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National Lipid Associations 2nd Annual Masters Summit during the week of the 80th Scientific Sessions of the American Heart Association

Orlando, Florida / November 3, 2007

Reported by: David Fitchett, MD, FRCPC

Terrence Donnelly Heart Centre, St. Michael’s Hospital, Toronto, Ontario

Associate Professor of Medicine, Division of Cardiology, University of Toronto, Toronto, Ontario

New Science of Cholesterol Metabolism: Synopsis

Understanding the relative contributions of mechanisms that determine circulating cholesterol levels is critical to improving hyperlipidemia control. At the 2nd Annual Masters Summit of the National Lipid Association, progress was reported in defining the interrelationship of hepatic cholesterol synthesis and dietary cholesterol absorption. The new detail with which molecular steps are being understood may add therapeutic targets and encourage the production of combination therapies to defuse homeostatic signalling that is thought to dilute single-agent efficacy.

Dr. David E. Cohen, Director of Hepatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, emphasized the role of the liver as a central mediator of cholesterol homeostasis. The liver is the primary source of new cholesterol synthesis, but it balances production in response to extrahepatic sources, including reverse cholesterol transport from the periphery and hydrolysis of stored cholesterol esters. The liver is also responsible for eliminating most cholesterol, primarily by converting it into bile salts. The rate of elimination is also influenced by the activity of HDL, which delivers cholesteryl esters to the liver, where they are removed from the circulation by specific hepatocyte receptors.

These functions are interdependent and not necessarily unidirectional. For example, only a proportion of dietary cholesterol absorbed from the diet enters into systemic circulation, according to Dr. Cohen. Most is excreted; similarly, approximately 50% of biliary cholesterol excreted by the liver into the intestine is eventually reabsorbed. A major responsibility for maintaining a balance between cholesterol entering the circulation and the elimination of cholesterol lies with the liver, which has a central role in mediating cholesterol synthesis, responding to reverse cholesterol transport, eliminating cholesterol through the biliary tree, and potentially signalling rates of intestinal cholesterol absorption. The variety of pathways potentially limits the efficacy of any intervention targeted at one single component of the system.

Until recently, the mechanism by which cholesterol is absorbed from the small intestine was not understood. Dr. Stephen D. Turley, Department of Internal Medicine, Southwestern Medical Center, Dallas, Texas, described three phases. The first is micellar solubilization of unesterified cholesterol, which facilitates migration of cholesterol to the brush border membrane (BBM) of the enterocytes that line the wall of the small intestine. The second is transport across the BBM by the Niemann-Pick C1 Like-1 (NPC1L1), a protein that has only recently been isolated. The third phase involves esterification of cholesterol into nascent chylomicrons. Dr. Turley conceded that some functions of the NPC1L1 are controversial, and it has not yet been uniformly accepted as the sole arbitrator of cholesterol transport into the enterocyte, but he noted that responsiveness to ezetimibe, a potent blocker of dietary cholesterol absorption, correlates with NPC1L1 binding.

The isolation of the specific mechanisms of dietary uptake of cholesterol provides several avenues for new treatments. In addition to inhibition of the activity of cholesterol transporters with such agents as ezetimibe, it may also be possible to develop other competitors. According to Dr. Peter J.J. Jones, Director, Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Winnipeg, plant sterols compete with cholesterol for incorporation into micelles or at transporter proteins to prevent cholesterol absorption. He cited studies in which absorption was reduced by as much as 40% in animal models using plant sterols. Soy protein has similar competitive action and results in reduced absorption and increased fecal cholesterol excretion.

Due to the interrelationship of mechanisms, the consensus of the National Lipid Association symposium was that optimal control of hyperlipidemia is not likely to be achieved by any single intervention. The most effective strategies are limited by feedback mechanisms that signal compensatory changes that encourage a regression back to the setpoint of circulating cholesterol. Although Drs. Cohen, Turley and Jones addressed different aspects of the homogeneity that characterizes lipid metabolism, they agreed upon an interdependence of these mechanisms. The complex processes controlling cholesterol synthesis, transport and elimination are now better understood with increasing detail. This has the potential for new avenues by which lipid metabolism can be controlled.

