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

What does weight loss with FORXIGA® (dapagliflozin) look like for your patients?

In patients taking FORXIGA®(dapagliflozin), absolute weight loss was shown to increase in proportion to BMI, across 10 clinical trials4*†‡

*FORXIGA® (dapagliflozin) is not indicated for weight loss. Weight change was a secondary endpoint in clinical trials.1

Change from baseline in body weight over time by BMI class4

 Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)
 Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)

Adapted from Shatskov A et al 2016

(P<0.0001)

BMI, body mass index.

There was a significant treatment-by-BMI subgroup interaction (P<0.0001) with body weight, suggesting a difference in treatment effect based on BMI. Absolute weight loss increased with baseline BMI and was greatest in patients with BMI ≥40 kg/m2 who received dapagliflozin 10 mg; across all baseline BMI categories patients generally lost 1%–2% of their baseline weight with dapagliflozin 5 mg and 2%–3% with dapagliflozin 10 mg. Similar proportions of patients across BMI subgroups achieved weight reductions of ≥5% with dapagliflozin 5 mg (9.7%–20.9%) and 10 mg (16.7%–24.4%); placebo (4.2%–6.7%). After 24 weeks of treatment with dapagliflozin 5 or 10 mg, 18%–29% of obese patients shifted 1 BMI category lower compared with 9%–13% of patients who received placebo.4

*FORXIGA® (dapagliflozin) is not indicated for weight loss. Weight change was a secondary endpoint in clinical trials.1

Change from baseline in body weight over time by BMI class 4

Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)
Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)

Adapted from Shatskov A et al 2016

(P<0.0001)
BMI, body mass index.
There was a significant treatment-by-BMI subgroup interaction (P<0.0001) with body weight, suggesting a difference in treatment effect based on BMI. Absolute weight loss increased with baseline BMI and was greatest in patients with BMI ≥40 kg/m2 who received dapagliflozin 10 mg; across all baseline BMI categories patients generally lost 1%–2% of their baseline weight with dapagliflozin 5 mg and 2%–3% with dapagliflozin 10 mg. Similar proportions of patients across BMI subgroups achieved weight reductions of ≥5% with dapagliflozin 5 mg (9.7%–20.9%) and 10 mg (16.7%–24.4%); placebo (4.2%–6.7%). After 24 weeks of treatment with dapagliflozin 5 or 10 mg, 18%–29% of obese patients shifted 1 BMI category lower compared with 9%–13% of patients who received placebo.4

*FORXIGA® (dapagliflozin) is not indicated for weight loss. Weight change was a secondary endpoint in clinical trials.1

Change from baseline in body weight over time by BMI class4

Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)
Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)

Adapted from Shatskov A et al 2016

(P<0.0001)
BMI, body mass index.
There was a significant treatment-by-BMI subgroup interaction (P<0.0001) with body weight, suggesting a difference in treatment effect based on BMI. Absolute weight loss increased with baseline BMI and was greatest in patients with BMI ≥40 kg/m2 who received dapagliflozin 10 mg; across all baseline BMI categories patients generally lost 1%–2% of their baseline weight with dapagliflozin 5 mg and 2%–3% with dapagliflozin 10 mg. Similar proportions of patients across BMI subgroups achieved weight reductions of ≥5% with dapagliflozin 5 mg (9.7%–20.9%) and 10 mg (16.7%–24.4%); placebo (4.2%–6.7%). After 24 weeks of treatment with dapagliflozin 5 or 10 mg, 18%–29% of obese patients shifted 1 BMI category lower compared with 9%–13% of patients who received placebo.4

*FORXIGA® (dapagliflozin) is not indicated for weight loss. Weight change was a secondary endpoint in clinical trials.1

Change from baseline in body weight over time by BMI class4

Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)
Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)

Adapted from Shatskov A et al 2016

(P<0.0001)
BMI, body mass index.
There was a significant treatment-by-BMI subgroup interaction (P<0.0001) with body weight, suggesting a difference in treatment effect based on BMI. Absolute weight loss increased with baseline BMI and was greatest in patients with BMI ≥40 kg/m2 who received dapagliflozin 10 mg; across all baseline BMI categories patients generally lost 1%–2% of their baseline weight with dapagliflozin 5 mg and 2%–3% with dapagliflozin 10 mg. Similar proportions of patients across BMI subgroups achieved weight reductions of ≥5% with dapagliflozin 5 mg (9.7%–20.9%) and 10 mg (16.7%–24.4%); placebo (4.2%–6.7%). After 24 weeks of treatment with dapagliflozin 5 or 10 mg, 18%–29% of obese patients shifted 1 BMI category lower compared with 9%–13% of patients who received placebo.4

*FORXIGA® (dapagliflozin) is not indicated for weight loss. Weight change was a secondary endpoint in clinical trials.1

Change from baseline in body weight over time by BMI class4

Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)
Change from baseline in body weight over time by BMI class (FORXIGA® vs placebo)

Adapted from Shatskov A et al 2016

(P<0.0001)
BMI, body mass index.
There was a significant treatment-by-BMI subgroup interaction (P<0.0001) with body weight, suggesting a difference in treatment effect based on BMI. Absolute weight loss increased with baseline BMI and was greatest in patients with BMI ≥40 kg/m2 who received dapagliflozin 10 mg; across all baseline BMI categories patients generally lost 1%–2% of their baseline weight with dapagliflozin 5 mg and 2%–3% with dapagliflozin 10 mg. Similar proportions of patients across BMI subgroups achieved weight reductions of ≥5% with dapagliflozin 5 mg (9.7%–20.9%) and 10 mg (16.7%–24.4%); placebo (4.2%–6.7%). After 24 weeks of treatment with dapagliflozin 5 or 10 mg, 18%–29% of obese patients shifted 1 BMI category lower compared with 9%–13% of patients who received placebo.4

