New Horizons in Lipid Management
New Horizons in Lipid Management
The view is now emerging that, despite evidence that there are a number of mechanisms involved in atherogenesis, the contributions of elevated levels of atherogenic lipoproteins containing apolipoprotein B-100, especially low-density lipoproteins (LDL), are assuming a dominant role. Observations on genetic variants, such as loss-of-function mutations at the PCSK9 locus, tell us that distinctly low levels of LDL are attended with a very low risk for atherosclerotic heart disease, suggesting that therapeutic goals should be lower than those established in the past. It is also apparent that a significant number of patients are either unable to reach appropriate levels of LDL with currently available therapeutic agents or are intolerant of those medications. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") are the most potent agents now available. Their activity can be enhanced dramatically by the addition of emerging antibodies that disable the PCSK9 protein, with the effect of increasing the functional endurance of the receptors. However, both of these therapeutic strategies are dependent on the existence of a functionally significant population of receptors and, failing the discovery of small-molecule inhibitors of PCSK9, will require the employment of expensive antibody therapeutics if that target is to be included. Thus, for those patients who lack sufficient numbers of functional receptors or who are drug intolerant, new avenues of therapy are needed.
In this issue of the Journal, Ballantyne et al. introduce a novel dual-effect, small-molecule therapy that plays 2 crucial roles in the central control pathways for lipids and carbohydrates. The first involves inhibition of adenosine triphosphate citrate lyase, the enzyme crucial for the production of adenosine triphosphate citrate essential to the synthesis of both fatty acids and cholesterol. The second effect attributable to this single, small molecule is the activation of adenosine monophosphate activated protein kinase (AMPK)—resident in the liver, striated muscle, and the brain—the protein that is at the heart of the directional control of energy substrates. It is effectively a sensor of the energy-depleted form of adenosine triphosphate (ATP) (i.e., AMP) and thus is able to redirect energy substrates at the time of need, such as during skeletal muscle activity. Its effect is concerted in several coordinated pathways, all of which increase the uptake and consumption of glucose and fatty acids and inhibit anabolic processes. These include increased beta-oxidation of fatty acids, gluconeogenesis, and increased numbers of mitochondria in the cell. There is evidence that AMPK also plays a role in the increased metabolic activity of mitochondria, at least in response to acute exercise, an activity that would contribute further to the consumption of fatty acids. In this setting, AMPK increases the activity of the peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PGC)-alpha, a transcription factor with a recognized role in the regulation of genes involved in ketogenesis and gluconeogenesis. This activity suggests that possible synergy could exist with PPAR-gamma agonists. At the same time, the activation of AMPK decreases the synthesis of cholesterol and of fatty acids and, thus, of triglycerides. Also, the complement of the Glut-4 glucose transporter in striated red muscle fibers is increased by translocation, an effect associated with exercise. In addition, AMPK appears to increase the phosphorylation of glucose by hexokinase in muscle cells, favoring the flux into muscle.
This array of metabolic-regulatory activities would suggest multiple effects of this agent, clearly on cholesterol metabolism, but also on diabetes and hypertriglyceridemia. The clinical trial excluded individuals with diabetes, so the former effect could not be appreciated. However, a suggestion that it may be expected arises from the observation that levels of insulin decreased among hyperinsulinemic individuals. Clearly, trials in diabetic patients should be undertaken because of the relationship between insulin resistance/overt diabetes and arteriosclerotic heart disease. Because many of the subjects did not have hypertriglyceridemia of significance, and because hypertriglyceridemia may result from different underlying metabolic derangements, the absence of a broad effect on triglyceride levels in this trial may also not reflect the whole potential impact on triglyceride metabolism.
The striking effect on LDL cholesterol levels, however, is the ≤27% reduction in at the upper dosage level which appears to be well tolerated, at least in the very short term, which suggests that this new avenue may have true benefit in individuals with elevated LDL cholesterol levels. The particular appeal of this strategy is that it might be expected to be independent of statin effects, acting to deplete the precursors of cholesterol and fatty acids. Thus, it might be expected to be of use in individuals unresponsive to, or intolerant of, statins. A caveat must be considered here, however: If statin intolerance in some individuals comes from the depletion of isoprenoid compounds in the HMG-CoA–mevalonate pathway, such as dolichol, or from decreased prenylation of proteins, then upstream impedance in the pathway could produce a similar effect. Further experience with agents in this class will inform this in time.
