The findings represent the first in a new wave of renal outcomes trials in the sodium glucose co-transporter 2 (SGLT2) inhibitor class, a game-changing group of type 2 diabetes drugs with many benefits beyond lowering blood glucose.
Investigators will present phase 3 results from the CREDENCE trial late Sunday, which could advance the position of the type 2 diabetes (T2D) drug canagliflozin weeks after Janssen Pharmaceuticals filed with FDA for an indication for chronic kidney disease (CKD) in patients with T2D. The findings will come 6 months after canagliflozin received an indication to reduce the risk of major cardiovascular (CV) events in patients with T2D.
Results for CREDENCE have been anticipated since July 2018, when an independent data monitoring committee ended the trial early after finding that canagliflozin, sold by Janssen as Invokana, met the prespecified criteria for efficacy. The findings from Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) will be presented in Melbourne, Australia, during the 2019 World Congress of Nephrology in Melbourne, Australia, hosted by the International Society of Nephrology.
The CREDENCE trial is the first dedicated phase 3 renal outcomes study of any sodium glucose co-transporter 2 (SGLT2) inhibitor in patients with T2D and CKD in addition to standard of care. The study randomized 4401 patients in a double-blind, event-driven, placebo-controlled, 2-arm, study. All patients had T2D and either stage 2 or stage 3 CKD. This was defined as an estimated glomerular filtration rate (eGFR) of ≥30 to <90 mL/min/ 1.73m2) and macroalbuminuria, defined as urinary albumin-to-creatinine ratio >300 to ≤5000 mg/g), who were receiving standard of care including a maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker.
Based on the results from CREDENCE, Janssen announced in a March 28, 2019, statement that it had submitted a supplemental New Drug Application (sNDA) to the FDA seeking a new indication for canagliflozin to reduce the risk of end-stage renal disease (ESRD), the doubling of serum creatine, as well as CV and renal death in adults with CKD and T2D. Canagliflozin is currently contraindicated for patients with severe renal impairment, end-stage renal disease, or patients on dialysis.
James F. List, MD, PhD, global therapeutic area head of Cardiovascular & Metabolism for Janssen said in a statement, “Today, millions of people living with type 2 diabetes and chronic kidney disease are at high risk of experiencing kidney failure, and unfortunately, we have not seen treatment innovation for these patients in almost 20 years. Janssen’s application is a significant step toward bringing a much-needed, new standard of care for those living with these serious conditions. We look forward to presenting the CREDENCE data at the ISN World Congress of Nephrology and working closely with the FDA to bring this important medicine as quickly as possible to people living with type 2 diabetes and chronic kidney disease.”
Besides lowering blood sugar, SGLT2 inhibitors have been found to reduce hypertension, help patients lose modest amounts of weight, and reduce hospitalization for heart failure. After a wave of cardiovascular outcomes trials (CVOTs) revealed unexpected benefits from the class, the American College of Cardiology and the American Heart Association recently added SGLT2 inhibitors to its primary prevention guidelines for patients with T2D and atherosclerotic cardiovascular disease.
The CREDENCE findings will be the first in a new wave of renal outcomes trials, representing the next phase of competition among the 3 top-selling drugs in the SGLT2 inhibitor class, which work by targeting a protein that affects reuptake of glucose by the kidneys back into the bloodstream. Patients who take the drug excrete glucose out of the body through the urine. Both AstraZeneca, maker of dapagliflozin (Farxiga), and Eli Lilly and Boehringer Ingelheim, makers of empagliflozin (Jardiance), have renal outcomes trials under way. DAPA-CKD for dapagliflozin is due to report in November 2020, and EMPA-KIDNEY for empagliflozin is due in June 2022.
In late February, the SGLT2 inhibitor dapagliflozin, sold as Farxiga by AstraZeneca, received approval for a label update expanding its use in patients with T2D and moderate renal impairment, defined as CKD with eGFR of 45-59 mL/min/1.73m2. The update extended to AstraZeneca’s Xigduo XR brand, which combines dapagliflozin with metformin HCI extended-release. The updated labels lower the eGFR threshold to 45mL/min/1.73m2 from 60mL/min/1.73m2. The drug remains contraindicated for patients with ESRD or in dialysis. This label change brought dapagliflozin in line with the other top-selling SGLT2 inhibitors, as both doses of empagliflozin, sold by Eli Lilly and Boehringer Ingelheim as Jardiance, and the 100 mg dose of canagliflozin are indicated for these patients. A drug in the class approved more recently, ertugliflozin (Steglatro, by Merck/Pfizer) is not recommended for patients with moderate renal impairment.
Janssen’s sNDA submission came a day after the American Diabetes Association announcement that it had updated 3 sections of its 2019 Standards of Medical Care in Diabetes (Standards of Care), to reflect results of a separate trial involving dapagliflozin, the Dapagliflozin Effect on Cardiovascular Events-Thrombosis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial. The CVOT presented in November 2018 at the American Heart Association found that dapagliflozin showed a reduction of hospitalization for heart failure and a reduction of progression of CKD.
DECLARE-TIMI 58 was a multi-national, randomized, double-blind, placebo-controlled phase 3B CVOT jointly led by the TIMI Study Group and Hadassah Medical Center conducted to assess the safety and efficacy of dapagliflozin for individuals with T2D and either CVD or multiple risk factors. It randomized approximately 17,150 patients and was the first CVOT with 2 co-primary endpoints: The primary endpoints were (1) incidence of CV death, myocardial infarction, or ischemic stroke and (2) incidence of CV death or hospitalization from heart failure.