HDL-raising: A good hypothesis gone bad

SNOWMASS, COLO. – The once highly attractive notion that boosting HDL cholesterol levels will reduce cardiovascular event rates is now dead, or more generously, it remains unsupported by evidence despite expenditure of billions of dollars on negative clinical trials.

"An iconic concept of HDL has not borne good fruit. It really isn’t what we don’t know that hurts us so much as the things that we think are true but just ain’t so – and that’s the story of HDL," Dr. Robert A. Vogel said at the annual cardiovascular conference at Snowmass sponsored by the American College of Cardiology.

Indeed, it now appears that the relationship between HDL and atherosclerosis is far more complicated than lipidologists thought. Evidence now suggests that HDL mass may not be as important as HDL function, which can switch between being anti- and pro-atherogenic in a matter of hours. And HDL may not even be playing an active role in cardiovascular risk; a low HDL may be associated with an increase in cardiovascular events simply because it is a marker for other cardiovascular risk factors, such as obesity, smoking, and insulin resistance.

"This has been a sea change in thinking for me. HDL is something I thought I understood. But I understood it a lot better 10 years ago than I do now," admitted Dr. Vogel of the University of Colorado, Denver.

HDL-raising drugs from multiple classes have now crashed and burned in large randomized trials with clinical endpoints. Thus, the idea that just because a drug does good things to the lipid profile it follows that the agent will also reduce cardiovascular risk "has to die," the cardiologist continued.

Take, for example, niacin.

"Metabolically, niacin does everything right – if you’re a lipidologist. Absolutely everything. It lowers triglycerides, lowers LDL, raises HDL, lowers total cholesterol, lowers C-reactive protein, and increases the beneficial large HDL particles. You would conclude from this that there would be no way niacin would not reduce cardiovascular risk," he explained.

That’s why the negative results of the National Institutes of Health–sponsored 3,414-patient AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglycerides and Impact on Global Health Outcomes) trial came as such a surprise. In AIM-HIGH, randomization to 1.5-2.0 g of extended-release niacin daily in patients on background simvastatin and, if need be, ezetimibe, had no impact on major cardiovascular events (N. Engl. J. Med. 2011;365:2255-67).

The final nail in niacin’s coffin came a few months ago in the form of Merck’s preliminary announcement of a negative result in the massive phase III Health Protection Study-2 THRIVE trial, in which nearly 26,000 subjects with cardiovascular disease and/or diabetes in the United Kingdom, Scandinavia, and China were randomized to 2 g of extended-release niacin plus the antiflushing agent laropiprant daily or placebo on top of background therapy with simvastatin plus or minus ezetimibe. During 3.9 years of prospective follow-up, niacin boosted HDL levels by 17% and reduced LDL by 20%, but it had no impact upon cardiovascular events and was associated with increased risk of serious adverse events.

"I’m going to say it twice: If you have a patient on niacin, take that patient off. Again, if you have a patient on niacin, take that patient off. There is no evidence base at the present time that a patient should be on niacin to reduce cardiovascular risk," Dr. Vogel stressed.

The investigational cholesterol ester transfer protein (CETP) inhibitors produce whopping increases in HDL but to date have proved to be a crushing disappointment in large clinical trials. In the ILLUMINATE trial, the CETP inhibitor torcetrapib raised HDL by 70% and lowered LDL by 30% – and yet it increased all-cause mortality by 60%. Development of torcetrapib has been discontinued.

In the 15,871-patient dal-OUTCOMES trial, the CETP modulator dalcetrapib also produced salutary effects on HDL and LDL, but with absolutely no change in cardiovascular events (N. Engl. J. Med. 2012;367:2089-99).

The only anti-CETP drug that still has a prayer of ever reaching the marketplace is anacetrapib. In the ongoing 1,625-subject DEFINE trial, it has produced a 140% increase in HDL and a 40% drop in LDL. But whether the drug improves clinical outcomes remains to be seen.

As for the fibrates, a meta-analysis of six major randomized trials showed these HDL-raisers had no impact on coronary heart disease (CHD) mortality.

