Author + information
- Received August 8, 2005
- Revision received October 31, 2005
- Accepted November 30, 2005
- Published online April 18, 2006.
- James M. McKenney, PharmD⁎,a,⁎ (, )
- Michel Farnier, MD, PhD†,
- Kwok-Wing Lo, MD‡,
- Harold E. Bays, MD§,b,
- Inna Perevozkaya, PhD¶,c,
- Gary Carlson, BS¶,c,
- Michael J. Davies, PhD¶,c,
- Yale B. Mitchel, MD¶,c and
- Barry Gumbiner, MD¶,c
- ↵⁎Reprint requests and correspondence:
Dr. James M. McKenney, National Clinical Research Inc., 2809 Emerywood Parkway, Suite 140, Richmond, Virginia 23294
Objectives This study sought to determine the long-term safety and efficacy of co-administered fenofibrate (FENO) and ezetimibe (EZE) in patients with mixed hyperlipidemia.
Background Both EZE and FENO offer complementary benefits to the lipid profile of patients with mixed hyperlipidemia.
Methods After completing the 12-week randomized, double-blind base study that compared EZE 10 mg, FENO 160 mg, FENO 160 mg plus EZE 10 mg, and placebo in patients with mixed hyperlipidemia, patients continued into a double-blind, 48-week extension phase. Those patients in the FENO plus EZE and FENO groups continued on their respective base study treatment, and patients in the EZE and placebo groups were switched to FENO plus EZE and FENO, respectively.
Results Of the 587 patients who completed the base study, 576 continued into the extension study (n = 340 in FENO plus EZE and n = 236 in FENO). The FENO plus EZE produced significantly greater reductions in low-density lipoprotein-cholesterol compared with FENO (−22% vs. −9%, respectively; p < 0.001). There were also significantly greater improvements in triglycerides, high-density lipoprotein cholesterol (HDL-C), total cholesterol, non–HDL-C, and apolipoprotein B with FENO plus EZE compared with FENO. Changes in apolipoprotein A-I and high-sensitivity C-reactive protein were similar between groups. Overall, FENO plus EZE was well tolerated during the extension study. The proportion of patients with consecutive elevations of alanine aminotransferase/aspartate aminotransferase ≥3 times upper limit of normal were similar between the FENO plus EZE (1.2%) and FENO (1.7%) groups. No cases of creatine phosphokinase elevations ≥10 times upper limit of normal or myopathy were observed in either group.
Conclusions Long-term, 48-week co-administration of FENO plus EZE was well tolerated and more efficacious than FENO in patients with mixed hyperlipidemia.
The cholesterol absorption inhibitor ezetimibe (EZE) effectively lowers low-density lipoprotein cholesterol (LDL-C) by inhibiting the intestinal absorption of dietary and biliary cholesterol without affecting absorption of triglycerides or fat-soluble vitamins (1). Fibrates have favorable effects on triglycerides, high-density lipoprotein cholesterol (HDL-C), and LDL particle size (2). Recently in patients with mixed hyperlipidemia, 12-week co-administration of fenofibrate (FENO) plus EZE was well tolerated and produced significant improvements in lipid profiles compared with either FENO or EZE alone (3). Thus, in the short term, the co-administration of FENO plus EZE, through their complementary mechanisms of action, provides another therapeutic option for treating patients with mixed hyperlipidemia. The present study examined the long-term safety and efficacy of co-administered FENO plus EZE in patients with mixed hyperlipidemia over 48 weeks.
Study design and results for the 12-week base study were published previously (3). For the base study, mixed hyperlipidemia was defined as a baseline LDL-C level of 130 to 220 mg/dl inclusive (100 to 180 mg/dl for patients with type 2 diabetes) and a baseline triglyceride level of 200 to 500 mg/dl inclusive. After completing the 12-week base study, which compared EZE 10 mg, FENO 160 mg, FENO 160 mg plus EZE 10 mg, and placebo, patients continued into the 48-week double-blind extension study unless there was a condition that would interfere with the patient’s ability to participate. Patients in the FENO plus EZE and FENO groups continued on their respective base study treatment, and those in the EZE and placebo groups were switched to FENO plus EZE and FENO, respectively. All patients were instructed to continue following the National Cholesterol Education Program (NCEP) Step I or comparable diet throughout the study. Follow-up visits were conducted at weeks 6, 12, 24, 36, and 48 of the extension study.
Safety and tolerability were evaluated by adverse experiences (AEs), laboratory measurements (specifically alanine aminotransferase [ALT], aspartate aminotransferase [AST], and creatine phosphokinase [CPK] levels), and physical examination findings for only the 48-week extension study. Results were not combined with the 12-week base study. The study investigators assessed the potential relationship of all AEs to drug treatment while blinded to treatment assignment (Appendix). The AEs of clinical interest that resulted in discontinuation included: consecutive, unexplained elevations of CPK ≥10 times the upper limit of normal (ULN) or ALT/AST ≥3 times ULN; myopathy (muscle symptoms accompanied by CPK ≥10 times ULN); persistent elevations in serum creatinine >1.8 mg/dl or >30% above the baseline value from base study for patients with baseline creatinine levels >1.0 mg/dl; persistent elevations in creatinine >50% above the baseline value of base study for patients with baseline creatinine levels ≤1.0 mg/dl. Beginning at week 12 of the extension, if the LDL-C concentration was >15 mg/dl above the patient’s NCEP Adult Treatment Panel III risk-specific LDL-C target as established at baseline, the patient was discontinued for lack of efficacy.
