg/dL versus, -28.5 mg/dL, P < 0.0001) and lower prevalence of hypoglycaemia (21.3% versus, 38.4%, P < 0.001). At 52 weeks, the adjusted mean (SE) reduction in HbA_1c(%) was greater in patients receiving combination treatment [−1.51 (0.07)] vs insulin [−1.26 (0.07)]. Body weight reduction, expressed as adjusted mean (SE) change from baseline, with the combination was [−1.83 (0.27) kg] vs weight gain with insulin [+2.75 (0.28) kg]. More patients on the combination (17.6%) vs insulin (9.1%) achieved HbA_1c <53 mmol/mol (7.0%) without hypoglycaemia than INS^[60]^[59]^[58].

In a 52-weeks phase III study, which evaluated dapagliflozin 10 mg and saxagliptin 5mg plus metformin in patients with type 2 diabetes mellitus compared to titrated glimepiride plus metformin, showed significant reductions in HbA1c (-1.38% versus, -1.14%, BL ~8.5%, P < 0.001), body weight (-3.22 kg versus, 0.89 kg, BL~90 kg, P = 0.001) and systolic blood pressure (SBP) (-2.6 MmHg versus, 1.0 MmHg, P = 0.007). The trial was conducted in 443 patients^[59]^[226].

Phase II/III

Results from a 12-week, double-blind trial demonstrated that dapagliflozin produced greater improvements across all key glycaemic measures studied, in patients with type 2 diabetes who were treated with high doses of insulin and commonly used oral anti-diabetes medications (OADs), compared with placebo (placebo plus OADs plus insulin). The trial enrolled 71 patients who were inadequately controlled by insulin and one or two baseline oral antidiabetics (metformin and/or pioglitazone or rosiglitazone). Patients were randomised to dapagliflozin 10mg, dapagliflozin 20mg or placebo, given once daily. At 12 weeks, the adjusted mean decreases in HbA1c from baseline were 0.61% in the dapagliflozin 10mg group and 0.69% in the dapagliflozin 20mg group, compared with an increase of 0.09% for placebo. The percentage of patients that achieved HbA1c of < 7% at 12 weeks was 13% for dapagliflozin 10mg and 4.3% for dapagliflozin 20mg, compared with 5.3% for placebo. The percentage of patients that achieved HbA1c decrease from baseline of ≥ 0.5% was 65.2% for both the dapagliflozin groups, compared with 15.8% for placebo. The change from baseline in fasting plasma glucose at 12 weeks was +2.4 mg/dL for dapagliflozin 10mg and -9.6 mg/dL for dapagliflozin 20mg, compared with +17.8 mg/dL for placebo. Decreases in body weight were 4.51kg, 4.3kg and 1.88kg in the dapagliflozin 10mg, 20mg and placebo groups, respectively^[68]^[214].

Phase II

The efficacy of dapagliflozin was examined in a 12-week, phase IIb trial in 389 treatment-naive patients in type 2 diabetes mellitus. Patients were assigned to receive either 2.5, 5, 10, 20 or 50mg of dapagliflozin, metformin 750mg (titrated up to 1 500mg) or placebo, once-daily. All doses of dapagliflozin were associated with significantly (p < 0.01) greater reductions in HbA1c than placebo. The change from baseline in HbA1c was −0.71%, −0.90%, −0.18% and −0.73% in recipients of dapagliflozin 2.5 and 50mg, placebo and metformin, respectively. The four highest doses of dapagliflozin were also associated with significantly (p < 0.01) greater reductions in fasting plasma glucose (FPG) than placebo. The change from baseline in FPG was −19.3, −30.5, −5.8 and −18.0 mg/dL in recipients of dapagliflozin 5mg and 50mg, placebo and metformin, respectively. Postprandial glucose (PPG) measures were also reduced to a greater extent with dapagliflozin than with placebo. Dapagliflozin also increased mean glucosuria values over 12 weeks, to 51.8-85.0 g/day, while metformin and placebo values were 5.6 and 5.7 g/day respectively. Mean percent body weight reductions were 2.7-3.4%, 1.7% and 1.2%, and reductions in BMI values were 0.9-1.1, 0.5 and 0.3 for the dapagliflozin, metformin and placebo arms respectively. Small dose-related mean 24 hour urine volume increases were seen at week 12 in the dapagliflozin groups, and dapagliflozin did not appear to affect appetite. Statistical comparisons were not applied to the metformin arm^[220]^[221].

