Fenofibrate Lowers Plasma Triglycerides and Increases LDL Particle Diameter in Subjects With Type 2 Diabetes

Subjects with type 2 diabetes have an increased risk of coronary artery disease (CAD). The typical dyslipidemia in type 2 diabetes consists of hypertriglyceridemia, low HDL cholesterol level, and preponderance of small, dense LDL particles. Epidemiological studies have linked all these lipid abnormalities with CAD. The Diabetes Atherosclerosis Intervention Study (DAIS) has recently reported that treatment with fenofibrate results in favorable changes in the plasma lipid profile and a significant reduction in the progression of CAD in subjects with type 2 diabetes (1). We have now determined the long-term effect of fenofibrate on LDL peak particle diameter in 46 Finnish DAIS study participants with type 2 diabetes.

The baseline characteristics in our DAIS subpopulation were similar to those in the whole cohort (2). Subjects were randomly assigned micronized 200 mg fenofibrate once daily (n=25) or placebo (n=21) for at least 3 years. Data obtained at randomization were used as the baseline data, and the data obtained at the final on-treatment visit were used as the on-treatment data. Biochemical analyses were performed as previously described (3). LDL peak particle diameter (LDL size) was obtained using polyacrylamide 2–10% gradient gels. Postheparin lipoprotein lipase (LPL) and hepatic lipase (HL) activities were measured as previously described (4). Posttreatment values between fenofibrate and placebo groups were compared with ANCOVA using respective baseline values as a covariate. Multivariate forward stepwise regression analysis was performed to find the determinants of the change in LDL diameter. Changes in plasma lipids and lipoproteins, HbA_1c, BMI, and lipase activities were used as independent variables.

LDL size, lipid and lipoprotein concentrations, LPL and HL activities, glycemic control, BMI, and sex distribution at baseline were similar in fenofibrate and placebo groups. Mean glycemic control, BMI, and HL activity did not change significantly in either group during the study. Treatment with fenofibrate was associated with significant changes in the plasma lipid profile. Specifically, LDL size was larger and plasma triglycerides, total and LDL cholesterol concentrations, and total cholesterol-to-HDL cholesterol ratio were lower in the fenofibrate group than in the placebo group at the end of the study (Table 1). The difference in HDL cholesterol concentration did not reach significance. LPL activity at the end of the study was higher in the fenofibrate group than in the placebo group.

In the fenofibrate group, only change in plasma triglycerides (r=−0.57, P=0.003) and change in HDL cholesterol (r=0.49, P=0.012) were significantly correlated with change in LDL diameter. Change in plasma triglycerides was, as expected, inversely correlated with change in HDL cholesterol (r=−0.49, P=0.013). The association between change in LPL activity and change in triglycerides was of borderline significance (r=−0.38, P=0.062). In the placebo group, only change in plasma triglycerides was significantly correlated with change in LDL diameter (r=−0.45, P=0.042). In multivariate regression analysis, the change in plasma triglyceride concentration was the only variable to enter the model, explaining 30% of the variation of LDL size in the fenofibrate group (P=0.003) and 16% in the placebo group (P=0.042).

The main result of our study is that long-term treatment with fenofibrate lowers plasma triglycerides and increases LDL peak particle diameter in subjects with type 2 diabetes. Almost all subjects in the fenofibrate group had a decrease in plasma triglyceride concentration, the average decrease being 0.7 mmol/l (36%). The decrease of plasma triglycerides was strongly associated with a significant increase in LDL peak particle diameter. It is likely that the increase in LPL activity is one of the mechanisms by which fenofibrate decreases plasma trigyceride concentration (5). These results add support to the theory that LDL size and composition can be modified by changes in ambient lipoprotein concentrations and lipoprotein-modifying enzyme activities.

Cross-sectional and prospective studies have linked small, dense LDL particles and CAD (6,7). However, close connections between LDL diameter and density, triglyceride-rich lipoproteins, and HDL cholesterol have made it difficult to determine which of these variables truly has a central role in the development of atherosclerosis. DAIS has recently reported that treatment with fenofibrate reduces the angiographic progression of CAD in type 2 diabetes (1). Based on our results, the change in LDL particle distribution toward larger, probably less atherogenic particles should be included as one potential mechanism accounting for the beneficial effect of fenofibrate. Further studies are required to elucidate the clinical significance of small, dense LDL particles.