Atherogenic Triad: The Deadly Phenotype of High Triglycerides, Low HDL-C and High sdLDL-P

Written By Ian Riddock
Medical Disclaimer: This article is for educational purposes only and should not be construed as medical advice. Always consult with a qualified healthcare provider for personalized medical guidance.

A CardioAdvocate Phenotype

Case Presentation: The Atherogenic Triad Defined

"Atherogenic Triad" refers to a particularly high-risk lipid profile phenotype characterized by:

  1. High triglycerides (TG): > 150 mg/dL
  2. Low HDL-C: < 50 mg/dL in women; < 40 mg/dL in men
  3. High small dense LDL particles (LDL-P): discordant to LDL-C reported on standard lipid panel

The Tim Russert Case Study

In June 2008, at 58 years of age, Tim Russert, moderator of NBC's "Meet The Press" and Chief of the Washington Bureau, died suddenly of a massive heart attack in the NBC studios despite prompt resuscitation efforts. He reportedly had no warning signs.

He was being treated for high blood pressure (hypertension) and high cholesterol (hyperlipidemia). He was known to be overweight and prediabetic. He had passed a stress test 6 weeks prior to his heart attack, though he had known asymptomatic coronary artery disease as evidenced by a Coronary Artery Calcium Score (CAC) of 210 in 1998 at age 48 (96th percentile rank by today's MESA Calculator standards).

His lipids were noted to be "acceptable" with:

  • LDL-C 68 mg/dL
  • HDL-C 37 mg/dL (up from the 20's)

His internist reported he had an "enlarged heart and significant coronary artery disease." Autopsy confirmed plaque rupture in the LAD and V-Fib arrest.

It likely would have been prevented had we had better awareness, education and focused treatment for this dangerous lipid phenotype. For a deeper look at how preventive cardiology has been held back, see The Widowmaker documentary. See What's Your ApoB? A Practical Approach to Lipid Management
📊 The Evidence: A 2012 analysis in the Journal of the American College of Cardiology demonstrated that discordance between LDL-C and LDL-P occurs in approximately 20% of patients — and when LDL-C is low but particle count is high, cardiovascular risk tracks with particle count, not cholesterol weight.

Flying Under the Radar: Why These Patients Are Missed

The Problem

These patients are frequently—invariably—overlooked. Healthcare providers are prone to underestimating risk for ASCVD events such as heart attack and stroke.

⚠️ Risk Alert: Patients with the atherogenic triad have up to a 3-fold increased risk of cardiovascular events compared to those with the same LDL-C but concordant particle counts. The false reassurance of a "normal" LDL-C in this setting is one of the most dangerous gaps in modern preventive cardiology.

Why Are They Missed?

  • Many providers lack the education to interpret the lipid panel appropriately
  • Most labs are incapable of alerting the provider to the fallacy of an inferior biomarker (LDL-C) in this particular situation
  • Reliance on an inferior biomarker (LDL-C) due to its legacy in doing a "pretty good job" for most will leave many in the dust
  • The particular inaccuracy of LDL-C in these patients is unfortunately in the wrong direction. These very high-risk patients suffer from an underestimation of LDL particle count due to measurement of cholesterol in cholesterol-depleted LDL particles
  • The more severe the atherogenic triad (the higher the TGs and lower the HDL-C), the worse LDL-C performs

Who Is at Risk?

In general, those with excess visceral adiposity, or "belly fat," are at highest risk. This typically includes patients with:

The typical scenario plays out like this: the lab fails to "flag" the LDL-C (since it's not out of range), the provider doesn't connect the dots between high TGs and low HDL-C, and the patient is congratulated on their "great cholesterol numbers." Meanwhile, their actual particle burden — and true cardiovascular risk — is far higher than anyone realizes.

CardioAdvocate Checklist

Review Your Lipid Panel

Questions to Ask Your Clinician

Deep Dive

The Tim Russert Story: Searching for Answers but Ignoring Non-HDL-C

Tim Russert was an iconic American journalist. The shock of his death prompted a search for answers that appeared in the New York Times and A Search for Answers in Russert's Death, with follow-up coverage by Heartwire from Medscape interviewing the nation's top experts.

They all tended to focus on non-lipid risk factors and seemed to ignore clues suggesting a classic misunderstanding of lipid biomarkers and the tremendous gap in education and awareness we continue to face in preventive cardiology.