This study was a post-hoc analysis of data pooled from 10 FORXIGA® (dapagliflozin) phase III,randomised double-blind, placebo-controlled, 24-week studies in adults (≥18 years of age) with type 2 diabetes (T2D) and body mass index (BMI) ≤45 kg/m2. The study aimed to assess the efficacy and safety of FORXIGA® (dapagliflozin) 5 and 10 mg once daily in subgroups of patients with T2D stratified by BMI category.

FORXIGA® (dapagliflozin) 5 or 10 mg or placebo were administered as: 

  •   Monotherapy in treatment-naive patients (NCT00528372)
  •   Initial combination therapy with metformin (NCT00859898)

Add-on to the following:

  • Metformin (NCT00855166, NCT00528879)    
  • Glimepiride (NCT00680745)
  • Pioglitazone(NCT00683878)
  • Sitagliptin ± metformin (NCT00984867)       
  • Insulin ± up to 2 other anti-diabetic medications (NCT00673231)
  • Usual care in patients with CVD (NCT01042977)
  • Usual care in patients with CVD and hypertension (NCT01031680)

Changes from baseline to week 24 in HbA1c, body weight, and systolic blood pressure were analysed in patients stratified by BMI (kg/m2) categories:

  • Normal weight: 18.5 ≥ 25 kg/m2
  • Overweight: 25 ≥ 30 kg/m2
  • Obese Class I: 30 ≥ 35 kg/m2
  • Obese Class II: 35 ≥ 40 kg/m2
  • Obese Class III: ≥ 40 kg/m2

Longitudinal repeated measures analyses were performed using a model that included baseline, treatment, subgroup, week, and the following interaction terms: week-by-treatment, week-by-baseline, treatment-by-subgroup, study-by-baseline, and week-by-treatment-by-subgroup.

Adverse events were recorded during the 24-week study period for each trial in the pooled data set.

*The use of FORXIGA® (dapagliflozin) with pioglitazone is not recommended.1

FORXIGA® (dapagliflozin) offers the secondary benefit of systolic blood pressure reduction, with significant changes at 12 weeks vs placebo12†‡

FORXIGA® (dapagliflozin) is not indicated for the management of high blood pressure.1

Change from baseline in systolic blood pressure at 12 weeks, vs placebo12

Change from baseline in systolic blood pressure at 12 weeks (FORXIGA® vs placebo)
Change from baseline in systolic blood pressure at 12 weeks (FORXIGA® vs placebo)

Adapted from Weber MA et al. 2016

Caution should be exercised in patients for whom a FORXIGA® (dapagliflozin)-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension, or elderly patients.1FORXIGA® (dapagliflozin) is not recommended in patients receiving loop diuretics as it may add to the diuretic effect and may increase the risk of dehydration and hypotension.1

ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; AHT, antihypertensive therapy; CI, confidence interval.

In a prespecified pooled analysis of 12 placebo-controlled studies, treatment with FORXIGA® (dapagliflozin) 10 mg resulted in a systolic blood pressure change from baseline of  -4.4 mmHg and diastolic blood pressure of -2.1 mmHg versus -0.9 mmHg and -0.5 mmHg diastolic blood pressure for the placebo group at Week 24.24

Data are longitudinal repeated measures analysis excluding data after rescue. At 12 weeks, n corresponds to the number of randomised subjects with non-missing baseline and Week 12 values. Significant p-value: Co-primary endpoints tested at alpha = 0.05.12

 

A multi-centre, randomised, double-blind, placebo-controlled Phase III clinical trial within 311 centres in 16 countries. Eligible patients were those with type 2 diabetes, inadequate glycaemic control (HbA1c 7·0%–10·5%; 53–91 mmol/mol), and inadequately controlled hypertension (systolic 140–165 mm Hg and diastolic 85–105 mm Hg). The study aimed to analyse the efficacy and safety of FORXIGA® (dapagliflozin) 10 mg for reduction of systolic blood pressure (BP) and HbA1c in 449 adult patients with type 2 diabetes (T2D) and inadequate glycaemic and BP control.

Patients were randomly assigned (1:1) to receive FORXIGA® (dapagliflozin) 10 mg once daily or matched placebo. Randomisation was stratified by type of additional antihypertensive medication use and insulin use. Randomisation was done by interactive voice response system. Patients with T2D and elevated BP (seated systolic 140 < 165 mm Hg + seated diastolic blood 85 < 105 mm Hg) were randomised to placebo (n=244) or FORXIGA® (dapagliflozin) 10 mg (n=225) for 12 weeks in addition to their multidrug regimen. The trial consisted of a qualification period (14 days or less after enrolment), a lead-in period (4 weeks), a double-blind treatment period (12 weeks), and a follow-up period (1 week).

The co-primary endpoints were changes from baseline to week 12 in seated systolic blood pressure and HbA1c. Secondary endpoints included change from baseline to week 12 in 24-hour ambulatory BP, seated diastolic BP, and serum uric acid.

Safety evaluations over the study period included adverse events, laboratory variables, and vital signs.