A phase IIa study showed positive results with dapagliflozin in the treatment of patients with type 2 diabetes. Dapagliflozin 5, 25 and 100mg doses were all associated with significant reductions in fasting serum glucose on day 13, compared with baseline (reductions of 14.5%, 17.3% and 21.9%, respectively). Additionally, placebo was associated with a 6.3% reduction in fasting serum glucose, over this time. This 14-day, randomised study involved 47 patients with type 2 diabetes who received dapagliflozin 5, 25, 100mg, or placebo, once-daily; metformin therapy was continued in patients who were already receiving treatment upon entry into the study^[225].

Results from a 12 week randomised phase II trial in 44 subjects with type 2 diabetes mellitus showed a significant improvement in overall glucose disposal rate with once-daily dapagliflozin 5mg compared with placebo^[204].

In the phase II EFFECT II trial, dapagliflozin in combination with omega-3 carboxylic acids significantly reduced liver fat percent from baseline in 84 efficacy evaluable patients with type 2 diabetes mellitus. The relative reduction in liver fat percentage for the combination dapagliflozin and omega-3 carboxylic acids was significant (-21%, adjusted p=0.046), but not significant for dapagliflozin (-13%) or omega-3 carboxylic acids (-15%) alone, as compared to placebo (-3%). Both dapagliflozin dapagliflozin in combination with omega-3 carboxylic acids significantly reduced body weight and abdominal subcutaneous and visceral fat volume as well as improved glucose control, including fasting glucose and 2 hour glucose during OGTT. The change in total liver fat volume was similar to liver fat percentage. The trial enrolled 223 patients with type 2 diabetes mellitus^[133]^[134].

Type 1 diabetes mellitus

Phase III

In the phase III DEPICT-1 trial, conducted in 727 patients with type 1 diabetes mellitus, dapagliflozin 5 mg and 10 mg, respectively, showed demonstrated a difference versus, placebo in HbA1c of -0.33% (95% CI: -0.49, -0.17) and -0.36% (95% CI: -0.53, -0.20) and percent change in body weight of -2.95% (95% CI: -3.83, -2.06) and -4.54% (95% CI: -5.40, -3.66)^[59]^[149].

Treatment with dapagliflozin showed efficacy in patients (n=815) with type 1 diabetes mellitus, in the phase III DEPICT 2 trial. Dapagliflozin at 5mg and 10mg, led to reductions [95% CI] in both HbA1c, of −2.2 (−3.7, −0.7) mmol/mol [−0.20% (−0.34%, −0.06%)] and −2.7 (−4.2, −1.2) mmol/mol [−0.25% (−0.38%, −0.11)], and body weight, of −4.42% (− 5.19%, −3.64%) and −4.86% (−5.63%, −4.08%) versus placebo, respectively^[147]^[148].

In the phase III DEPICT-2 trial, conducted in 813 patients with type 1 diabetes mellitus through 24 weeks, dapagliflozin 5 mg and 10 mg, respectively, demonstrated a difference versus, placebo in HbA1C of -0.37% (95% CI: -0.49, -0.26) and -0.42% (95% CI: -0.53, -0.30) (BL~8.4, P < 0.0001) and percent change in body weight of -3.21% (95% CI: -3.96, -2.45) and -3.74% (95% CI: -4.49, -2.99) (P < 0.0001)^[59]^[148].