Another phenotype of dyslipidemia in which benefit may be shown is familial combined hyperlipidemia, in which the underlying mechanism is thought to be overproduction of very-low-density lipoproteins (VLDL), which are then metabolized to LDL. This is believed to be the most prevalent disorder of circulating lipids now recognized, and it is responsible for a significant part of the burden of coronary artery disease in Europe and North America. Reduction of triglyceride synthesis and increased oxidation of fatty acids in the liver would be expected to decrease the flux of triglycerides in VLDL, and the reduction in cholesterol synthesis would be expected to reduce intrahepatic cholesterol, up-regulating LDL receptors in receptor-competent individuals. It will be important to determine whether synergistic activity will occur when this agent is administered with other lipid-lowering medications, especially statins.
The report is very early in the development of this agent, restricted to short-term data on only 177 subjects, and excludes individuals with diabetes and other metabolic disorders of importance. Observation for adverse events will have to be extended for a long period and in much larger cohorts, because some adverse events may be observed only in patients with predisposing genetic factors. For example, there are data suggesting that ATP citrate lyase has a role in regulating histone acetylation and perhaps in other biologically important acetylation processes, even affecting cell growth and replication. The long-term effect of this action must be appreciated in human subjects.
The exciting aspect of the development of this new agent is that it embarks on a new avenue of metabolic regulation. Another example of targeted therapy is the emergence of compounds that inhibit SRBI protein activity. As the molecular participants in pathways such as the AMPK regulatory system become characterized in detail, and the detailed 3-dimensional structure of key elements such as ATP citrate lyase and AMPK become known (the proteins are dimeric and trimeric, respectively, and are now characterized in detail), small-molecule inhibitors or activators can be identified by array technology. It is expected that the application of the understanding of crucial pathways of metabolic regulation will reveal a host of new targets for rational therapeutic intervention.
The view is now emerging that, despite evidence that there are a number of mechanisms involved in atherogenesis, the contributions of elevated levels of atherogenic lipoproteins containing apolipoprotein B-100, especially low-density lipoproteins (LDL), are assuming a dominant role. Observations on genetic variants, such as loss-of-function mutations at the PCSK9 locus, tell us that distinctly low levels of LDL are attended with a very low risk for atherosclerotic heart disease, suggesting that therapeutic goals should be lower than those established in the past. It is also apparent that a significant number of patients are either unable to reach appropriate levels of LDL with currently available therapeutic agents or are intolerant of those medications. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") are the most potent agents now available. Their activity can be enhanced dramatically by the addition of emerging antibodies that disable the PCSK9 protein, with the effect of increasing the functional endurance of the receptors. However, both of these therapeutic strategies are dependent on the existence of a functionally significant population of receptors and, failing the discovery of small-molecule inhibitors of PCSK9, will require the employment of expensive antibody therapeutics if that target is to be included. Thus, for those patients who lack sufficient numbers of functional receptors or who are drug intolerant, new avenues of therapy are needed.
In this issue of the Journal, Ballantyne et al. introduce a novel dual-effect, small-molecule therapy that plays 2 crucial roles in the central control pathways for lipids and carbohydrates. The first involves inhibition of adenosine triphosphate citrate lyase, the enzyme crucial for the production of adenosine triphosphate citrate essential to the synthesis of both fatty acids and cholesterol. The second effect attributable to this single, small molecule is the activation of adenosine monophosphate activated protein kinase (AMPK)—resident in the liver, striated muscle, and the brain—the protein that is at the heart of the directional control of energy substrates. It is effectively a sensor of the energy-depleted form of adenosine triphosphate (ATP) (i.e., AMP) and thus is able to redirect energy substrates at the time of need, such as during skeletal muscle activity. Its effect is concerted in several coordinated pathways, all of which increase the uptake and consumption of glucose and fatty acids and inhibit anabolic processes. These include increased beta-oxidation of fatty acids, gluconeogenesis, and increased numbers of mitochondria in the cell. There is evidence that AMPK also plays a role in the increased metabolic activity of mitochondria, at least in response to acute exercise, an activity that would contribute further to the consumption of fatty acids. In this setting, AMPK increases the activity of the peroxisome proliferator-activated receptor (PPAR)-gamma coactivator-1 (PGC)-alpha, a transcription factor with a recognized role in the regulation of genes involved in ketogenesis and gluconeogenesis. This activity suggests that possible synergy could exist with PPAR-gamma agonists. At the same time, the activation of AMPK decreases the synthesis of cholesterol and of fatty acids and, thus, of triglycerides. Also, the complement of the Glut-4 glucose transporter in striated red muscle fibers is increased by translocation, an effect associated with exercise. In addition, AMPK appears to increase the phosphorylation of glucose by hexokinase in muscle cells, favoring the flux into muscle.
