Coadministration of Ezetimibe-Simvastatin and Fenofibrate in Patients With Mixed Hyperlipidemia

Linda Brookes, MSc

Disclosures

July 28, 2006

Editorial Collaboration

Medscape &

Presenter: Michel Farnier, MD, PhD (Point Medical, Dijon, France)

Target lipid values are difficult to achieve in mixed hyperlipidemia -- a metabolic disorder characterized by the constellation of elevated low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, and triglycerides plus reduced HDL cholesterol -- and combination therapy is recommended in these patients. Clinical trials of this approach, assessing the coadministration of simvastatin plus fenofibrate or ezetimibe plus fenofibrate have shown success, significantly reducing LDL cholesterol, non-HDL cholesterol, and triglycerides, as well as increasing HDL cholesterol in patients with mixed hyperlipidemia.[1,2] A study of treatment with all 3 drugs -- ezetimibe-simvastatin administered as a fixed-dose combination, coadministered with fenofibrate -- showed even greater reductions in LDL cholesterol and triglycerides together with greater increases in HDL cholesterol.[3]

Study Design

The study was a randomized, placebo-controlled comparison of the effects of daily treatment with fenofibrate 160 mg, ezetimibe-simvastatin 10/20 mg, ezetimibe-simvastatin 10/20 mg plus fenofibrate 160 mg, or placebo over 12 weeks.

Patients were eligible for randomization provided that they had:

  • LDL cholesterol

    • 130-220 mg/dL (3.4-5.7 mmol/L) or

    • 100-180 mg/dL (2.6-4.7 mmol/L) plus diabetes

  • Triglycerides

    • 150-500 mg/dL (1.7-5.7 mmol/L)

  • No coronary heart disease (CHD), CHD risk equivalent (except type 2 diabetes), or CHD 10-year risk > 20%.

The primary endpoint of the study was percentage of change in LDL cholesterol with coadministration of ezetimibe-simvastatin plus fenofibrate vs fenofibrate.

Patients and Treatment

After a placebo run-in period, 611 patients (mean age, 55 years; 52% male; 78% white) were randomized in the trial to fenofibrate (n = 184), ezetimibe-simvastatin (n = 184), ezetimibe-simvastatin plus fenofibrate (n = 183), or placebo (n = 60).

At baseline, 62% of patients had metabolic syndrome (NCEP ATP III criteria)[4] and 9% had diabetes. Baseline lipids (mean values) were:

  • LDL cholesterol, 162 mg/dL (4.2 mmol/L);

  • Triglycerides, 230 mg/dL (2.6 mmol/L);

  • HDL cholesterol, 45 mg/dL (1.2 mmol/L);

  • Non-HDL cholesterol, 209 mg/dL (5.4 mmol/L);

  • Apolipoprotein (apo) B, 1.6 g/L; and

  • Apo A-1, 1.5 g/L.

Plus, on the basis of apo B assessment, 60% of the patients had atherogenic small, dense LDL particles (subtype pattern B).

Primary Endpoint

Similar statistically significant reductions in LDL cholesterol were seen with coadministration of ezetimibe-simvastatin and ezetimibe-simvastatin plus fenofibrate, both vs fenofibrate or placebo (Table 1).

Table 1. Median Percentage of Change in LDL Cholesterol
Placebo Ezetimibe-
Simvastatin
Fenofibrate Ezetimibe-
Simvastatin
+ Fenofibrate
LDL cholesterol (% change) -3.5* -47.1 -15.7* -45.8
*P < .001 for the comparison with ezetimibe-simvastatin plus fenofibrate

LDL = low-density lipoprotein

Of note, the reductions in LDL cholesterol were similar in patients with triglycerides < 250 mg/dL or ≥ 250 mg/dL. Both treatments that included fenofibrate were associated with an improvement in LDL particle size, with a decrease in small, dense LDL particles and an increase in larger LDL particles (pattern A). No change in LDL size patterns was seen in the ezetimibe-simvastatin group.

Other Lipids

Mean reductions of 50% in triglycerides and non-HDL cholesterol and of 45% in apo B were seen in the triple-therapy group, all significantly greater than the other treatment groups (Table 2). Increases in HDL cholesterol and apo A-I were similar in the 2 groups that received fenofibrate.