Results from the DIVERSITY-CVR in patients with type II diabetes mellitus patients showed that both dapagliflozin (Dapa) and sitagliptin (Sita) demonstrated comparable efficacy in HbA1c improvement without hypoglycemia. The levels of HbA1c were identical in both the groups (-0.7 ± 0.8 vs-0.7 ± 0.8%, Dapa vs Sita, respectively) after 24 weeks. Sita achieved more stable glycemic control than Dapa with respect to daily glucose variability as assessed by flash glucose monitoring (FGM) system. In the Sita group, the 24 hours standard deviation and coefficients of variation were significantly reduced compared with the Dapa group (-8.2 ± 9.8 vs-5.9 ± 10.1 mg/dL and -1.6 ± 4.0 vs0.5 ± 4.5%, respectively, both p<0.05). Also, a significant reduction was reported in the continuous overall net glycemic action calculated every 2 and 6 hours in Sita group (- 9.5 ± 10.7 vs-5.8 ± 10.3 mg/dL) vs Dapa group (-12.7 ± 15.2 vs-9.1 ± 16.8 mg/dL, both p < 0.05). However, no significant differences in mean of daily difference of blood glucose were observed between the both groups. The number and duration of hypoglycemic {<3.0 mmol/L (<54 mg/dL)} or hyperglycemic {>10.0 mmol/L (>180 mg/dL)} events in 24 hours and 23:00- 6:00 were comparable between the groups. Results were reported from 315 patients^[188]^[189].

Pooled data from the phase III DEPICT 1 and 2 trial demonstrated decreased HbA1c, systolic blood pressure (BP) and weight in the dapagliflozin (DAPA) cohort at week 24 and 52, in comparison with placebo (PBO). Insulin (INS) dose was decreased with DAPA 5 mg (−8.3%) and 10 mg (−10.5%) but increased with placebo (+1.4%), at week 24. Reduction in HbA1c ≥0.5% without severe hypoglycemia at week 24 with 5 mg cohort, 10 mg cohort and placebo cohort was observed in 232 (44.4), 240 (46.1), and 119 (22.6) patients, respectively (p value < 0.0001). Reduction in HbA1c ≥0.5% without severe hypoglycemia at week 52 with 5 mg cohort, 10 mg cohort and placebo cohort was observed in 190 (36.4), 193 (37.0), and 117 (22.2) patients, respectively (p value < 0.0001)^[146]. Decreased HbA1c with 5 mg cohort was 0.46%, 0.34% and 0.40%, for DAPA 10 mg cohort 0.51%, 0.43% and 0.36% in patients with type 1 diabetes lasting less than 12.9 years, from 12.9 to 23.5 years and in patients with disease duration of more than 23.5 years. HbA1C increased 0.13%, and decreased 0.05% and 0.08% with placebo in the same duration cohorts, at week 24. Weight reduction in the DAPA 5 mg cohort was 2.92 kg, 3kg and 3.35 kg, for DAPA 10 mg cohort 2.98 kg, 3.87 kg and 4.30 kg respectively. For PBO, weight increased 0.19 kg, decreased 0.39 kg and 0.10 kg in the same duration cohorts, at week 24. More number of patients in the 5 mg DAPA/INS (38.5%) and 10 mg DAPA/INS (42.4%) groups achieved a reduction in HbA1c of =0.5%, without weight gain, than in the PBO/INS group (10.8%). A larger proportion of patients on 5 mg DAPA/INS and10 mg DAPA/INS versus those on PBO/INS showed a reduction in HbA1c of =0.5%, without hypoglycaemia or DKA (43.9% and 45.3% vs. 22.1%, respectively). Furthermore, the ORs of patients achieving both composite endpoints were greater in the DAPA/INS groups versus the PBO/INS group^[200]^[199]^[148]^[149].

Phase II:

Treatment with dapagliflozin reduced mean daily blood glucose levels, compared with placebo, in 70 adult patients with type 1 diabetes mellitus who were on stable insulin in a phase IIa trial. In this double-blind trial, patients were randomised to receive dapagliflozin (1-10mg), or placebo once daily for 14 days. The mean change in daily blood glucose from baseline through day seven was -15.7, -13.9, -29.5, and -41.3 mg/dL for the dapagliflozin 1, 2.5, 5 and 10mg dose arms, respectively. The mean change in daily glucose for the placebo arm was -20.4 mg/dL. Treatment with dapagliflozin (5 or 10mg) resulted in a reduction in total daily insulin dosing at day seven, compared with placebo^[150].

