Low HDL is not dangerous when low-density lipoprotein and triglycerides are low

Dr. Sergio FazioJuly 11, 2016

June's featured paper has the title "Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? New Insights from the Framingham Offspring Study" and is published in Circulation: Cardiovascular Quality and Outcomes. The paper is published by a multi-institutional team of authors, and the study was designed by OHSU physician-scientist Dr. Sergio Fazio, in collaboration with Dr. Michael Miller of the University of Maryland.

For years, medical science dubbed high-density lipoprotein (HDL) the "good cholesterol" because high HDL levels were associated with lower event rates of cardiovascular disease (CVD). 

Now there is a growing body of knowledge that challenges the notion that the inverse relationship between HDL level and CVD rates is causal and exploitable for therapeutic purposes. 

"After the failures of many old and new drugs in CVD outcome studies, it is no longer expected that raising HDL cholesterol levels will reduce CVD risk," said Sergio Fazio, M.D., Ph.D., professor of medicine, OHSU School of Medicine, and director, Center for Preventive Cardiology in the Knight Cardiovascular Institute. "The value of high levels of HDL as protective against CVD has been questioned by recent Mendelian randomization studies."

Studying low HDL

This month's featured paper by a multi-institutional team of scientists, including Dr. Fazio, takes it a step further. The team set out to answer a different angle on that same question: Whether isolated, low HDL is a true risk contributor for CVD. 

The paper was selected by Mary Heinricher, Ph.D., associate dean for basic research in the OHSU School of Medicine. "There has been a lot of discussion lately about high-density lipoprotein (HDL) cholesterol, and whether it is an independent predictor of cardiovascular disease," she said. "A particularly high-profile controversy arose around a recent paper saying that increased levels of this 'good' cholesterol might not necessarily be protective, and drugs that directly increase HDL have not been successful in clinical trials. This large study tells us that, as with so many things in biology and medicine, 'It depends.'"

Demonstrating an intuition

"Established knowledge from several classic epidemiologic studies maintains that low HDL is a strong risk predictor, inversely related to the future development of CVD," explained Dr. Fazio. "However, the vast majority of subjects with low HDL also have elevated triglyceride (>150 mg/dl) and inappropriate low-density lipoprotein, known as LDL (>100 mg/dl). The concept that HDL continues to be a predictor of CVD risk when LDL and TG are perfectly within the desirable range has been intuited but never demonstrated."

The team set out to change that. It selected a strategy that avoided the need for complex biostatistical modeling, such as figuring out the predictive value of low HDL when other lipid parameters are also contributing to risk. 

"We did lose some statistical power in the process, as it is rare for people to have low HDL and normal levels of LDL and triglycerides," said Dr. Fazio. 

To study the question, the team used the Framingham Offspring Cohort, a mostly Caucasian population. The work began as collaboration between OHSU scientists and Michael Miller, M.D., professor of medicine at the University of Maryland School of Medicine, and then expanded to include researchers with population science and clinical trial expertise. It was driven by Irene Predazzi, Ph.D., then a postdoctoral fellow in Dr. Fazio's lab, and now a scientist at Illumina.

"Not dangerous"

"We found that when HDL is low but other lipid parameters are perfectly normal, contribution to CVD risk is minimal," concluded Dr. Fazio. "It is still better to have higher HDL, but not as much as when other lipid parameters are also abnormal. Low HDL is not dangerous if the rest of the lipid profile looks splendid."

He added, "This also makes sense mechanistically, as the value of HDL should be in keeping the artery wall clean, a process that may not be that important when the forces that lay waste are not in place. In other words, the cleaning crew may be on strike but you won't even notice it if you don't make a mess in the first place."

Next steps

Dr. Fazio said that other groups will likely work at replicating and validating the results. 

"Here at OHSU, we are taking it to the experimental level to study the effect of low HDL in animal models of atherosclerosis (arterial plaque) formation and regression," said Dr. Fazio. "These studies will improve our knowledge of the effect of HDL on the vasculature, and give us clues on novel targets of therapy to reduce plaque growth and increase its shrinkage.



Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? New Insights From the Framingham Offspring Study. Circ Cardiovasc Qual Outcomes. 2016 May;9(3):206-12. doi: 10.1161/CIRCOUTCOMES.115.002436. Epub 2016 May 10. Author List: Bartlett J, Predazzi IM, Williams SM, Bush WS, Kim Y, Havas S, Toth PP, Fazio S, Miller M

More Published Papers

Pictured above: Dr. Sergio Fazio.

About the OHSU School of Medicine Paper of the Month

The OHSU School of Medicine spotlights a recently published faculty research paper each month. The goals are to describe to the public the exceptional research happening at OHSU as well as inform our faculty of the innovative work underway across the school’s departments, institutes and disciplines. The monthly paper is selected by Associate Dean for Basic Research Mary Heinricher, Ph.D.