Even the hallowed and robust inverse relation between HDL level and cardiovascular risk described 27 years ago in the Framingham Heart Study (JAMA 1986;256:2835-8) has come under question. This inverse association wasn’t evident in the dal-OUTCOMES trial, and was of only borderline significance in the 10,001-patient Treating to New Targets (TNT) trial (N. Engl. J. Med. 2007;357:1301-10).

"The Framingham data are not quite so right. In these large clinical trials, the inverse relationship between HDL and cardiovascular events was seen only at very low HDL levels – below 30 mg/dL – and not across the broad spectrum," according to the cardiologist.

The most persuasive challenge to the concept that raising HDL will translate into reduced risk of CHD comes from a recent genetic analysis, Dr. Vogel continued. This ambitious project, sponsored by the National Institutes of Health, the Wellcome Trust, the European Union, the British Heart Foundation, and the German government, tracked the prevalence of 14 genetic variants associated with increased HDL in 20 studies totaling more than 100,000 subjects, including nearly 21,000 with a myocardial infarction. The presence of these HDL-raising genes was not associated with reduced risk of MI (Lancet 2012;380:572-80).

What can physicians committed to evidence-based medicine do at this point to prevent cardiovascular events in their patients with low HDL?

Prescribe a statin, regardless of their LDL level, Dr. Vogel said. A consistent finding in the landmark statin trials was that patients with low baseline HDL levels were at higher risk of coronary events, and therefore statin therapy had its biggest benefit. That benefit wasn’t due to the drugs’ small effect on HDL, but rather to their LDL-lowering.

In addition, considerably weaker evidence suggests fibrates may have a limited role in reducing cardiovascular risk in two selected populations. One is in patients with mild to moderate chronic kidney disease, for whom a recent meta-analysis of 10 clinical trials including nearly 17,000 participants showed fibrate therapy reduced the risk of major cardiovascular events by 30% and the risk of cardiovascular mortality by 40% (J. Am. Coll. Cardiol. 2012;60:2061-71). Dr. Vogel rates this evidence worthy of a level IIb recommendation, meaning "you might consider a fibrate in folks with mild to moderate chronic impairment of renal function."

Another group of patients in which fibrate therapy might reasonably be considered are those with a triglyceride level in excess of 200 mg/dL and an HDL level below 35 mg/dL. In subgroup analyses of virtually all of the major fibrate clinical trials, a benefit was shown in that subgroup. Dr. Vogel gives fibrate therapy in such patients a IIb recommendation as well.

As for lifestyle modification as a means of boosting HDL, moderate alcohol consumption, physical exercise, smoking cessation, and weight loss have all been shown to increase HDL. All of these are healthful behaviors, but there is very little hard data to show whether the cardiovascular benefits come from the increase in HDL or some other mechanism.

"If you want to do something in terms of lifestyle modification, tell your patients to run from bar to bar," he quipped.

Dr. Vogel reported having no financial conflicts.

[email protected]

SNOWMASS, COLO. – The once highly attractive notion that boosting HDL cholesterol levels will reduce cardiovascular event rates is now dead, or more generously, it remains unsupported by evidence despite expenditure of billions of dollars on negative clinical trials.

"An iconic concept of HDL has not borne good fruit. It really isn’t what we don’t know that hurts us so much as the things that we think are true but just ain’t so – and that’s the story of HDL," Dr. Robert A. Vogel said at the annual cardiovascular conference at Snowmass sponsored by the American College of Cardiology.

Indeed, it now appears that the relationship between HDL and atherosclerosis is far more complicated than lipidologists thought. Evidence now suggests that HDL mass may not be as important as HDL function, which can switch between being anti- and pro-atherogenic in a matter of hours. And HDL may not even be playing an active role in cardiovascular risk; a low HDL may be associated with an increase in cardiovascular events simply because it is a marker for other cardiovascular risk factors, such as obesity, smoking, and insulin resistance.

"This has been a sea change in thinking for me. HDL is something I thought I understood. But I understood it a lot better 10 years ago than I do now," admitted Dr. Vogel of the University of Colorado, Denver.

HDL-raising drugs from multiple classes have now crashed and burned in large randomized trials with clinical endpoints. Thus, the idea that just because a drug does good things to the lipid profile it follows that the agent will also reduce cardiovascular risk "has to die," the cardiologist continued.