This array of metabolic-regulatory activities would suggest multiple effects of this agent, clearly on cholesterol metabolism, but also on diabetes and hypertriglyceridemia. The clinical trial excluded individuals with diabetes, so the former effect could not be appreciated. However, a suggestion that it may be expected arises from the observation that levels of insulin decreased among hyperinsulinemic individuals. Clearly, trials in diabetic patients should be undertaken because of the relationship between insulin resistance/overt diabetes and arteriosclerotic heart disease. Because many of the subjects did not have hypertriglyceridemia of significance, and because hypertriglyceridemia may result from different underlying metabolic derangements, the absence of a broad effect on triglyceride levels in this trial may also not reflect the whole potential impact on triglyceride metabolism.
The striking effect on LDL cholesterol levels, however, is the ≤27% reduction in at the upper dosage level which appears to be well tolerated, at least in the very short term, which suggests that this new avenue may have true benefit in individuals with elevated LDL cholesterol levels. The particular appeal of this strategy is that it might be expected to be independent of statin effects, acting to deplete the precursors of cholesterol and fatty acids. Thus, it might be expected to be of use in individuals unresponsive to, or intolerant of, statins. A caveat must be considered here, however: If statin intolerance in some individuals comes from the depletion of isoprenoid compounds in the HMG-CoA–mevalonate pathway, such as dolichol, or from decreased prenylation of proteins, then upstream impedance in the pathway could produce a similar effect. Further experience with agents in this class will inform this in time.
Another phenotype of dyslipidemia in which benefit may be shown is familial combined hyperlipidemia, in which the underlying mechanism is thought to be overproduction of very-low-density lipoproteins (VLDL), which are then metabolized to LDL. This is believed to be the most prevalent disorder of circulating lipids now recognized, and it is responsible for a significant part of the burden of coronary artery disease in Europe and North America. Reduction of triglyceride synthesis and increased oxidation of fatty acids in the liver would be expected to decrease the flux of triglycerides in VLDL, and the reduction in cholesterol synthesis would be expected to reduce intrahepatic cholesterol, up-regulating LDL receptors in receptor-competent individuals. It will be important to determine whether synergistic activity will occur when this agent is administered with other lipid-lowering medications, especially statins.
The report is very early in the development of this agent, restricted to short-term data on only 177 subjects, and excludes individuals with diabetes and other metabolic disorders of importance. Observation for adverse events will have to be extended for a long period and in much larger cohorts, because some adverse events may be observed only in patients with predisposing genetic factors. For example, there are data suggesting that ATP citrate lyase has a role in regulating histone acetylation and perhaps in other biologically important acetylation processes, even affecting cell growth and replication. The long-term effect of this action must be appreciated in human subjects.
The exciting aspect of the development of this new agent is that it embarks on a new avenue of metabolic regulation. Another example of targeted therapy is the emergence of compounds that inhibit SRBI protein activity. As the molecular participants in pathways such as the AMPK regulatory system become characterized in detail, and the detailed 3-dimensional structure of key elements such as ATP citrate lyase and AMPK become known (the proteins are dimeric and trimeric, respectively, and are now characterized in detail), small-molecule inhibitors or activators can be identified by array technology. It is expected that the application of the understanding of crucial pathways of metabolic regulation will reveal a host of new targets for rational therapeutic intervention.
