Optimizing the Safety of the Newer Diabetes Medications in Patients with Diabetes and Kidney Disease

Sodium glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP- 1RA) are rapidly changing the therapeutic landscape for patients with diabetes and kidney disease, but are underutilized in high-risk populations. Randomized controlled trials (RCTs) have robustly demonstrated the cardiovascular and renoprotective benefits of these agents. For the first time in decades, we have new drugs to slow kidney disease progression, yet newer medication classes are still underprescribed in patients with DKD. One of the major prescribing barriers is the lack of safety data in real-world patients with DKD, a complex, older population with multimorbidity and polypharmacy, who are at greater risk for adverse events and drug-drug interactions (DDIs), but who are underrepresented or excluded from RCTs. This dearth of safety data cannot be addressed by RCTs, since the RCTs were powered for effectiveness, not safety, did not represent real-world patients with DKD who are an older, frailer population, and did not address DDIs in this population with a high burden of polypharmacy. Yet, over time, these drugs should and will be prescribed to a broader spectrum of patients with DKD. Methodologically rigorous studies using large, national healthcare databases are an ideal vehicle to address these knowledge gaps with much larger sample sizes than in RCTs across the broad spectrum of patients with DKD. Our overarching goal is to develop a framework to optimize the safety of newer diabetes medications in real-world patients with DKD. We will investigate kidney-related and other safety outcomes that were not systematically evaluated in RCTs in patients with DKD, using a new- user, active comparator cohort approach (Aim 1). We will develop two safety monitoring approaches to assess both anticipated and unanticipated adverse event signals associated with the newer diabetes medications as they are used in real-world patients with DKD (Aim 2). Patients with DKD are at higher risk for DDIs since they are older with impaired kidney function and have more multimorbidity and polypharmacy. We propose a novel two-stage screening approach to detect and evaluate clinically relevant drug-drug interactions that could affect the safety profile of newer diabetes medications in patients with DKD (Aim 3). This proposal will advance our understanding of these drugs’ safety and, thus, will help overcome barriers to prescribing in patients with DKD who may largely benefit from them. The filling of critical knowledge gaps and new insights regarding safe prescribing will significantly influence the clinical management of patients with DKD.