Season 1 Episode 4: Cholesterol

Cholesterol is one of the most talked-about molecules in medicine — and one of the most misunderstood.  It’s essential for life, but when carried in the wrong lipoproteins, it becomes the driving force behind atherosclerosis. 

 In this episode of LipidCurious, we step away from the headlines and hype to explore what cholesterol really means for clinical practice and board prep. 

Here’s what we’ll unpack together:

1.     The Cholesterol paradox — why it’s both essential and dangerous.

2.     How cholesterol is carried and measured in blood.

3.     LDL-C in clinical practice — Targets, Percent Reduction, and How Low is Too Low 

Bonus: The Visual Guide for this episode is waiting for you — click here. For the full collection of visuals across episodes, visit the Podcast page.

Download the Free LipidCurious Starter Kit here

Questions or feedback? Reach out at hello@lipidcurious.com

Disclaimer: This podcast is for educational purposes only. It is NOT medical advice.

Transcript

SEASON 1, EPISODE 4: CHOLESTEROL

Welcome back to LipidCurious — the podcast dedicated to demystifying lipids for medical boards and real-world clinical practice.
I’m your host, Dr. Vishnu Priya Pulipati — a board-certified Endocrinologist and Lipidologist.

This is Season 1, Episode 4 — Cholesterol.

Here’s what we’ll unpack together:

1.     The Cholesterol paradox — why it’s both essential and dangerous.

2.     How cholesterol is carried and measured in blood.

3.     LDL-C in clinical practice — Targets, Percent Reduction, and How Low is Too Low 

Before we start — I want to say a big thank you. The encouragement and feedback I’ve received from friends, colleagues, mentors, and listeners has been incredible — and it’s what gives me the confidence to keep building this space. 

This episode comes with a bonus visual handout in the show notes. I’ve attached images to the earlier episodes too. For the complete set, visit www.lipidcurious.com. Special thanks to Dr. Thomas Dayspring, whose work inspired many of the visuals. And yes, I may have borrowed my toddler’s coloring pens for this masterpiece, so please be kind with your art critiques. 

Quick reminder: this podcast is educational only — not medical advice.

Alright, let’s get into it.

The Cholesterol Paradox:Cholesterol is not the villain it’s made out to be. We literally cannot survive without it. Every cell membrane relies on cholesterol for structure and stability. It’s also the backbone for steroid hormones, and the starting point for vitamin D and bile acids.

Cholesterol is a type of sterol predominantly found in animals. Structurally, it has four fused hydrocarbon rings — plus a hydroxyl group and a short hydrocarbon tail. 

Our dependence on cholesterol is so deep that the liver makes about 80% of the cholesterol. Only about 20% comes from diet. 

The same molecule that sustains life can also drive atherosclerosis — especially when it ends up in the wrong place, in the wrong lipoproteins. 

What about dietary cholesterol? For decades, eggs and shrimp were demonized. But for most people, they only modestly affect blood cholesterol. The real culprits are: Saturated fats, Trans fats, severe genetic conditions — such as familial hypercholesterolemia.

So yes, enjoy your eggs, just watch what they’re cooked in — butter and bacon fat can change the whole equation.

That’s the paradox in a nutshell: cholesterol is indispensable, but misplaced cholesterol fuels the world’s leading killer, atherosclerosis.

How Cholesterol is Carried and Measured

In the body, cholesterol exists in two main forms:

• Free cholesterol — sitting in cell membranes, ready to be used.
• Cholesteryl esters — cholesterol linked to a fatty acid, the storage and transport form inside lipoproteins.

When you check a standard lipid panel, what you’re really seeing is cholesterol cargo inside lipoproteins, reported in mg/dL.

Here’s the quick lab tour:

• Total cholesterol — everything lumped together. Not very useful by itself.
• LDL-C — cholesterol mass in LDL particles. This is usually calculated by the Friedewald equation, though this can be less reliable at LDL <70 mg/dL or triglycerides >400 mg/dL. The gold standard is Direct LDL-C by ultracentrifugation – accurate but expensive and time consuming.
• HDL-C — cholesterol in HDL particles. Typically identified as a good cholesterol, but raising it pharmacologically hasn’t reduced cardiovascular risk; it’s more marker than target.
• Non-HDL-C — often overlooked, but powerful. It sums all atherogenic cholesterol: LDL, VLDL, IDL, Lp(a). — which you calculate by subtracting HDL from total cholesterol. 

So why the obsession with LDL-C? Because decades of evidence point the same way: high LDL particles cause atherosclerosis. The issue isn’t that LDL exists — it’s how much is circulating.

LDL-C is only tip of the iceberg— it’s the cholesterol inside LDL particles. ApoB gaining traction: they reflect the number of particles, not just their cargo.  

Despite their clear advantages, ApoB and non-HDL-C aren’t yet routine primary targets — mostly because large trials historically used LDL-C as the endpoint. But newer evidence shows they’re superior, especially for assessing residual risk in patients whose LDL-C is already low on statins. 

LDL-C in Clinical Practice

The guiding principle in lipidology is simple: Lower LDL-C for longer is better for reducing ASCVD risk. 