His internist stated: "If there's one number that's a predictor of mortality, it's waist circumference." The article continued: "But, Dr. Newman added, most people would rather focus on their LDL cholesterol, instead of taking measures to reduce their waist size. He was doing nearly all he could to lower his risk…and still it was not enough…if there is any lesson in his death, his doctors said, it is a reminder that heart disease can be silent."

The description of his lipids represents an all-too-familiar misinterpretation:

"Mr. Russert's cholesterol was not high, and medicine controlled his high blood pressure pretty well. But, he added, Mr. Russert was 'significantly overweight.' He also had a dangerous combination of other risk factors: high triglycerides, a type of fat in the blood, and a low level of HDL, the 'good cholesterol' that can help the body get rid of the bad cholesterol that can damage arteries."

Adiposopathy and Beyond

Dr. Eric Topol was interviewed about Russert's case and noted that much has been made of his abdominal obesity as a risk factor. However, he pointed out: "There are a lot of people walking around with obesity, but only a fraction have plaque-rupture events that are fatal, so we need to pick out that tiny fraction who are at increased risk and we need better means to do that."

A stress test, Topol emphasized, is of no value for identifying arteries at risk of causing sudden cardiac death. "The cardiology community still doesn't get it, that stress testing isn't the way to pick up plaque ruptures."

Dr. Topol suggested that inflammatory markers such as CRP and other genomic markers may have helped. However, whether inflammatory markers would have been helpful is unclear. The predictive value of CRP seems to fall apart when accounting for visceral adiposity or "adiposopathy." For a deep exploration of the inflammation debate, see The Itch that Rashes: Inflammation.

Tim Russert had metabolic syndrome — in fact, he had all 5 criteria. The more criteria of metabolic syndrome one has, the higher the likelihood of an elevated CRP. Having 5 of 5 criteria all but guarantees elevated CRP.

🦶 Foot Stomper
Stress Tests Don't Prevent Sudden Death. A normal stress test does NOT mean you're safe. Stress tests identify flow-limiting blockages — they cannot detect the unstable, lipid-rich plaques that rupture and cause heart attacks. Tim Russert passed his stress test 6 weeks before he died.

Primordial Prevention and CAC Scores

Six years after his death, questions continued about what could've been done, prompting a review by the LA Times. His CAC score of 210 was characterized as "'moderate' coronary disease," though this did not account for high percentile rank, which is considered "high risk" and consistent with premature coronary artery disease.

Dr. Prediman Shah accurately opined: "We obviously need, in addition to screening, widespread attention to cardiac health through lifestyle modification and probably much earlier detection of the disease at a stage where you can actually arrest its progress. If you detect disease in a 58-year-old, it's a different ballgame than if you detect it in the 30s or 40s. The later you detect it, the less effect therapy will have in halting the progression."

Tim Russert's disease was detected in his 40s. His CAC was performed when he was 48, not 58. Who knows what it was at the time of his death?

There are now CAC guidelines from the National Lipid Association that provide insight in not only how aggressively to treat such patients, but also in how often to reassess their risk. In general, CAC is expected to increase by 20-30% following treatment with aggressive lipid-lowering therapy (statins) due to the notion that such plaque is becoming more dense (and hopefully more stable), which increases the CAC score. Newer AI-driven platforms such as Cleerly are advancing our ability to characterize plaque composition beyond simple calcium scoring.

The Role of Discordance and Non-HDL-C

What is apparent in this conversation around the search for answers is that non-HDL-C was not mentioned. Tim Russert's non-HDL-C value would have undoubtedly been helpful to know and a discussion about the "residual risk" as it pertains to "discordance" with lipid biomarkers would have been educational, informative and most likely preventative.

The numerous articles published in an effort to search for answers show that the clinical community should learn, adopt and prevent similar tragedies.

Why Clinicians Fail to Implement Guidelines

The NCEP ATP III Report on High Blood Cholesterol guidelines, with an update published in 2003, clearly recommended non-HDL-C as the preferred biomarker in the setting of elevated TGs for exactly this reason: you underestimate risk by focusing on LDL-C when triglycerides are elevated.

By stating his "cholesterol" was not high, while at the same time describing high triglycerides and low HDL-C, suggests that the non-HDL-C was neither considered nor optimized.

Despite the most popular cholesterol guideline recommendations of that era being widely disseminated, we know that medicine moves slowly. New evidence takes on average up to 17 years to infiltrate mainstream clinical practice. That is way too long. We can and should do better.

🦶 Foot Stomper
Non-HDL-C Has Been Recommended Since 2001 — and It's Still Ignored. Guidelines told us two decades ago to use non-HDL-C when triglycerides are elevated. Most labs still don't report it. Most providers still don't calculate it. If your lab doesn't list it, do the math yourself: Total Cholesterol minus HDL-C. It could save a life.

Understanding the Atherogenic Triad: Discordance Explained

In this dangerous lipid "phenotype," when reviewing the lipid panel we observe that the "calculated" LDL-C may be slightly "elevated," "normal" or even "low" (we use quotes here because what defines normal is a matter of debate).

LDL-C is a "calculated" metric and represents the mass concentration of cholesterol contained within LDL particles. It therefore represents a "surrogate" for LDL particles.

LDL particles are what are being deposited in the endothelium (inner lining) of the blood vessel wall and are the main driver of atherosclerosis. All that is required for atherosclerosis to take place is cumulative exposure to LDL particles.

Therefore, having an accurate biomarker which serves to identify one's likely cumulative exposure to LDL particles is paramount to accurately assessing atherothrombotic risk (potential for plaque rupture or plaque complication).

While LDL-C is the most commonly used and easily obtainable biomarker, it is by no means the most accurate.

Whenever two biomarkers which are meant to represent the same disease risk diverge in opposite directions, we call this "discordance." Such is the case here.

When TGs are high and HDL-C is low, the LDL particles are often much higher than what the LDL-C would suggest. In this situation, LDL-C goes down, while LDL-P goes UP! This is discordance. And the higher the TGs go up and the lower the HDL-C goes down, the worse the situation gets, meaning the worse LDL-C performs.

We can also see a situation where LDL-C overestimates LDL particle count. This occurs in those with LDL particles that are chalked full of cholesterol, so-called large buoyant or "fluffy" particles.

Reporting LDL-C serves most of the population well in approximating LDL-P and therefore ASCVD risk. However, in those with the "atherogenic triad," reporting the LDL-C may miss the mark badly and underestimate ASCVD risk considerably.

🦶 Foot Stomper
It's the Particles, Stupid. LDL-C measures the weight of cholesterol in your LDL. But it's the number of LDL particles — not the weight of their cargo — that drives atherosclerosis. In the atherogenic triad, LDL-C goes DOWN while particle count goes UP. That's why ApoB is the better test.

The concept of discordance is also important in patients with Familial Hypercholesterolemia (FH), where ApoB measurement helps refine risk assessment beyond what LDL-C alone provides.

Unfortunately, the typical scenario plays out like this:

  • The lab fails to "flag" the LDL-C (since it's not out of range)
  • Sadly, most providers do not possess the education, nor the time while scanning the labs, to pick up on the clues of "high TGs" and "low HDL-C" which may alert them to this discordance
  • The patient is often congratulated on their remarkably low or optimal LDL-C and given a pat on the back
  • The patient leaves the visit with nobody the wiser that there is anything amiss with their lipid panel and ASCVD risk
  • Naturally, these extremely high-risk patients are inevitably undertreated

How to Stop Missing the Atherogenic Triad

Answers and Solutions

  • Use the correct biomarkers
  • Advocate for change
    • If you're a clinician, lead by example and educate your colleagues, staff and patients
    • If you're a patient, you may have to advocate for yourself, find the right specialist or even help educate your provider
    • Advocate to the lab to include non-HDL-C
    • Advocate to the lab to include appropriate ranges of biomarkers

Blood Tests: Biomarkers Explained

Check ApoB

  • May be used as the preferred biomarker for all patients with high TG, diabetes, obesity, metabolic syndrome or "very low LDL-C" for screening, diagnosis, risk management (Ia ESC/EAS)
  • No fasting required
  • This is the most accurate biomarker reflecting all "atherogenic particles"
  • Every atherogenic (plaque-causing) lipoprotein contains exactly one ApoB
  • Therefore, measuring ApoB reflects your circulating atherogenic particle count
  • LDL-P can be measured with advanced lipid panels but are not as validated and reproducible as ApoB
  • ApoB is validated across the country and inexpensive
🦶 Foot Stomper
ApoB Is the Single Best Lipid Test You're Not Getting. One ApoB molecule = one atherogenic particle. It's cheap, doesn't require fasting, and captures everything LDL-C misses — especially in patients with high triglycerides. If you remember one thing from this article: ask for your ApoB.

Non-HDL-C (Total Cholesterol minus HDL-C)

  • As good or better than LDL-C when triglycerides are elevated
  • Recommended over LDL-C when TG high (> 150 mg/dL) — see Follow the Leader: Lipid Guidelines
  • Despite this guideline recommendation (since ~2001), it is seldom followed in clinical practice
  • Reflects LDL-C + other atherogenic cholesterol, mainly VLDL-C
  • Despite recommendations, many labs don't list Non-HDL-C in report
  • If not listed, can be manually calculated (TC - HDL-C), but "nobody likes to do math in a busy clinic"
  • If your lab doesn't list Non-HDL-C, request that they do — it's not hard and comes "free" in standard Lipid panel
  • No fasting required

So why do we continue to use LDL-C? Great question. Mostly because it's cheap, available, standardized (?), and would probably cause mass hysteria if we replaced it overnight. It works pretty good. But we do have better tools. Only YOU can advocate for better.

LDL-C (Primary Biomarker)

  • Primary biomarker for initial routine lipid panel screening due to availability, familiarity and legacy
  • Calculated metric. Usually not directly measured
  • A surrogate for LDL particles
  • Friedewald equation no longer the preferred way to calculate LDL-C but remains most common
  • Hopkins-Martin or NIH are the preferred equations
  • If LDL-C is not being calculated using preferred equations, ask your lab to change
  • Less accurate if TGs > 150 mg/dL
  • The higher the TGs, the worse LDL-C performs (discordance)
  • The more LDL-C is lowered (< 70 mg/dL), the less accurately it reflects LDL particles and ApoB

HDL-C (Important Caveat)

  • Never has been a target or goal of therapy in any cholesterol guideline
  • HDL-C tells us nothing about the functionality of HDL particles — see Too Much of a Good Thing: HDL
  • High HDL-C can be seen with dysfunctional HDL, where HDL cannot offload cholesterol and the concentration goes up
  • Conversely, low HDL-C has been seen with highly efficient HDL, where HDL is so efficient at offloading cholesterol that the concentration is low (e.g., Apo A-1 Milano)
  • Until an HDL functional assay is developed, HDL-C or HDL-P will not be particularly helpful in lipid management
  • Stop saying "good cholesterol." It's dumb. And dangerous.
  • Years of poor public health messaging has set us back. We're trying to undo this
  • Giving out "points" for high HDL-C may underestimate risk
  • Women typically have higher HDL-C than men — another example of missing the mark in assessing CV risk in women
  • Caveat: There may be value in seeing a low HDL-C on a lipid panel — it may alert the clinician to a problem, particularly the "atherogenic triad." But only if they are trained to look at TG and then observe or calculate the non-HDL-C discrepancy to LDL-C.
🔍 Nuance: The "good cholesterol" label for HDL has done immeasurable damage to public understanding. HDL-C is a marker, not a target. No drug that raises HDL-C has ever reduced cardiovascular events. What matters is HDL function — and we don't yet have a clinical test for that.

Triglycerides (TGs)

  • Not themselves known to be directly causal to atherosclerosis (though this continues to be investigated)
  • If > 500 mg/dL (severe): The primary objective is to treat the TGs to avoid the risk of pancreatitis
    • Pancreatitis is much more likely with TG > 1000 mg/dL, but since TGs fluctuate considerably, a fasting level > 500 mg/dL is severe and warrants urgent attention
  • If 150-499 mg/dL: Look for and address associated comorbidities (diabetes and dysglycemia, obesity and visceral adiposity, metabolic syndrome, fatty liver disease)
  • "Atherogenic Triad" Alert: High TGs, low HDL-C, high sdLDL-P should alert you to high likelihood of elevated ApoB and discordance to LDL-C (lower LDL-C may be misleading and underestimates risk)

TC/HDL-C Ratios

  • Let's just get rid of ratios
  • Focus on LDL-C, non-HDL-C and ApoB. That's all you really need
  • In fact, if you just focused on ApoB, you'd be doing great

LDL-P (LDL Particle Count)

  • Should reflect and be concordant with ApoB
  • In general, can be used in place of ApoB to account for discordance or inaccuracies with LDL-C (residual risk)
  • In our experience, LDL-P is not as well standardized as ApoB. We have observed not-too-infrequent cases of discordance between ApoB and LDL-P
  • ApoB is preferred over LDL-P
  • ApoB/LDL-P discordance is a much more advanced and nuanced discussion with many gaps in knowledge. Use clinical judgment.
  • If ApoB > LDL-P: Treat ApoB
  • If LDL-P > ApoB: Look for other cardiometabolic comorbidities (diabetes and dysglycemia, high TG, fatty liver, obesity) and treat. It may be prudent to consider more aggressive treatment of LDL-P. If no other cardiometabolic features present, consider LDL-P a false positive.
  • Consider also checking Lp(a), which contributes to ApoB count and carries independent cardiovascular risk

Small Dense LDL-P vs Large Buoyant LDL-P

  • Hint: They're all bad
  • "Size Doesn't Matter" — when it comes to LDL particles. They are all atherogenic.
  • No convincing data exists demonstrating increased atherogenicity to small dense LDL-P once total LDL-particle number is accounted for
  • Measuring sub-particle fractions does not appear to provide additional clinical value apart from measuring ApoB or total LDL-particle count
  • Caveat: There may be some value in measuring advanced lipid subfractions in the individual with insulin resistance who has the "Pattern B" (old nomenclature for sdLDL-P) phenotype and is transitioning to a "Pattern A" (large buoyant LDL-P) through optimal treatment pathways, thereby providing some "proof" of progress.

CardioAdvocate Treatment Approach

Treatment is aimed at treating all associated comorbidities based upon individual risk and goals, using lifestyle interventions and pharmacotherapy as appropriate. For detailed treatment targets, see Follow the Leader: Lipid Guidelines.

Severe Hypertriglyceridemia: > 500 mg/dL

Objective: Prevent pancreatitis, which has the potential to cause one of the more serious illnesses one may ever see in an ICU and can be absolutely devastating.

Lifestyle Modifications

  • Low Fat Diet
    • Nearly 0 fat for 1st week
    • Then begin to incorporate unsaturated fats
    • Then reduce simple carbohydrates

Pharmacotherapy

  • Statins + Fibrates or EPA or EPA/DHA formulations of PUFA
  • Icosapent Ethyl (Vascepa): 2 grams twice daily
  • Lovaza (EPA/DHA)
  • Niacin (if TG remain > 500 mg/dL despite above measures)
    • Warning: Nobody uses Niacin anymore — its byproducts are linked to vascular inflammation
  • Pioglitazone, insulin if still > 500 mg/dL
  • Referral to lipid specialist — consider genetic conditions:
    • Familial Chylomicronemia Syndrome (FCS)
    • Multifactorial Chylomicronemia Syndrome (MCS)

Hypertriglyceridemia: 135-499 mg/dL

Lifestyle Modifications

  • Weight loss
  • Calorie restriction
  • Reduce simple carbohydrates significantly
  • Exercise
    • Cardio
    • Pumping Iron — increase lean muscle mass
  • Reduce alcohol intake
  • Eliminate drugs known to raise TGs (e.g., HCTZ)

Drug Therapy

  • Statins are preferred first line for TG > 200 mg/dL (Ia ESC/EAS)
  • EPA/DHA formulations of PUFA
    • Icosapent Ethyl (Vascepa): 2 grams twice daily
      • Indicated and recommended for cardiovascular risk reduction for high-risk patients with DM or ASCVD when TG remain > 135 mg/dL despite statins
    • Lovaza (EPA/DHA)

The Bottom Line

The Atherogenic Triad Is Real. Recognize It. Treat It Aggressively.

Patients with high triglycerides, low HDL-C, and small dense LDL particles represent a particularly dangerous cardiovascular phenotype that is frequently missed because standard LDL-C measurement provides false reassurance.

The case of Tim Russert demonstrates the tragic consequences of this oversight. Despite being identified as high-risk through CAC screening and having clear markers of the atherogenic triad, the appropriate lipid biomarkers were not recognized or optimized.

If you or a loved one has this lipid pattern, insist on:

  • ApoB measurement
  • Non-HDL-C calculation
  • Referral to a cardiometabolic specialist
  • Aggressive treatment targeted at particle number, not just LDL-C
"It's the particles, stupid"

CardioAdvocate helps people understand what matters — and how to speak up about it.

Closing Disclaimer: This article reflects evidence-based clinical practice and expert opinion in lipidology and preventive cardiology. Individual treatment decisions should be made in consultation with a qualified healthcare provider. The information provided is educational and not intended as a substitute for professional medical advice, diagnosis, or treatment.
Ian Riddock
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