Updates on HDL and Triglycerides
Updates on HDL and Triglycerides
Lipid regulators are the largest therapeutic class of drugs sold in the United States and statins are the most potent lipid-lowering drugs available. These agents, together with therapeutic lifestyle changes such as diet and exercise, are the foundation for primary and secondary prevention of coronary artery disease (CAD).
Despite the tremendous success of statin therapy compared to earlier lipid-lowering agents (e.g., bile acid sequestrants and fibrates), a majority of statin-treated patients continue to show evidence of dyslipidemia. For more than half of these individuals, there remains a need for further lowering of low-density lipoprotein cholesterol (LDL-C) or triglyceride (TG) levels. Moreover, in all the statin trials, there remains a substantial residual risk in the treated groups, even among aggressively-treated patients. This suggests the presence of additional modifiable mechanisms of the underlying atherosclerotic process.
The next frontier of lipid intervention is focusing on non-LDL particles and the greatest potential may exist for raising levels of high-density lipoprotein cholesterol (HDL-C). Population studies have consistently shown that HDL-C levels are a strong, independent inverse predictor of cardiovascular disease. Indeed in epidemiologic, lipid intervention, and serial angiographic trials, levels of HDL-C correlate more strongly with atherosclerosis and overall coronary heart disease (CHD) risk than does LDL-C.
In the Framingham Heart Study, for example, risk is highest in patients presenting with the combination of high LDL-C and low HDL-C, but risk remains substantial even in patients with relatively low LDL-C who also have low HDL-C. Overall, a 1% increase in serum concentrations of HDL-C decreases cardiovascular risk by 2-3%.
High-density lipoproteins are fairly complex macromolecules and decades of research on the function of HDL have yielded considerable insights and confusion. For example, until recently, inhibition of cholesteryl ester transfer protein (CETP) was considered a promising means of raising HDL-C levels by decreasing the transfer of cholesterol esters from HDL-C to LDL-C particles. The efficacy of this approach, using torcetrapib, a novel CETP inhibitor, was demonstrated in a pair of studies published in early 2000 in the Journal of the American College of Cardiology (Slide 1).
(Enlarge Image)
Slide 1.
Efficacy of Torcetrapib in Individuals with Below-Average HDL-C Levels on a Background of Atorvastatin
Yet later that same year, Pfizer informed the U.S. Food and Drug Administration (FDA) that it was suspending all clinical trials evaluating combination torcetrapib/atorvastatin therapy after data from the patient outcome study called ILLUSTRATE suggested that mortality was significantly higher in patients who received this combination versus atorvastatin alone. (To read the FDA statement, click here.) Shortly thereafter, Kastelein and colleagues published a pair of imaging studies to assess the impact of torcetrapib/atorvastatin on atherosclerotic disease progression. The RADIANCE studies evaluated two different populations: patients with heterozygous familial hyperlipidemia (RADIANCE 1; n = 904) and patients with mixed hyperlipidemia (RADIANCE 2; n = 752).
For either population, the addition of torcetrapib to atorvastatin had no incremental benefit over atorvastatin alone. Indeed, if anything, there was a trend toward harm, with the combination therapy leading to disease progression while atorvastatin alone led to disease regression based on mean common carotid intima-medial thickness (Slide 2). This disease progression occurred despite robust increases in HDL-C and decreases in LDL.
(Enlarge Image)
Slide 2.
RADIANCE 1 and 2 Studies: Change in Mean Common Carotid IMT
It is unclear if the negative data with torcetrapib were due to CETP inhibition in general or adverse effects of the particular agent used, including both the blood pressure increases noted and the production of an "inactive" HDL that lacked significant reverse cholesterol transport. Complicating the clinical relevance of HDL-C is the recent suggestion that in systemic inflammatory states, including acute coronary syndrome (ACS), HDL-C may convert from being anti-inflammatory to proinflammatory.
Despite the fact that torcetrapib studies have largely been a "bust" in terms of outcomes data, HDL-C remains a viable clinical target for reduction of CHD. In early 2008, for example, a large Veterans Administration study demonstrated a strong inverse relationship between HDL-C and CHD risk even among patients with very low levels of LDL-C (mean <50 mg/dl) that are well below the aggressive "optional" guidelines. Yet, despite these very low LDL-C levels, for every 10-mg/dl reduction in HDL-C there was a 10% increase in major CHD events.
In an accompanying editorial, Carl J. Lavie, MD, FACC, and Richard V. Milani, MD, FACC, encouraged clinical awareness and intervention based on proven therapies, such as exercise training, weight reduction, moderate doses of alcohol, niacin, and certain fibrates that not only raise HDL-C but also stimulate reverse cholesterol transport. Based on the available evidence, they said, using such measures should translate into a strong reduction in CHD risk.
