Pamela A. Popper, Ph.D., N.D.

Wellness Forum Health

Another attempt to develop a drug that increases HDL levels has failed, according to an announcement at the American College of Cardiology annual meeting (2016).

The drug, evacetrapib, reduced LDL cholesterol and more than doubled HDL cholesterol levels.  But in a study including over 12,000 patients, the drug made no difference in outcomes; 256 people taking the drug had heart attacks as compared to 255 taking placebo; 92 patients taking the drug had a stroke, as compared to 95 in the placebo group; and 434 patients taking the drug died from cardiovascular disease, as compared to  444 patients taking placebo. Eli Lily, the maker of evacetrapib, stopped the study in October.[i]

This is not surprising. Two other drugs designed to increase HDL cholesterol also failed. Dalcetrapib was ineffective, and Torcetrapid, made by Pfizer, lowered LDL levels by 46%, and when used with Lipitor, raised HDL by 106 mg/dl. But patients taking the drug combo had a higher risk of cardiovascular events and death than those taking the placebo.

Cardiologists seem mystified at these results. Peter Libby, a cardiologist at Harvard, said that evacetrapib “was the great hope” and that “All of us would have put money on it.”  Another cardiologist, Dr. Paul Thompson at Hartford Hospital, seemed to have a more realistic perspective and said, “It may be that the LDL level is less important than how it gets changed.”[ii] In other words, all methods of improving biomarkers do not produce positive results.

Evacetrapib is one of a new class of cholesterol-lowering drugs called PCSK-9 inhibitors. The FDA approved the class based on their ability to lower cholesterol levels for certain groups of patients, including those who cannot tolerate statin drugs. Clinical trials have been conducted to see if drops in cholesterol resulting from the drugs translate into fewer events and deaths, with little success so far. The drug companies are determined to prove their worth due to their profit potential – the drugs can cost up to $14,000 per year, while regular statin drugs are cheap.

I’m confident that the drug companies will eventually be granted approval to sell these drugs, not based on their merit, but rather based on persistence and the fact that most drugs submitted for initial approval or for additional uses are eventually approved by the FDA. But I’m also confident that taking these drugs will not result in significant and meaningful improvement in outcomes because they are based on a theory about HDL cholesterol which is incorrect, and is based on observational studies showing that people who have higher plasma levels of HDL have a lower incidence of cardiovascular events. Therefore, the reasoning goes, increasing HDL levels should reduce the risk of events and deaths. The problem is that it doesn’t. In addition to the trials already mentioned, the ACCORD trial concluded that fenofibrate increased HDL but did not reduce cardiovascular events.[iii]  The HPS2-THRIVE trial showed that nicotinic acid increased HDL cholesterol but increased the incidence of cardiovascular events[iv]. The AIM-HIGH trial, which also used nicotinic acid, raised HDL but had no effect on event incidence.[v] This should be enough proof to put the matter to rest, but the potential for profit is likely to eclipse both common sense and patient safety.

While concern about HDL levels is not warranted, concern about plasma cholesterol levels is. A study including 356,222 men between the ages of 35 and 57 showed that serum cholesterol levels are directly related to the risk of coronary heart disease and CHD deaths. The authors wrote, “These data of high precision show that the relationship between serum cholesterol and CHD is not a threshold one, with increased risk confined to the two highest quintiles, but rather is a continuously graded one that powerfully affects risk for the great majority of middle-aged American men.”

But not all methods of lowering plasma cholesterol levels result in the same outcomes.  Statins drugs lower cholesterol, but do not significantly reduce the incidence of events. Crestor reduces the risk of major cardiovascular events by only 1.2%,[vi] and Lipitor reduces the risk of major cardiovascular events by 1.6%,[vii] and as a class, statins do not reduce mortality when used for primary prevention, even with high risk patients.[viii]

On the other hand, Dr. Caldwell Esselstyn’s long-term study of patients using diet to treat coronary artery disease resulted in completely different outcomes. With his first group of patients, cholesterol dropped an average of over 100 mg/dl and remained so at 5 years of follow up.[ix]  Esselstyn reported the results of 198 patients, with 0.6% incidence rate in compliant patients, vs 62% incidence rate for patients who were not compliant with his dietary plan, which lowers cholesterol.[x] It seems clear that diet is a better way to lower cholesterol than taking drugs.