Pre-diabetic state

In the phase II PRE-D trial, HbA_1c decreased after 6 weeks of dapagliflozin treatment. All groups showed reductions of around 1 mmol/mol at 13 weeks. Metformin, and to a lesser extend dapagliflozin, decreased fasting plasma glucose. Fasting serum insulin was reduced by 19-25% in all treatment groups, except for exercise at 13 weeks. The iAUC_glucose increased by 66% in metformin arm, and iAUC_insulin decreased somewhat in dapagliflozin and exercise arm^[192]^[193].

The results from the phase III DAPA-CKD trial demonstrated reduction in composite measure of worsening of renal function by 39% compared to placebo (p<0.0001) in patients with chronic kidney disease and elevated urinary albumin excretion. The absolute risk reduction (ARR) reported was 5.3% over the median time in study of 2.4 years. The trial also met secondary endpoints, including significantly reducing death from any cause by 31% with ARR of 2.1%, (p=0.0035) compared to placebo^[183]^[181].

Chronic heart failure

Phase III: The updated results from the phase III DAPA-HF trial in patients with chronic heart failure demonstrated prevention in diabetes after receiving dapagliflozin. Cox proportional hazards model data showed dapagliflozin reduced new-onset diabetes by 32%, with 4.9% of patients receiving dapagliflozin developed T2D, compared to 7.1% in the patients receiving placebo. In an additional exploratory analysis, those patients who did develop diabetes during the trial experienced a 70% increase in mortality, after adjustments for baseline features. Risk of worsening heart failure or death from cardiovascular causes was lowered among the patients receiving dapagliflozin compared to those who received the placebo, regardless of the presence or absence of diabetes^[176]. Earlier data showed that trial met its primary endpoint as dapagliflozin treatment along with standard of care reduced the incidence of cardiovascular (CV) death and the worsening of heart failure. Data from five analyses of phase III DAPA-HF trial for dapagliflozin showed reduced risk of primary composite endpoint compared to placebo in heart failure (HF) in patients with reduced ejection fraction (HFrEF), without T2D. With dapagliflozin, relative risk of composite of worsening of HF or CV death was reduced by 27% among participants without diabetes (absolute risks 9.2% vs 12.7%, n=2605; HR 0.73 [95% CI 0.60, 0.88]) and by 25% in patients with diabetes (14.6% vs 19.4%, n=2139; HR 0.75 [95% CI 0.63, 0.90]). An improvement in the KCCQ total score for dapagliflozin compared to placebo was seen at 4 months, and the magnitude of the improvement was amplified at 8 months. Fewer patients had significant deterioration (=5 points), and more experienced small (=5 points), moderate (=10 points) and large (=15 points) clinically meaningful improvements in total KCCQ score. Post-hoc analysis showed reduction in the risk of the composite of worsening HF or CV death versus placebo in 4 weeks. Subgroup analysis indicated that treatment effects of dapagliflozin versus placebo were consistent over a broad spectrum of left ventricular ejection fraction (LVEF) (p interaction = 0.205 for primary composite outcome)^[172]. Earlier reported data showed that dapagliflozin reduced the composite of CV death or worsening of heart failure by 26% (HR = 0.74, 95% CI: 0.65-0.85; p < 0.0001) (absolute risk reduction [ARR] = 4.9% [16.3% vs 21.2% patients with event, respectively) and demonstrated a reduction in each of the individual components of the composite endpoint. Data indicated a 30% decrease (p<0.0001) in the risk of experiencing a first episode of worsening heart failure and an 18% decrease (p=0.0294) in the risk of dying from CV causes. Effect of dapagliflozin on the primary composite endpoint was generally consistent. Treatment with dapagliflozin resulted in a significant improvement in patient reported outcomes measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score and a nominally significant reduction in all-cause mortality by 17% (7.9 vs 9.5 patients with an event per 100 patient-years)^[159]^[174]. Updated results from the sub-analysis demonstrated that treatment with dapagliflozin was associated with 28% relative risk reduction (absolute risk reduction 19.9% vs 26.3%, HR 0.72 [95% CI 0.59-0.86]) for the composite of CV death or worsening HF event in patients with CKD (estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73m² at baseline) and by a similar magnitude in those patients without CKD (13.8% vs 17.6%, HR 0.76 [95% CI 0.63, 0.92]). Dapagliflozin also attributes to long-term decline in glomerular filtration rate (GFR) in patients with HF after the expected initial small reduction in eGFR^[173]^[171]