The primary efficacy variable was percent change in LDL-C from baseline of the base study to study end point in the extension. Secondary efficacy end points included percent change from baseline to study end point in total cholesterol (TC), HDL-C, triglycerides, non–HDL-C, apolipoprotein B, apolipoprotein A-I, and high-sensitivity C-reactive protein (hs-CRP).
A central laboratory performed all clinical laboratory analyses of safety and efficacy variables as described previously (3).
Inferential testing was limited to a pre-specified number of safety parameters, including myopathy, persistent ALT and/or AST elevations ≥3 times ULN, persistent CPK elevations ≥10 times ULN, planned or performed cholecystectomy (pooled end point including performed cholecystectomy or diagnosed cholecystitis, cholangitis, or cholelithiasis), and serum creatinine ≥1.5 mg/dl. Proportions of patients were compared between treatments with the Fisher exact test. Given the differences in average duration of exposure to active therapy between groups in the present study, examining the crude incidence rates may be misleading. Therefore, adjusted incidence rates per 1,000 patient-years were calculated for the pre-specified safety parameters listed above based on cumulative patient-years available for each treatment (i.e., adjusted incidence rate = number of events/exposure [expressed in 1,000 patient-years]). The efficacy analysis was an all-patients-treated approach with an end point defined as percent change from baseline to the average of all measurements available throughout extension. A parametric analysis of covariance (ANCOVA) model with terms for treatment and baseline triglyceride values was used to compare each efficacy variable between treatment groups. Because triglycerides and hs-CRP were not normally distributed, a nonparametric ANCOVA was used to assess between-group differences. Least-squares mean or median differences between treatment groups with corresponding 95% CIs were summarized.
Of the 587 patients who completed the 12-week base study, 576 patients continued into the 48-week extension study (N = 340 for FENO plus EZE and N = 236 for FENO; Table 1).During the extension phase, a greater proportion of participants in the FENO group discontinued treatment compared with those in the FENO plus EZE group, primarily because of the failure to meet the LDL-C efficacy criterion (Table 2).Thus, average exposure to study treatment was less in the FENO group (212.3 days) compared with the FENO plus EZE group (271.3 days).
The FENO plus EZE resulted in significantly greater percent reductions from baseline to average extension end point in LDL-C, TC, triglycerides, non–HDL-C, and apolipoprotein B compared with FENO (Table 3).The percent increase in HDL-C, but not apolipoprotein A-I, was significantly greater with FENO plus EZE versus FENO. Reductions in median hs-CRP levels were not different between treatments.
The FENO plus EZE was well tolerated during the 48-week extension study. Both groups were similar with regard to incidence of treatment-related AEs and discontinuations because of treatment-related AEs, respectively (Table 4).Five patients had treatment-related serious AEs in the extension study: three in the FENO group (angioneurotic edema, pancreatitis, polyarthropathy) and two in the FENO plus EZE group (cholangitis, cholecystitis). A patient on FENO plus EZE died in the extension study from a cerebral hemorrhage that the investigator reported was definitely not caused by study treatment.
No patient experienced CPK elevations ≥10 times ULN or myopathy. The proportion of patients with consecutive elevations of ALT and/or AST ≥3 times ULN was low and similar between treatment groups (Table 4). The proportion of patients with planned or performed cholecystectomy was not significantly different between treatments (Table 4). To account for differences in exposure to treatments, rates of planned or performed cholecystectomy were adjusted for exposure (expressed in 1,000 patient-years) and were still not significantly different between FENO plus EZE and FENO groups (15.9 per 1,000 patient-years [95% CI 4.3 to 40.7] vs. 7.3 per 1,000 patient-years [95% CI 0.2 to 40.6], respectively). The proportion of patients with serum creatinine ≥1.5 mg/dl was not significantly different between groups (Table 4). The results of all other measures of safety did not suggest any clinically meaningful differences between treatment groups.
Co-administration of FENO plus EZE provided superior lipid-altering effects compared with FENO during the 48-week extension study. In the present study, FENO plus EZE produced an incremental LDL-C reduction of 13.5% compared with FENO. This was consistent with the incremental reduction observed for FENO plus EZE versus FENO in the base study (3) and also that observed with EZE plus statin versus statin monotherapy (4). Improvements in TC, non–HDL-C, TG, HDL-C, and apolipoprotein B were also greater in the co-administration group. The results from the extension study were generally consistent with those from the base study, and the small differences in efficacy between studies (TG and HDL-C) may be because the extension study was not randomly assigned and was imbalanced.
