FORXIGA® (dapagliflozin)

FORXIGA® (dapagliflozin) is a highly selective SGLT2 inhibitor for type 2 diabetes mellitus, with 4-year safety and efficacy data, that removes glucose and its associated calories via the kidney.1

FORXIGA® (dapagliflozin) proven clinical trial data

Significant results demonstrated across 7 randomised controlled trials3,6-10 up to 4 years in duration11

Reductions in HbA1c with FORXIGA® (dapagliflozin) when added to metformin across baselines3,6-10*

Reductions in HbA<sub>1c</sub> when FORXIGA<sup>®</sup> is added to background metformin across baselines
Reductions in HbA<sub>1c</sub> when FORXIGA<sup>®</sup> is added to background metformin across baselines


*Phase 3/4 studies with HbA1c reductions as a primary endpoint.3,6-10

-1.32% reduction was a secondary endpoint in Bailey CJ et al.6

N.B. It is not possible to directly compare results from different trials

A 24-week, multicentre, randomised, double blind, active-controlled, parallel-group phase 3 study. Eligible patients were aged ≥18 years with type 2 diabetes and inadequate glycaemic control, defined as HbA1c ≥8.0% and ≤12.0% (64-108 mmol/mol) at screening.

Patients had to be stable on metformin therapy (≥1500 mg/day) for ≥8 weeks before screening and have C-peptide concentrations ≥1.0 ng/mL and a body mass index ≤45.0 kg/m2 at screening. At the beginning of a 4-week lead-in period, patients who had been on stable metformin therapy for at least 8 weeks before screening were switched to the nearest metformin extended release dose (1500-2000 mg/day) for the lead-in period and for the duration of the 24-week double blind treatment period. Patients were randomised 1:1:1 using a centralised blocked randomisation schedule. Patients were randomised 1:1:1 using centralised blocked randomised schedule to receive either; saxagliptin (5 mg/day) + forxiga (10 mg/day) + metformin; forxiga (10 mg/day) + metformin + placebo or; saxagliptin (5 mg/day) + metformin + placebo.

The primary endpoint was the adjusted mean change from baseline in HbA1c after 24 weeks of double-blind treatment. Secondary endpoints were adjusted mean change from baseline at 24 weeks in 2-h postprandial glucose, adjusted mean change from baseline at 24 weeks in fasting plasma glucose, adjusted mean proportion of patients achieving a therapeutic glycaemic response, defined as HbA1c <7.0% (53 mmol/mol), after 24 weeks, and the adjusted mean change from baseline in bodyweight.

Safety assessments included adverse events, hypoglycaemic events, laboratory abnormalities, and vital signs.

This was a 52-week randomised, double-blind, parallel-group, active-controled, phase ||| , noninferiority trial with a 156-week extension period, conducted at 95 sites in 10 countires. The study aimed to evaulate the saftey and efficacy of FORXIGA® (dapagliflozin). 10mg + metformin (<1500 mg/day) vs glipizide + metformin (>1500 mg/day) in patients with inadequate glycaemic control (HbA1c 6.5% and ≤10%) receiving oral antidiabetic medication including metformin. 

After a 2-week, single-blind, placebo lead-in period, patients were randomised in a 1:1 ratio using a computer-generated randomisation scheme to receive double-blind treatment with FORXIGA® (dapagliflozin) or glipizide. During the first 18-week period, patients were uptitrated from starting doses of FORXIGA® (dapagliflozin) 2.5 mg/day or glipizide 5 mg/day, rising to 10 mg/day or 20 mg/day, respectively, until glycaemic control was achieved or the maximum tolerable dose was reached. Following, patients entered a 34-week maintenance period during which no further uptitration was allowed.

The primary endpoint was absolute change in HbA1c from baseline to week 52. Key secondary end points were absolute change in total body weight from baseline to week 52, the proportion of patients reporting at least one episode of hypoglycaemia, and the proportion of patients achieving a bodyweight decrease ≥5% from baseline to week 52.

Safety assessments included adverse events (of special interest urinary tract and genital infections), hypoglycaemic events, laboratory abnormalities, and vital signs.

Values for the additional 104-week extension (to week 208) is now available.11

A randomised, double-blind, placebo-controlled, parallel-group, phase III study with a 6-week lead-in period, 24-week treatment period, and a 4-week follow-up period. The study was conducted between June 2010 and March 2013, at 32 sites, in adults aged ≥18 years. Inclusion criteria included adults inadequately controlled blood glucose (HbA1c at screening ≥7.5% and ≤10.5%) and on stable metformin monotherapy (≥8 weeks, ≥1500mg/day).

