Combination of fenofibrate plus low-dose nicotinic acid added to statin treatment in type 2 diabetes: An open-label, crossover study.

BACKGROUND

Plasma lipid abnormalities commonly persist in patients with diabetic dyslipidemia in spite of statin monotherapy.

OBJECTIVE

The aim of this study was to determine whether fenofibrate plus low-dose nicotinic acid adequately improves the lipoprotein profile in patients with diabetic dyslipidemia who are being treated with a statin.

METHODS

In this open-label, crossover study, patients with type 2 diabetes mellitus who were receiving statin treatment were enrolled at the Lipid Clinic of the Veterans Affairs Medical Center, Dallas, Texas, and administered simvastatin 20 mg/d for 8 weeks. At the end of the 8-week period, fenofibrate 160 mg/d was added for 8 weeks, followed by the addition of extended-release nicotinic acid 1 g/d for an additional 8 weeks. The first subject was recruited on September 25, 2003, and the last subject was recruited on September 28, 2004. Liver function tests, creatine phosphokinase activity, and blood glucose levels were assessed every 4 weeks to assess tolerability. Levels of fasting plasma lipids and lipoprotein cholesterol were measured every 8 weeks on 3 consecutive days in each patient; C-reactive protein, lipoprotein pattern, and glycosylated hemoglobin levels were assessed once every 8 weeks. Plasma levels of total cholesterol, triglycerides, very-low-density lipoprotein plus intermediate-density lipoprotein cholesterol (VLDL+IDL-C), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B were also measured.

RESULTS

Twenty-six patients were enrolled in the study and 20 patients (18 men, 2 women; mean [SD] age, 58.8 [6.5] years) completed it. The mean plasma triglyceride level was significantly decreased (-29.2%; P= 0.004) and the mean HDL-C level was significantly increased (+13.5%; P < 0.001) with 3-drug treatment (simvastatin + fenofibrate + extended-release nicotinic acid) compared with simvastatin monotherapy. Significant reductions in plasma levels of VLDL+IDL-C (-35.7%; P = 0.001), VLDL+IDL-apolipoprotein B (-30%; P = 0.005), non-HDL-C (-12.9%; P = 0.001), and total-apolipoprotein B (-17.9%; P < 0.001) were seen with the 3-drug treatment compared with simvastatin alone. Compared with simvastatin monotherapy, simvastatin + fenofibrate-treated (2-drug treatment) patients had significantly lower plasma levels of triglycerides (-24.9%; P = 0.014) and significantly higher levels of HDL-C (+5.4%; P = 0.008). Significant reductions were also seen in levels of VLDL+IDL-C (-28.6%; P = 0.004), VLDL+IDL-apolipoprotein B (-26.7%; P < 0.001), non-HDL-C (-9.1 %; P= 0.004), and total-apolipoprotein B (-12.3%; P < 0.001) in the 2-drug treatment group compared with the simvastatin monotherapy group. The administration of 3-drug treatment was associated with improved responses in all lipoprotein fractions, although only the increase in HDL-C level was statistically significant (+7.7%; P = 0.008) compared with 2-drug treatment.

CONCLUSIONS

Treatment with the 3-drug regimen was associated with a significant reduction in triglyceride levels compared with simvastatin monotherapy. However, there was not a significant incremental reduction in triglyceride levels when nicotinic acid was added to the 2-drug treatment, suggesting that the triglyceride-lowering effect of fenofibrate + nicotinic acid is not cumulative. To obtain clinically meaningful responses, particularly for the treatment of elevated HDL-C, higher doses of nicotinic acid might be required.