Efficacy and Safety of Dapagliflozin in Patients with Type 2 Diabetes and Moderate Renal Impairment (Chronic Kidney Disease Stage 3A): The DERIVE Study

Presentation Number: OR27-1
Date of Presentation: March 19, 2018, 2018

Paola Fioretto, MD, PhD1, Stefano Del Prato, MD2, Ronald Goldenberg, MD3, Francesco Giorgino, MD, PhD4, Daniel Reyner, DrPH, MS5, Anna Maria Langkilde, MD, PhD6, C. David Sjӧstrӧm, MD, PhD6, Peter Sartipy, MSc, PhD6.
1University of Padova, Padova, Italy, 2University of Pisa, Pisa, Italy, 3LMC Diabetes & Endocrinology, Thornhill, ON, Canada, 4University of Bari Aldo Moro, Bari, Italy, 5AstraZeneca, Gaithersburg, MD, USA, 6AstraZeneca, Gothenburg, Sweden.

Abstract

Dapagliflozin (DAPA) is a selective inhibitor of sodium glucose co-transporter 2 (SGLT2), which causes glucosuria and lowering of blood glucose in patients with type 2 diabetes (T2D). SGLT2 inhibitors also lead to body weight (BW) and blood pressure (BP) reductions. The extent of glucose lowering with DAPA is dependent on renal function and the amount of filtered glucose. Previous studies have shown that the glycemic efficacy of SGLT2 inhibitors is attenuated in patients with T2D and moderate renal impairment (chronic kidney disease [CKD] Stage 3; eGFR 30-59 mL/min/1.73m2); however, beneficial effects on BW and BP have been observed in this population. DERIVE (NCT02413398) randomized 321 patients with T2D (HbA1c 7-11%) and moderate renal impairment (CKD Stage 3A; eGFR 45-59 mL/min/1.73m2), and assessed the efficacy and safety of DAPA 10 mg vs placebo (PBO) over 24 weeks. The primary endpoint was mean change from baseline (BL) in HbA1c at Week 24. Secondary endpoints were mean changes from BL in BW, fasting plasma glucose (FPG) and systolic BP (SBP) at Week 24. Patients were randomized to DAPA 10 mg (N=160) or PBO (N=161); randomization was stratified by background glucose-lowering medication. BL values were balanced between treatment arms. At Week 24, DAPA significantly decreased HbA1c vs PBO (difference vs PBO [95% CI]: −0.34% [−0.53, −0.15], p<0.001). DAPA also significantly reduced BW (difference vs PBO [95% CI]: −1.43% [−2.15, −0.69], p<0.001); FPG (difference vs PBO [95% CI]: −16.59 mg/dL [−26.73, −6.46], p=0.001) and SBP (difference vs PBO [95% CI]: −3.1 mmHg [−6.3, 0.0], p<0.05). DAPA was associated with decreases from BL in eGFR compared with PBO after 4 weeks (difference vs PBO [95% CI]: −4.87 mL/min/1.73m2 [−6.69, −3.05]), 12 weeks (−4.71 mL/min/1.73m2 [−6.94, −2.49]), and 24 weeks (−2.60 mL/min/1.73m2 [−5.03, −0.16]), but returned to baseline at Week 27 (3-weeks post last dose) (difference vs PBO [95% CI]: 0.61 mL/min/1.73m2 [−1.59, 2.81]). In the DAPA group, one patient met a pre-defined safety objective of worsening renal insufficiency (defined as patients reaching confirmed eGFR <30 mL/min/1.73 m2). Overall, DAPA was well-tolerated with a safety profile comparable to that previously established. Adverse events (AEs) were balanced between treatment arms, with fewer AEs and serious AEs reported with DAPA vs PBO (AEs: 41.9 vs 47.8%; serious AEs: 5.6 vs 8.7%, respectively). The numbers of AEs leading to discontinuation of study medication were also balanced between DAPA and PBO (1.9% in both groups). Patients in the DAPA and PBO arms had similar frequencies of urinary tract infection (2.5 vs 3.7%), genital infection (1.9 vs 1.2%), and hypoglycemia (12.5 vs 13.7%). No bone fractures were reported in the study. These findings of the DERIVE study support the positive benefit/risk profile of DAPA 10 mg for the treatment of patients with T2D and CKD Stage 3A. Funded by AstraZeneca*Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Disclosures

  P. Fioretto: Advisory Board Member; Self; AstraZeneca, Eli Lilly & Company, Boehringer Ingelheim. Speaker; Self; AstraZeneca, Eli Lilly & Company, Boehringer Ingelheim. S. Del Prato: Advisory Board Member; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, GlaxoSmithKline, Intarcia, Jansen Pharmaceuticals, Merck & Co., Novartis Pharmaceuticals, Novo Nordisk, Servier, Sanofi, Takeda. Research Investigator; Self; Merck & Co., Novartis Pharmaceuticals, Boehringer Ingelheim, AstraZeneca. Speaker; Self; Boehringer Ingelheim, Novartis Pharmaceuticals, Takeda. R. Goldenberg: Advisory Board Member; Self; Amgen Inc, Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Jansen Pharmaceuticals, Merck, Novo Nordisk, Sanofi, Takeda, Valeant. Research Investigator; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Jansen Pharmaceuticals, Merck, Novo Nordisk, Sanofi, Takeda. Speaker; Self; Amgen Inc, Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Jansen Pharmaceuticals, Merck, Novo Nordisk, Sanofi, Servier, Mylan, Valeant. F. Giorgino: Advisory Board Member; Self; AstraZeneca. Consulting Fee; Self; AstraZeneca, Sanofi, Abbott Laboratories, Boehringer Ingelheim, Eli Lilly & Company, Merck, MedImmune, Roche Diabetes Care. Grant Recipient; Self; Eli Lilly & Company, Takeda, LifeScan. Research Investigator; Self; Eli Lilly & Company. Speaker; Self; AstraZeneca, Eli Lilly & Company. D. Reyner: Employee; Self; AstraZeneca. A. Langkilde: Employee; Self; AstraZeneca. Stock Owner; Self; AstraZeneca. C. Sjӧstrӧm: Employee; Self; AstraZeneca. Stock Owner; Self; AstraZeneca. P. Sartipy: Employee; Self; AstraZeneca. Stock Owner; Self; AstraZeneca.