Finally, despite all the encouraging data, with HDL-C it is possible to have too much of a good thing. A study by van der Steeg et al. in a February 2008 issue of JACC combines data from a clinical study (the IDEAL [Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering] trial) and the epidemiologic longitudinal study EPIC Norfolk. After adjusting for levels of apolipoprotein (apo) B and apoA-I, very high values of HDL-C (>70 mg/dl) and HDL particle size (>9.5 nm) were associated with increased risk of CAD (Slide 3). The results suggest that large HDL particles increase cardiac risk, possibly by serving as cholesterol donors rather than scavengers.
(Enlarge Image)
Slide 3.
Risk Estimates of HDL-C Levels after Adjusting for Apolipoprotein (apo) B and apoA-I in the IDEAL Study
Historically, elevated TG levels have predicted CHD events in univariate analysis but weaken after adjustment for other covariates, such as plasma glucose and HDL-C, to which TG levels are strongly and inversely correlated. Nevertheless, even after adjusting for HDL-C, population-based prospective studies suggest an independent effect of TG on CHD events. Moreover, combined hyperlipidemia (i.e., elevated LDL-C and TG) promotes CHD to a significantly greater extent than either high LDL-C or TG alone.
Also, like HDL-C, the association of plasma TGs with CAD is complex. In the Prospective Cardiovascular Munster (PROCAM) study, CAD risk increased proportionately with TGs up to 800 mg/dl but began to diminish in persons with levels above 800 mg/dl. In addition, the risk associated with TGs ≥200 mg/dl was dependent on concomitant low HDL-C or elevated LDL/HDL ratio in both PROCAM and in the Helsinki Heart Study.
Considering that the specific risk of elevated TGs in patients achieving optimal LDL reduction is unclear, Miller and colleagues studied the effect of TG levels on outcomes in patients enrolled in the PROVE IT-TIMI 22 trial. The trial randomized post-ACS patients to either atorvastatin 80 mg/day or pravastatin 40 mg/day. In a paper published in JACC in April 2008, the investigators reported that subjects with TG <150 mg/dl were at reduced risk for future events, independent of the LDL level (Slide 4). Those with LDL <70 mg/dl and TG <150 mg/dl were at the lowest risk (Slide 5). Thus, both LDL-C and TG levels are important therapeutic parameters in post-ACS patients.
(Enlarge Image)
Slide 4.
Risk of Recurrent Events Using Selected Cutpoints of LDL-C and TG in PROVE IT-TIMI 22
(Enlarge Image)
Slide 5.
Impact of Triglyceride Levels and LDL-C on Death, MI, and Recurrent ACS in PROVE IT-TIMI 22
One group in particular is at extreme risk of developing CAD with even mild elevations of TGs. Hopkins and colleagues studied a large series of patients with premature familial CAD and population-based controls. They calculated CAD risk across the spectrum of plasma TG levels and tested for interactions with other elements of the metabolic syndrome. They found a strongly increased risk for premature familial CAD with elevated plasma TGs. Importantly, this excess risk begins at a low and relatively common TG elevation of just 200 mg/dl and was independent of plasma HDL-C (Slide 6), other elements of the metabolic syndrome, and other CAD risk factors. In addition, for the first time, they provided a quantitative, population-based estimate of the markedly elevated risk of CAD associated with type III hyperlipidemia, which results from impaired removal of TG-rich lipoprotein remnants.
(Enlarge Image)
Slide 6.
Odds Ratios for Premature CAD is Strong, Graded, and Independent of HDL
In this interview, three authorities on lipid disorders discuss possible treatment options for the management of hypertriglyceridemia and low HDL-C levels and the clinical usefulness of HDL as a biomarker for the detection and prevention of CHD.
Editor's note: Patients with cardiometabolic risk factors represent a group at high lifetime risk for CVD. These patients frequently have dyslipoproteinemia (low HDL cholesterol, increased triglycerides, and/or an increased number of small LDL particles). The April 15, 2008, issue of JACC features Lipoprotein Management in Patients with Cardiometabolic Risk: Consensus Conference Report from the American Diabetes Association and the American College of Cardiology Foundation. To access this report, coauthored by Dr. Davidson, please click here.
[No authors listed.] National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary JAMA 2001;285:2486-97. (For the full report, click here.)
Grundy SM, Cleeman JI, Bairey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-732. (click here.)
Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008; 51:1512-1524.