Expected Date	Event Type	Description	Updated
30 Jun 2021	Regulatory Status	AstraZeneca expects regulatory decision for Chronic heart failure (In the elderly, In adults) in China (PO) in the first half of 2021 (3516870)	19 Nov 2020
31 Dec 2020	Regulatory Status	AstraZeneca announces intention to submit regulatory filings for Chronic heart failure in the US, the EU, Japan and China in or after 2020 (AstraZeneca pipeline, April 2019)	24 Feb 2020
31 Dec 2020	Trial Update	AstraZeneca in collaboration with Uppsala Clinical Research Center (UCR) and Minap plans a phase III DAPA-MI trial in Heart failure in United Kingdom in fourth quarter of 2020 ^[184]	20 Jul 2020
31 Dec 2020	Regulatory Status	AstraZeneca expects regulatory decision for Chronic heart failure (In the elderly, In adults) in Japan (PO) in Q4 2020 (3516870)	19 Nov 2020
31 Dec 2020	Regulatory Status	AstraZeneca announces intention to submit regulatory filings for Renal failure in the US, the EU, Japan and China in Q4 2020 (3516870)	19 Nov 2020
12 Nov 2020	Trial Update	Astrazeneca plans a phase II MIRACLE trial for Heart failure (Combination therapy) in November 2020 (NCT04595370)	03 Nov 2020
30 Jun 2020	Regulatory Status	AstraZeneca expects regulatory decision for Type II diabetes and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors from cardiovascular outcomes trial in China in the first half of 2020 ^[180]	04 Dec 2019
30 Jun 2020	Regulatory Status	FDA assigns PDUFA action date in second quarter of 2020 for dapagliflozin for Chronic heart failure ^[157]	08 May 2020
31 Dec 2019	Regulatory Status	AstraZeneca expects regulatory decision for Type I diabetes mellitus in the US in the second half of 2019 ^[23]	20 Feb 2019
31 Dec 2019	Regulatory Status	AstraZeneca announces intention to submit regulatory applications for Type-2 diabetes mellitus (add-on therapy, patients at high risk of a cardiovascular event) in European Union in 2019 ^[55]	23 Mar 2020
31 Dec 2019	Regulatory Status	AstraZeneca announces intention to submit regulatory applications for Type-2 diabetes mellitus (add-on therapy, patients at high risk of a cardiovascular event) in USA in 2019 ^[55]	24 Oct 2019
31 Jul 2019	Regulatory Status	AstraZeneca expects regulatory decision for Type I diabetes mellitus in the EU and Japan in the first half of 2019 ^[23]	20 Feb 2019
30 Jun 2019	Regulatory Status	AstraZeneca announces intention to submit regulatory applications for Type-2 diabetes mellitus in China in first half of 2019 (AstraZeneca pipeline, April 2019)	03 May 2019
12 Apr 2019	Trial Update	AstraZeneca plans the phase III DETERMINE-reduced trial for Heart failure in USA, Brazil, Argentina, Canada, Denmark, South Korea, Slovakia, South Africa and Sweden in April 2019 (PO) (NCT03877237) (700305493)	29 Apr 2019
05 Apr 2019	Trial Update	AstraZeneca plans the phase III DETERMINE trial for Heart failure in USA, Argentina, Bulgaria, Canada, Denmark, Italy, South Korea, Slovakia, South Africa and Sweden in April 2019 (PO) (NCT03877224)	30 Apr 2019
31 Dec 2018	Regulatory Status	AstraZeneca announces intention to submit regulatory applications for Type-1 diabetes mellitus in USA in the second half of 2018 ^[55]	05 Feb 2019
05 Nov 2018	Trial Update	AstraZeneca plans the DS Navigation phase III trial for Type II diabetes mellitus in China and Vietnam (700298343), (NCT03608358)	28 Mar 2019
30 Aug 2018	Trial Update	AstraZeneca plans the phase III DELIVER trial for Heart failure in USA, Brazil, Canada, Czech Republic, Hungary, Japan, Mexico, Netherlands, Peru, Romania, Russian Federation, Saudi Arabia, Spain, Taiwan and Vietnam (NCT03619213) (9247946)	31 Aug 2018
30 Jun 2018	Regulatory Status	AstraZeneca announces intention to submit regulatory applications for Type-1 diabetes mellitus in European Union in the first half of 2018 ^[55]	22 May 2018
31 Oct 2017	Trial Update	AstraZeneca plans a phase III trial for Type-2 diabetes mellitus (In children, In adolescents, Adjunctive treatment) (PO) (NCT03199053) (EudraCT2015-005042-66)	29 Jan 2020

