Darren K. McGuire, MD, MHSc
Results from the CREDENCE and CARMELINA clinical trials, both of which targeted patients with type 2 diabetes and chronic kidney disease (CKD), will be presented at 7:30 a.m. Tuesday in N-Hall E (North, Exhibition Level).
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.
ADAMeetingNews.org asked CARMELINA study co-chair Darren K. McGuire, MD, MHSc, to discuss the background, objective, and significance of the study. Dr. McGuire is Distinguished Teaching Professor and the Dallas Heart Ball Chair for Research on Heart Disease in Women at the University of Texas Southwestern Medical Center.
Study Background
Dr. McGuire: Up to 40 percent of people with type 2 diabetes will develop CKD and a substantial number will progress to advanced stages of CKD, including end-stage kidney disease (ESKD). People with type 2 diabetes and any level of CKD have an increased risk of death, cardiovascular events, heart failure events, and kidney failure, as well as a reduced quality of life. In addition, individuals with CKD tend to be less well controlled for CV risk factors and have lower glycemic goal attainment. This is particularly marked for those with advanced kidney disease. Thus, there’s a substantial need to develop treatments that might preserve kidney function in diabetes, and also treatments that safely improve glycemic control in this high-risk population. However, data regarding the safety and efficacy of antihyperglycemic therapies in people with existing kidney disease are generally limited, including advanced CKD.
CARMELINA Objective/Methods
Dr. McGuire: CARMELINA was a multicenter, international, randomized, double-blind trial in patients with type 2 diabetes at high risk for CV and kidney disease outcomes with a median trial follow-up of 2.2 years. It was conducted at 605 centers in 27 countries and included adults with type 2 diabetes, A1C 6.5–10.0 percent, at high CV risk, or high renal risk.
The trial was event driven until a minimum of 611 participants had experienced a primary outcome event (time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke [3P-MACE]). The key secondary outcome was time to first occurrence of a composite of adjudication-confirmed renal death, ESKD, or a sustained decrease of ≥40 percent in eGFR (estimated glomerular filtration rate) from baseline. It was anticipated that 432 participants would experience the key kidney outcome event during the same period needed to accrue the 611 3P-MACE events. Additional analyzed outcomes included effects on heart failure, UACR (urine albumin-to-creatinine ratio), hyperglycemia, and hypoglycemia.
CARMELINA Significance
Dr. McGuire: The primary results of the CARMELINA trial (JAMA 2019; 321:69-79) demonstrated 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. 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. These data therefore advance the evidence base for treatment options in people with reduced kidney function, where many therapies are contraindicated or are to be used with high caution.
The presentation at the Scientific Sessions will provide further updates of results from this first large and dedicated cardio-renal outcome trial in people with type 2 diabetes, including further analyses of effects in the more vulnerable participants, i.e., those with the poorest renal function and the elderly.
More about CREDENCE
The CREDENCE trial is the first randomized, double-blind, clinical outcome trial specifically designed and powered to assess the effects of an SGLT2 inhibitor, canagliflozin, compared to placebo on major kidney outcomes. The trial was stopped early at a planned interim analysis on the advice of the Data Monitoring Committee, having achieved prespecified efficacy criteria. Data from CREDENCE presented at the Scientific Sessions could have substantive impact on clinical practice for type 2 diabetes patients at high renal risk.
