I Treat Cholesterol Differently Now: Statins, PCSK9s, Ezetimibe & Gene Editing

There is a drug in clinical trials right now that could permanently fix your cholesterol with a single infusion. Once. That's where we're headed. But ther…

Published May 7, 20261:02:56The Longevity Show

Part three of the modern lipid playbook, and the one about treatment. Dr. Lin opens with her own case rather than a case study: a paternal family history of stroke, sudden cardiac arrest, aortic dissection and a heart transplant, and her own ApoB coming back at 128. What follows is an honest accounting of the full toolkit, from a $4 generic with more outcome data behind it than almost any drug in medicine, to a twice-yearly injection most patients have never heard of, to a base-editing therapy with published phase one data.

Two ideas do most of the work. First, the trial data does not show a floor: IMPROVE-IT, FOURIER and its open-label extension all found that patients who went lower kept doing better, with no cognitive or cancer signal at LDLs below 20. Second, exposure is cumulative — what Dr. Lin calls cholesterol years. Treating at 40 instead of 60 is not twenty extra years of therapy, it is preventing plaque from forming at all.

The other throughline is that why your number is high should change which drug you get. Lp(a), familial hypercholesterolemia and pharmacogenomics each point somewhere different, and Dr. Lin works through her own genotype results on air — including the ABCG2 variant that explained her statin muscle aches. The tiers near the end are a starting point for a conversation with your clinician, not a prescription.

Before you watch

ApoB is the treatment target, not LDL-C. When the two disagree — which happens more often than most practices acknowledge — risk tracks with ApoB. The targets discussed: under 80 for primary prevention, under 70 for high risk, under 55 for very high risk including anyone post-event.
The trial data does not show a floor. IMPROVE-IT drove LDL to 54 versus 70 and saw fewer events; FOURIER reached a median of 30 with 15% fewer cardiovascular deaths; its open-label extension followed patients up to 8.6 years, some below 20, with no cognitive or cancer signal.
Exposure is cumulative, so timing matters as much as the number. Starting at 40 rather than 60 prevents plaque from forming rather than just adding years of therapy — the reasoning behind the 2026 ACC/AHA move to start the statin conversation at 30.
Muscle pain is real but frequently not the statin. Reported by 1–10%, true myopathy under 0.1%, rhabdomyolysis around 1 in 10,000 patient-years. In the SAMSON trial, 90% of symptoms attributed to the statin also occurred on placebo — an argument for re-challenge with a different agent rather than abandoning the class.
Pharmacogenomics can explain an individual's intolerance. Roughly 15% carry an SLCO1B1 variant that raises muscle risk, worst with simvastatin. The FDA label already advises Asian patients start rosuvastatin at 5 mg because of ABCG2 Q141K — the variant Dr. Lin found she carries, which had her getting roughly 1.5× the drug exposure her dose implied.
Ezetimibe is the most underused cheap option. Roughly 15–25% additional LDL reduction on top of a statin for about $15, with essentially no muscle or liver signal, and IMPROVE-IT outcome data behind it.
For high risk, injectables are a first step rather than a last resort. PCSK9 inhibitors add 50–65%; FOURIER and ODYSSEY OUTCOMES both showed ~15% event reduction. Inclisiran gives similar LDL lowering on two injections a year, though its cardiovascular outcomes trial has not reported yet.
Lifestyle is foundational and, for some numbers, insufficient. Diet moves ApoB 10–20% (up to 20–30% with soluble fiber in highly adherent people); exercise moves it only 5–10%. Diet, exercise and weight loss have no meaningful effect on Lp(a) — anyone claiming otherwise is usually selling something.
Elevated Lp(a) has no approved drug today, and that is the honest answer. Pelacarsen, olpasiran, zerlasiran and lepodisiran all show 80–95% reductions in phase two with outcomes data expected between 2026 and 2028. Until then the approach is to treat every other risk factor harder.

Chapters

Questions

Should I be tracking ApoB instead of LDL cholesterol?

Dr. Lin's position is yes — ApoB is the treatment target and LDL-C is the proxy. When the two disagree, cardiovascular risk tracks with ApoB. It is a simple add-on at most labs and is endorsed by the major medical bodies. The thresholds discussed are under 80 for primary prevention, under 70 for high risk, and under 55 for very high risk. Recheck 8–12 weeks after starting or changing therapy, then every 6–12 months once stable.

I stopped a statin because of muscle pain. Does that mean I can't take one?

Not necessarily. True statin myopathy affects under 0.1% of patients, and in the SAMSON trial 90% of symptoms people attributed to their statin also occurred on placebo. That does not mean the pain isn't real — Dr. Lin experienced it herself. It means the cause may not be what you assume. The usual next steps are a re-challenge with a different statin or lower dose, and checking whether an SLCO1B1 or ABCG2 variant explains it. If genuine intolerance is documented, bempedoic acid, ezetimibe, PCSK9 inhibitors and inclisiran all remain available. Any change belongs with your clinician.

Can diet and exercise fix high cholesterol without medication?

Sometimes, and it depends on where you are starting. Replacing saturated with unsaturated fat plus soluble fiber can lower ApoB 10–20%, and up to 20–30% in very adherent people. Exercise contributes only about 5–10% to ApoB specifically, though it matters enormously for cardiovascular health overall. For someone with an ApoB above 100, plaque on imaging, or a strong family history, the episode's view is that lifestyle alone will not get you there. Taking a statin or an injectable alongside good habits is not a failure of discipline.

What can I do about elevated Lp(a) right now?

No approved therapy meaningfully lowers Lp(a) today, and diet, exercise and weight loss do not move it — it is roughly 90% inherited. Statins may even raise it slightly; PCSK9 inhibitors lower it 20–30%, which is real but not sufficient on its own. The practical approach is to know your number (a one-time test, since it doesn't change much over a lifetime), treat every other risk factor more aggressively to compensate, and watch the pipeline. Several agents are in phase three outcomes trials now.

Is the gene-editing therapy something I could get soon?

Not soon. VERVE-101 uses base editing to switch off PCSK9 with a single infusion and showed roughly 55% LDL reduction in its phase one, but the FDA placed a clinical hold on US trials pending further safety review, and a successor is in development. Because the change is permanent, regulators will require long-term safety data no other drug class faces. A realistic estimate for a first approval in a common lipid disorder is the early 2030s.

What should I actually ask at my next appointment?

Five questions from the episode: What is my ApoB? Has my Lp(a) ever been tested? Given my family history, am I being treated aggressively enough? If statins aren't getting me to goal, what is next — ezetimibe, a PCSK9 inhibitor, or inclisiran? And what does my cardiovascular imaging show, and how should it change my targets? If there isn't time in the visit, ask for a dedicated follow-up on lipid management.

The Longevity Letter