Commentary

The important reduction in the risk of cardiovascular (CV) events associated with statin treatment with lower LDL-C levels has been the basis for revisions in treatment targets. In September 2006, the Canadian Cardiovascular Society issued new guidelines with a 50% reduction of LDL-C and a target LDL of <2.0 mmol/L for patients at high risk (defined as a calculated 10-year risk >20%, or established coronary heart disease, peripheral vascular disease, cerebrovascular disease or diabetes). Statins have potent lipid-lowering properties. However, the dose response is not linear: for each doubling of the dose, the anticipated additional reduction in LDL is only approximately 6%. Consequently, if the patient does not achieve the LDL target with a low-dose statin, going to the maximum dose will only reduce LDL by a further 15% to 18%. The development of an inhibitor of dietary cholesterol absorption has provided a second strategy for LDL reduction. In clinical studies with the cholesterol absorption inhibitor ezetimibe, the reduction in LDL, additional to that achieved with statins alone, is approximately 20%.

Cholesterol Mechanisms

Cholesterol is vital to normal human physiology as an important component of cell membrane structure, as well as a precursor for the synthesis of steroid hormones and bile acids. As excess cholesterol can be toxic to human cells, there is the need for a tightly regulated system to maintain levels within the appropriate window of physiologic need. Although cholesterol synthesis is mainly extrahepatic, the liver plays a central role in regulating LDL-C levels. The liver is the main site for both LDL and VLDL production and receptor-mediated clearance of LDL from the plasma. Furthermore, the liver is the only site where cholesterol is catabolized and subsequently eliminated in the bile. This process is dependent on multiple and interrelated mechanisms of synthesis, dietary absorption, reverse cholesterol transport from the periphery by HDL and elimination in feces. Although a variety of factors are important for cholesterol homeostasis, an important factor for the control of cholesterol is the balance between synthesis of LDL and intestinal absorption. In normal cholesterol metabolism, the rate of cholesterol lost in the feces each day equals the rate of new cholesterol availability, whether from synthesis or dietary intake. In an adult, the average loss of cholesterol by any means is approximately 1.6 g/day. This is equal to the new synthesis of approximately 1.2 g/day and 0.4 g/day from diet. The control of cholesterol absorption is complex, and involves multiple factors that include genetic factors, the size of the enterohepatic cholesterol pool, dietary composition and bowel transit time.

In the liver, the rate-limiting step of cholesterol synthesis is the enzyme HMG CoA reductase. Although marked reductions of circulating LDL-C may be achieved with inhibition of the HMG CoA reductase, homeostatic mechanisms may attempt to maintain the hepatic cholesterol pool. An important extra-hepatic source of cholesterol is from small intestinal absorption of cholesterol and bile acids. Approximately 50% of the 2.4 g/day of cholesterol reaching the small bowel (2 g from bile and 0.4 g from diet) is reabsorbed and the remaining 1.2 g excreted in the feces.

The first specific cholesterol absorption inhibitor, ezetimibe, was recognized for its ability to prevent transport. Ezetimibe has been shown to specifically inhibit the NPC1L1 protein responsible for cholesterol transport across the enterocyte BBM. Deletion of the NPC1L1 gene in animal models has an important effect on cholesterol absorption and eliminates the effect of ezetimibe.

Effect on LDL Levels

Inhibition of cholesterol synthesis with a statin has a more profound effect on LDL-C levels than inhibition of intestinal cholesterol uptake with ezetimibe. With the most recent generation of statins, an LDL reduction of more than 50% is possible. In contrast, ezetimibe typically reduces LDL by approximately 20%, an effect that is additive to the LDL lowering with the statin when the two agents are combined. However, the variation of response to both statins and ezetimibe is large. For example, the LDL-C reduction with atorvastatin varies from a high of 55% to a low of only 5%, with a median reduction of approximately 35%. Three recent studies have shown that patients with a poor response to a statin will have a larger than average response to ezetimibe. This observation supports the hypothesis that patients with a high intestinal absorption of cholesterol tend to have a low hepatic synthesis.

The combination of a statin with the cholesterol absorption inhibitor ezetimibe results in lower LDL-C than that achieved with the statin alone and a greater opportunity to achieve treatment targets. The combination of rosuvastatin 40 mg and ezetimibe 10 mg daily was shown in the EXPLORER trial to reduce LDL-C by 70%. However, in patients who do not require this degree of LDL reduction to reach treatment targets, there is still a rationale for combining a statin and cholesterol absorption inhibitor. The cholesterol absorption inhibitor permits relatively low doses of statins to be employed, reducing the incidence of dose-related adverse effects, such as muscle-related side effects and liver dysfunction.

