Marked HDL reductions may occur with fenofibrate plus thiazolidinedione

Patients with type 2 diabetes taking fenofibrate plus a thiazolidinedione may experience significant reductions in high-density lipoprotein (HDL) cholesterol, according to a recent study.

Researchers used data from the ACCORD Lipid Trial, a subset of the ACCORD Trial, to examine how frequently extremely low HDL levels occurred and whether they were associated with fenofibrate and thiazolidinedione treatment. The original objective of the ACCORD Lipid Trial was to test whether fenofibrate plus a statin would lower cardiovascular disease (CVD) event rates compared with a statin alone in high-risk patients with type 2 diabetes. Patients began taking open-label simvastatin at the randomization visit and began taking fenofibrate or placebo 1 month later.

The maximum dose of simvastatin was 40 mg/d; fenofibrate was initially administered at 160 mg/d, but the dose was decreased to 48 mg/d during the trial in patients whose estimated glomerular filtration rate was 50 mL/min/m² or lower. Most of the patients in ACCORD were taking rosiglitazone as a thiazolidinedione, although a few were taking pioglitazone. The main outcome measure of the current study was occurrence of extremely low HDL cholesterol levels during the ACCORD Lipid Trial. An extremely low HDL level was defined as less than 25 mg/dL. The study results were published online Dec. 2 by Diabetes Care.

Of 10,251 ACCORD patients, 5,518 were included in the ACCORD Lipid Trial. Enrollment took place from Jan. 11, 2011, until Oct. 29, 2005, and patients were followed until March 1 and June 30, 2009 (mean follow-up, 4.7 years; range, 4 to 8 years). Six hundred twenty-seven of the 10,251 patients were reported to have an HDL level below 25 mg/dL at an annual follow-up visit. The researchers found that extremely low HDL cholesterol levels were much more common in patients who were randomly assigned to receive fenofibrate than in those who were randomly assigned to receive placebo (10.1% vs. 4.9%; P<0.001). In addition, extremely low HDL levels were associated with concurrent treatment with both fenofibrate and a thiazolidinedione, occurring in 7.2% of patients on both drugs at 24 months after randomization and 7.0% at 48 months compared with 2.2% and 3.6%, respectively, in those receiving only fenofibrate.

The authors extrapolated that according to their data, up to 5% of patients with type 2 diabetes treated with fenofibrate and a thiazolidinedione could develop iatrogenic, significant decreases in HDL cholesterol. They noted that they could not rule out the possibility of large HDL decreases in some patients treated with fenofibrate alone or a thiazolidinedione alone, but they pointed out that they had found no increased overall prevalence of low HDL cholesterol levels in patients who were not taking a thiazolidinedione versus baseline. The authors also stressed that their study was not designed or powered to determine the potential effect of the HDL reductions on mortality. However, they concluded that clinicians should be aware of the potential for marked HDL reductions in patients with type 2 diabetes taking fenofibrate, especially in combination with a thiazolidinedione.

“Although the mechanism of iatrogenic reduction in HDL-[cholesterol] with combined fenofibrate and [thiazolidinedione] treatment is unknown and there is as yet no definitive proof of lack of harm, if the magnitude of the reduction in HDL-[cholesterol] is significant it may be appropriate to discontinue either fenofibrate or the [thiazolidinedione], and monitor HDL-[cholesterol] levels to confirm return to baseline levels,” the authors wrote.