2007 transcript with Dr. Ballantyne regarding Reliant Combos study (Omacor plus simvastatin)
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Changes in Lipoprotein-Associated Phospholipase A2 During Treatment With Omega-3-Acid Ethyl Esters: An Expert Interview With Christie M. Ballantyne, MD
Faculty and Disclosures
Editor's Note:
At the American Heart Association (AHA)'s 8th Annual Conference on Arteriosclerosis, Thrombosis and Vascular Biology (April 19-21, 2007; Chicago, Illinois), Christie Ballantyne, MD, Professor, Department of Medicine; Associate Chief, Atherosclerosis and Lipoprotein Section, Baylor College of Medicine, Houston, Texas, and coinvestigators presented new data from a study of prescription omega-3-acid ethyl esters (Omacor; Reliant Pharmaceuticals, Liberty Corner, New Jersey) added to a statin for treatment of persistent hypertriglyceridemia.[1] In the study, which was funded by Reliant, combined treatment with Omacor plus simvastatin was found to reduce levels of lipoprotein-associated phospholipase A2 (Lp-PLA2), a proinflammatory enzyme that has been shown to be an independent predictor of cardiovascular risk.[2-8] The reduction in Lp-PLA2 seen in the Omacor plus simvastatin group in this study was associated with changes in concentrations of small low-density lipoprotein (LDL) particles and large high-density lipoprotein (HDL) particles.
The study involved 254 subjects (men and women aged 19-79 years) who had been taking simvastatin 40 mg/day and following the National Cholesterol Education Program (NCEP) Therapeutic Lifestyle Changes diet for 8 weeks, but who at the end of this period had fasting triglycerides = 200 mg/dL and < 500 mg/dL and LDL cholesterol levels < 10% above NCEP/Adult Treatment Panel III (ATP III) goals. Over the following 8 weeks, all subjects received open-label simvastatin 40 mg plus randomization to either double-blinded Omacor 4 g/day or a matching placebo 4 g/day. Compared with placebo plus simvastatin, Omacor plus simvastatin did not further reduce LDL cholesterol levels, but resulted in significant reductions in non-HDL cholesterol (9.0% vs 2.2%; P < .0001), triglycerides (29.5% vs 6.3%; P < .0001), and apolipoprotein B (4.2% vs 1.9%; P = .023). Lp-PLA2 was significantly reduced in the Omacor plus simvastatin treatment group compared with placebo plus simvastatin (-10.7% vs -1.4%; P = .002). The Lp-PLA2 response was not significantly related to changes in LDL or HDL cholesterol levels, but was associated with changes in LDL (r = 0.297, P = .002) and HDL (r = 0.249, P = .012) particle concentrations in the Omacor plus simvastatin group, and with changes in different LDL and HDL subfractions. The change in proatherogenic small, dense, electronegative LDL particle concentration was associated with the Lp-PLA2 response (r = 0.258, P = .009). This finding was consistent with previous studies showing that Lp-PLA2 is enriched in these particles. Dr. Ballantyne and his coinvestigators recommended further investigation of the underlying mechanisms of the impact of Omacor plus simvastatin treatment on small LDL particle concentration and overall Lp-PLA2 concentration.
Medscape: Why would patients with dyslipidemia need a compound like Omacor in addition to statin therapy?
Dr. Ballantyne: As physicians, we are basically very pleased with the great evidence that we have for statins as first-line therapy for hypercholesterolemia, and they are used in these patients worldwide. Over the past decade, however, there has been an evolution in the typical cardiovascular risk profile, unfortunately led by the United States, with high rates of obesity, diabetes, and metabolic syndrome. We have seen a shift in the profile from straightforward high LDL cholesterol to a much more common pattern that we call mixed dyslipidemia. It is a combination of high LDL cholesterol and high triglycerides, and it is particularly common in people with diabetes. In the UK Heart Protection Study (HPS), simvastatin was shown to be effective in reducing the risk for major vascular events in nondiabetic and diabetic subjects with coronary disease, but, unfortunately, the subjects with diabetes and coronary disease still had a very high event rate of > 30% over the 5 years of the study.[9,10] So the important question remained: "What do we do after we have administered a statin?" That is the fundamental clinical question. More specifically it is, "What would the benefits be for another drug beyond a statin?" A number of options have been pursued, some of which have been successful, such as cholesterol absorption inhibitors (eg, ezetimibe), and some not so successful, such as the recent failure of the investigational cholesteryl ester transfer protein (CETP) inhibitor torcetrapib.[11] There is also the issue of whether we would add a fibrate. Another option would be to add prescription omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) ethyl esters, as found in Omacor, in combination with a statin. So we designed a study to evaluate the safety and efficacy of Omacor as an adjunct to diet and simvastatin therapy in patients with high triglycerides.