Take, for example, niacin.

"Metabolically, niacin does everything right – if you’re a lipidologist. Absolutely everything. It lowers triglycerides, lowers LDL, raises HDL, lowers total cholesterol, lowers C-reactive protein, and increases the beneficial large HDL particles. You would conclude from this that there would be no way niacin would not reduce cardiovascular risk," he explained.

That’s why the negative results of the National Institutes of Health–sponsored 3,414-patient AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglycerides and Impact on Global Health Outcomes) trial came as such a surprise. In AIM-HIGH, randomization to 1.5-2.0 g of extended-release niacin daily in patients on background simvastatin and, if need be, ezetimibe, had no impact on major cardiovascular events (N. Engl. J. Med. 2011;365:2255-67).

The final nail in niacin’s coffin came a few months ago in the form of Merck’s preliminary announcement of a negative result in the massive phase III Health Protection Study-2 THRIVE trial, in which nearly 26,000 subjects with cardiovascular disease and/or diabetes in the United Kingdom, Scandinavia, and China were randomized to 2 g of extended-release niacin plus the antiflushing agent laropiprant daily or placebo on top of background therapy with simvastatin plus or minus ezetimibe. During 3.9 years of prospective follow-up, niacin boosted HDL levels by 17% and reduced LDL by 20%, but it had no impact upon cardiovascular events and was associated with increased risk of serious adverse events.

"I’m going to say it twice: If you have a patient on niacin, take that patient off. Again, if you have a patient on niacin, take that patient off. There is no evidence base at the present time that a patient should be on niacin to reduce cardiovascular risk," Dr. Vogel stressed.

The investigational cholesterol ester transfer protein (CETP) inhibitors produce whopping increases in HDL but to date have proved to be a crushing disappointment in large clinical trials. In the ILLUMINATE trial, the CETP inhibitor torcetrapib raised HDL by 70% and lowered LDL by 30% – and yet it increased all-cause mortality by 60%. Development of torcetrapib has been discontinued.

In the 15,871-patient dal-OUTCOMES trial, the CETP modulator dalcetrapib also produced salutary effects on HDL and LDL, but with absolutely no change in cardiovascular events (N. Engl. J. Med. 2012;367:2089-99).

The only anti-CETP drug that still has a prayer of ever reaching the marketplace is anacetrapib. In the ongoing 1,625-subject DEFINE trial, it has produced a 140% increase in HDL and a 40% drop in LDL. But whether the drug improves clinical outcomes remains to be seen.

As for the fibrates, a meta-analysis of six major randomized trials showed these HDL-raisers had no impact on coronary heart disease (CHD) mortality.

Even the hallowed and robust inverse relation between HDL level and cardiovascular risk described 27 years ago in the Framingham Heart Study (JAMA 1986;256:2835-8) has come under question. This inverse association wasn’t evident in the dal-OUTCOMES trial, and was of only borderline significance in the 10,001-patient Treating to New Targets (TNT) trial (N. Engl. J. Med. 2007;357:1301-10).

"The Framingham data are not quite so right. In these large clinical trials, the inverse relationship between HDL and cardiovascular events was seen only at very low HDL levels – below 30 mg/dL – and not across the broad spectrum," according to the cardiologist.

The most persuasive challenge to the concept that raising HDL will translate into reduced risk of CHD comes from a recent genetic analysis, Dr. Vogel continued. This ambitious project, sponsored by the National Institutes of Health, the Wellcome Trust, the European Union, the British Heart Foundation, and the German government, tracked the prevalence of 14 genetic variants associated with increased HDL in 20 studies totaling more than 100,000 subjects, including nearly 21,000 with a myocardial infarction. The presence of these HDL-raising genes was not associated with reduced risk of MI (Lancet 2012;380:572-80).

What can physicians committed to evidence-based medicine do at this point to prevent cardiovascular events in their patients with low HDL?

Prescribe a statin, regardless of their LDL level, Dr. Vogel said. A consistent finding in the landmark statin trials was that patients with low baseline HDL levels were at higher risk of coronary events, and therefore statin therapy had its biggest benefit. That benefit wasn’t due to the drugs’ small effect on HDL, but rather to their LDL-lowering.

