Forxiga receives marketing authorisation for treatment of type 2 diabetes
AstraZeneca Pharmaceuticals (Ireland) Ltd wishes to announce that the European Commission has granted marketing authorisation for Forxiga (dapagliflozin) tablets for the treatment of type 2 diabetes.
Forxiga tablets are indicated as a once-daily oral medication to improve glycaemic control in adult patients with type 2 diabetes. They are intended to be used as an adjunct to diet and exercise in combination with other glucose-lowering medications, including insulin, or as a monotherapy in metformin-intolerant patients.
Forxiga is a selective and reversible inhibitor of sodium-glucose cotransporter 2 (SGLT2) which is primarily responsible for renal glucose reabsorption. Forxiga acts independently of insulin secretion and action. It improves both fasting and post-prandial plasma glucose levels by reducing renal glucose reabsorption leading to urinary glucose excretion, a mode of action not seen in any other currently available treatments for type 2 diabetes.
The marketing authorisation is based on the results of a broad clinical development programme that included 11 double-blind, randomised, placebo-controlled Phase III clinical trials involving 5,693 patients randomised to Forxiga once daily or placebo. The results demonstrated that a higher proportion of patients with type 2 diabetes treated with Forxiga compared to placebo achieved the goal of HbA1c < 7%.1
A head to head comparison study was also conducted to assess the long-term safety and efficacy of add-on Forxiga compared to those of add-on glipizide in patients with type 2 diabetes inadequately controlled with metformin.2
Study design
After a 2-week single-blind lead-in period, 814 patients with type 2 diabetes inadequately controlled with metformin (HbA1c > 6.5% and ≤ 10%) were randomised to receive dapagliflozin or glipizide treatment, commencing at dapagliflozin 2.5mg or glipizide 5mg and then up-titrated over 18 weeks, to a maximum dose of 10mg and 20mg, respectively.
Primary end point was HbA1c non-inferiority at 1 year, and key secondary end points included change in total body weight and proportion of patients with hypoglycemia at 1 year (previously reported results).3 Maintenance of dapagliflozin efficacy at 2 years as well as safety and tolerability at 2 years were also measured.2
Forxiga non inferior to glipizide in reduction of HbA1c
HbA1c adjusted mean change from baseline with dapagliflozin was found statistically non-inferior to glipizide (both -0.52%) at 1 year (Figure 1). At the end of year 2, change from baseline in HbA1c with dapagliflozin was -0.32% vs -0.14% with glipizide (Figure 1).
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Secondary benefit of weight loss with Forxiga
Initial weight reduction with dapagliflozin and weight gain with glipizide after 1 year remained stable at 2 years (Figure 2). Dapagliflozin mean reduction in body weight at 2 years was -3.70 kg, compared to +1.36kg weight gain for glipizide (weight difference vs glipizide at 2 years: -5.06kg).
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Fewer patients experienced any hypoglycaemic episodes with Forxiga compared to glipizide
The proportion of patients with hypoglycaemic episodes over 2 years was tenfold less with dapagliflozin (4.2%) than with glipizide treatment (45.8%), with the majority of first episodes occurring in the first year (Figure 3).
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Safety and tolerability
Overall adverse events, drug-related adverse events and adverse events leading to study discontinuation were balanced across treatment groups. Dapagliflozin treatment was associated with a greater proportion of patients reporting vulvovaginitis, balanitis and related events or events suggestive of urinary tract infection compared to glipizide. Most episodes of vulvovaginitis and balanitis were mild or moderate, responded to standard treatment, and rarely resulted in discontinuation from Forxiga treatment.1
Similarly, the extensive clinical development programme demonstrated that Forxiga had a positive benefit-risk profile across a wide range of patient populations (e.g. gender, age, race). Researchers found consistent results with secondary benefits, such as a reduction in body weight, in the double-blind, randomised, placebo-controlled clinical trials.1
The clinical programme also demonstrated that the frequency of hypoglycaemia depended on the type of background therapy used in each study.
For studies of Forxiga in monotherapy, as add-on to metformin or as add-on to sitagliptin (with or without metformin), the frequency of minor episodes of hypoglycaemia was similar (< 5%) between treatment groups, including placebo, up to 2 years of treatment. Across all studies, major events of hypoglycaemia were uncommon and comparable between the groups treated with Forxiga or placebo.1
Conclusion
“Many Europeans with type 2 diabetes are not reaching treatment goals, increasing their risk of developing complications, so there is a critical need for new treatments”, said John Wilding, Professor of Medicine and Honorary Consultant Physician, Head of Diabetes and Endocrinology Clinical Research Unit, University Hospital Aintree, UK. “Forxiga provides physicians with a completely new option to help improve glycaemic control that complements commonly used glucose-lowering treatments like metformin and insulin with additional benefits of weight loss.”
Forxiga is the first medicine in the new SGLT2 class to gain regulatory authorisation for the treatment of type 2 diabetes. It is not indicated as a weight loss product or for the management of obesity, and has only been studied for the treatment of type 2 diabetes.
References:
1- Forxiga Summary of Product Characteristics
2- Nauck M. et al. Poster 40-LB. Presented at the 71st Scientific Sessions of the American Diabetes Association, San Diego, California, June 24-28, 2011.
3- Nauck M. et al. Diabetes Care 2011. 34(9): 2015-22.