Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia
Frederick F Samaha*, James McKenney, LeAnne T Bloedon, William J Sasiela and Daniel J Rader About the authors
Correspondence *University of Pennsylvania Medical Center, Philadelphia VA Medical Center, 8th Floor Cardiology, MC 111C, 3900 Woodland Avenue, Philadelphia, PA 19104, USA
Tel: +1 215 823 6324
Email rick.samaha@va.gov
Clinical context
See the accompanying Clinical Context article by Joy and Hegele. [doi:10.1038/ncpcardio1251]
Summary
Background Many patients with coronary heart disease do not achieve recommended LDL-cholesterol levels, due to either intolerance or inadequate response to available lipid-lowering therapy. Microsomal triglyceride transfer protein (MTP) inhibitors might provide an alternative way to lower LDL-cholesterol levels. We tested the safety and LDL-cholesterol-lowering efficacy of an MTP inhibitor, AEGR-733 (Aegerion Pharmaceuticals Inc., Bridgewater, NJ), alone and in combination with ezetimibe.
Methods We performed a multicenter, double-blind, 12-week trial, which included 84 patients with hypercholesterolemia. Patients were randomly assigned ezetimibe 10 mg daily (n = 29); AEGR-733 5.0 mg daily for the first 4 weeks, 7.5 mg daily for the second 4 weeks and 10 mg daily for the last 4 weeks (n = 28); or ezetimibe 10 mg daily and AEGR-733 administered with the dose titration described above (n = 28).
Results Ezetimibe monotherapy led to a 20–22% decrease in LDL-cholesterol concentrations. AEGR-733 monotherapy led to a dose-dependent decrease in LDL-cholesterol concentration: 19% at 5.0 mg, 26% at 7.5 mg and 30% at 10 mg. Combined therapy produced similar but larger dose-dependent decreases (35%, 38% and 46%, respectively). The number of patients who discontinued study drugs owing to adverse events was five with ezetimibe alone, nine with AEGR-733 alone, and four with combined ezetimibe and AEGR-733. Discontinuations from AEGR-733 were due primarily to mild transaminase elevations.
Conclusions Inhibition of LDL production with low-dose AEGR-733, either alone or in combination with ezetimibe, could be an effective therapeutic option for patients unable to reach target LDL-cholesterol levels.
Introduction
Guidelines on the optimum intensity of LDL-cholesterol lowering have evolved in step with findings from clinical trials. The National Cholesterol Education Program (NCEP) guidelines from 2001 set the target level at below 2.6 mmol/l (100 mg/dl) for high-risk patients with coronary heart disease or its risk equivalent.1 These guidelines were updated in 2004 to provide an optional therapeutic target of below 1.8 mmol/l (70 mg/dl) for very high-risk patients (those with additional risk factors, such as diabetes).2 In 2006, the spectrum of patients to which the lower value applied was broadened to include all patients with atherosclerotic disease. Furthermore, a minimum of 30–40% reduction in LDL was recommended for patients at moderate and high risk.3 Unfortunately, at least 20% of high-risk patients do not achieve these LDL-cholesterol targets, with those in the highest risk group being the least likely to do so.4 This difficulty might be due partly to statin intolerance. The rate of statin discontinuation owing to adverse events, observed in clinical trials and clinical practice, ranges from 1% to 7% and is mainly caused by myalgias.5 In a 52-week lipid efficacy study of five different statins, the rate of discontinuations due to adverse events was even higher (4–13%).6 Furthermore, there are patients for whom high-dose statins are contraindicated, such as those taking amiodarone,7 or with clinical factors that raise the risk of rhabdomyolysis.8 Because statin-intolerant patients have few other options for achieving treatment goals, there is an unmet clinical need for additional therapies that can lower LDL-cholesterol levels.
