HDL Function Improved With Olive Oil-Enriched Mediterranean Diet: PREDIMED Study

Adhering to the Mediterranean diet, one that is enriched with extra virgin olive oil and nuts, appears to increase the function of HDL cholesterol in subjects at high risk for cardiovascular disease, a new analysis shows.

Specifically, these individuals had improved cholesterol efflux capacity—the ability of HDL particles of extract excess cholesterol from the circulation for delivery to the liver for metabolization or excretion—and other improvements in HDL functionality.

Those who ate a Mediterranean diet, especially when it contained added olive oil, had modest improvements in other key measures of HDL function, such as the ability of HDL to esterify cholesterol, increased HDL antioxidant capacity, and increased HDL vasodilatory capacity when compared with baseline and/or individuals who consumed a low-fat diet.

This latest analysis, led by Alvaro Hernáez, PharmD (Hospîtal del Mar Medical Research Institute, Barcelona, Spain), and published February 13, 2017, in Circulation, included 296 individuals at high cardiovascular risk participating in the PREDIMED study. They analyzed HDL function from stored samples before and after 1 year of randomization to the three diets—low fat or Mediterranean enriched with either nuts or olive oil—and compared the changes with baseline values and across diets.

In the PREDIMED trial, which was published in 2013, investigators showed that a Mediterranean diet supplemented with olive oil or nuts significantly reduced the risk of major cardiovascular events by approximately 30% when compared with a low-fat diet. The latest analysis, say investigators, suggests the research might “contribute to the discovery of novel therapeutic targets that may improve HDL function in humans.”

Shifting Toward Function, Not Just HDL Numbers  

Speaking with TCTMD, Anand Rohatgi, MD (University of Texas Southwestern Medical Center, Dallas), said there have been aspects of the Mediterranean diet studied with respect to the effect of HDL function, but to date, no study has addressed the impact of an overall dietary pattern on different measures of HDL function.

“It has been known that the Mediterranean diet does tend to raise HDL cholesterol levels,” he said. “That was shown in the overall PREDIMED trial, but really, beyond that, not much was known about function. And HDL has a variety of functions, not just one, and any studies that have been done are generally focused on one nutrient or one function. This study was impressive because it looked at an overall dietary pattern and it looked at it within the context of a large randomized controlled trial, one that was shown to improve outcomes. They also looked at a comprehensive set of HDL functions.”

Rohatgi, who was not involved in the PREDIMED analysis, said the research community has shifted toward investigating the function of HDL cholesterol rather than simply raising HDL cholesterol levels. He noted that while low HDL is associated with an increased risk of cardiovascular disease, there have been several studies showing that HDL levels “don’t seem to track with some of the functions, that it doesn’t reflect a variety of the things that HDL does.”

Importantly, there have been several high-profile failures of therapies designed to raise HDL cholesterol levels. For example, three different drugs that raise HDL by inhibiting the cholesteryl ester transfer protein (CETP) have failed to pan out, while two large cardiovascular outcomes studies with niacin were also negative.

Cholesterol Efflux Capacity the Most-Studied Function

In their analysis, Hernáez and colleagues studied 100 individuals assigned to the Mediterranean diet enriched with olive oil, 100 assigned to the same diet enriched with nuts, and 96 subjects assigned to the low-fat diet. Both Mediterranean diets significantly increased cholesterol efflux capacity relative to the baseline level, but not relative to the low-fat diet.

Additionally, they analyzed other steps in the reverse cholesterol transport pathway, noting that the ability to esterify cholesterol increased in the Mediterranean/olive oil dietary arm relative to baseline and compared with the low-fat diet. Similarly, CETP activity also decreased among those consuming a Mediterranean diet supplemented with olive oil relative to baseline but not compared with the low-fat diet. Markers of HDL antioxidant capacity were also improved, mainly with the diet enriched with olive oil, and there were improvements in the production of nitric oxide. 

In an editorial, Daniel Rader, MD (University of Pennsylvania Perelman School of Medicine, Philadelphia), notes there was a trend toward lower HDL cholesterol levels even though cholesterol efflux capacity increased. He adds that both diets, regardless of whether they were supplemented with olive oil or nuts, had similar effects, “indicating that it was the Mediterranean diet, not the olive or nuts, that had this effect of HDL cholesterol efflux capacity.”

Rader postulates some potential ways in which the diet increases the ability of HDL to remove excess cholesterol from the periphery, but says the mechanism still remains largely unknown. Rohatgi agreed that more research is needed.

“There’s not a great handle on what’s driving cholesterol efflux in people,” he told TCTMD. “Is it a particular protein? Is it a lipid? Is it a combination? Is it something genetic? Once that’s better clarified, then therapeutic targets become much easier to focus on. The reason the PREDIMED study is helpful is because it takes a known intervention that’s related to improved outcomes and figures out the effect on HDL function. So the next step will be [determining] what it is about the Mediterranean diet that led to these changes.”

Rohatgi added that cholesterol efflux capacity is the most widely studied function of HDL. In 2014, when analyzing patients in the Dallas Heart Study, Rohatgi and colleagues showed that individuals with higher levels of cholesterol efflux capacity had a significantly lower risk of developing cardiovascular disease than those with less functional HDL. On their own, HDL cholesterol levels were not inversely associated with cardiovascular risk. Rohatgi noted that their results have since been validated in other cohorts.   

HDL levels vary by sex and ethnicity, with women and African-Americans having higher values than men and non-African-American individuals, respectively. Going forward with studies of HDL and its function, researchers will really need to characterize the findings across these different populations, said Rohatgi.