This post hoc analysis of a 52-week safety and efficacy study of fenofibric acid in combination with moderate-dose statin demonstrated that in patients who were at goal for LDL-C (<100 mg/dL), but had persistent elevated TG (>200 mg/dL) after 12 weeks of treatment with a moderate dose-statin, the long-term addition of fenofibric acid resulted in significant improvements in non–HDL-C, ApoB, HDL-C, and TG. In addition, the proportion of patients achieving optimal levels of non–HDL-C, ApoB, HDL-C, and TG, as well as combined targets of these variables and LDL-C increased from baseline to final visit with the addition of fenofibric acid to moderate-dose statin.
The NCEP ATP III guidelines recognize elevated TG as a marker of atherogenic remnant lipoproteins and increased cardiovascular risk [5
]. The ATP III recommends non–HDL-C, a measure of the cholesterol content in LDL, intermediate-density lipoprotein (IDL), and very–low-density lipoprotein (VLDL) as a secondary treatment target (after LDL-C) in patients with TG ≥
200 mg/dL. Along with LDL-C and non–HDL-C, the American Diabetes Association/American College of Cardiology Foundation consensus report has recommended ApoB as both a marker for CHD risk and a target in patients with cardiometabolic risk, whose typical lipoprotein profile includes high TGs and/or low HDL-C [10
]. The patients in this analysis, at goal for LDL-C but with elevated TGs despite treatment with moderate-dose statin monotherapy, qualify for the addition of a niacin or a fibrate based on treatment guidelines. As such, both non–HDL-C and ApoB levels were improved from baseline to week 12 and were sustained until week 52 with the addition of fenofibric acid to moderate-dose statin therapy. Furthermore, median TG levels decreased to near 150 mg/dL at final visit and mean HDL-C levels significantly increased to >40 mg/dL at final visit in this subgroup of patients.
In this analysis, the mean baseline LDL-C at the start of the extension study was 79 mg/dL. After the addition of fenofibric acid to moderate-dose statin therapy, mean LDL-C increased to 87 mg/dL resulting in 21.1% of patients no longer having LDL-C <100 mg/dL at the final visit. However, the percentage of patients with optimal non–HDL-C levels (<130 mg/dL) increased by 12% and those with optimal ApoB levels (<90 mg/dL) increased by 27% at final visit. These results suggest that the net effect of adding fenofibric acid to moderate-dose statin therapy is an increase in LDL particle size (as measured by the increase in cholesterol content in the LDL fraction) and a reduction in atherogenic particle number as measured by ApoB. The increase in LDL-C noted in this subgroup of patients with hypertriglyceridemia is not unexpected, as baseline TGs have been shown to influence the LDL-C–lowering effect of statin
fibrate combinations (greater reductions with low baseline TGs) [11
]. In patients with high TG, treatment with fibrates results in an increase in measured LDL-C content, likely because of fibrate-induced increased lipolysis of TG-rich VLDL particles [12
] and/or a shift in LDL particle size [14
]. Despite the benefits in LDL particle size and number, and improvements in other lipid parameters, a patient’s CHD risk should be considered when making treatment decisions for patients whose LDL-C is >100 mg/dL. The primary aim of treatment, according to NCEP ATP III guidelines, is to achieve LDL-C goal (<100 mg/dL for high-risk patients, <130 mg/dL for moderate-risk patients, and <160 mg/dL for low-risk patients). Combination therapy may be considered to treat the secondary non–HDL-C goal in patients with TG ≥
200 mg/dL only after the LDL-C goal has been reached.
In the present study, the proportion of patients with optimal HDL-C increased by 29%, and 70% of the patients had TG <200 mg/dL by final visit.
As a result, a higher percentage of patients had optimal levels of multiple parameters such as LDL-C
ApoB, and LDL-C
TG with the addition of fenofibric acid to moderate-dose statin for 52 weeks. As TG levels at final visit remained ≥200 mg/dL in 30% of the patients, we compared the baseline TG values of patients who achieved optimal TG versus those whose TG was not optimal. Patients whose TG remained at or above the threshold at final visit started with much higher baseline TG values (median 281 mg/dL) than those whose TG dropped below the threshold (median 242 mg/dL). Although statin monotherapy is known to reduce TG levels, the final median TG of 152.0 mg/dL in our study represents a substantial reduction in TG from a baseline median of 249.5 mg/dL with the addition of fenofibric acid to moderate-dose statin therapy.
Other treatment strategies for normalizing multiple lipid parameters in patients with mixed dyslipidemia include the addition of nicotinic acid or omega 3-fatty acids to statin therapy. Both strategies have been evaluated in long-term safety and efficacy studies and have resulted in improvements of lipid parameters other than LDL-C [18
]. Addition of omega-3 fatty acids (as eicosapentaenoic acid) to statin therapy has been shown in one study to significantly reduce major coronary events in patients with hypercholesterolemia although the study did not require elevated TG for patients to enroll [19
], while outcomes studies are ongoing to demonstrate the incremental benefit of adding niacin to statin treatment. It should be noted that although the combination of fenofibrate and simvastatin in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study did not significantly reduce the rate of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death compared with simvastatin alone, a prespecified analysis demonstrated a 31% relative risk reduction in cardiovascular events in patients with both high TG (≥204 mg/dL) and low HDL-C (≤34 mg/dL) compared to treatment with statin alone [20
]. The data from ACCORD are consistent with other fibrate trials showing that a subset of patients with elevated TGs and low HDL-C have cardiovascular benefit [21
As mentioned earlier, guidelines recommend non–HDL-C and ApoB as additional secondary targets in patients with TG ≥
200 mg/dL [5
]. The NEPTUNE II study, a national survey estimating goal attainment with statin therapy, found that achievement of the combined LDL-C
non–HDL-C targets among patients with TG ≥
200 mg/dL ranged from 78% in the low-risk category to 27% in the high-risk category [27
]. In a separate post hoc study of metabolic syndrome patients, the combined target of LDL-C
non–HDL-C was achieved by 67% of patients after 6 weeks of treatment with rosuvastatin 40 mg [28
]. The current analysis suggests that combination therapy with fenofibric acid
moderate-dose statin may offer a strategy to improve these goal attainment observations.
Bays et al. have previously reported the safety findings for the overall population of the open-label extension study [9
]. The addition of fenofibric acid to moderate-dose statin for 52 weeks in the current analysis was well tolerated. The incidence of myalgia and myositis was low; no rhabdomyolysis was reported. Elevations in liver enzymes were rare in this subgroup. Incidence of CK elevations was low, as were elevations in creatinine. Similar to the overall population, no new or unexpected adverse events were observed with 52-week exposure to fenofibric acid in combination with moderate-dose statin in the present analysis.
The primary limitations of this study are the open-label nature of the extension study, the post hoc nature of the analysis, and small size (N
92) of the subgroup. Other limitations of the study are that all patients were treated with combination therapy and no comparisons with placebo or individual monotherapies were made. Additionally, although this analysis evaluated the effects of adding fenofibric acid to moderate-dose statin therapy on several lipid and apolipoprotein parameters, only reductions in LDL-C has been correlated with favorable cardiovascular outcomes.