“What’s Your ApoB?”
Lipid Phenotypes
Patient A: The Repeat Offender (The Heart Attack Survivor)
Cardiologist: “Your LDL-C isn’t too bad at 92 mg/dL and after your heart attack we put you on the highest dose of atorvastatin 80 mg which is what is recommended in the guidelines.
CardiAwarness.com Advocate: Not true. Those were older controversial guidelines (2018 ACC/AHA Cholesterol Guidelines) which de-emphasized LDL-C goals and set the preventive community back a decade! Newer guidelines recommend additional non-statin therapies in such high risk patients. Newer international guidelines emphasize even lower LDL-C goals. See Follow the Leader - A Statement About Lipid Guidelines.
Advocating for Change:
- Remember who we consider our highest risk patients
- Have a patient-centered discussion focusing on risk, benefit, cost of therapy balanced against cost of another ASCVD event.
- Remember, it’s a person, not a population.
- Use multiple guidelines
- Use expert consensus documents
- Consider expert white papers and “calls to action”
Patient B: Atherogenic Triad:
Provider: “Your LDL-C is very low - this is fantastic!”
Patient: “But my triglycerides (TG) are high, what do you recommend?”
Provider: “We really only treat the LDL-C, which is low in you. But you can work on diet and exercise if you want to get your triglycerides down”
The CardiAwareness.com Advocate: Not true.
When TG’s are elevated (> 150 mg/dL), we need to be focusing on non-HDL-C, or better yet, Apo B. This has been in the guidelines for decades, but rarely performed.
Advocating for Change:
- Pay attention to triglycerides when scanning the lipid profile.
- Use the proper lipid biomarkers: non-HDL-C, Apo B.
- TG’s and HDL-C are not targets, per se, but the presence of high TG’s and low HDL-C should alert us to use the preferred biomarkers of non-HDL-C and Apo B.
Patient C (true personal story): Hiding in Plain Site - Familial Hypercholesterolemia
Patient: “I’ve had high cholesterol since I was 20 and nothing ever works. It runs in my family”
Cardiologist: “Well, you’re 40 now and we’ve tried a couple of statins over the years and they don’t seem to be doing much, so let’s just stop and focus on diet and exercise”
Patient: “What about those newer drugs.”
Cardiologist: “They’re expensive and if the statins didn’t work, it’s probably just your genetics.”
The CardiAwareness.com Advocate: Yikes. Run. Familial Hypercholesterolemia (FH) is caused by a genetic defect that most commonly impacts the LDL receptor (LDLR gene). Most lipid lowering drugs like statins, ezetimibe, PCSK9 inhibitors and bempedoic acid ultimately work by upregulating LDL receptors, which then clear LDL from plasma. Patients with high LDL-C who do not respond as expected to therapies that increase LDL receptors should raise suspicion for an underlying genetic condition affecting LDL receptors, such as FH. It’s not that uncommon, 1 in 250 people.
Advocating for Change:
- It’s not ok to dismiss high LDL-C in the family as “well, that’s just you.”
- It’s not ok to identify someone with high LDL-C at a young age and allow them to drift through the decades untreated.
- It’s not ok to declare a less than desired response to statins as futile and give up on the patient. Especially in the modern era of robust non-statin therapies.
- The opportunity was not only missed on this patient, but their family members, by failing to perform cascade screening.
Patient D: Too Much of a GOOD Thing - Dysfunctional HDL
Lousy Cholesterol (LDL-C) is high, but so is your Healthy Cholesterol (HDL-C), so your RATIO is perfect!”
Patient: “So my GOOD cholesterol makes up for my BAD cholesterol?
Provider: “That’s right, let’s just keep an eye on it for now”
The CardiAwareness.com Advocate: Not true.
Levels of HDL-C tell us nothing about HDL functionality. Higher levels of LDL-C increase the risk of atherosclerosis, even if HDL-C is high.