One potential therapeutic target is the assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Microsomal triglyceride transfer protein (MTP) is an intracellular lipid-transfer protein found in the endoplasmic reticulum and which is responsible for transferring lipid molecules onto apoB. This transfer forms part of the assembly of triglyceride-rich lipoproteins, such as chylomicrons in the intestine and VLDL in the liver.9 Patients with the genetic disorder abetalipoproteinemia have loss-of-function mutations in the microsomal triglyceride transfer protein gene (MTTP),10 resulting in extremely low plasma concentrations of cholesterol and triglycerides and absense of chylomicrons, VLDL and LDL.11 The elucidation of the mechanistic basis for this disease led to the concept that small-molecule inhibitors of MTP could reduce LDL-cholesterol levels. Indeed, preclinical studies in animal models showed that inhibition of MTP significantly reduced serum cholesterol levels and slowed the formation of atherosclerotic plaques.12, 13 Furthermore, MTP inhibition significantly reduced LDL-cholesterol levels in patients with homozygous familial hypercholesterolemia.14
Clinical applications of MTP inhibitors have been focused primarily on high-dose monotherapy to produce substantial reductions in LDL-cholesterol levels (particularly for patients with homozygous familial hypercholesterolemia); however, this strategy has been associated with an unacceptable rate and severity of gastrointestinal and hepatic adverse events, thereby prohibiting its use in a broader population of patients with hyperlipidemia. Because these side effects are thought to be directly linked to the mechanism of MTP-inhibition, we hypothesized that much lower doses would yield clinically useful LDL-cholesterol-lowering results but would be better tolerated. In addition, we also hypothesized that the LDL-cholesterol-lowering effects of the MTP inhibitor AEGR-733 (Aegerion Pharmaceuticals Inc., Bridgewater, NJ; previously BMS-201038, Bristol-Myers Squibb, New York, NY) at these reduced doses would be additive to those of the cholesterol absorption inhibitor ezetimibe, because the two drugs have different mechanisms. To test our hypotheses we evaluated the LDL-cholesterol-lowering efficacy of AEGR-733, both alone and in combination with ezetimibe, in patients with moderate hypercholesterolemia.
Methods
This clinical trial is registered on Clinicaltrials.gov (registry number NCT00405067 assigned on 28 November 2006).
Study patients
This trial was approved by a central investigational review board (ASPIRE Institutional Review Board LLC, San Diego, CA). Before the study started, all potential participants signed an informed consent form approved by the review board. Hypercholesterolemic patients of 18–70 years of age from six geographically distinct lipid treatment centers within the US were eligible. Patients with 0–1 risk factors were required to have an LDL-cholesterol concentration between 4.1 and 6.5 mmol/l (160 and 250 mg/dl), and those with more than two risk factors were required to have an LDL-cholesterol concentration between 3.4 and 6.5 mmol/l (130 and 250 mg/dl). Baseline LDL-cholesterol was the mean of measurements obtained at the first two clinic screening visits. The main exclusion criteria were uncontrolled hypertension, creatinine levels greater than 221 
mol/l (2.5 mg/dl), liver disease or transaminase levels greater than 1.5 times the upper limit of normal, symptomatic congestive heart failure, diabetes, plasma triglyceride levels greater than 4.5 mmol/l (400 mg/dl), or an acute cardiovascular event within the prior 6 months. Patients receiving concomitant lipid-lowering therapy were required to discontinue these medications 4 weeks before screening and throughout the trial. AEGR-733 was manufactured in accordance with current Good Manufacturing Practices.
Study design
This was a phase II, prospective, randomized, double-blind study. Participants initially underwent a 2–6-week eligibility screening process to assess their ability to follow a low-fat diet (<20% of energy from total fat and <7% of energy from saturated fat) to ensure that lipid values were within the range stipulated in the inclusion criteria and to wash-out any prior lipid-lowering drugs. The active treatment part of the protocol was a 12-week treatment period with interim visits at weeks 4 and 8. Patients continued to follow the low-fat diet and received diet counseling throughout the study.