Table 2. Median Percentage of Change in Other Lipids
Placebo Ezetimibe-
Simvastatin
Fenofibrate Ezetimibe-
Simvastatin
+ Fenofibrate
Triglycerides -3.1* -28.6* -41.3* -50.0
Non-HDL cholesterol -1.7* -45.2* -21.0* -50.5
Apo B 0.0* -39.0* -20.1* -44.7
HDL cholesterol 1.1* 9.3* 18.2 18.7
Apo A-I 1.6* 6.6* 10.8 11.1
Apo = apolipoprotein; HDL = high-density lipoprotein

*P < .001 vs ezetimibe-simvastatin plus fenofibrate
Inflammatory Markers

Reductions in high-sensitivity C-reactive protein (CRP) were similar in the 2 groups taking ezetimibe-simvastatin, and the decreases in fibrinogen were similar in the 2 groups taking fenofibrate (Table 3).

Table 3. Median Percentage of Change in High-Sensitivity CRP and Fibrinogen
Placebo Ezetimibe-
Simvastatin
Fenofibrate Ezetimibe-
Simvastatin
+ Fenofibrate
High-sensitivity CRP -6.8* -31.0 -12.1* -38.3
Fibrinogen -4.3* -3.4* -14.2 -13.2
*P < .001 vs ezetimibe-simvastatin plus fenofibrate

CRP = C-reactive protein
Safety and Tolerability

Over the short-term trial, all treatments were well tolerated. The safety profile of ezetimibe-simvastatin plus fenofibrate was similar to the profiles for fenofibrate monotherapy and ezetimibe-simvastatin (Table 4).

Table 4. Adverse Events (%)
Placebo Ezetimibe-
Simvastatin
Fenofibrate Ezetimibe-
Simvastatin
+ Fenofibrate
≥ 1 adverse events 30.0 35.3 47.3 39.3
Drug-related adverse events 6.7 7.1 12.5 8.7
Serious adverse events 3.3 0.5 1.6 0
Drug-related serious adverse events 0 0 0.5 0

Discontinuations due to adverse events were similar in the triple- and dual-therapy groups (Table 5).

Table 5. Discontinuations (%) Due to Adverse Events
Placebo Ezetimibe-
Simvastatin
Fenofibrate Ezetimibe-Simvastatin
+ Fenofibrate
Discontinuation due to adverse events 1.7 2.7 3.3 2.7
Discontinuation due to drug-related adverse events 0 1.6 3.3 2.2
Discontinuation due to serious adverse events 1.7 0 0.5 0
Discontinuation due to serious drug-related serious adverse events 0 0 0.5 0

Increases in levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) to ≥ 3 the upper limit of normal (ULN) occurred in 6 patients (3.3%) on fenofibrate monotherapy and 5 patients (2.8%) in the triple-therapy groups. Two patients (1.1%) in the fenofibrate monotherapy group had increases in creatine kinase levels to ≥ 10 x ULN.

Implications

In this study, triple therapy with ezetimibe-simvastatin plus fenofibrate produced an approximate 50% decrease in atherogenic parameters and a 20% increase in HDL cholesterol. Prof. Farnier concluded by showing that these improvements were greater than those previously shown in studies of dual therapy, including fenofibrate (Table 6).

Table 6. Comparison of Combined Therapies With Fenofibrate in Mixed Hyperlipidemia
Lipid Parameter Simvastatin 20 mg +
Fenofibrate 160 mg[1]
Ezetimibe 10 mg +
Fenofibrate 160 g[2]
Simvastatin 20 mg +
Ezetimibe 10 mg +
Fenofibrate 160 mg
LDL cholesterol (%) -31.2 -20.4 -45.8
Non-HDL cholesterol (%) -35.3 -30.4 -50.5
Triglycerides (%) -43.0 -44.0 -50.0
HDL cholesterol (%) +18.6 -19.0 +18.7
HDL = high-density lipoprotein; LDL = low-density lipoprotein

Thus, it appears that mixed therapy with a fairly low-dose statin, a cholesterol absorption inhibitor, and fenofibrate may be the best approach to patients at risk because of mixed hyperlipidemia.

References
  1. Grundy SM, Vega GL, Yuan Z, et al. Effectiveness and tolerability of simvastatin plus fenofibrate for combined hyperlipidemia (the SAFARI trial). Am J Cardiol. 2005;95:462-468. Abstract

  2. Farnier M, Freeman MW, Macdonell G, et al; the Ezetimibe Study Group. Efficacy and safety of the coadministration of ezetimibe with fenofibrate in patients with mixed hyperlipidaemia. Eur Heart J. 2005;26:897-905. Abstract

  3. Farnier M, Roth E, Gil-Extremera B, et al. Efficacy and safety of co-administered ezetimibe/simvastatin and fenofibrate in patients with mixed hyperlipidemia. Atherosclerosis. 2006;7(suppl):174. Abstract Tu-W27:3.

  4. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. Abstract

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