Detecting Renal Protective Effects Of Antidiabetic Medications Among Patients With Type Ii Diabetes Mellitus And Diabetic Kidney Disease

Abstract

Diabetic Kidney Disease (DKD) is a serious renal related complication for patients with both type 1 and type II diabetes; approximately 30-40% of type II diabetes cases will develop DKD. Regular management of DKD includes dietary modification, losing weight, changing lifestyle, monitoring blood glucose levels, managing hypertension and using antidiabetic medications. However, the selection of antidiabetic medications for delaying or preventing renal impairment is limited. Although some Randomized Controlled Trials (RCTs) for estimating the effect of these drugs on DKD have been completed for few antidiabetic medications, such as sodium-glucose cotransporter-2 inhibitors (SGLT2i) and a few other antidiabetic drugs, the trials of many other antidiabetic medications have not been tested or are incomplete. Some investigations have been conducted on DKD using electronic health record (EHR data), the recent FLOW clinical trial (NN9535-4321) shows that Ozempic, a GLP-1RA medication, can effectively treat patient with DKD, but renal effects of various antidiabetic medications like DPP-4 inhibitors on DKD remain unknown. Better understanding of how antidiabetic medications affect renal function in clinical settings, and implementation of best practices for DKD management care are truly needed. The overall goal of this research is to identify renal protective effects of antidiabetic medications (ADMs) among type II diabetes mellitus patients progressing to DKD. To address this goal, three studies were conducted in this dissertation. The first study aims to analyze trends of antidiabetic medication use in patients with type II diabetes mellitus and DKD. We illustrate the trends of common ADM utilization from five years before to five years after patients’ DKD diagnoses. The study demonstrated informative ADM use change patterns before and after DKD diagnosis, and showed that ADM use changes were consistent with practice guidelines from the American Diabetes Association (ADA) and other diabetic organizations. This systematically reflected how healthcare providers adjusted ADMs as patients progressed towards DKD in the real world. The second study researched comparative effectiveness in combinations of antidiabetic medications on renal impairment of type II diabetes. Three combination groups, metformin-GLP-1 RA, metformin-DPP-4i and metformin-other antidiabetic medications (oADMs), were identified in this study. The study indicated that the combination of metformin-GLP-1 RA treatment is associated with beneficial effects on renal function and reduction of all cause death compared to combination metformin-DPP-4i treatment and combination metformin-other ADMs treatment. The metformin-DPP-4i group did not show protective effects on kidney function or reduction of all-cause death when comparing metformin with either combination of metformin-GLP-1 RA or combination of metformin- other antidiabetic medications (oADMs). The third study focused on a competing-risk analysis for renal impairment events, death and antidiabetic medications among patients with type II diabetes mellitus. Three combination groups – metformin-GLP-1 RA, metformin-DPP-4i and metformin-oADMs were also used to analyze the time to renal events. This study evaluated the marginal probability of a renal impairment event in the presence of death as a competing risk in patients with Type II Diabetes Mellitus (T2DM) with different combination treatments of ADMs. This research revealed that the metformin-GLP-1 RA treatment group had less risk to develop a 50% eGFR decline, or composite outcome with 50% eGFR decline, ESRD, dialysis and renal transplantation, compared to the metformin-DPP-4i group and metformin-oADMs group. However, the metformin-DPP-4i group did not show protective effects in evaluating risk to develop those renal events compared to the metformin-DPP-4i group and metformin-oADMs group. All studies demonstrated that the EHR-based health data of T2DM patients with DKD is a great source for clinical informatics research with respect to the effectiveness of ADMs. This dissertation provided an unprecedented picture of how ADMs were adjusted by healthcare providers as patients had been diagnosed with DKD in the real world. We also successfully identified the combination ADM therapy cohorts and compared the effectiveness of ADM combinations on kidney function among T2DM patients. Research results showed that the combination of metformin-GLP-1 RA treatment is associated with beneficial effects on renal function and reduction of all cause death compared to combination metformin-DPP-4i treatment and combination metformin-other ADMs treatment. The metformin-DPP-4i group did not show protective effects on kidney function or reduction of all cause death compared to either combination of metformin-GLP-1 RA or combination of metformin-oADM. Survival analyses and competing risk analysis can be successfully applied to research comparative effectiveness of ADMs, as death was computed as a competing risk. The cause-specific regression model and the Fine-Gray subdistribution hazard model presented similar results in assessing renal impairment events among the different combinations of ADMs.