The patients were randomly assigned one of three treatments according to a computer-generated randomization code issued by the central coordinating center. In treatment group 1, patients received 10 mg ezetimibe daily plus placebo for 12 weeks. In treatment group 2, patients received 5.0 mg AEGR-733 for the first 4 weeks, 7.5 mg for the second 4 weeks, and 10 mg for the last 4 weeks, plus placebo for 12 weeks. In treatment group 3 patients received AEGR-733 (with the same dosing schedule as group 2) plus 10 mg ezetimibe daily for 12 weeks. The placebos were identical in appearance to either the ezetimibe tablets or the AEGR-733 tablets, dependent on which they replaced. The patients were instructed to take the study medication in the morning with breakfast. Patient randomization was not stratified by baseline characteristics because the small sample size in this study would have made such stratification difficult.
Study visit data
During the study visits at 4, 8 and 12 weeks, data were collected from history, physical examinations, electrocardiograms, concomitant medications and on assessment of study drug adherence, which was done by conducting pill counts on the returned drug supply from the patients. Blood samples for laboratory analyses were obtained after a 12 h fast. Plasma was separated from samples, immediately frozen at -20 °C, and shipped to the core laboratory on dry ice.
Laboratory assays
Total cholesterol, HDL cholesterol, and triglyceride levels were measured enzymatically on an autoanalyzer (Cobas Fara II, Roche Diagnostic Systems, Basel, Switzerland). Levels of apoB and apolipoprotein A-I (apoA-I) were measured by immunonephelometry on a BNII analyzer (Dade Behring, Brussels, Belgium), and lipoprotein (a) levels were measured by immunoturbidity.
Tracking and recording of adverse events
In addition to the collection of all clinical adverse events, patients also completed the previously validated Gastrointestinal Symptom Rating Scale,15, 16 which consists of five symptom clusters: reflux, abdominal pain, constipation, diarrhea and indigestion. The scale ranges from 1 to 7 (least to most severe symptoms).17
Liver function tests were done at each study visit. In any patient who experienced an increase in transaminase levels to more than three times the upper limit of normal on two consecutive occasions the study drug was discontinued, and participants were followed up until transaminase levels returned to baseline. These patients did not enter the study again.
Data analyses
The primary data analyses were performed by an independent statistician employed by the Data Coordinating Center (PharmaNet, Princeton, NJ). The investigators had complete access to the primary data and the data analyses. Normally distributed continuous variables are reported as mean 
SD, and categorical variables as counts and percentages. Differences in continuous variables between treatment groups were assessed by analysis of variance (ANOVA) and t-tests. Within-group differences were assessed with paired t-tests. Differences in categorical variables between treatment groups were assessed by 
2 tests. All reported P values are two-tailed. All patients who received at least one dose of study drug or placebo in any group were included in the analyses of drug safety and tolerability.
The efficacy analyses included all randomized patients who completed the study. The primary outcome of the study was percentage change in LDL cholesterol from baseline after each of the 4-week treatment periods. This time frame was based on expected maximum effects of ezetimibe within 4 weeks18, 19 and the known LDL-cholesterol-lowering effects of MTP inhibitors.14 Secondary outcomes were percentage changes in other serum lipoproteins (total cholesterol, non-HDL, VLDL, triglycerides, HDL cholesterol, lipoprotein (a), apoB and apoA-I), change in body weight and overall safety and tolerability.
Sample size estimates
The main comparison used for the sample size was 10 mg ezetimibe alone versus 10 mg AEGR-733 in combination with 10 mg ezetimibe. We estimated that ezetimibe alone would produce an 
18% decrease in LDL-cholesterol.19 Based on data from an earlier unpublished phase I study; we also estimated that the combination with AEGR-733 would produce an additional 20% decrease in LDL-cholesterol. We calculated, therefore, that an enrollment target of 25 patients per group with a 20% dropout rate would yield 90% power (SD 19%). Significance was set at P = 0.05.
Results
Patients
A total of 85 patients were enrolled and randomized (28–29 in each treatment group). The baseline characteristics of these patients are summarized in Table 1. Sixty-seven patients completed the study, 17 discontinued therapy completely owing to adverse events and 1 was lost to follow-up before final efficacy data were obtained (Figure 1).
Figure 1 Study profile.
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Table 1 Baseline characteristics of all randomized patients.