Medscape: This was the COMBination of Omacor and Simvastatin (COMBOS) study?
Dr. Ballantyne: Yes. The COMBOS study enrolled subjects with high triglyceride levels (= 200 mg/dL and < 500 mg/dL) who all received simvastatin 40 mg, along with which they were randomized to additional placebo or Omacor.[12] Overall there was, as expected, a significant reduction in levels of triglycerides and non-HDL, but no further reduction in LDL cholesterol. What was particularly interesting was that we also saw an additional reduction in Lp-PLA2, which decreased from 231 ± 6.3 ng/mL (mean ± SEM) at baseline to 200 ± 5.5 ng/mL. There are a lot of data on emerging markers for cardiovascular risk that we can look at in addition to LDL cholesterol levels. Obviously we look at HDL cholesterol, triglycerides, and blood pressure in addition to LDL cholesterol, but there has been a great deal of interest in newer markers, particularly those related to inflammation, such as Lp-PLA2 or C-reactive protein (CRP). What we found in this study was an additional reduction in Lp-PLA2 of 10.7%, and that was actually quite interesting because, in general, Lp-PLA2 levels correlate more strongly with the levels of LDL cholesterol.
Medscape: How strongly is Lp-PLA2 associated with LDL?
Dr. Ballantyne: In humans, about 70% to 80% of the enzyme is associated with LDL and the remaining 20% with HDL. So what was of interest in our study was that the LDL cholesterol level did not change and yet the level of Lp-PLA2 decreased.
Medscape: Don't statins also lower Lp-PLA2?
Dr. Ballantyne: Statins or fenofibrate also lowers Lp-PLA2 activity by 20% to 30%, but this is probably directly related to the marked concomitant reduction in levels of LDL cholesterol. In our study, we saw about a 10% reduction in Lp-PLA2 with no overall reduction in LDL cholesterol, but there was an association with changes in LDL particle concentrations and HDL particle concentrations. In particular, the reduction in Lp-PLA2 was associated with the change in small LDL particles. This is of particular interest because this enzyme is not distributed evenly among the different LDL particles; Lp-PLA2 preferentially associates with the smaller and denser fractions that are believed to be more proatherogenic.[13,14] Small LDL particles are more electronegative than large LDL particles and have been shown to be highly enriched in Lp-PLA2, with up to 5-fold higher Lp-PLA2 activity. There is a strong inverse relation between LDL particle size and serum triglyceride level. The smaller, denser particles are enriched in triglycerides and there is a different fatty acid composition of those particles. In our study, we were using therapy with omega-3 fatty acids, primarily eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), which decreased the small dense LDL particles. There was no effect on LDL cholesterol levels, but the LDL particles changed and the triglyceride content and fatty acid composition of these particles changed, and we saw a reduction in Lp-PLA2. So this is somewhat of a novel finding, because one would have predicted that if LDL cholesterol levels were lowered by 40% to 50%, levels of Lp-PLA2 would also be reduced. So the statin observation was straightforward, but this finding is more interesting in that there appears to be a specific subset of particles that are enriched in this enzyme and that this is influenced by adding omega-3-acid ethyl esters to simvastatin therapy.
Medscape: So Omacor plus simvastatin reduced the number of small, dense LDL particles, but did it change the other lipid particles?
Dr. Ballantyne: When we looked at the correlation of changes we saw that, although there was no overall effect on LDL cholesterol levels, there was a reduction in non-HDL cholesterol and apolipoprotein B (apoB), and there were some changes in specific subsets of particles. Those data were not presented at the meeting. What we showed in our presentation was that the effect of Omacor plus simvastatin therapy showed a correlation (r = 0.258) between the change in small LDL particles and the change in Lp-PLA2; in other words, they were in the same direction. So as the concentration of small particles decreased, so did levels of Lp-PLA2.
Medscape: Did Omacor also have an effect on medium and large HDL?
Dr. Ballantyne: Yes. Overall, HDL cholesterol levels increased.
Medscape: Was that related to the effect on LDL?