In addition, considerably weaker evidence suggests fibrates may have a limited role in reducing cardiovascular risk in two selected populations. One is in patients with mild to moderate chronic kidney disease, for whom a recent meta-analysis of 10 clinical trials including nearly 17,000 participants showed fibrate therapy reduced the risk of major cardiovascular events by 30% and the risk of cardiovascular mortality by 40% (J. Am. Coll. Cardiol. 2012;60:2061-71). Dr. Vogel rates this evidence worthy of a level IIb recommendation, meaning "you might consider a fibrate in folks with mild to moderate chronic impairment of renal function."

Another group of patients in which fibrate therapy might reasonably be considered are those with a triglyceride level in excess of 200 mg/dL and an HDL level below 35 mg/dL. In subgroup analyses of virtually all of the major fibrate clinical trials, a benefit was shown in that subgroup. Dr. Vogel gives fibrate therapy in such patients a IIb recommendation as well.

As for lifestyle modification as a means of boosting HDL, moderate alcohol consumption, physical exercise, smoking cessation, and weight loss have all been shown to increase HDL. All of these are healthful behaviors, but there is very little hard data to show whether the cardiovascular benefits come from the increase in HDL or some other mechanism.

"If you want to do something in terms of lifestyle modification, tell your patients to run from bar to bar," he quipped.

Dr. Vogel reported having no financial conflicts.

[email protected]

SNOWMASS, COLO. – The once highly attractive notion that boosting HDL cholesterol levels will reduce cardiovascular event rates is now dead, or more generously, it remains unsupported by evidence despite expenditure of billions of dollars on negative clinical trials.

"An iconic concept of HDL has not borne good fruit. It really isn’t what we don’t know that hurts us so much as the things that we think are true but just ain’t so – and that’s the story of HDL," Dr. Robert A. Vogel said at the annual cardiovascular conference at Snowmass sponsored by the American College of Cardiology.

Indeed, it now appears that the relationship between HDL and atherosclerosis is far more complicated than lipidologists thought. Evidence now suggests that HDL mass may not be as important as HDL function, which can switch between being anti- and pro-atherogenic in a matter of hours. And HDL may not even be playing an active role in cardiovascular risk; a low HDL may be associated with an increase in cardiovascular events simply because it is a marker for other cardiovascular risk factors, such as obesity, smoking, and insulin resistance.

"This has been a sea change in thinking for me. HDL is something I thought I understood. But I understood it a lot better 10 years ago than I do now," admitted Dr. Vogel of the University of Colorado, Denver.

HDL-raising drugs from multiple classes have now crashed and burned in large randomized trials with clinical endpoints. Thus, the idea that just because a drug does good things to the lipid profile it follows that the agent will also reduce cardiovascular risk "has to die," the cardiologist continued.

Take, for example, niacin.

"Metabolically, niacin does everything right – if you’re a lipidologist. Absolutely everything. It lowers triglycerides, lowers LDL, raises HDL, lowers total cholesterol, lowers C-reactive protein, and increases the beneficial large HDL particles. You would conclude from this that there would be no way niacin would not reduce cardiovascular risk," he explained.

That’s why the negative results of the National Institutes of Health–sponsored 3,414-patient AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglycerides and Impact on Global Health Outcomes) trial came as such a surprise. In AIM-HIGH, randomization to 1.5-2.0 g of extended-release niacin daily in patients on background simvastatin and, if need be, ezetimibe, had no impact on major cardiovascular events (N. Engl. J. Med. 2011;365:2255-67).

The final nail in niacin’s coffin came a few months ago in the form of Merck’s preliminary announcement of a negative result in the massive phase III Health Protection Study-2 THRIVE trial, in which nearly 26,000 subjects with cardiovascular disease and/or diabetes in the United Kingdom, Scandinavia, and China were randomized to 2 g of extended-release niacin plus the antiflushing agent laropiprant daily or placebo on top of background therapy with simvastatin plus or minus ezetimibe. During 3.9 years of prospective follow-up, niacin boosted HDL levels by 17% and reduced LDL by 20%, but it had no impact upon cardiovascular events and was associated with increased risk of serious adverse events.

