A pilot study of fenofibrate to prevent kidney function loss in type 1 diabetes

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SUMMARY Despite improvements in the past 20 years in glycemic and blood pressure control, and the introduction of “reno-protective” drugs such as renin-angiotensin system blockers (RASB), the overall incidence of end- stage kidney disease (ESKD) in type 1 diabetes (T1D) remains high. To seek new treatments to prevent diabetic kidney disease (DKD) and/or slow its progression to ESKD in T1D, we have established a unique consortium of high-quality academic centers, which we have named PERL (Preventing Early Renal Function Loss in Diabetes) to emphasize the focus on intervening relatively early in the course of DKD in T1D, when renal damage can more likely be slowed or stopped. Findings from the FIELD and ACCORD trials suggest a reno-protective effect of the PPAR-alpha agonist fenofibrate, raising the exciting possibility of using this inexpensive generic drug to prevent GFR decline in persons with T1D. These data, however, were obtained through post-hoc analyses of T2D populations with clinical characteristics optimized for CVD studies. Thus, a clinical trial specifically designed to evaluate effects on GFR decline is required to firmly establish a DKD indication for fenofibrate in T1D. As a first step, and in response to FOA PAS-20-160 “Small R01s for clinical trials targeting diseases within the mission of NIDDK”, we have designed a pilot study including 40 participants with T1D and early-to-moderate DKD, at high risk of ESKD, who will be enrolled at two of the PERL sites and randomized in a 1:1 ratio to treatment with fenofibrate or placebo for 18 months. Through this pilot study we will: 1. Define the nature of the acute effect of fenofibrate on kidney function. It remains unclear whether the eGFR reduction observed at the beginning of fenofibrate treatment is an artifact of fenofibrate-induced changes in creatinine production and/or renal tubular handling, or corresponds to an actual reduction in GFR. We will resolve this controversy, which has crucial implications for the pivotal trial design, by directly measuring GFR by plasma iohexol disappearance – a methodology in which PERL sites are experienced. 2. Generate further data on the long-term effects of fenofibrate on GFR decline in persons with T1D and DKD who are at high risk of rapid GFR decline and ESKD. The positive effects of fenofibrate in FIELD and ACCORD were observed in individuals who were not selected for having DKD and who, if untreated, had a mean GFR decline barely above the physiological decline due to aging. To make a compelling case for a pivotal trial for kidney outcomes, it is crucial to generate preliminary data on the effectiveness and safety of this drug in persons selected for having DKD and being rapidly progressing towards ESKD. 3. Determine the effects of fenofibrate on biomarkers of increased risk of fast GFR decline. A salutary effect of fenofibrate on one or more of these biomarkers will corroborate any trend of a fenofibrate benefit identified in Aim 2. With the results of this pilot, we will be optimally prepared to apply to NIDDK for support of a pivotal trial to establish a kidney indication for fenofibrate in T1D.