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Effect of AEGR-733 on apolipoprotein B levels
Patients assigned to the combination of ezetimibe plus AEGR-733 experienced dose-dependent reductions in LDL ranging from 35% to 46% (Figure 2 and Table 2; P <0.001 versus ezetimibe alone). Patients assigned ezetimibe monotherapy experienced a 20–22% decrease in LDL-cholesterol levels after 12 weeks of therapy (Figure 2 and Table 2). Patients assigned to AEGR-733 monotherapy experienced dose-dependent reductions in LDL-cholesterol concentrations ranging from 19% to 30% (Figure 2 and Table 2; P = 0.013 for a greater LDL reduction with 10 mg AEGR-733 alone versus 10 mg ezetimibe alone). Patients receiving AEGR-733 monotherapy also experienced dose-dependent decreases in concentrations of total cholesterol (23% at 10 mg), non-HDL cholesterol (27% at 10 mg) and apoB (24% at 10 mg); these reductions were all greater than those observed with ezetimibe monotherapy (Table 3). Further reductions in total cholesterol, non-HDL cholesterol, and apoB levels were observed in the group receiving combination therapy (Table 3). Triglycerides did not change significantly from baseline in any of the three groups (Table 3). Patients receiving AEGR-733 either alone or in combination with ezetimibe experienced a significant decrease in lipoprotein (a) compared with those receiving ezetimibe alone (Table 3).
Figure 2 Percentage change from baseline in LDL-cholesterol levels at each of the study visits, by treatment group.
Error bars represent SD of the mean. aEZ versus EZ + AEGR, P <0.001. bAEGR versus EZ + AEGR, P <0.001. cAEGR versus EZ + AEGR, P = 0.015. dEZ versus AEGR, P = 0.016. eAEGR versus EZ + AEGR, P = 0.013. Abbreviations: AEGR, AEGR-733; EZ, ezetimibe.
Full figure and legend (18K)Figures & Tables indexDownload Power Point slide (222K)Table 2 Changes in LDL-cholesterol levels after 12 weeks of therapy.
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Table 3 Changes in non-LDL lipids after 12 weeks of therapy.
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Effect of AEGR-733 on apolipoprotein A levels
Patients receiving AEGR-733, alone or with ezetimibe, experienced decreases of 7% or more in HDL-cholesterol levels, which were significantly different from the 6% increase observed with ezetimibe monotherapy (P < 0.001 for each between-group difference; Table 3). Similar changes in apoA-I were seen (Table 3).
Changes in weight
After 12 weeks, patients assigned ezetimibe monotherapy experienced a mean weight loss of 0.2 1.9 kg (0.1%); those assigned AEGR-733 monotherapy experienced a mean weight loss of 0.7 2.0 kg (1.0%); and those assigned combined AEGR-733 plus ezetimibe experienced a mean weight loss of 1.4 2.6 kg (1.4%); only the latter change was significant (P = 0.013). However, the weight loss was not significantly different in the combination group from that for the group receiving ezetimibe alone.
Safety
Of the 85 patients enrolled, 18 (20%) either stopped or were taken off study medication before completion of the study (Table 4), mainly owing to mildly elevated transaminase levels. This adverse event occurred in 9 of 56 (18%) patients who took AEGR-733, either alone or in combination with ezetimibe, compared with none of the 29 patients assigned to ezetimibe alone. Transaminase levels returned to baseline in all these patients over the course of the protocol-specified, 2-week follow-up. One patient in the combined AEGR-733 plus ezetimibe group, and two patients in each of the AEGR-733-only and ezetimibe-only groups, dropped out of the study because of gastrointestinal side effects (Table 4). The adverse effects were mild (mean gastrointestinal symptom rating scores 
2). Patients receiving AEGR-733 alone experienced slightly more gastrointestinal symptoms, and the severity was greater than in the other groups only for constipation (P = 0.007; Table 4).
Table 4 System-specific adverse events.