"I’m going to say it twice: If you have a patient on niacin, take that patient off. Again, if you have a patient on niacin, take that patient off. There is no evidence base at the present time that a patient should be on niacin to reduce cardiovascular risk," Dr. Vogel stressed.

The investigational cholesterol ester transfer protein (CETP) inhibitors produce whopping increases in HDL but to date have proved to be a crushing disappointment in large clinical trials. In the ILLUMINATE trial, the CETP inhibitor torcetrapib raised HDL by 70% and lowered LDL by 30% – and yet it increased all-cause mortality by 60%. Development of torcetrapib has been discontinued.

In the 15,871-patient dal-OUTCOMES trial, the CETP modulator dalcetrapib also produced salutary effects on HDL and LDL, but with absolutely no change in cardiovascular events (N. Engl. J. Med. 2012;367:2089-99).

The only anti-CETP drug that still has a prayer of ever reaching the marketplace is anacetrapib. In the ongoing 1,625-subject DEFINE trial, it has produced a 140% increase in HDL and a 40% drop in LDL. But whether the drug improves clinical outcomes remains to be seen.

As for the fibrates, a meta-analysis of six major randomized trials showed these HDL-raisers had no impact on coronary heart disease (CHD) mortality.

Even the hallowed and robust inverse relation between HDL level and cardiovascular risk described 27 years ago in the Framingham Heart Study (JAMA 1986;256:2835-8) has come under question. This inverse association wasn’t evident in the dal-OUTCOMES trial, and was of only borderline significance in the 10,001-patient Treating to New Targets (TNT) trial (N. Engl. J. Med. 2007;357:1301-10).

"The Framingham data are not quite so right. In these large clinical trials, the inverse relationship between HDL and cardiovascular events was seen only at very low HDL levels – below 30 mg/dL – and not across the broad spectrum," according to the cardiologist.

The most persuasive challenge to the concept that raising HDL will translate into reduced risk of CHD comes from a recent genetic analysis, Dr. Vogel continued. This ambitious project, sponsored by the National Institutes of Health, the Wellcome Trust, the European Union, the British Heart Foundation, and the German government, tracked the prevalence of 14 genetic variants associated with increased HDL in 20 studies totaling more than 100,000 subjects, including nearly 21,000 with a myocardial infarction. The presence of these HDL-raising genes was not associated with reduced risk of MI (Lancet 2012;380:572-80).

What can physicians committed to evidence-based medicine do at this point to prevent cardiovascular events in their patients with low HDL?

Prescribe a statin, regardless of their LDL level, Dr. Vogel said. A consistent finding in the landmark statin trials was that patients with low baseline HDL levels were at higher risk of coronary events, and therefore statin therapy had its biggest benefit. That benefit wasn’t due to the drugs’ small effect on HDL, but rather to their LDL-lowering.

In addition, considerably weaker evidence suggests fibrates may have a limited role in reducing cardiovascular risk in two selected populations. One is in patients with mild to moderate chronic kidney disease, for whom a recent meta-analysis of 10 clinical trials including nearly 17,000 participants showed fibrate therapy reduced the risk of major cardiovascular events by 30% and the risk of cardiovascular mortality by 40% (J. Am. Coll. Cardiol. 2012;60:2061-71). Dr. Vogel rates this evidence worthy of a level IIb recommendation, meaning "you might consider a fibrate in folks with mild to moderate chronic impairment of renal function."

Another group of patients in which fibrate therapy might reasonably be considered are those with a triglyceride level in excess of 200 mg/dL and an HDL level below 35 mg/dL. In subgroup analyses of virtually all of the major fibrate clinical trials, a benefit was shown in that subgroup. Dr. Vogel gives fibrate therapy in such patients a IIb recommendation as well.

As for lifestyle modification as a means of boosting HDL, moderate alcohol consumption, physical exercise, smoking cessation, and weight loss have all been shown to increase HDL. All of these are healthful behaviors, but there is very little hard data to show whether the cardiovascular benefits come from the increase in HDL or some other mechanism.

"If you want to do something in terms of lifestyle modification, tell your patients to run from bar to bar," he quipped.

Dr. Vogel reported having no financial conflicts.

[email protected]