Organisation	Involvement	Countries
Bristol-Myers Squibb	Originator	USA
AstraZeneca	Owner	United-Kingdom
Sun Pharmaceutical Industries	Market Licensee	India
Ono Pharmaceutical	Market Licensee	Japan
AstraZeneca KK	Market Licensee	Japan
Toho University	Collaborator	Japan
University Medical Center Hamburg-Eppendorf	Collaborator	Germany
Uppsala University	Collaborator	Sweden
Saitama Medical University	Collaborator	Japan
Kyushu University	Collaborator	Japan
Bayer	Collaborator	Germany
Novo Nordisk Foundation	Collaborator	Denmark
University Medical Center Groningen	Collaborator	Netherlands
Japan Society for Patient Reported Outcome (PRO)	Collaborator	Japan

Brand Name	Organisations	Indications	Countries
Andatang	AstraZeneca	Type 2 diabetes mellitus	China
Farxiga	AstraZeneca	Type 2 diabetes mellitus	USA
Forxiga	AstraZeneca, Ono Pharmaceutical	Type 2 diabetes mellitus	Philippines, Japan, Thailand, Russia, China, Argentina, Canada, Ukraine, Israel, Brazil, Australia, Hong Kong, Singapore, Ireland, Chile, Indonesia, Malaysia, Switzerland, European Union, Cyprus
Oxra	Sun Pharmaceutical Industries	Type 2 diabetes mellitus	India

Indication	Region	Company	Phase	Expected Launch Year	Probability of Success%	Patent Expiry Year	Expected Generic Entry	Last Update
Chronic kidney disease DAPA-CKD	Wrld (50% US)	AstraZeneca, Bristol Myers (Evaluate^)	III	2021	80	2026	01 Jan 2026	07 Jul 2020
Diabetes	ex US, ex Japan	AstraZeneca, Ono	Marketed	2013	100	2026	01 Jan 2026	07 Jul 2020
Diabetes	Japan	AstraZeneca, Ono	Marketed	2014	100	2030	01 May 2030	07 Jul 2020
Diabetes	US	AstraZeneca, Ono	Marketed	2014	100	2026	01 Jan 2026	07 Jul 2020
Heart Failure HF-REF	ex US	AstraZeneca, Bristol Myers (Evaluate^)	III	2020	90	2026	01 Jan 2026	07 Jul 2020
Heart Failure HF-REF	US	AstraZeneca, Bristol Myers (Evaluate^)	Filed	2020	90	2026	01 Jan 2026	07 Jul 2020

Indication	Region	2016	2017	2018	2019	2020	2021	2022	2023	2024	2025	Last Update
Chronic kidney disease DAPA-CKD	Wrld (50% US)	0	0	0	0	0	150	300	450	600	600	07 Jul 2020
Diabetes	ex US, ex Japan	378	585	800	1006	1280	1472	1649	1764	1870	1982	07 Jul 2020
Diabetes	Japan	72	99	120	130	139	148	153	153	153	153	07 Jul 2020
Diabetes	US	457	489	591	537	526	526	553	580	609	640	07 Jul 2020
Heart Failure HF-REF	ex US	0	0	0	0	0	145	320	530	780	780	07 Jul 2020
Heart Failure HF-REF	US	0	0	0	0	50	125	200	350	550	550	07 Jul 2020
Total		907	1173	1511	1673	1995	2566	3175	3827	4562	4705

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