Fenofibrate Reduces Progression to Microalbuminuria Over 3 Years in a Placebo-controlled Study in Type 2 Diabetes

Results From the Diabetes Atherosclerosis Intervention Study (DAIS)

Ansquer J, Foucher C, Rattier S, Taskinen M, Steiner G, for the DIAS Investigators. Am J Kidney Dis. 2005;45:485-493.

Because microalbuminuria is an important predictor of both nephropathy and cardiovascular disease, interventions to prevent or delay microalbuminuria can have a significant impact on morbidity and mortality. The Diabetes Atherosclerosis Intervention Study (DIAS) aimed to reduce diabetic complications through treatment with micronized fenofibrate. The DIAS has already demonstrated that fenofibrate treatment is associated with a significant reduction in the progression of focal coronary atherosclerosis. This study used a representative subsample of 314 DIAS participants to determine whether correction of lipid abnormalities with fenofibrate was an effective method of reducing the progression of urinary albumin excretion among people with type 2 diabetes.

DIAS study participants had mild or moderate lipid abnormalities but no history of significant renal disease (defined as proteinuria of 500 mg/24 hours or albumin excretion of ≥200 µg, creatinine and/or creatinine levels of ≥1.7 mg/dL for men and ≥1.6 mg/dL for women). Timed overnight urine collections performed by participants were used to assess albumin excretion. Two or 3 baseline measures were taken prior to randomization, then blood and urine samples were collected at yearly intervals after randomization to placebo or 200 mg of micronized fenofibrate for a minimum of 3 years. For the purposes of analysis, participants were divided into 3 categories according to baseline albumin excretion rate: normoalbuminuria (albumin <20 µg/min), microalbuminuria (albumin = 20 µg/min to 200 µg/min), and macroalbuminuria (albumin ≥200 µg/min). All but 3 participants either had normoalbuminuria or microalbuminuria. Analysis of baseline characteristics revealed no significant clinical or biological differences between the placebo and treatment groups.

The results of the study demonstrated that fewer participants progressed from normoralbuminuria to some degree of albuminuria (progressors) in the fenofibrate group than in the control group (P=.031), a result that remained significant even after controlling for blood pressure (P=.037). At study end, among participants with normoalbuminuria at baseline, there were 3 progressors (3%) in the fenofibrate group compared with 20 (22%) in the placebo group (P<.001). Among patients who were treated with fenofibrate, progressors had a higher body mass index (BMI) and systolic blood pressure (SBP) than either regressors or participants who showed no change in albumin. Regressors were those participants who had some degree of albuminuria at baseline but returned to normoalbuminuria during the study.

Correlates of baseline albumin excretion included weight, BMI, SBP, diastolic blood pressure (DBP), A1C, triglycerides, creatinine, total homocysteine, and fibrinogen (all P<.05). Among placebo participants, albumin excretion at study end was significantly correlated with SBP, DBP, and A1C (all P<.05). Among fenofibrate participants, albumin excretion at study end was significantly correlated with creatinine level, SBP, and BMI (all P<.05). When data from both groups were analyzed together, changes in urinary albumin were unrelated to changes in homocysteine, creatinine, and fibrinogen levels. Changes in urinary albumin were related to changes in urinary creatinine in the placebo group and changes in weight in the fenofibrate group.

Overall, the results of this study support the hypothesis that micronized fenofibrate treatment can reduce the progression of urinary albumin excretion among people with type 2 diabetes. However, the study had limitations. First, during the course of the study, blood pressure and A1C were not optimally controlled, and study follow-up was not designed to assess the persistence of the treatment effect after the withdrawal of fenofibrate. Also, the small sample size of primarily early-stage type 2 diabetes patients and short study duration precluded the assessment of endpoints that would allow for comparison with angiotensin receptor blocker (ARB) trials. In spite of the limitations, these results demonstrate the importance of lipid control in the prevention of diabetic nephropathy.