Dr. Ballantyne: As triglycerides decrease, there tend to be fewer small dense LDL particles and a greater increase in larger HDL particles. They tend to be related inversely with each other.
Medscape: What are the implications of the effects of Omacor plus simvastatin on small dense LDL particles and Lp-PLA2?
Dr. Ballantyne: These findings are encouraging, but there are 2 major issues that need to be addressed. First, more basic research needs to be done in terms of understanding the mechanism of the effects we saw. This was a clinical study, and what we saw are associations, but to understand them more specifically we need to determine the mechanism of the alterations in the small dense LDL particles and why we are removing those particles and whether that is why Lp-PLA2 is no longer decreasing, or whether something has changed in this particle so that the enzyme no longer binds to it. In our study, we had an intervention in a prospective randomized trial; we saw that there was a reduction in Lp-PLA2 levels, and we saw some interesting associations that were consistent with prior observations that a specific subspecies of LDL particles -- small dense LDL -- is enriched with Lp-PLA2. These particles are triglyceride-enriched, and they have some abnormalities in fatty acid composition. Using a therapy that lowers triglycerides that changes particle composition for triglycerides and alters particle size also lowers Lp-PLA2. That is all intriguing, but those are associations, and the exact molecular mechanisms have not been identified.
On the clinical level, the very important but simple question is, "What do we do for a patient with mixed hyperlipidemia after we have given a statin?" This study demonstrates that one option would be to add omega-3-acid ethyl esters, which have benefits on triglycerides, non-HDL cholesterol, and apoB. There is no benefit on the LDL cholesterol level, but there is a reduction in Lp-PLA2. That is somewhat intriguing in terms of whether there could be any event reduction by using this therapy, and this has to be tested in a prospective trial. In a recently published randomized clinical trial,[15] the Japan EPA Lipid Intervention Study (JELIS), 1.8 g/day of EPA, similar to the amount of EPA in Omacor used in our study, was given with a statin in patients with total cholesterol = 6.5 mmol/L (256.6 mg/dL). Compared with statin alone, the EPA/statin combination reduced major coronary events by 19%. We do not know what the Lp-PLA2 levels were in the JELIS trial, however.
Medscape: So the effect of Lp-PLA2 could be part of the benefit of this therapy, theoretically? Since Lp-PLA2 has been shown in many large studies to be a risk marker for cardiovascular disease, does that mean that lowering it with Omacor therapy must have a beneficial effect in the prevention of cardiovascular disease?
Dr. Ballantyne: I would say that it is encouraging. It does not show causality, that it would reduce cardiovascular events, because as you pointed out, it is a risk marker. We do not know whether it is a risk factor, although there is a good biological plausibility that it is. It would be interesting to get data from large trials with omega-3-acid ethyl esters in the future, or if investigators from recent trials such as JELIS have banked plasma they could look at Lp-PLA2 changes to examine whether they were predictive of events. One pharmaceutical company (GlaxoSmithKline, London, United Kingdom) has a large program to develop small-molecule inhibitors of Lp-PLA2 (led by darapladib in phase 2/3, with 2 follow-up compounds in phase 1) to further reduce the risk for cardiovascular disease.
Medscape: Can the research on Lp-PLA2 you mentioned be done in animal models, or does Lp-PLA2 distribution differ in animals?
Dr. Ballantyne: You need to probably do a lot of this research in humans or primates. In contrast to humans, Lp-PLA2 in several animal species, including mouse, dog, and rabbit, is predominantly associated with HDL rather than LDL.
Medscape: Will the COMBOS data lead to any expansion of the use of Omacor in the United States?
Dr. Ballantyne: The current indication in the United States for Omacor is as an adjunct to diet to reduce very high (= 500 mg/dL) triglycerides in adult patients. The COMBOS study was part of the clinical research for a new indication for Omacor to be used as an adjunct to diet and statin therapy in patients who have mixed dyslipidemia, which is a much more common condition than just high triglycerides. Submission of the COMBOS data in support of the expanded use of Omacor was made in December 2006 and is under review by the FDA.[16]
Medscape: In COMBOS, Omacor was given with simvastatin 40 mg. What about other doses and other statins?
Dr. Ballantyne:Omacor could be used in various doses with simvastatin or other statins, but this study specifically examined a dosage of Omacor 4 g daily plus simvastatin 40 mg daily, which we know is a very good evidence-based dose of simvastatin.
Supported by an independent educational grant from Reliant Pharmaceuticals
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