Eligible patients completed a 6-week, single-blind, placebo lead-in period during which they were maintained on open-label metformin at their pre-enrolment dose (≥1500 mg/day). Patients completing the lead-in period were randomised (stratified by site) 1:1:1 to FORXIGA®(dapagliflozin) 5mg, FORXIGA®(dapagliflozin) 10mg, or placebo, randomised by a computer-generated randomisation scheme using an interactive voice response system.

The primary endpoint was mean change from baseline in HbA1c at week 24 for each FORXIGA®(dapagliflozin) group vs placebo. Secondary endpoints included changes from baseline at week 24 in fasting plasma glucose, 2-hour postprandial glucose, total body weight, and the proportion of patients achieving a therapeutic glycaemic response (HbA1c <7.0%).

Safety assessments included adverse events, changes in blood pressure and hypoglycaemic events.

A 52-week, multicentre, randomised, parallel-group, double-blind, active-controlled phase IV study. The study aimed to evaluate the efficacy and safety of FORXIGA® (dapagliflozin) and FORXIGA® (dapagliflozin) + saxagliptin compared with glimepiride when added to metformin in patients with type 2 diabetes who required additional glycaemic control. 939 patients aged ≥18 years from sites in 5 countries. Patients were randomised 1:1:1 using centralised blocked randomised schedule to receive either; saxagliptin (5 mg/day) + forxiga (10 mg/day) + metformin; forxiga (10 mg/day) + metformin + placebo or; saxagliptin (5 mg/day) + metformin + placebo.

The primary outcome was change HbA1c from baseline to end of treatment at week 52. Key secondary endpoints included: proportion of patients reporting at least one episode of symptomatic hypoglycaemia (≤50 mg/dL [≤2.8 mmol/L]), change from baseline in body weight and fasting plasma glucose at week 52.

Safety assessments included adverse events (of special interest urinary tract and genital infections and ketoacidosis) and hypoglycaemic events.

A phase III, multicentre, randomised, double-blind, placebo-controlled, parallel-group, 24-week clinical study, plus a 78-week extension period, to evaluate the efficacy and safety of FORXIGA® (dapagliflozin) 10 mg + metformin (>1500 mg/day) vs placebo + metformin (>1500 mg/day) in adult patients with type 2 diabetes who had inadequate glycaemic control.

Patients were enrolled into a 2-week, single-blind, lead-in period in which patients received placebo to assess compliance. Patients who successfully completed the lead-in period were randomly assigned 1:1:1:1 by a central interactive voice response system to double-blinded groups of once-daily FORXIGA® (dapagliflozin) 2.5 mg, 5 mg, or 10 mg, or matching placebo before the morning meal for 24 weeks. Randomisation was stratified by investigation site, and randomisation schedules were computer-generated.

The primary outcome was change from baseline in HbA1c at 24 weeks. Key secondary endpoints included changes in fasting plasma glucose concentration and total body weight at week 24, proportion of patients achieving a therapeutic glycaemic response (defined as HbA1c <7% (53 mmol/mol) at week 24, and change in HbA1c percentage at week 24 for patients with a baseline HbA1c of 9% (75 mmol/mol or more).

Safety assessments included adverse events (of special interest urinary tract and genital infections), changes in blood pressure and hypoglycaemic events. Outcomes for the 78-week extension (to week 102) were presented by Bailey CJ et al. at the 71st Scientific Sessions of the American Diabetes Association 2011.

DURATION-8 was a 28 week, multicentre, double-blind, randomised, active-controlled phase 3 trial at 109 sites in six countries, and a subsequent ongoing 52-week extension. Adults (aged ≥18 years) with type 2 diabetes and inadequate glycaemic control (HbA1c 8–12% [64–108 mmol/mol]) despite stable metformin monotherapy (≥1500 mg/day) were randomly assigned 1:1:1. 695 patients were randomly assigned to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily FORXIGA® (dapagliflozin) 10 mg oral tablets (n=231), exenatide with FORXIGA®(dapagliflozin) - matched oral placebo (n=231; n=1 untreated), or FORXIGA® (dapagliflozin) with exenatide matched placebo injections (n=233). Randomisation was stratified by baseline HbA1c (<9.0% vs ≥9.0% [<75 mmol/mol vs ≥75 mmol/mol]). The intention-to-treat population comprised 685 participants (mean HbA1c 9.3% [SD 1.1]; 78 mmol/mol), of whom 611 (88%) completed the study. The primary endpoint was change in HbA1c from baseline to week 28. Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28, and 2 h postprandial glucose at week 28; the proportion of patients with an HbA1c less than 7.0% (<53 mmol/mol) at week 28; change in weight at week 28; the proportion of patients with weight loss of 5% or more at week 28; and change in systolic blood pressure at week 28. Analyses were by intention-to-treat.

Safety assessments included adverse events, laboratory abnormalities, vital signs, and hypoglycaemic events. Values for the 52-week extension now published.14