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Discussion
In this prospective, randomized trial AEGR-733 provided a dose-dependent reduction in LDL cholesterol, reaching a 30% reduction with 10 mg daily monotherapy and a 46% reduction when combined with 10 mg ezetimibe daily. Both of these regimens provided significantly greater lowering effects than ezetimibe monotherapy. Concentrations of other apo-B-containing lipoproteins, including total cholesterol, non-HDL cholesterol and lipoprotein (a), were similarly reduced by AEGR-733.
Patients receiving AEGR-733 experienced a 5–9% reduction in HDL-cholesterol levels, with corresponding reductions in apoA-I. This effect is similar to that observed in two prior studies of MTP-inhibitors.14, 20 In a study of patients with homozygous familial hypercholesterolemia AEGR-733 (studied as BMS-201038) administered at higher doses than used here produced approximately a 10% decrease in HDL-cholesterol; however, this effect was only observed with the lowest dose of BMS-201038.14 In another study, CP-346086 (30 mg/day; Pfizer, Groton, CT), also produced approximately a 10% decrease in HDL-cholesterol levels after 14 days of treatment.20 The decrease in HDL-cholesterol concentrations caused by MTP-inhibition might be attributable to at least three potential mechanisms: first, low-fat diets are known to reduce HDL-cholesterol levels,21, 22 and MTP inhibition might reduce intestinal fat absorption, thus potentially mimicking the effects of a low-fat diet; second, MTP inhibition could directly reduce the secretion of apoA-I from the intestine, liver, or both, through an unknown mechanism; and third, patients with abetalipoproteinemia have increased catabolism of apoA-I,23 which suggests that MTP inhibition promotes this effect. Further work is necessary to define the mechanisms by which MTP inhibition reduces HDL-cholesterol, and whether this effect has clinical implications. Given the association between low HDL-cholesterol and increased risk of cardiovascular events, such a decrease as we observed could be a serious drawback to MTP-inhibitor therapy. An appropriately designed outcomes study would be essential to answer the question of whether the additional LDL lowering obtained with MTP inhibition would outweigh any potential adverse effect associated with a decrease in HDL-cholesterol level.
The investigators observed a 72% reduction in LDL-cholesterol and a 75% reduction in triglyceride levels in patients administered CP-346086.20 This reduction in LDL-cholesterol is considerably greater than the one we observed with the highest dose of AEGR-733 (30%). Moreover, we saw no change in triglyceride levels with MTP inhibition. The different effects on plasma LDL and triglycerides might relate to differences in dose or timing. With regard to dose, increases in hepatic and intestinal triglyceride content have been shown to correlate with plasma lipid lowering.20 By using low-dose MTP inhibition to minimize intestinal and liver fat accumulation, we might also have minimized the ability of AEGR-733 to lower triglyceride levels. The use of CP-346086 in the previous study was associated with a higher incidence of gastrointestinal side-effects.20 Furthermore, in animal models a 2.9-fold increase in intestinal triglycerides and a 3.6-fold increase in hepatic triglycerides have been shown at doses of CP-346086 equivalent to those in human studies.20 With regard to timing, we measured fasting triglyceride levels, and, as previously demonstrated, the greatest effect seems to occur on postprandial triglyceride elevation due to intestinal MTP inhibition.20
Changes in weight observed with combination therapy could be a result of reduced fat absorption caused by MTP inhibition, which is an established mechanism for other weight loss drugs.24 AEGR-733 was fairly well tolerated from a gastrointestinal standpoint. MTP is required for chylomicron assembly and secretion and, therefore, inhibition of the protein could potentially cause steatorrhea. To minimize the possibility of gastrointestinal side effects due to MTP inhibition, we instructed all patients to follow a diet containing less than 20% fat. In addition, we used low doses of AEGR-733 and titrated the dose, in order to allow the intestine to become accustomed to inhibition of MTP.