Therapeutic intensity should match patient risk, preferences, and tolerance. Here’s a quick framework: 

• Very high risk — ASCVD plus additional risk enhancers. Goal LDL-C <55 mg/dL.
• High risk — ASCVD or diabetes mellitus with risk factors. Goal LDL-C <70 mg/dL.
• Moderate risk — goal LDL-C <100 mg/dL.
• Low risk — lifestyle is the priority.

You can find a summary of major US guidelines and secondary causes in the free LipidCurious Starter Kit at lipidcurious.com.

Now, let’s anchor this with a hypothetical case — and highlight high-yield pearls.

Mr. R is a 58-year-old man with type 2 diabetes and a prior stent. His LDL-C started at 160 mg/dL. After high-intensity statin and ezetimibe therapy, it’s now 72 mg/dL.

This raises the teaching point — is 72 good enough, or do we aim lower?

If you’re thinking 70 mg/dL is the traditional goal, you’re right. But have you ever wondered why 70? Not 64 or 76? It was a round, memorable cutoff that reflected outcomes seen in mid-2000s clinical trials — an interpretation of data, not a physiologic threshold. 

But here’s the nuance: With cardiovascular disease and diabetes, most guidelines classify him as very high risk and suggest a target <55 mg/dL. 

And notice — his LDL-C has dropped from 160 to 72, more than a 50% reduction from baseline. That’s powerful, because percent reduction often predicts outcomes even better than absolute target, especially when LDL-C starts out high. But in very high-risk patients, you want both: the percent drop and the absolute target to give us confidence that we’re truly reducing cardiovascular risk.  

Now — what if we add PCSK9 inhibitor and his LDL falls to 22 mg/dL? Should we worry?

There isn’t a strict cutoff. LDL-C of <40–50 mg/dL is generally considered low, and <20–30 mg/dL very low. Overall, the evidence supports the safety of low LDL-C.

Physiology: Newborns and hunter-gatherers often live in the LDL-C 30–70 range. 

Genetics: People with PCSK9 loss-of-function mutations can live lifelong with LDLs in the teens and have lower heart disease risk. By contrast, rare inherited conditions like abetalipoproteinemia or hypobetalipoproteinemia do cause severe complications, those problems stem from the underlying disorder — not from low LDL-C itself. 

Trials: Across landmark studies — statins (PROVE-IT), ezetimibe (IMPROVE-IT), and PCSK9 inhibitor evolocumab (FOURIER) — patients who achieved LDL <30 mg/dL had fewer cardiovascular events, with no new safety signals.

Yes, JUPITER trial hinted at a slight increase in diabetes, and pooled alirocumab data suggested more cataracts below 25 mg/dL — but overall, the benefits have consistently outweighed the risks. 

Even in long-term follow-up, like the FOURIER-open label extension of 8 years, people with LDLs less than 20 mg/dL kept benefiting, without new red flags. Inclisiran’s early data are showing the same reassuring pattern. 

In large PCSK9 inhibitor trials, like FOURIER and ODYSSEY, therapy was sometimes reduced or paused if LDL remained <15 mg/dL. But importantly, that was a trial safety protocol — not evidence that harm occurs at those levels.

Physiology, genetics, and trials all point the same way — lower LDL-C has been safe.Don’t reflexively back off just because LDL-C is very low — instead, confirm by repeating or using direct LDL-C if available, reassess, and individualize based on the patient.

So back to our case — how might we approach it if Mr. R’s LDL-C is confirmed to be very low on repeat checks?

This is an area with multiple opinions, since there’s no strict cutoff. Decisions often depend on clinician experience, their core therapeutic philosophy, patient factors such as overall individual risk, preference, medication tolerance, cost, and the risks of polypharmacy.

I’ve observed experienced mentors who were comfortable leaving patients at very low LDL-C, and those patients often did well. At the same time, it’s important to consider how well that applies to broader populations — and to acknowledge the limited long-term safety data at very low LDL-C levels.  

One framework comes from the 2018 ACC statement: if LDL is <25 mg/dL on two consecutive checks while on a PCSK9 inhibitor, clinical judgment is recommended, since the long-term safety of such very low levels is still being studied. 

Within that teaching framework, some clinicians might choose to monitor Mr. R closely, while others may modestly de-escalate therapy — for example, by discontinuing ezetimibe or lowering statin dose. To be clear, this is an educational reflection only, not medical advice.

So here’s the takeaway for this episode: 

1.    Cholesterol is essential for life but harmful when misplaced in atherogenic particles.

2.    In clinical practice, both absolute LDL-C targets and percent reduction matter — especially in very high-risk patients.

3.    Physiology, genetics, and trials all agree: lower LDL-C is better and safe, but decisions should always be individualized.

Next episode in 2 weeks — Lipoproteins and Their Journey: Exogenous and Endogenous Pathways. 

Thanks again for joining me on LipidCurious. If you found today helpful, I’d love to hear your feedback. You can reach me at hello@lipidcurious.com

Be sure to subscribe or follow, so you don’t miss what’s next.

Until next time — stay curious, and stay confident.
Signing off, Dr. Pulipati.

Bonus: The Visual Guide for this episode is waiting for you — click here. For the full collection of visuals across episodes, visit the Podcast page.

Download the Free LipidCurious Starter Kit here

Questions or feedback? Reach out at hello@lipidcurious.com