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New FDA Extension for Farxiga and Xigduo XR

Mar 26, 2019
 
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy

Dapagliflozin’s updated package insert confirms efficacy and safety profile for patients with moderate chronic kidney disease.

Dapagliflozin is an antidiabetic agent that belongs to the class of sodium-glucose cotransporter 2 (SGLT-2) inhibitors. This medication works by enhancing glucose elimination via urine.

Dapagliflozin is supplied as brand name Farxiga and in a combination form with metformin HCL extended-release with brand name Xigduo XR. The U.S. Food and Drug Administration (FDA) approved the use of dapagliflozin for glycemic management as an adjunct to physical activities and diet for patients with type 2 diabetes mellitus in January of 2014.

Recently, it was announced by the drug manufacturer AstraZeneca that the FDA has approved a new label update for dapagliflozin. This update broadens the use of dapagliflozin in patients with type 2 diabetes and moderate chronic kidney disease (glomerular filtration rate [eGFR] of 45-59 mL/min/1.73 m2 ).

Originally dapagliflozin use was contraindicated in patients with eGFR 60 mL/min/1.73 m2. The new label expansion lowers the eGFR threshold to 45 mL/min/1.73 m2, therefore it offers the potential benefits of this medication to renally impaired patients with type 2 diabetes mellitus.

The new FDA approval on the label update is founded on the results of the DERIVE trial. This study was designed as the phase 3 trial to evaluate the efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment  with an eGFR of 45 to 59 mL/min/1.73 m2, otherwise known as chronic kidney disease stage 3A.

The DERIVE trial was a double-blind, parallel group, phase 3 study, conducted in 88 centers in the USA, Canada, Bulgaria, the Czech Republic, Italy, Poland, Spain and Sweden. This study included 321 individuals and randomized them with a 1:1 ratio into two arms. The study arm received dapagliflozin 10 mg versus or matching placebo for control arm for 24 weeks. The duration of study was divided into four periods, consisted of a 2-week screening period, a 4-week single-blind placebo lead-in period, a 24-week double-blind treatment period and a 3-week post-treatment follow-up period.

Participants were patients with type 2 diabetes who had an HbA1C of 7% to 11%  for a minimum of 12 months and were diagnosed with stage 3A CKD. Any patient with a history of diabetes insipidus, diabetic ketoacidosis or hyperosmolar nonketotic coma, and symptoms indicating poorly managed diabetes such as 2 or more major hypoglycaemic episodes within 3 months preceding to enrolment, were excluded from the study.

The primary efficacy outcome of DERIVE were defined as average change in HbA1c from baseline to the end of treatment period (Week 24). Additionally, secondary efficacy outcomes included an average change from baseline in fasting glucose, body weight, and seated systolic blood pressure at Week 24.

The safety objectives were the occurrence of any of the following adverse events: genital and urinary tract infections, hypotension/dehydration/hypovolaemia, renal impairment/failure, bone fractures and diabetic ketoacidosis (DKA). Moreover, average change in heart rate, from the baseline to the end of treatment period (week 24), average change in eGFR from the baseline to the end of treatment period, and to the end of post-treatment follow-up period were considered as safety objectives.

Results of the data analysis of the DERIVE trial presented that patients in the study arm who received dapagliflozin 10 mg experienced significant improvement HbA1c over 24 weeks of treatment period when compared to patients in control arm. The adjusted mean change in HbA1c difference between dapagliflozin and placebo was −0.34%  with P < 0.001. In terms of change in body weight, seated systolic blood pressure, and reduction in fasting glucose, dapagliflozin showed a significant improvement over the course of 24 weeks with P < 0.001, P < 0.05, and  P = 0.001 respectively.

In addition, it was noted that the average reduction of eGFR with dapagliflozin was -3.23 mL/min/1.73m2 in comparison to placebo -0.63 mL/min/1.73m2. Prevalence of any adverse events were seen with 41.9% of patients who were on dapagliflozin versus 47.8% of patients in placebo arm. Occurrence of adverse events included in the study objectives were reported to be 10.6% of patients with dapagliflozin and 6.2% with placebo. Urinary tract infection and pollakiuria were the most common side effects. There were no reported bone fractures or amputations in the study.

These results gave additional confirmation regarding the efficacy and safety profile for dapagliflozin, which led to the recent label extension. The newly approved label update allows dapagliflozin to be considered as a treatment option for a larger population of patients with type 2 diabetes with impaired renal function and provide them with a potential benefit for their glycemic management.

Practice Pearls:

  • Patients who received dapagliflozin had significant reductions in HbA1C compared with placebo.
  • Patients who received dapagliflozin had significant reductions in body weight, fasting glucose, and blood pressure compared with placebo.
  • The new FDA label extension approval broaden the use of dapagliflozin in CKD 3A patients.

References:

Fioretto, Paola et al. “Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study” Diabetes, obesity & metabolism vol. 20,11 (2018): 2532-2540.

“US FDA Approves Expanded FARXIGA and XIGDUO XR Labels for Use in Patients with Type 2 Diabetes and Moderate Renal Impairment.” AstraZeneca US, 27 Feb. 2019, www.astrazeneca-us.com/content/az-us/media/press-releases/2019/us-fda-approves-expanded-farxiga-and-xigduo-xr-labels-for-use-in-patients-with-type-2-diabetes-and-moderate-renal-impairment-02272019.html.

Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy