Too Much of a GOOD Thing? Dysfunctional HDL
Case Presentation
A 54-year-old woman is referred to the cardiology prevention clinic for a severely elevated coronary artery calcium score (CAC) of 310 on a CAC CT scan.
She reports that since her mid-20s, her total cholesterol has at times been over 300 mg/dL and her LDL-C has always been fairly high, around 150 mg/dL. However, she was told not to worry about it because her HDL-C is also "super high," around 120 mg/dL, making her ratio "okay."
She is otherwise very fit and healthy, exercising at a high level about 5–6 days a week. She eats a whole foods diet, rarely containing red meat. She has never smoked and drinks a couple of glasses of wine weekly.
Given that she is in her 50s, she decided to get a CAC CT screening test along with all of her other screenings for cancer and is shocked by the results.
Flying Under The Radar
Common, but poor advice: "Yeah, your LDL-C is a bit high, but your HDL-C is also high and that makes up for it. Overall your ratio is great, so you have nothing to worry about. Besides, you're super fit. Keep doing what you're doing!"
This is an unfortunate and important cause of "residual risk" in women particularly, since women tend to have higher HDL-C levels on average than men. But it can certainly be seen with men as well.
HDL-C, which stands for High Density Lipoprotein Cholesterol, is the mass sum of all the cholesterol contained within High Density Lipoproteins and is measured in milligrams per deciliter (mg/dL) of blood.
HDL-C, as a biomarker, tells us nothing about cardiac risk. Why? Because the actual cholesterol concentration itself doesn't tell us how HDL is functioning in its role in reverse cholesterol transport (bringing cholesterol from peripheral tissues back to the liver).
Scientists are trying hard to develop "functionality" assays but some argue it will never be accomplished. High density lipoprotein (HDL) is a very complex lipoprotein that is not only involved in reverse cholesterol transport (RCT) but also has other important functions that are anti-inflammatory, antioxidant, antithrombotic, and immune-modulating.
Unfortunately, many clinicians continue to use outdated methods for analyzing lipid profiles, namely ratios and awarding "bonus points" for having high HDL-C levels.
The HDL Paradox
In general, it is believed that having low HDL-C is bad and having high HDL-C is good. But this is not always the case.
There are examples of genetic variants (Apo A1 Milano), where HDL-C is in the teens, yet this population of Italians has one of the highest concentrations of centenarians in the world. It's felt that their HDL is so efficient at reverse cholesterol transport that the HDL particle does not need to carry a lot of cholesterol.
On the other end of the spectrum, there are those with very high HDL-C—for instance, >100 mg/dL—where the HDL is inefficient at RCT and the HDL particle becomes overloaded with cholesterol.
CardioAdvocate Checklist
Patient Review of Lipid Panel
- Focus on LDL-C and nonHDL-C. These biomarkers are surrogates for ApoB-containing particles. This is what determines atherogenic risk.
- Triglycerides: While not themselves the appropriate biomarker for determining ASCVD risk, they are important for recognizing other concomitant diseases when elevated. For more on this, see "Atherogenic Triad."
- HDL-C: Look at it. See if it's low or really high, as it might alert you to other problems. But it is NOT itself to be used in ASCVD risk assessment.
- If TG > 150 mg/dL: ALWAYS look at nonHDL-C. If not reported, you must calculate it: TC − HDL-C. Compare to reference ranges (30 points higher than the LDL-C reference range).
Clinician Assessment
- Do NOT use lipid ratios for risk assessment
- Focus on LDL-C and ApoB as primary atherogenic markers
- Calculate nonHDL-C when TG > 150 mg/dL
- Identify dysfunctional HDL phenotypes that may hide behind high HDL-C values
- Consider CAC scoring or other imaging for patients with high HDL-C but other risk factors
- Educate patients that high HDL-C does not "make up for" high LDL-C
Deep Dive
The Outdated Model of "Good" and "Bad" Cholesterol
Every day in the preventive cardiology clinic, considerable time is spent refuting and re-educating patients (and their referring providers) that there is no such thing as "good" cholesterol. It's not their fault—medical education often moves slowly and entrenched models, when inaccurate, are tough to undo.
For many years, describing HDL as GOOD cholesterol and LDL as BAD cholesterol was a convenient and simple way to explain their respective roles in cholesterol metabolism to the general public.
It was long observed in various trials that low HDL-C was associated with higher rates of cardiovascular disease and higher HDL-C concentrations seemed to offer protection against heart disease. Naturally, this observation sparked investigation into drug therapies that could raise HDL-C.
HDL Functionality vs. HDL Cholesterol
As a biomarker, HDL-C tells us nothing about HDL functionality. When looking at HDL-C on the lipid panel, it's tempting to react positively to a high level and negatively to a low level, but that doesn't tell the full story.
This is not to say that one shouldn't look at HDL-C on the lipid panel. It may offer clues to some sort of "phenotype" or other disease pathology. But one must not look at HDL-C or any of its ratios and make any assumptions about how HDL is behaving.
Dysfunctional HDL: The Hidden Risk
In the case of very high HDL-C, the danger in assuming it's protective or may make up for a high LDL-C (nice ratio) is that risk may be inappropriately ignored or downplayed by both the patient and their provider. This is a very important cause of residual risk, and what should be an obvious one—they are "hiding in plain sight."
Patients with dysfunctional HDL may fail to seek appropriate screening and/or fail to receive appropriate therapy and counseling. The case presented above exemplifies this perfectly: a woman with a severely elevated CAC score was essentially reassured for decades because her HDL was high.
Apo A1 Milano: The Exception
On the other end of the spectrum and perhaps less consequential if "missed" is the story of Apo A1 Milano, where very low levels of HDL-C are protective due to highly functional HDL.
Apo A1 Milano is a heterozygous gene mutation with a single amino acid substitution, first discovered in a family in Northern Italy in 1980. The condition manifests as VERY low levels of HDL-C and moderate hypertriglyceridemia, but unlike others with a similar lipid phenotype, does not lead to an increased risk in ASCVD and is associated with increased longevity.
Naturally, this sparked interest in the development of therapies. A trial studying the Effect of Recombinant ApoA-I Milano on Coronary Atherosclerosis in Patients With Acute Coronary Syndromes showed plaque regression with intravascular ultrasound (IVUS), obviously a promising result. However, this was not observed in subsequent trials.
Enthusiasm has been tempered after the 2024 publication of the large-scale RCT (randomized controlled trial) AEGIS II in The New England Journal of Medicine, which showed no improvement in MACE with Apo A1 infusions after acute myocardial infarction (AMI).
The Pitfalls of Raising HDL-C
AIM HIGH Trial: Niacin and the HDL-C Hypothesis
If one wanted to make all of the lipid panel metrics look pretty, Niacin would appear to be the perfect lipid-lowering therapy. It lowers LDL-C, it lowers triglycerides, and it raises HDL-C.
While statins have been King of lipid-lowering therapies since 1987, it's well known that those with low HDL-C (and high triglycerides) identify a population of patients with significant residual risk. In its heyday, Niaspan (extended release Niacin, FDA approved in 1997) was heavily utilized as an adjunct to or in place of statins.
Then AIM-HIGH was published. This was a National Institutes of Health (NIH) / National Heart, Lung, and Blood Institute (NHLBI) secondary prevention RCT of ~3,400 patients designed to assess cardiovascular outcomes when using Niacin on top of simvastatin + ezetimibe for those already at LDL-C goal but with low HDL-C.
It was halted after 3 years due to futility, despite raising HDL-C from a median of 35 mg/dL to 42 mg/dL, reducing TG from 164 mg/dL to 122 mg/dL, and lowering LDL-C from 74 mg/dL to 62 mg/dL.
HPS2-THRIVE: Off-Target Effects
The HPS2-THRIVE trial essentially killed Niacin. This was a massive RCT studying ~25,000 patients over 4 years with established vascular disease on statin therapy. It compared extended-release Niacin-laropiprant or placebo.
There was no significant risk reduction. There were significant adverse events including:
- Worsening diabetes control and new-onset diabetes
- Gastrointestinal issues (peptic ulcers, diarrhea, indigestion)
- Musculoskeletal problems (myopathy, muscle weakness/dysfunction)
- Serious skin-related adverse events
- Unexpected increase in serious infection
- Increased serious bleeding
Importantly, the musculoskeletal side effects of myopathy were 10 times worse in China than in Europe. This is a good example of why we need large-scale randomized trials assessing outcomes. It doesn't do anybody any good to improve biomarkers if the off-target effects cause significant harm.
Niaspan, or extended-release Niacin, has been discontinued.
CETP Inhibitors: How Lipid Biomarkers Continue to Fool Us
The history of the development of CETP inhibitors is a fascinating story and teaches us many lessons about biomarkers, drug development, and understanding biology.
Cholesteryl Ester Transfer Protein (CETP) is a protein that transfers cholesterol esters from HDL to other ApoB-containing lipoproteins such as LDL, in exchange for triglycerides. CETP inhibitors were developed initially in an effort to raise HDL-C as we chased that HDL-C theory.
Torcetrapib: Off-Target Effects (2007)
Torcetrapib was the first CETP inhibitor studied in the ILLUMINATE Trial, a large RCT looking at 15,000 patients with high cardiovascular risk on atorvastatin + torcetrapib or atorvastatin alone.
Despite raising HDL-C 72% and lowering LDL-C 25%, the trial was terminated early due to an increase in death and cardiac events. The failure was attributed to "off-target" effects, namely an average increase in systolic blood pressure of 5.4 mmHg. This may seem small, but as an average, it is considerable.
Dalcetrapib: Futility (2012)
The dal-OUTCOMES trial was a large-scale RCT of ~15,000 high-risk secondary prevention patients. This study was terminated due to futility. Despite raising HDL-C by 40%, there was no significant risk reduction, and there was minimal change in LDL-C.
Evacetrapib: Trial Too Short (May 2017)
A third attempt was undertaken with Evacetrapib in the ACCELERATE trial, where it was felt that perhaps a CETP inhibitor that both raises HDL-C and lowers LDL-C might work.
Again, another large RCT of ~12,000 high-risk patients failed to show a benefit. This was perplexing at the time, since there was a whopping 133% increase in HDL-C and a 31% decrease in LDL-C.
Why did Evacetrapib fail? The mechanism of LDL-C reduction differed from statins. With statins and virtually all other LDL-C/ApoB-lowering therapies, the mechanism is through upregulation of LDL receptors and clearance of ApoB particles from the plasma. With Evacetrapib, CETP inhibition caused significant reduction in LDL-C with a notable decrease in small dense LDL particles (60–70%), but not as significant a change in overall LDL particle count (22%) or ApoB (20%).
The modest reduction in total LDL particle count, combined with a relatively short 2-year investigation period, may not have been long enough to see a statistically significant change.
Anacetrapib: It Worked, But Not Worth It (September 2017)
The HPS3-TIMI55-REVEAL study with Anacetrapib was published soon after. This was a very large RCT of ~30,000 patients with ASCVD who were already very well controlled, with mean LDL-C of 61 mg/dL. HDL-C increased by 43 mg/dL (104% relative increase) and nonHDL-C dropped 17%.
There was a small (11%), but statistically significant reduction in cardiovascular outcomes and consistent with the expected risk reduction from a 17% lowering of nonHDL-C. Thus, the positive results were felt to be due to anacetrapib's ability to lower LDL-C, rather than any other mechanism.
Despite positive results, its manufacturer, Merck, opted not to seek regulatory approval due to weak evidence.
What the CETP Story Reinforced
- HDL is a complex lipoprotein involved in many functions besides reverse cholesterol transport
- HDL-C, as a biomarker, does not tell us how HDL is functioning
- Favorable changes in lipid biomarkers by a drug may be offset by deleterious off-target effects
- Intensity matters (not all drugs in a class are equivalent)
- Mechanisms matter (the only benefit appears to be seen with its ability to upregulate LDL receptors)
- LDL biomarkers matter (lowering LDL-C without commensurate lowering of total ApoB may not produce the intended clinical result)
- Persistence pays off? Are we getting closer to an effective agent?
Obicetrapib: A New Hope (In Phase 3 Development)
Just when we thought the CETP class was dead, two brilliant lipidologists resurrected another CETP inhibitor. Abandoned by a large pharmaceutical company, they believe they may have found an agent that might finally crack the code and founded NewAmsterdam Pharma Corporation.
Obicetrapib has shown positive results in Phase 3 clinical trials:
BROOKLYN: The first of 4 trials, looking at LDL-C reduction in those with heterozygous familial hypercholesterolemia (HeFH) not at goal on statin therapy. - Achieved its primary endpoint, lowering LDL-C 41%.
BROADWAY: Evaluated patients with ASCVD or HeFH not at goal on maximum existing lipid-lowering therapies. - 21% reduction in MACE at 1 year (exploratory) - Lowers Lp(a) - Lowers small LDL-P - Improves glycemic metrics - Perhaps the reduction in cardiovascular risk goes beyond LDL
PREVAIL: Ongoing large-scale RCT looking at Major Adverse Cardiovascular Events (MACE) outcomes in those with ASCVD (secondary prevention) on top of maximum tolerated lipid-lowering therapy.
Beyond the Heart: CETP Inhibition and the Brain
Just when we thought the CETP story couldn't get more interesting, there is now intense interest in early signals that CETP inhibition may influence brain lipid metabolism and Alzheimer's disease pathology.
In a 2026 paper published in the American Journal of Preventive Cardiology, Davidson, Kastelein, and colleagues outlined three proposed mechanisms by which CETP inhibition could target cholesterol dysregulation in Alzheimer's disease:
- Anti-atherosclerotic effects on the cerebral vasculature: By lowering LDL-C and ApoB and raising HDL-C, CETP inhibition may reduce the burden of cerebrovascular atherosclerosis, which is a known contributor to cognitive decline and vascular dementia.
- Increased monomeric ApoA-I crossing the blood-brain barrier: Free ApoA-I is small enough to enter the central nervous system. Once there, it may assist in amyloid-beta clearance and reduce neuroinflammation. CETP inhibitors increase circulating ApoA-I by inhibiting the transfer of cholesterol esters from HDL to ApoB-containing particles, thereby generating more free, lipid-poor ApoA-I.
- Enhanced transport of lipophilic antioxidants: CETP inhibition increases the concentration of neuroprotective carotenoids (lutein, zeaxanthin) and alpha-tocopherol (vitamin E) carried within HDL particles. These antioxidants may help reduce oxidative stress in the brain, a key driver of neurodegenerative disease.
Genetic and Epidemiological Evidence
The biological plausibility is supported by consistent genetic and epidemiological data. Individuals with naturally reduced CETP function (through genetic variants) have been observed to have preserved cognition and lower dementia risk compared to those with higher CETP activity. This relationship appears especially relevant in APOE4 carriers, who are at significantly elevated risk for Alzheimer's due to dysfunctional lipid transport within the brain.
BROADWAY Biomarker Analysis: Early Signals
Perhaps the most compelling finding comes from a biomarker analysis of the BROADWAY trial. Over 12 months, obicetrapib significantly modified Alzheimer's disease biomarker trajectories compared to placebo, including markers of tau pathology (p-tau217, p-tau181), amyloid burden (amyloid-beta 42:40 ratio), neurodegeneration (neurofilament light chain), and neuroinflammation (GFAP). These effects were most pronounced in APOE4/E4 homozygotes—precisely the population at greatest genetic risk for Alzheimer's.
The study also found that among ASCVD patients enrolled in the trial, 29% had cognitive performance consistent with mild cognitive impairment and 55% had elevated p-tau217 levels, highlighting the substantial overlap between cardiovascular disease and early Alzheimer's pathology.
These findings are still early and observational. However, they raise the possibility that CETP inhibition with obicetrapib may offer benefits beyond cardiovascular risk reduction—a tantalizing prospect for a drug class that was nearly abandoned.
The Bottom Line
Key Takeaways
- HDL-C is NOT a reliable indicator of cardiovascular risk on its own
- High HDL-C does NOT "make up for" high LDL-C—discard this outdated thinking
- Dysfunctional HDL can exist with very high HDL-C levels, creating "hidden" residual risk
- Focus on LDL-C and ApoB as primary atherogenic biomarkers
- Calculate nonHDL-C when triglycerides are > 150 mg/dL
- Do NOT use lipid ratios for risk assessment—they are misleading
- Just because a drug raises HDL-C does not mean it reduces cardiovascular events
- Biomarker improvements without clinical outcome benefits should be viewed with skepticism
- If you have high HDL-C, don't assume you're at low risk—discuss comprehensive risk assessment with your provider
- CETP inhibition research has evolved beyond HDL-C raising; early signals suggest potential benefits for brain lipid metabolism and Alzheimer's disease pathology—stay tuned
