HDL Cholesterol: Apparently, There’s A Limit To How High It Should Be

Even these good cholesterols can turn bad, and an extremely high level may mean having more of the bad ones.

Being the leading cause of death in the world, cardiovascular diseases (CVDs) account for ~32% of global mortality. In the U.S. alone, a person dies every 33 seconds from heart disease, and ~805,000 people have had a heart attack at least once. To make things worse, 1 in 5 of the attack are silent — that the person is not aware of it, but the damage is done anyway.

As a rule of thumb, we’re told that on our health report, the level of LDL or the “bad” cholesterol should be as low as possible, whereas for the value of HDL or the “good” cholesterol, the higher it is, the better.

But as science progresses, it turns out that having more HDL cholesterols does not equal good cardiovascular health. And surprisingly, HDL cholesterols (hereafter referred to as HDL-c) can sometimes be the bad kind.

The Seed of the HDL-c Hypothesis

The first to propose the HDL-c hypothesis related to cardiovascular disease (CVD) is perhaps Barr and colleagues back in 1951. In their study, they examined the protein and lipid components in the plasma — the liquid portion of the blood — of people with certain diseases.

And when comparing individuals with coronary artery diseases to those who are healthy, the former group presented lower levels of HDL-c, among other factors. In awe, the researchers wrote in their paper,

“The outstanding fact in our observations is the relative and absolute reduction in alpha lipoprotein [HDL-c] in atherosclerosis [narrowing of arteries due to plaques].”

In 1977, the Framingham Heart Study, a long-term cohort study focusing on the human cardiovascular system, conducted a four-year follow-up on 2,815 men and women aged 49 to 82. The study revealed that individuals with low HDL-c levels (< 40 mg/dL in men and < 50 mg/dL in women) had higher incidences of coronary heart disease. These findings, which appeared consistent even in younger populations aged ≥20 years, led the authors to conclude,

“…it now appears clear that at all ages the HDL cholesterol level is an important index to the risk of coronary heart disease.”

Later, a meta-analysis of four studies — totaling 12,252 individuals — gave more numbers. They reported a 2–3% decrease in CVD risks and a 3.7%-4.7% decrease in CHD mortality rates for every 1 mg/dL increase in HDL-c levels.

Since 1987, statins have been used to lower LDL cholesterol and mitigate the risk of CVDs. But while they have succeeded in reducing the overall risk of heart diseases, the outcome has been somewhat unsatisfactory, resulting in only a 20% decrease in the risks of major CVD events (which translates to 25–48 fewer cases per 1000 people). And individuals treated with statins still face a residual cardiovascular risk of >20% of CVD incidences.

The HDL hypothesis sparked an idea within the scientific community: If raising HDL-c levels leads to fewer CVD incidences, combining a drug that increases HDL-c with statins might provide more protection against CVD than using statins alone.

HDL-c: What Makes It The Good Cholesterol

Contrary to LDL cholesterols, which transport cholesterols from the liver to the peripheral cells, HDL-c does the exact opposite; it brings excess cholesterols from the cells back to the liver to be excreted — a process called reverse cholesterol transport.

And contrary to statins, which work by inhibiting the liver’s production of LDL cholesterol, the concept behind drugs aimed at raising HDL-c is to prevent the liver from removing (or metabolizing) HDL-c, thereby maintaining high levels of these cholesterols in the bloodstream.

The HDL-c Paradox

Clinical trials for drugs that raise HDL-c, however, don’t seem to support this notion. For example,

• Fibrate, a class of drugs that increases HDL-c by 5%–18%, reduces the risk of CVD events mainly in patients who present syndromes of insulin resistance or type 2 diabetes, such as overweight, high glucose levels, high blood pressure, and dyslipidemia (abnormal levels of fats and cholesterols). When combined with statins, however, it did not reduce rates of CVD events in individuals with type 2 diabetes compared to statin therapy alone.
• Niacin, which raises HDL-c by 15%–35%, did not reduce the number of deaths, heart attacks, or strokes in participants, regardless of whether they had a history of heart disease or if they took statins.
• CETP inhibitors, which increase HDL by 30%–133%, gave variable outcomes. Some studies found no effect on CVD events, some reported a decrease in CVD incidences, while some even showed an increase in CVD occurrences and deaths.

On top of that, a 2016 study discovered that individuals with gene defects affecting the liver’s ability to clear HDL-c, resulting in exceptionally high levels of HDL-c in the bloodstream, are 1.79 times more prone to developing CVDs than those without these defects.

Collectively, these studies tell us an important point: HDL cholesterol level, at least by itself, is a poor indicator of cardiovascular health.

“the measure is inherently imperfect”

“…while epidemiological evidence supports HDL-C as a biomarker for CVD risk, the measure is inherently imperfect,” Furtado et al., researchers from Harvard T.H. Chan School of Public Health, wrote in one of their papers published in the Journal of the American Heart Association last year.