Abstract
Lipid regulators are the largest therapeutic class of drugs sold in the United States and statins are the most potent lipid-lowering drugs available. These agents, together with therapeutic lifestyle changes such as diet and exercise, are the foundation for primary and secondary prevention of coronary artery disease (CAD).
Despite the tremendous success of statin therapy compared to earlier lipid-lowering agents (e.g., bile acid sequestrants and fibrates), a majority of statin-treated patients continue to show evidence of dyslipidemia. For more than half of these individuals, there remains a need for further lowering of low-density lipoprotein cholesterol (LDL-C) or triglyceride (TG) levels. Moreover, in all the statin trials, there remains a substantial residual risk in the treated groups, even among aggressively-treated patients. This suggests the presence of additional modifiable mechanisms of the underlying atherosclerotic process.
Targeting HDL-C
The next frontier of lipid intervention is focusing on non-LDL particles and the greatest potential may exist for raising levels of high-density lipoprotein cholesterol (HDL-C). Population studies have consistently shown that HDL-C levels are a strong, independent inverse predictor of cardiovascular disease. Indeed in epidemiologic, lipid intervention, and serial angiographic trials, levels of HDL-C correlate more strongly with atherosclerosis and overall coronary heart disease (CHD) risk than does LDL-C.
In the Framingham Heart Study, for example, risk is highest in patients presenting with the combination of high LDL-C and low HDL-C, but risk remains substantial even in patients with relatively low LDL-C who also have low HDL-C. Overall, a 1% increase in serum concentrations of HDL-C decreases cardiovascular risk by 2-3%.
High-density lipoproteins are fairly complex macromolecules and decades of research on the function of HDL have yielded considerable insights and confusion. For example, until recently, inhibition of cholesteryl ester transfer protein (CETP) was considered a promising means of raising HDL-C levels by decreasing the transfer of cholesterol esters from HDL-C to LDL-C particles. The efficacy of this approach, using torcetrapib, a novel CETP inhibitor, was demonstrated in a pair of studies published in early 2000 in the Journal of the American College of Cardiology (Slide 1).
(Enlarge Image)
Slide 1.
Efficacy of Torcetrapib in Individuals with Below-Average HDL-C Levels on a Background of Atorvastatin
Yet later that same year, Pfizer informed the U.S. Food and Drug Administration (FDA) that it was suspending all clinical trials evaluating combination torcetrapib/atorvastatin therapy after data from the patient outcome study called ILLUSTRATE suggested that mortality was significantly higher in patients who received this combination versus atorvastatin alone. (To read the FDA statement, click here.) Shortly thereafter, Kastelein and colleagues published a pair of imaging studies to assess the impact of torcetrapib/atorvastatin on atherosclerotic disease progression. The RADIANCE studies evaluated two different populations: patients with heterozygous familial hyperlipidemia (RADIANCE 1; n = 904) and patients with mixed hyperlipidemia (RADIANCE 2; n = 752).
For either population, the addition of torcetrapib to atorvastatin had no incremental benefit over atorvastatin alone. Indeed, if anything, there was a trend toward harm, with the combination therapy leading to disease progression while atorvastatin alone led to disease regression based on mean common carotid intima-medial thickness (Slide 2). This disease progression occurred despite robust increases in HDL-C and decreases in LDL.
(Enlarge Image)
Slide 2.
RADIANCE 1 and 2 Studies: Change in Mean Common Carotid IMT
It is unclear if the negative data with torcetrapib were due to CETP inhibition in general or adverse effects of the particular agent used, including both the blood pressure increases noted and the production of an "inactive" HDL that lacked significant reverse cholesterol transport. Complicating the clinical relevance of HDL-C is the recent suggestion that in systemic inflammatory states, including acute coronary syndrome (ACS), HDL-C may convert from being anti-inflammatory to proinflammatory.
Despite the fact that torcetrapib studies have largely been a "bust" in terms of outcomes data, HDL-C remains a viable clinical target for reduction of CHD. In early 2008, for example, a large Veterans Administration study demonstrated a strong inverse relationship between HDL-C and CHD risk even among patients with very low levels of LDL-C (mean <50 mg/dl) that are well below the aggressive "optional" guidelines. Yet, despite these very low LDL-C levels, for every 10-mg/dl reduction in HDL-C there was a 10% increase in major CHD events.
In an accompanying editorial, Carl J. Lavie, MD, FACC, and Richard V. Milani, MD, FACC, encouraged clinical awareness and intervention based on proven therapies, such as exercise training, weight reduction, moderate doses of alcohol, niacin, and certain fibrates that not only raise HDL-C but also stimulate reverse cholesterol transport. Based on the available evidence, they said, using such measures should translate into a strong reduction in CHD risk.
