A Pilot Randomized Clinical Trial to Assess Feasibility, Safety, and Efficacy of Rapid, Simultaneous Therapy Initiation in Chronic Kidney Disease and Type 2 Diabetes: RAPID-CKD

About This Grant

PROJECT SUMMARY Chronic kidney disease (CKD) is one of the leading causes of mortality worldwide. CKD affects ~10% of individuals globally, and the prevalence of CKD continues to rise. Approximately ~1 in 3 adults with CKD have type 2 diabetes (T2D). At any stage of CKD, patients with concurrent T2D and CKD are at heightened risk of cardiovascular disease and are six times more likely to die from cardiovascular complications than progressing to kidney failure. Given the high cardio-kidney risk, the guidelines advocate the use of various evidence-based therapies, including renin-angiotensin system inhibitors (RASi), sodium-glucose cotransporter 2 inhibitors (SGLT2i), nonsteroidal mineralocorticoid receptor antagonists (ns-MRA), and glucagon-like peptide-1 receptor agonists (GLP-1RAs). Subgroup analyses in landmark trials suggest a potential additive effect of these therapies compared to RASi individually. This beneficial effect is similar to heart failure (HF), where clinical trials have demonstrated the superiority of combination therapy without a significant increase in adverse events. However, usual clinical practice in CKD often involves a slow and sequential initiation of medications, which takes 18-24 months to initiate all four therapies, potentially delaying the benefits of combined therapy and increasing the risk of adverse outcomes and nonadherence during the interim period. A protocolized, rapid, and simultaneous initiation of multiple therapies over 8 weeks, akin to the intensive approach in HF, may improve outcomes and yield greater early reduction in major adverse cardiovascular events and CKD progression compared to the usual slow and sequential approach. However, the data from HF are not generalizable to CKD, and it is unknown if the rapid and simultaneous approach in CKD will lead to more hyperkalemia, acute kidney injury (AKI), and other safety events. For this purpose, we propose a pilot randomized trial to evaluate the feasibility, safety, and preliminary efficacy of rapid, simultaneous algorithm-based CKD therapy initiation versus usual care in patients with T2D and CKD over 6 months. Patients with T2D and CKD, with an estimated glomerular filtration rate (eGFR) of 45 to ≤90 mL/min/1.73 m2 and urine albumin-creatinine ratio (UACR) >200 mg/g, will be included. We will provide feasibility metrics in terms of enrollment, retention, adherence, and discontinuation to inform a larger, event-driven clinical trial. Furthermore, we will provide preliminary data on safety (≥30% decline in eGFR) and efficacy (change in UACR) of rapid and simultaneous therapy initiation in patients with T2D and CKD. The overarching hypothesis is that the rapid, simultaneous initiation of all four guideline- directed CKD therapies in patients with T2D and CKD will provide a greater reduction in cardiovascular and kidney events compared to usual care, without unacceptably higher risks, such as AKI and hyperkalemia.