HDL-c Subspecies

Besides reverse cholesterol transport, HDL-c is known for its other beneficial roles, such as anti-inflammatory effect, antioxidant activity, maintaining healthy blood flow and blood vessel walls, and anti-thrombotic effects (preventing the formation of blood clots that lead to heart diseases).

Like other cells, HDL-c functions by interacting with the surrounding environment through specific proteins on its surface. To date, scientists have identified at least 285 proteins associated with HDL-c, each playing a role in certain functions. The presence or absence of these proteins thus determines the functional role and subtypes of the HDL-c.

And considering the various functional roles of these cholesterols, Furtado hypothesized that the distinct subspecies of HDL-c could have varying impacts on disease progression; some subspecies may provide therapeutic benefits, while others may have detrimental effects.

For example, apoC3 is a small proinflammatory protein. And its presence in HDL-c was associated with higher risks of CVDs compared to those lacking apoC3.

In contrast, HDL-c subspecies that included the proteins apoC1 or apoE were associated with lower risks of CVD. However, if both apoE and apoC3 proteins are present, the protective effect of apoE against CVD will be counteracted by the presence of apoC3.

“…perhaps these drugs [that raise HDL-c] didn’t work [in reducing risks of CVDs] because even though they increased overall HDL cholesterol, it was the bad kinds that went up,” Furtado speculated.

The Bad Kind Of The Good Cholesterol

To find out whether his speculation is true, Furtado, who led the 2022 study, decided to identify the structure of the HDL-c that was increased resulting from the use of CETP inhibitors.

What the researchers did

In their study, the researchers collected blood samples from participants enrolled in two trials that tested CETP inhibitors. The first study, the ILLUMINATE trial, was sponsored by Pfizer and utilized the CETP inhibitor torcetrapib. The second study, known as ACCENTUATE trial, was funded by Eli Lilly and used the CETP inhibitor evacetrapib.

They then compared the plasma levels of HDL-c in the blood samples of both the intervention group and the placebo group at two time points: before and three months after the intervention. Subsequently, they quantified the various HDL-c subtypes based on the presence of 17 specific proteins.

What the researchers found

From baseline to three months after the intervention, torcetrapib and evacetrapib increased the total concentration of apoA1 — the main component of HDL-c — by 30% and 60%, respectively.

And according to subtypes, the key findings were:

• HDL-c that contains apoC3, a dysfunctional HDL subspecies, increased the most among all subspecies (↑ 50% by torcetrapib and ↑ 99% by evacetrapib).
• The nonprotective subtype, characterized by the presence of both apoE and apoC3 in HDL-c, was also increased for both drugs.
• Specifically, torcetrapib did not increase the concentration of the protective subtype of HDL-c, those that contain apoE but lack apoC3.

Overall, “the changes in apoA1 concentrations in protein-defined [HDL-c] subspecies elicited by Torcetrapib and Evacetrapib result in an altered [HDL-c] profile that may be less protective, which could contribute to the lack of clinical benefit from pharmaceutical CETP inhibition,” the authors concluded.

“One of the most important things to come out of this study is to underscore the need to learn more about HDL subspecies to find out what functions these proteins perform,” Furtado said.

Moving on, “We need to find out which HDL subspecies are protective and which ones are detrimental. Once we know that, we can work to produce therapies that will target increases of the good types of HDL or reductions of the bad,” he continued.

What Does This Mean For Us?

Essentially, it no longer holds true that the higher the HDL-c levels, the better it is for cardiovascular health. While low levels of HDL-c can still indicate poor cardiovascular health, abnormally high levels of HDL-c may suggest metabolic impairments or that the HDL-c may become dysfunctional.

So, what is a low level, and how high is too high?

In 2017, a retrospective study that analyzed the health data of 116 508 individuals from the general population of Copenhagen found that the concentration of HDL-c associated with the lowest risk of all-cause mortality was,

• For men: 1.9 mmol/L or 73 mg/dL
• For women: 2.4 mmol/L or 93 mg/dL

And the association between HDL-c and all-cause mortality was U-shaped for men and women. That is, both low and extremely high HDL cholesterol concentrations are associated with higher risks of mortality:

And below is a summary of their findings on the relationship between mortality and low/high HDL-c concentrations:

This means that the range we should aim for would be 1.0–2.0 mmol or 39–77 mg/dL for men and 1.0–2.5 mmol or 39–97 mg/dL for women.

And while we can’t control the kind of HDL-c we have, one thing we can do to improve HDL-c functionality is to practice a healthy lifestyle. Poor health or lifestyles such as diabetes and cigarette smoking, for instance, can reduce the anti-oxidative capacity of HDL-c cholesterol, leading to increased dysfunctional (the bad kind of) HDL cholesterols.

Preventing unhealthy habits, plus exercising at least 120 minutes a week with a minimum of 30 minutes per session would most likely help increase HDL-c levels in a beneficial way.

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