The safety profile for long-term co-administration of FENO plus EZE was similar to that of FENO in this study. Groups did dramatically differ in the overall rate of discontinuations, which was mainly attributable to an imbalance in the number of patients who discontinued because of the protocol-specified lack of LDL-C efficacy criterion used in the extension, which was more than double in the FENO group versus the FENO plus EZE group. This imbalance was related to the greater lipid efficacy of FENO plus EZE compared with FENO. As a result of this difference, patients in the FENO plus EZE group averaged approximately 8.5 more weeks of treatment exposure than those in the FENO group.
No clinically important elevations in CPK or cases of myopathy were observed in either treatment group during the extension. The incidence of elevated ALT and/or AST levels ≥3 times ULN was low and was not different between treatment groups. Fenofibrate increases cholesterol excretion into the bile, which may lead to cholelithiasis (5). Ezetimibe has inconsistent effects on biliary cholesterol in animal models (6). There seems, however, to be no evidence, based on short-term clinical study data available to date, that EZE monotherapy increases the risk of gallstones in patients with primary hypercholesterolemia (1,7,8). In this study, most randomized patients had numerous risk factors, including hyperlipidemia, obesity, age, female gender, and type 2 diabetes, that would predispose them to an increased risk for gallstones (9). Patients were excluded from the present study for a history of gallbladder disease and not previously having been treated with cholecystectomy. The proportion of patients with performed or planned cholecystectomy was not significantly different between groups when expressed as either the proportion of patients with events or the incidence rates adjusted for group differences in patient exposure to treatments. This study was, however, not designed to assess infrequently occurring AEs such as cholecystectomy, and only a much larger, longer-term study could conclusively assess these infrequent biliary AEs.
Although modest increases in the incidence of serum creatinine level ≥1.5 mg/dl were found in both treatment groups, the proportion of patients with these elevated creatinine levels did not differ between groups. The increase in both groups might have been anticipated, because FENO is known to increase creatinine levels (5). The overall safety profile of co-administered FENO plus EZE in this longer-term 48-week study was consistent with the findings in the shorter 12-week base study (3). Furthermore, considering the greater mean duration of treatment exposure for patients in the FENO plus EZE group compared with those in the FENO group in this study, the comparable safety findings between treatment groups support co-administration of FENO plus EZE as a well-tolerated therapy.
In summary, the long-term FENO plus EZE therapy was a more effective treatment option than FENO, and was well-tolerated for up to 48 weeks of treatment for patients with mixed hyperlipidemia in this study.
For a list of the extension study investigators, please see the online version of this article.
↵a Dr. McKenney has received speaking honorarium for AstraZeneca, KOS, Merck, and Pfizer and grant support from AstraZeneca, GSK, KOS, Merck, Pfizer, and Takeda, and has provided consulting services to AstraZeneca, KOS, Merck, Pfizer, and Sankyo.
↵b Dr. Bays, in over a decade of clinical research, has served as a clinical investigator for (and has received research grants from) pharmaceutical companies such as Abbott, Alteon, Arena, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, Boehringer Mannheim, Bristol Myers Squibb, Esperion, Fujisawa, Ciba Geigy, GelTex, Glaxo, Genetech, Hoechst Roussel, KOS, Kowa, Lederle, Marion Merrell Dow, Merck, Merck Schering Plough, Miles, Novartis, Parke Davis, Pfizer, Pliva, Purdue, Reliant, Roche, Rorer, Regeneron, Sandoz, Sankyo, Sanofi, Searle, Shering Plough, SmithKline Beacham, Takeda, TAP, UpJohn, Upsher Smith, Warner Lambert, and Wyeth-Ayerst. He has also served as a consultant, speaker, and/or advisor to and for pharmaceutical companies such as AstraZeneca, Aventis, Bayer, Bristol Myers Squibb, KOS, Merck, Merck Schering Plough, Metabasis Therapeutics, Microbia, Novartis, Ortho-McNeil, Parke Davis, Pfizer, Roche, Sandoz, Sankyo, Sanofi Aventis, Shering Plough, SmithKline Beacham, Takeda, UpJohn, and Warner Lambert.
↵c Drs. Perevozkaya, Carlson, Davies, Mitchel, and Gumbiner are employees of Merck and may hold stocks or stock options in Merck.
This study was funded by Merck/Schering-Plough Pharmaceuticals, North Wales, Pennsylvania.
- Abbreviations and Acronyms
- adverse experience
- alanine aminotransferase
- aspartate aminotransferase
- creatine phosphokinase
- high-density lipoprotein-cholesterol
- high-sensitivity C-reactive protein
- low-density lipoprotein-cholesterol
- total cholesterol
- upper limit of normal
- Received August 8, 2005.
- Revision received October 31, 2005.
- Accepted November 30, 2005.
- American College of Cardiology Foundation
- Knopp R.H.,
- Gitter H.,
- Truitt T.,
- et al.
- Farnier M.,
- Freeman M.,
- Macdonell G.,
- et al.
- ↵(2003) Product Information: TRICOR (fenofibrate tablets) (Abbott Laboratories, North Chicago, IL) February.
- ↵(2005) Product Information: ZETIA (ezetimibe) (Merck/Schering-Plough Pharmaceuticals, North Wales, PA) March.