New data show investigational compound dapagliflozin demonstrated significant reductions in blood sugar levels when added to sitagliptin in adults with type 2 diabetes at 24 weeks, with results maintained over 48 weeks

AstraZeneca and Bristol-Myers Squibb Company today announced results from a Phase 3 clinical study that showed the investigational compound dapagliflozin 10 mg demonstrated significant reductions in blood sugar levels (glycosylated hemoglobin levels, or HbA1c) compared with placebo at 24 weeks when either agent was added to existing sitagliptin therapy (with or without metformin) in adult patients with type 2 diabetes. The results were maintained over a 24-week extension and similar results were observed when the data were stratified by background therapy. The findings were presented today at the 72nd American Diabetes Association (ADA) Scientific Sessions in Philadelphia, PA.

The study also demonstrated significant reductions in total body weight and fasting plasma glucose (FPG) levels in patients taking dapagliflozin added to sitagliptin (with or without metformin), with results maintained throughout the duration of the study extension.

Patients were actively questioned at each study visit for signs, symptoms or events suggestive of genital infections and urinary tract infections. These events were more frequent with the dapagliflozin treatment group compared to the placebo treatment group, and were generally mild to moderate in intensity, with most patients responding to standard treatment.

“Type 2 diabetes is a complex disease that often requires patients to take multiple treatments to control their blood sugar levels, with DPP4 inhibitors being some of the most widely prescribed therapies,” said Serge Jabbour, M.D., Division Director of Endocrinology, Thomas Jefferson University. “In this study, dapagliflozin, in addition to diet and exercise, resulted in reduced blood sugar levels when added to sitagliptin, a DPP4 inhibitor. These findings add to our understanding of the effect of dapagliflozin in combination with commonly prescribed type 2 diabetes treatments.”

Dapagliflozin, an investigational oral compound, is a selective and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2), which works independently of insulin. Dapagliflozin is under joint development by Bristol-Myers Squibb and AstraZeneca, and is being investigated to evaluate its safety and efficacy in improving glycemic control in adults with type 2 diabetes as an adjunct to diet and exercise, for once-daily use as a monotherapy and in combination with other glucose-lowering drugs. If approved, dapagliflozin would potentially be the first in the new SGLT2 inhibitor class for the treatment of type 2 diabetes, a disease where high unmet medical need exists. In a comprehensive clinical trial program of 19 studies, dapagliflozin has been studied together with diet and exercise as a monotherapy, and as an add-on therapy to commonly prescribed diabetes medications, including metformin, sulfonylurea (glimepiride), thiazolidinedione (pioglitazone), and insulin (with or without other diabetes therapies).

In January 2012, the US Food and Drug Administration (FDA) issued a complete response letter regarding the New Drug Application (NDA) for dapagliflozin for the treatment of adults with type 2 diabetes, requesting additional clinical data to allow a better assessment of the benefit-risk profile for dapagliflozin. In April 2012, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion recommending the approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products including insulin, and as a monotherapy in metformin intolerant patients. The CHMP positive opinion for dapagliflozin will now be reviewed by the European Commission, which has the authority to approve medicines for the European Union.

About the Study

This was a 24-week, Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study with a 24-week blinded extension. The study compared the efficacy of dapagliflozin to placebo in patients with type 2 diabetes who are inadequately controlled on sitagliptin monotherapy or on sitagliptin plus metformin therapy. The primary efficacy endpoint at 24 weeks was mean change in HbA1c from baseline for dapagliflozin 10 mg compared to placebo, both added to sitagliptin (with or without metformin) in adults with type 2 diabetes who had inadequate glycemic control. The 24-week extension was designed to assess the maintenance of efficacy with the dapagliflozin treatment group, as well as safety and tolerability over 48 weeks.

The study included 447 adults with type 2 diabetes (aged ≥ 18 years) with inadequate glycemic control (HbA1c ≥ 7.0% and ≤ 10.0%) who were on a stable dose of sitagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor (with or without metformin).

Patients were randomized equally to receive dapagliflozin or placebo added to sitagliptin alone (stratum 1) or added to sitagliptin plus metformin (stratum 2). Patients in stratum 1 received dapagliflozin 10 mg or placebo added to sitagliptin 100 mg/d. Patients in stratum 2 received dapagliflozin 10 mg or placebo added to sitagliptin 100 mg/d plus metformin ≥ 1500 mg/d.

Study Results

Patients (n = 223) receiving dapagliflozin 10 mg added to sitagliptin with or without metformin demonstrated significantly greater improvements in glycemic control at the end of 24 weeks compared to patients (n = 224) taking placebo added to sitagliptin with or without metformin, with a change in baseline in HbA1c of -0.48% (p-value < 0.0001, Last Observation Carried Forward [LOCF]).

Additional results of the key primary and secondary endpoints included the following:

• Dapagliflozin added to sitagliptin (stratum 1) resulted in a greater reduction in HbA1c compared to placebo added to sitagliptin, with a change in HbA1c of -0.56% (p-value < 0.0001, LOCF).
• Dapagliflozin added to sitagliptin and metformin (stratum 2) resulted in a greater reduction in HbA1c compared to placebo added to sitagliptin plus metformin, with a change in HbA1c of -0.40% (p-value < 0.0001, LOCF).
• Reductions in HbA1c were notable at four weeks (the first recorded time point) and maintained to 48 weeks.
• Patients with a higher baseline HbA1c (≥ 8.0%) receiving treatment with dapagliflozin achieved greater reductions in HbA1c.
• Significant reductions in body weight were observed with dapagliflozin compared to placebo in the entire treatment cohort (–1.89 kg, LOCF), stratum 1 (–1.85 kg, LOCF) and stratum 2 (–1.87 kg, LOCF), and were sustained out to 48 weeks.
• Significant differences were also observed in adjusted mean FPG in patients who received dapagliflozin.

Patients in the dapagliflozin group did not show a statistically significant change from baseline in placebo subtracted seated systolic blood pressure (SBP, baseline ≥ 130 mm Hg) compared to placebo: -5.98 mm Hg (n = 101; dapagliflozin) vs. -5.12 mm Hg (n = 111; placebo) at week 24 (-0.86 (SE 1.47), p-value = 0.5583).

Over 24 weeks, 18.8% of patients receiving dapagliflozin discontinued for lack of efficacy or were rescued for meeting pre-specified rescue criteria vs. 41.5% receiving placebo.

Over the 48-week treatment period, the proportion of patients experiencing at least one adverse event was 66.2% in the dapagliflozin group compared to 61.1% in the placebo group. The most common adverse events occurring in ≥ 4.0% of the study population were as follows: nasopharyngitis, back pain, urinary tract infection, pharyngitis, arthralgia and headache.

The proportion of patients who experienced at least one serious adverse event was 6.7% in the dapagliflozin group compared to 8.0% in the placebo group. In either treatment group, 3.1% discontinued treatment due to an adverse event. Hypoglycemia was reported in 5.3% of the dapagliflozin group compared to 6.2% in the placebo group.

The proportion of patients with diagnoses of genital infections was 9.3% in the dapagliflozin group compared to 0.4% in the placebo group. The proportion of patients with diagnoses of urinary tract infections was 5.8% in the dapagliflozin group and 3.5% in the placebo group.

Adverse events suggestive of renal impairment or failure were observed in eight patients in the dapagliflozin group (3.6%) and four patients in the placebo group (1.8%). In four patients in the dapagliflozin group and in one patient in the placebo group, a decrease in renal creatinine clearance was reported.