Advocating for Change:
- Stop using terms like Healthy or Good cholesterol to describe HDL-C. There is no such thing. It is not only erroneous, but dangerous. The truth is, we don’t know how HDL is performing based upon HDL-C levels. High levels could be a bad thing. Low levels could be a good thing.
- Stop using ratios. It’s lazy, misleading and wrong, particularly when including HDL-C (see above).
- Until we get a functional assay for HDL, we just don’t know what a particular HDL-C concentration means.
Flying Under the Radar
Why do these cases go undertreated?
The above lipid “phenotypes” are all examples of patients who are routinely missed everyday in the clinic.
If the frontline provider (PCP) doesn’t understand the lipid panel, the screening process for ASCVD risk falls apart. But if the PCP does their part and appropriately recognizes the problem and then refers the patient to a specialist, such as a cardiologist, who doesn’t understand lipids, we’re in real trouble. At that point, the patient may feel they have nowhere left to go, or are never the wiser that they remain at heightened risk for the #1 killer amongst us. They may feel reassured by the specialist, never questioning their advice and spend many years undertreated.
A checklist of targeted recommendations based on published guidelines
CardiAwareness.com Advocate Checklist:
- Obtain a lipid panel
- Nonfasting is ok initially
- If abnormal (i.e. TG > 175 mg/dL) - repeat with fasting (Lipid measurements in the management of cardiovascular diseases: Practical recommendations a scientific statement from the national lipid association writing group - Journal of Clinical Lipidology)
- Which lipid biomarkers matter most for ASCVD risk assessment?
- We evaluate NonHDL-C (Total Cholesterol minus HDL-C), LDL-C, ApoB, Lp(a), TG and HDL-C (kinda in that order)
- It’s prioritized based upon the biomarker’s significance to the pathogenesis of atherosclerosis, availability, superiority, pragmatism, cost and insurance requirements
- Non-HDL-C and ApoB best reflect causal atherogenic particles and can be done nonfasting (!)
- LDL-C when compared to non-HDL-C (the delta) gives us a clue about the existence of “discordance”
- Non-HDL-C should not deviate by > 30 mg/dL from LDL-C
- Some say 15-20 mg/dL, particularly with lower values
- The higher the delta the greater the discordance to LDL particles (ApoB)
- The greater the likelihood of high amounts of sdLDL-P (small dense LDL particles)
- But ALL LDL-P sizes are still bad
- It’s just high sdLDL-P are less likely to be recognized by LDL-C/non-HDL-C measurements
Non-HDL-C
- NLA Classification:
- ≥ 220 mg/dL - Very High
- Lab should flag as “Severe hypercholesterolemia” in all
- Rule out genetic disorders, particularly Familial Hypercholesterolemia (link to FH topic)
- 190-219 mg/dL - High
- Lab should flag as “Severe hypercholesterolemia” in children
- 160-189 mg/dL - Borderline High
- 130-159 mg/dL - Above Desirable
Going into detail on the evidence behind the recommendations and history of treatment for this phenotype.
Far too many clinicians continue to struggle with the basic lipid panel. When the providers don’t understand it, it’s no surprise when patients are confused. In hindsight this is in large part due to poor teaching and public messaging over several decades. Unfortunately, medicine evolves this way sometimes. We learn from our mistakes and try to correct them. But when so entrenched in common practice, overcoming that clinical inertia requires widespread campaigning and advocacy.
LDL-C is calculated, in most places using a Friedewald equation, which includes TGs.
There are better calculators such as “Martin-Hopkins” or “NIH”
Even a “direct” LDL-C is inaccurate when TGs are significantly elevated. You need to be looking at non-HDL-C when TG > 150 mg/dL. Perhaps even better, check an ApoB
What about small dense LDL vs big and fluffy LDL?
Short answer: they’re all atherogenic. Size doesn’t matter after accounting for the number of Apo B particles. “It’s the particles, stupid.”
