Landmark phase 3 study shows ‘significant’ renal failure risk reduction in type 2 diabetes
Canagliflozin reduces the risk of renal and cardiovascular (CV) events and has an acceptable safety profile consistent with previous studies in people with type 2 diabetes, according to a major international study.
The CREDENCE (Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation) study met its primary endpoint showing that canagliflozin reduced the risk of composite of doubling of serum creatinine, end-stage kidney disease (ESKD) and renal or CV death by 30% [HR: 0.70; 95% CI:0.59 to 0.82; p<0.0001].
The findings were consistent across the individual components of the primary composite endpoint, as well as across all 15 subgroups tested.
Kidney disease develops in approximately 40% of people with type 2 diabetes. We have been waiting for new drugs to help us manage these patients for almost 20 years. The exciting results from the CREDENCE study provide renewed optimism for these patients. Professor David Wheeler
In addition, the CREDENCE trial achieved several further secondary endpoints which include; canagliflozin reduced the risk of the secondary renal endpoint composite of doubling of serum creatinine, ESKD, and renal death by 34% [HR0.66; 95% CI: 0.53 to 0.81; p<0.0001].; canagliflozin reduced the risk of major adverse cardiac events (MACE) (composite of non-fatal myocardial infarction, non-fatal stroke and CV death) by 20% [HR: 0.80; CI: 0.67 to 0.95; p=0.0121]; the risk of CV death and hospitalisation for heart failure by 31% [HR: 0.69; 95% CI: 0.57 to 0.83; p=0.0001]; and the risk of hospitalisation for heart failure alone by 39% [HR: 0.61; 95% CI: 0.47 to 0.80; p=0.0003]. In regard to safety data, the incidence rates of adverse events and serious adverse events were numerically lower for patients treated with canagliflozin as compared to placebo. There were no observed differences in the incidence of lower limb amputations (HR: 1.11; 95% CI: 0.79 to 1.56) or adjudicated fractures (HR: 0.98; 95% CI: 0.70 to 1.37).
Professor David Wheeler, Professor of Kidney Medicine at University College London, UK and Honorary Consultant Nephrologist at the Royal Free NHS Foundation Trust, University College London, said: “Kidney disease develops in approximately 40% of people with type 2 diabetes. We have been waiting for new drugs to help us manage these patients for almost 20 years. The exciting results from the CREDENCE study provide renewed optimism for these patients.”
Andrea Brown, spokesperson for the National Kidney Federation, said: “Effectively managing chronic kidney disease is a rapidly growing challenge for the NHS and we welcome any research that helps improve the management of this debilitating complication of type 2 diabetes. The exciting research from CREDENCE is the first positive dedicated trial of an antidiabetic agent in this area, showing how under-recognised the irreversible impact of chronic kidney disease and type 2 diabetes has been up until now.”
The data from CREDENCE provides an important update regarding slowing the progression of chronic kidney disease for this group of people with type 2 diabetes. The trial, which was stopped early in July 2018 due to a conclusive signal of efficacy in the prevention of the primary endpoint, was conducted in more than 4,400 adults with type 2 diabetes at 659 sites worldwide, including 37 locations across the UK.
In the UK, canagliflozin is indicated for the treatment of adults with insufficiently controlled type 2 diabetes as an adjunct to diet and exercise. The initiation dose is 100mg once daily in adults with an eGFR of ≥ 60 mL/min/1.73 m and can be increased to 300mg once daily if tighter glycaemic control is needed. Canagliflozin should not be initiated if eGFR is < 60 mL/min/1.73m. In patients tolerating canagliflozin whose eGFR falls persistently below 60 mL/min/1.73m the dose should be adjusted to or maintained at 100mg once daily. Canagliflozin should be stopped if eGFR falls persistently below 45 mL/min/1.73m.
|Professor John Wilding, Consultant Diabetologist, Liverpool
“The CREDENCE study looked at a specific group of people with type 2 diabetes and kidney disease who are very likely to develop kidney failure, requiring dialysis and kidney transplantation. It showed that canaglifolozin substantially reduced this risk (by 30%) over 2.5 years and confirmed findings from other trials showing reductions in heart attacks, heart failure and stroke in people with type 2 diabetes.”
|Julie Brake, Diabetes Specialist Nurse, Liverpool
“The study population in CREDENCE closely matched the characteristics of people we regularly see in practice which gives real value to the results. The important question around fractures and amputations has been well addressed with the comprehensive data from the study results.”
|Phillip Newland Jones, Consultant Pharmacist, Southampton
“While other studies have hinted at the renal benefits of SGLT2 inhibitors, none have been designed and specifically focussed on renal endpoints and mortality associated with them. CREDENCE is different from other studies and is built from a cohort of patients that covers a range of severities of kidney disease. From a clinical perspective it provides useful data to support identification of the right treatment, for the right person and reminds us that one must look deeper than the glucose related benefits of diabetes medicines when considering the holistic support of people with diabetes.”
|Professor Wasim Hanif, Consultant Diabetologist, Birmingham
“The CREDENCE trial adds to the body of evidence on the role of SGLT-2 inhibitors in Cardio-Metabolic-Renal management of people with type 2 diabetes. In a high risk population for progression to End stage renal disease it demonstrated a 34% reduction which has a huge clinical benefit to my patients. Additionally, it showed cardiovascular benefit with reassurance around side effects previously ascribed with this class of agents.”