The results of two major outcome trials — CREDENCE and CARMELINA — targeting patients with type 2 diabetes and chronic kidney disease (CKD) were presented on Tuesday, June 11, the final day of the 79th Scientific Sessions in San Francisco, CA.
CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) was designed to primarily assess progression of kidney disease and secondarily cardiovascular (CV) outcomes. CARMELINA (Cardiovascular and Renal Microvascular outcome study with Linagliptin in Patients with Type 2 Diabetes Mellitus) primarily assessed CV outcomes and secondarily kidney disease progression.
CREDENCE results show canagliflozin improves CV and renal outcomes in type 2 diabetes patients with CKD
For patients with CKD and type 2 diabetes, the SGLT2 inhibitor canagliflozin has a renal and cardiovascular protective effect in reducing the progression of kidney impairment, according to results of the CREDENCE trial presented at the Scientific Sessions. CREDENCE is the first study in 18 years to demonstrate that a drug can improve cardiovascular and renal outcomes in patients with type 2 diabetes and CKD, regardless of their previous history of cardiovascular disease.
CREDENCE was a randomized, double-blind controlled trial that ended early after a planned interim analysis indicated an overwhelming benefit. At the time the study was stopped, 4,401 participants with a mean age of 63 years and an average duration of type 2 diabetes of 15.8 years had enrolled and received follow-up for an average 2.62 years. The study participants had A1C levels between 6.5 percent and 12 percent, with an estimated glomerular filtration rate (eGFR) between 30 to 90 milliliters/minute/1.73 meters2. The participants were assigned to receive 100mg of oral canagliflozin daily or placebo.
“We found that canagliflozin reduced the risk of end-stage kidney disease, doubling of serum creatinine, or renal or cardiovascular death by 30 percent, and reduced dialysis, transplantation, or renal death by 28 percent,” said CREDENCE co-investigator Meg Jardine, MD, PhD, Associate Professor of Medicine at the University of New South Wales in Australia and Program Head at the George Institute for Global Health. “Additionally, we saw no observed difference in canagliflozin for fracture or amputation, and safety was as you would otherwise expect from the class.”
CARMELINA trial demonstrates safety of linagliptin in type 2 diabetes patients at high risk for CV or renal disease
When added to usual care in patients with type 2 diabetes at increased risk of cardiovascular and/or renal disease, the DPP-4 inhibitor linagliptin resulted in cardiovascular and renal events comparable to placebo over a median period of 2.2 years across a broad range of age and kidney function variables, according to results from the CARMELINA trial.
CARMELINA was a large, international, randomized, placebo-controlled, multicenter noninferiority trial conducted from 2013 to 2016 at 605 clinic sites in 27 countries. The study included 6,979 adults with type 2 diabetes who were randomized to receive placebo or 5 mg of linagliptin once daily plus usual diabetes care. The primary outcome measure was the time to first occurrence of the composite of CV events (CV death, nonfatal myocardial infarction, or nonfatal stroke). The key secondary outcome was time to first occurrence of a composite of adjudication-confirmed renal death, end-stage kidney disease, or a sustained decrease in eGFR of 40 percent or greater from baseline.
“We observed no increased risk for CV, heart failure, or kidney outcomes with linagliptin relative to placebo, hence demonstrating safety in this vulnerable population enriched for the presence of CKD,” said CARMELINA study co-chair Darren K. McGuire, MD, MHSc, Distinguished Teaching Professor and the Dallas Heart Ball Chair for Research on Heart Disease in Women at the University of Texas Southwestern Medical Center.
“In addition, we observed a significant risk reduction for worsening of albuminuria and significantly improved glycemic control with linagliptin versus placebo, without increasing risk for hypoglycemia,” he continued. “These data advance the evidence base for treatment options in people with reduced kidney function, for whom many therapies are contraindicated, or at least used with high caution.”