How do various lipid drugs work?
Statins:
- Inhibits HMG-CoA Reductase
- Reduces hepatic synthesis of cholesterol
- Depletes cholesterol pool in liver
- Upregulates LDLR (LDL receptor) leading to increased clearance of LDL from plasma
- May cause hyperabsorption of cholesterol through intestines
Ezetimibe:
- NPC1-Like 1 protein inhibition
- Reduces intestinal absorption of cholesterol
- Reduces delivery of cholesterol to liver thereby depleting cholesterol pool
- Upregulates LDLR leading to increased clearance of LDL from plasma
PCSK9i
- mAb binds with PCSK9
- PCSK9 binds to LDL receptors, signaling degradation of the entire complex of Apo B particle and LDLR in the lysosome
- Therefore PCSK9 inhibitors, reduces degradation of LDLR by preventing PCSK9 from attaching to LDLR and delivering it to the lysosome
Inclisiran (Leqvio)
- Small interfering messenger RNA (simRNA)
- Prevents the manufacturing of the protein PCSK9i by inhibiting translation of mRNA in the cytoplasm
- Select to the liver
- Lack of PCSK9 in the liver allows for more LDLR to clear atherogenic particles (LDL)
- No impact on DNA
Bempedoic Acid
- Inhibits adenosine triphosphate-citrate lyase (ACL) which inhibits cholesterol synthesis
- Reduces cholesterol pool in liver
- Upregulates LDLR leading to increased clearance of LDL from plasma
EPA/DHA
- Reduces hepatic production of VLDL
- Increases postprandial activity of LPL
Lipid Blood Testing
- Age of initial lipid testing
- Beginning age 20 years old (ACC/AHA Class I)
- Lipid panel by age 2
- In children or adolescents with family history of early CVD or significant hypercholesterolemia, to rule out FH or other rare forms
- Many experts argue that everyone should have a lipid panel by age 2
- Little downside
- Huge potential to miss devastating disease; leading to a shortened lifespan fraught with multiple preventable ASCVD events
- Children/adolescents with obesity or other metabolic risk factors to rule out lipid disorders or metabolic syndrome
- Repeat Testing
- At least every 5 years
- Or with any change in risk factors (NLA recommendation)
- Weight gain
- Co-morbidities
- Secondary causes of dyslipidemia
- Premature ASCVD events in 1st degree relatives
- Other changes - clinical judgement
- Lipid testing should be performed at 4-6 week intervals after each adjustment
- 4 weeks is all it takes to see the maximal response to adjustments in therapyFasting is preferred (NLA recommendation) but not required
- If non-fasting, use NonHDL-C -> not impacted by fasting state
- ApoB also not impacted by fasting state
- If non-fasting TG > 400 mg/dL, repeat lipid panel in fasting state (ACC/AHA Class I)
- Nonfasting has many advantages
- Patients traveling long ways
- Already in the office and due for testing
- Improves compliance with lab testing
- Saves the patient another trip, gas expense etc
Lipid Goals:
It depends on risk. Below are examples of lipid goals based upon risk categories defined by various guidelines. Please note, these guidelines are created by different organizations and they sometimes use different terms to classify risk. Other times they may use the same terms but define the risk differently. It’s confusing, but we attempt to break it down a bit.
Also, see Follow the Leader - A Statement About Lipid Guidelines
Extreme Risk: This is the terminology used by the joint Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm – 2020 Executive Summary - ScienceDirect
- Progressive ASCVD including unstable angina
- Established clinical ASCVD plus DM, CKD3 or HeFH
Very High Risk: This is the terminology used by the 2019 Joint European Society of Cardiology/European Atherosclerosis Society Dyslipidemia Guidelines (2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk | European Heart Journal | Oxford Academic)
- Recurrent events (more than 1)
- Extensive atherosclerotic cardiovascular disease
- Higher global cardiovascular risk scores.
- LDL-C