There is considerable misunderstanding about the importance of higher HDL levels, which has been the driving force behind expensive and futile attempts to increase HDL levels with drugs and supplements. This misunderstanding also results in bad advice for people who eat a health-promoting low-fat and plant based diet; they are often told that their HDL cholesterol is too low.  The role of HDL cholesterol is to clean up inflammation and to remove LDL cholesterol from the bloodstream. Adopting a low-fat plant-based diet lowers LDL cholesterol and reduces the need for HDL, and the liver reduces production in response. Studies have shown that individuals who eat a plant-based diet have lower risk of coronary artery disease even though they typically have lower HDL levels.[xi] [xii]

Additionally, a growing body of research is showing that it’s not how high plasma levels of HDL are, but rather how metabolically powerful the HDL molecules are.

Cholesterol efflux capacity is a marker for HDL function and is a measurement for reverse cholesterol transport.  High efflux capacity is related to lower risk of cardiovascular disease and events. One study concluded, “Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level.”[xiii] In fact studies show that “cholesterol efflux capacity plays a more important role in preventing coronary artery disease and events, independent of cholesterol levels.”[xiv]

So the better strategy for lowering both cholesterol and the risk for coronary artery disease, events, and death is to adopt a low-fat plant-based diet. The plan, unlike a blockbuster drug, will not generate billions of dollars in sales, but it will improve the health of hundreds of millions of people and save a few billion dollars in healthcare costs.

[i] Evacetrapib Fails to Reduce Major Adverse Cardiovascular Events:Trial discontinued after drug shows no clinical benefit, despite impacts on cholesterol

[ii] Gina Kolata “Dashing Hopes, Study Shows a Cholesterol Drug Had No Effect on Heart Health.” New York Times April 3 2016

[iii] The ACCORD Study Group “Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus.” NEJM 2010;362:1563-1574

[iv] The HPS2-THRIVE Collaborative Group. “Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients.” NEJM 2014;371:203-212

[v] The AIM-HIGH Investigators. “Niacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy.” NEJM 2011;365:2255-2267



[viii] Ray K, Seshasai S, Erqou S et al. “Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants.” Arch Intern Med 2010 June 28;170(12):1024-2031

[ix] Esselstyn C, Ellis S, Medendorp S, Crowe T. “A strategy to arrest and reverse coronary artery disease: a 5-year longitudinal study of a single physician’s practice.” J Fam Practice 1995 Dec;41(6):560-568

[x] Esselstyn C, Gendy G, Doyle J, Golubic M, Roizen M. “A Way to Reverse CAD?”

The Journal of Family Practice  July 2014 Vol 63, No 7

[xi] Roberts C, Ng C, Hama S, Eliseo A, Barnard R. “Effect of a short-term diet and exercise intervention on inflammatory/anti-inflammatory properties of HDL in overweight/obese men with cardiovascular risk factors.” J Appl Physiol 2006, 101:1727–1732.

[xii] Ferdowsian H, Barnard N. “Effects of plant-based diets on plasma lipids.” Am J Cardiol 2009, 104:947–956.

[xiii] Khera A, Cuchel M, de la Llera-Mova M et al. “Cholesterol Efflux Capacity, High-Density L

ipoprotein Function, and Atherosclerosis.” N NEJM; 364:127-135

[xiv] Zhang J, Xu J, Wang J et al. “Prognostic Usefulness of Serum Cholesterol Efflux Capacity in Patients With Coronary Artery Disease.” Am J Cardiol Feb 15 2016;117(4):508-514