Aattaining Target LDL Levels

Clinical trials have demonstrated that the reduction of CV events is related to the amount LDL-C is reduced and the level of LDL-C achieved. An important proportion of patients treated with statins fail to reach even the relatively modest LDL target of <2.5 mmol/L. To achieve the current LDL goal of <2.0 mmol/L in high-risk patients, maximum doses of the most potent of the currently available statins will often not be sufficient. Analyses of the TNT (Treating to New Targets) Clinical trials have demonstrated that the reduction of CV events is related to the amount LDL-C is reduced and the level of LDL-C achieved. An important proportion of patients treated with statins fail to reach even the relatively modest LDL target of <2.5 mmol/L. To achieve the current LDL goal of <2.0 mmol/L in high-risk patients, maximum doses of the most potent of the currently available statins will often not be sufficient. Analyses of the TNT (Treating to New Targets) trial showed that reduction of LDL below current targets further reduced CV risk. Combination strategies are likely to be necessary to achieve the large LDL reductions needed to improve outcomes of high-risk patients. Other combination therapies for the treatment of dyslipidemias are likely to become more common as information becomes available about the relative advantages of raising HDL and reducing elevated triglycerides. However, the data on the benefits of reducing LDL are overwhelming and have made LDL-C lowering the primary lipid target for CV risk reduction.

Multiple studies have indicated that patients at the highest risk of CV events are the least likely to achieve treatment goals. In the NEPTUNE II survey of 4885 patients, 76% of patients with a single risk factor achieved an LDL target of <2.5 mmol/L. However, success was less in those at highest risk. Only 55% of patients with diabetes and 40% with other coronary heart disease (CHD) risk equivalents reached LDL-C goals. Furthermore, only 20% reached the current target of LDL <2.0 mmol/L.

Other Risk Factors and Emerging Trials

LDL is the most important modifiable CV risk factor. Clinical trials conducted over the past decade have shown that each incremental reduction in LDL has been associated with a commensurate reduction in CV events, regardless of the statin used. Although the current goal for high-risk patients is now <2.0 mmol/L, it is not clear if this provides maximum protection. In a post-hoc analysis of the PROVE-IT TIMI 22 trial (with an average LDL of 1.6 mmol/L for the patients on atorvastatin 80 mg), benefit was related to the LDL-C achieved on treatment. Patients with an LDL-C of <1.0 mmol/L had an event rate 39% lower than those with LDL-C of 2.1 to 2.6 mmol/L—thus, achievement of LDL-C levels below current targets may have additional benefit.

The residual burden of events in high-risk patients who receive optimal LDL-C-lowering therapy remains substantial. This underscores the need to continue to aggressively pursue new treatment strategies. In secondary prevention of CV disease, important reductions in event rates are observed in those receiving the most aggressive lipid-lowering therapy, yet residual risk remains high. For example, the 22% reduction in the composite end point of major CV events for those receiving aggressive LDL lowering in the TNT trial was related to a five-year event rate of 10.9% in those treated less aggressively. As a result, 8.7% of patients in the optimal therapy group still had an event. This translates into a residual risk of almost 80%. Similar residual risks have been observed in most secondary prevention trials, including PROVE-IT.

Some of the residual risk may be attributed to other modifiable risks, including suboptimally controlled hypertension or diabetes. Other lipid abnormalities, such as low HDL, may be a modifiable risk factor. Currently, niacin is the only effective and available agent that increases HDL. However, poor tolerability limits its use. As a consequence, maximal LDL lowering remains the best strategy that is supported by robust clinical trial data. Combination therapy provides an opportunity to increase the proportion of patients at or below LDL goals with a low risk of adverse events. Whilst other risk reduction strategies deserve attention and additional research is needed to identify new opportunities, it is important to pursue goals for which there is evidence-based guidance.

Summary

The liver synthesizes VLDL-C, the precursor for LDL, from two cholesterol sources: de novo synthesis and cholesterol returning to the liver especially from the enterohepatic circulation. Inhibiting two of the major contributors to the cholesterol pool with statins and ezetimibe results in a greater reduction of LDL-C than by using either agent alone. Combination therapy has been advocated in other disease states where two or more drugs with separate mechanisms of action can increase efficacy in low and well-tolerated doses. The additive benefits of statins and a cholesterol absorption inhibitor on interdependent pathways make this strategy particularly attractive in control of hyperlipidemia.