Targeting LDL cholesterol to reduce heart disease risk now questioned

By Angela Betsaida B. Laguipo, BSNAug 4 2020

For many years, health experts have warned that high levels of bad cholesterol or low-density lipoprotein (LDL) are critical drivers for the development of cardiovascular disease. Now, a new study claims that decades of research have failed to show benefit of targeting the bad cholesterol to reduce the risk of cardiovascular disease.

Published in the journal BMJ Evidence-Based Medicine, a team of researchers set out to determine if controlling LDL cholesterol levels could benefit health by reducing the risk of potentially fatal diseases, including heart disease.

Low-density lipoprotein collects and deposits in the walls of the blood vessels, increasing the chances of health problems such as heart disease, high blood pressure, and stroke.

LDL particles in the blood stream Low-density lipoprotein (LDL) particles transport the water insoluble lipids in blood plasma from the liver to other organs and tissues. Image Credit: Juan Gaertner / Shutterstock

No validation

Worldwide, millions of people are currently taking cholesterol-lowering drugs, called statins, based on the recommendations of the most recent guidelines on cholesterol management. The 2018 American Heart Association (AHA) and the American College of Cardiology (ACC) cholesterol guidelines aim to reduce cardiovascular disease risk by establishing targets for lowering LDL cholesterol.

Though this approach is supported by substantial evidence, it has not been validated for decades. The team wanted to test the validity of the approach by reviewing the clinical outcomes of randomized controlled trials of cholesterol reduction.

Drug treatment to reduce cholesterol levels to new target levels is recommended in four moderate to high-risk patients, including those who already experienced a cardiovascular event such as heart attack and stroke, adult diabetic patients, those with an estimated 10-year cardiovascular risk is 7.5 percent, and those with LDL levels of more than 190 mg/dL.

The study

Though lowering LDL levels is an established part of preventive treatment, the researchers said it had not been validated. To arrive at their findings, they reviewed all published clinical trials and compared treatment with one of the three types of cholesterol-lowering drugs, statins, PCSK9, and ezetimibe, with the regular care or placebo for about a year in people who are at risk.

The researchers categorized each of the 35 trials to whether they met the LDL cholesterol reduction target recommended in the AHA/ACC guidelines.

The team computed for the number of patients who would need treatment to prevent a cardiovascular event and the reduction in absolute risk in each study that showed positive results.

They found that more than three-quarters of all the trials reported no positive effect on the risk of death, and nearly half of the studies reported no positive impact on the risk of future cardiovascular disease.

"Recommending cholesterol-lowering treatment based on estimated cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results of numerous cholesterol lowering randomized controlled trials call into question the validity of using low-density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease," the researchers wrote in the paper.

Further, the researchers revealed that 13 of the clinical trials met the LDL cholesterol reduction target, but only one has reported a positive impact on the risk of death. Another five studies reported a decline in the risk of cardiovascular events.

Of the 22 trials that did not meet the LDL lowering target, 14 showed a decline in the risk of cardiovascular events, while four revealed a positive impact on the risk of death.

The team recognizes that some of the 35 studies and trials were not designed to assess the clinical outcomes of the participants. However, the team emphasized that while setting targets to lower LDL levels based on risk should avert cardiovascular disease in patients at highest risk, while avoiding unnecessary treatment in low-risk individuals.

Because LDL cholesterol is considered essential for the development of cardiovascular disease, "it seems intuitive and logical to target [it]," say the researchers.

But they add: "Considering that dozens of [randomised controlled trials] of LDL-cholesterol reduction have failed to demonstrate a consistent benefit, we should question the validity of this theory."

And they conclude: "In most fields of science the existence of contradictory evidence usually leads to a paradigm shift or modification of the theory in question, but in this case the contradictory evidence has been largely ignored, simply because it doesn't fit the prevailing paradigm."

Cardiovascular disease and statin use

Cardiovascular disease remains the leading cause of death across the globe. Of the 56.9 million deaths worldwide in 2016, more than half were due to the top ten causes of mortality, wherein ischemic heart disease and stroke are the world's biggest killers, accounting for a combined 15.2 million deaths in the same year.

For 15 years, the two conditions remained as the top killers in the world.

Between 2002 and 2013, statin use in the United States doubled, and cholesterol levels declined. Despite these numbers, cardiovascular deaths appear to be increasing.

In other countries such as Sweden, the increasing use of cholesterol-lowering drugs did not correlate with any significant reduction in heart attacks or deaths. In Belgium, only a very modest reduction in cardiovascular events was reported from 1999 to 2005, but primarily in older adults who are not taking statins.

The data shows that even if people use statins, there has been no reduction in the risk of cardiovascular events and death. What's more, there is evidence that the use of statins may lead to unhealthy behaviors that will increase the risk of cardiovascular disease.