Finally, despite all the encouraging data, with HDL-C it is possible to have too much of a good thing. A study by van der Steeg et al. in a February 2008 issue of JACC combines data from a clinical study (the IDEAL [Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering] trial) and the epidemiologic longitudinal study EPIC Norfolk. After adjusting for levels of apolipoprotein (apo) B and apoA-I, very high values of HDL-C (>70 mg/dl) and HDL particle size (>9.5 nm) were associated with increased risk of CAD (Slide 3). The results suggest that large HDL particles increase cardiac risk, possibly by serving as cholesterol donors rather than scavengers.
(Enlarge Image)
Slide 3.
Risk Estimates of HDL-C Levels after Adjusting for Apolipoprotein (apo) B and apoA-I in the IDEAL Study
Triglycerides
Historically, elevated TG levels have predicted CHD events in univariate analysis but weaken after adjustment for other covariates, such as plasma glucose and HDL-C, to which TG levels are strongly and inversely correlated. Nevertheless, even after adjusting for HDL-C, population-based prospective studies suggest an independent effect of TG on CHD events. Moreover, combined hyperlipidemia (i.e., elevated LDL-C and TG) promotes CHD to a significantly greater extent than either high LDL-C or TG alone.
Also, like HDL-C, the association of plasma TGs with CAD is complex. In the Prospective Cardiovascular Munster (PROCAM) study, CAD risk increased proportionately with TGs up to 800 mg/dl but began to diminish in persons with levels above 800 mg/dl. In addition, the risk associated with TGs ≥200 mg/dl was dependent on concomitant low HDL-C or elevated LDL/HDL ratio in both PROCAM and in the Helsinki Heart Study.
Considering that the specific risk of elevated TGs in patients achieving optimal LDL reduction is unclear, Miller and colleagues studied the effect of TG levels on outcomes in patients enrolled in the PROVE IT-TIMI 22 trial. The trial randomized post-ACS patients to either atorvastatin 80 mg/day or pravastatin 40 mg/day. In a paper published in JACC in April 2008, the investigators reported that subjects with TG <150 mg/dl were at reduced risk for future events, independent of the LDL level (Slide 4). Those with LDL <70 mg/dl and TG <150 mg/dl were at the lowest risk (Slide 5). Thus, both LDL-C and TG levels are important therapeutic parameters in post-ACS patients.
(Enlarge Image)
Slide 4.
Risk of Recurrent Events Using Selected Cutpoints of LDL-C and TG in PROVE IT-TIMI 22
(Enlarge Image)
Slide 5.
Impact of Triglyceride Levels and LDL-C on Death, MI, and Recurrent ACS in PROVE IT-TIMI 22
One group in particular is at extreme risk of developing CAD with even mild elevations of TGs. Hopkins and colleagues studied a large series of patients with premature familial CAD and population-based controls. They calculated CAD risk across the spectrum of plasma TG levels and tested for interactions with other elements of the metabolic syndrome. They found a strongly increased risk for premature familial CAD with elevated plasma TGs. Importantly, this excess risk begins at a low and relatively common TG elevation of just 200 mg/dl and was independent of plasma HDL-C (Slide 6), other elements of the metabolic syndrome, and other CAD risk factors. In addition, for the first time, they provided a quantitative, population-based estimate of the markedly elevated risk of CAD associated with type III hyperlipidemia, which results from impaired removal of TG-rich lipoprotein remnants.
(Enlarge Image)
Slide 6.
Odds Ratios for Premature CAD is Strong, Graded, and Independent of HDL
In this interview, three authorities on lipid disorders discuss possible treatment options for the management of hypertriglyceridemia and low HDL-C levels and the clinical usefulness of HDL as a biomarker for the detection and prevention of CHD.
Editor's note: Patients with cardiometabolic risk factors represent a group at high lifetime risk for CVD. These patients frequently have dyslipoproteinemia (low HDL cholesterol, increased triglycerides, and/or an increased number of small LDL particles). The April 15, 2008, issue of JACC features Lipoprotein Management in Patients with Cardiometabolic Risk: Consensus Conference Report from the American Diabetes Association and the American College of Cardiology Foundation. To access this report, coauthored by Dr. Davidson, please click here.
Guidelines
[No authors listed.] National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary JAMA 2001;285:2486-97. (For the full report, click here.)
Grundy SM, Cleeman JI, Bairey Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-732. (click here.)
Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein Management in Patients With Cardiometabolic Risk: Consensus Conference Report From the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol 2008; 51:1512-1524.
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