In our study, 16% of the patients administered AEGR-733, either alone or in combination with ezetimibe, and none of the patients administered ezetimibe alone discontinued study drugs due to rises in aminotransferase levels. We do not know whether any of these patients would have experienced resolution or further worsening of transaminase elevation with continued use of AEGR-733, but transaminase levels returned to baseline in all these patients. No patients exhibited elevations in bilirubin, a marker of acute hepatotoxic effects, or experienced overt hepatic dysfunction. Most patients in this study (82%) did not experienced transaminase elevation, suggesting that at these doses patients might be able to use MTP inhibitors without experiencing transaminase elevation.
More of the patients taking AEGR-733 than of those given combination therapy experienced transaminase elevation. This outcome might be spurious and we can only speculate on a mechanism by which this could have occurred. The primary lipid-lowering effect of ezetimibe is thought to be attributable to inhibition of the intestinal Niemann-Pick C1–like 1 lipid transporter. This transporter is, however, also expressed in human liver, where it facilitates cholesterol uptake and thus allows the retention of biliary cholesterol by hepatocytes,25 and ezetimibe disrupts this process.25 This effect could, theoretically protect against hepatic lipid accumulation when ezetimibe is combined with an MTP inhibitor. Further studies that measure hepatic lipid accumulation would be required to test this.
Our study has some limitations. First, it was relatively short, and longer-term trials will be needed to fully address the durability of the LDL-cholesterol-lowering effect, the ability of patients to maintain drug adherence over time, and the safety profile with longer term use. Second, the patients in our study followed a low-fat diet; the efficacy and tolerability of the MTP inhibition could differ in patients following higher-fat diets. Although several animal studies have shown that MTP inhibition protects against atherosclerosis,26, 27, 28 a beneficial effect of LDL-cholesterol-lowering, by MTP inhibition, on atherosclerotic cardiovascular disease has not yet been demonstrated in humans. Assessment of the risk-to-benefit ratio for MTP inhibitors, in patients at different levels of cardiovascular disease risk, will be needed before clinical use of this class of drugs can be recommended.
Nevertheless, based on our findings, we envision a potential role for MTP inhibition alone or in combination with other lipid-lowering therapies (e.g. ezetimibe) for patients who are statin intolerant. Furthermore, trials are underway to investigate a potential role for MTP inhibition in patients who have been unable to achieve LDL-cholesterol target levels on statin therapy alone. The use of MTP inhibition in statin-intolerant patients with insulin resistance, type 2 diabetes mellitus, or both, might also be appropriate. Given the neutral effect on triglyceride levels and the small decrease in HDL-cholesterol levels we observed, however, we suggest caution in these patients. The higher incidence of transaminase elevation and the potential mechanism by which this might occur (e.g. hepatic fat accumulation) suggest that patients with nonalcoholic fatty liver disease should not be treated with MTP inhibitors unless data from future studies show that this can be done safely. In summary, MTP inhibition with AEGR-733 might offer a treatment option for patients who cannot tolerate statin therapy or who experience insufficient LDL lowering with currently available therapies.
Key points
- Many patients with coronary heart disease cannot achieve current target levels for LDL-cholesterol owing to either intolerance or inadequate response to conventional lipid-lowering therapy; new treatment strategies are required
- A possible therapeutic approach is inhibition of microsomal triglyceride transfer protein, which is essential for the assembly and secretion of apolipoprotein-B-containing lipoproteins
- AEGR-733, alone and in combination with ezetimibe, had notable LDL-cholesterol-lowering effects in patients with hyperlipidemia
- The main side effect associated with AEGR-733 was elevation in transaminase concentrations, which returned to baseline values after cessation of therapy; gastrointestinal side effects were minor
- Low-dose microsomal triglyceride transfer protein inhibitors, alone or in combination with ezetimibe, could be an effective therapeutic option for patients unable to reach target LDL levels with conventional therapy
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Competing interests
This study was funded by Aegerion Inc.
FF Samaha Samaha is funded by Abbott laboratories, Aegerion Inc., and Merck Inc.
J McKenney provides consulting services for Abbott Laboratories, Aegerion Inc., AstraZeneca, Daiichi Sankyo and Merck Inc.
WJ Sasiela is an employee of Aegerion Inc.
DJ Rader is a stockholder and member of the scientific advisory board in Aegerion Inc.
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