@jahman57 Why Zetia + Nexletol may appear to be doing “nothing”.

What you are describing does happen, and there are several plausible explanations—often more than one at the same time.

1. These drugs lower LDL less than statins.
Zetia (ezetimibe) typically lowers LDL by ~15–25%.
Nexletol (bempedoic acid) lowers LDL by ~15–20%.
Together, the average LDL reduction is ~30–35%.

If someone:
Started with very high LDL, or
Previously had large LDL reductions on statins
…the change can feel disappointing or negligible, even though the drugs are working within their expected range.

2. Underlying genetic cholesterol disorders.
If LDL remains very high despite therapy, possibilities include:

Familial hypercholesterolemia (FH) (even milder or late-diagnosed forms).
Other inherited lipid metabolism issues.

In these cases:
Oral medications often cannot overcome the genetic signal
Injectable therapies may be needed (see below).

3. Absorption or metabolic variability:

Some people:
Absorb less ezetimibe from the gut
Metabolize bempedoic acid differently
Have liver pathways that respond weakly to these mechanisms.
This is not rare and usually not detectable without trial-and-error treatment.

4. Secondary causes raising cholesterol:

Even if medications are correct, LDL may stay high if something else is driving it, such as:

Hypothyroidism.
Insulin resistance or diabetes.
Chronic kidney disease.
High saturated-fat intake.
Certain medications (steroids, some psych meds, etc.).
If these aren’t addressed, lipid drugs can look ineffective.

5. Statin intolerance is real—but often complex.
True statin intolerance does occur, especially:

Muscle pain, stiffness, weakness
Symptoms returning consistently with re-challenge.

However, some patients tolerate:

Very low-dose statins (e.g., once or twice weekly).
Hydrophilic statins (pravastatin, rosuvastatin) better than others.
That said, if symptoms are reproducible, forcing statins is not appropriate.
What usually works when this happens:

If LDL remains high despite Zetia + Nexletol, guidelines typically move to PCSK9 therapy, such as:

Repatha (evolocumab).
Praluent (alirocumab).

These:
Lower LDL by 50–60%.
Are not statins.
Rarely cause muscle symptoms.
Work well in statin-intolerant patients.
Some people also benefit from:
Inclisiran (twice-yearly injection).
Combination therapy tailored to genetics and risk.
Why they may feel “no symptoms”:

That part is actually expected:
High cholesterol does not cause symptoms.
Muscle pain comes from medications, not cholesterol itself.
Cardiovascular risk accumulates silently over years.
So feeling fine does not mean cholesterol isn’t a problem.

Bottom line:

This situation is:
Not rare.
Not a failure.
Often a sign that stronger, non-statin therapy is needed.
A lipid specialist or preventive cardiologist would likely:

Rule out secondary causes.
Confirm true statin intolerance.
Consider PCSK9 inhibitors or inclisiran.

Here are links to trustworthy sources that support the key points from the above explanation about Zetia (ezetimibe), Nexletol (bempedoic acid), statin intolerance, and other non-statin LDL-lowering therapies:

1. Non-statin therapies:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8635697/ (PMC article on non-statin options and guidelines) �
PMC

2. Ezetimibe (Zetia) reduces LDL by about 15–25% non-statin option:
https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia/cholesterol-medications �
http://www.heart.org

3. Bempedoic acid (component of Nexletol / Nexlizet) statin-intolerant
https://consultqd.clevelandclinic.org/statin-intolerance-and-new-lipid-lowering-treatments �
Cleveland Clinic
NEXLIZET & NEXLETOL prescribing info page (with indication for statin-intolerant patients):
https://www.nexlizethcp.com/statin-intolerance-evidence/ (trial and safety details for bempedoic acid) �
ESPNEX

4. Study showing additive LDL lowering from ezetimibe + bempedoic acid:
https://www.tctmd.com/news/bempedoic-acidezetimibe-combo-lowers-ldl-cholesterol-high-risk-patients �
tctmd.com
Wikipedia summary of LDL reductions with the combination:
https://en.wikipedia.org/wiki/Bempedoic_acid/ezetimibe �
Wikipedia

5. PCSK9 inhibitors (e.g., evolocumab & alirocumab) statin-intolerant patients:
https://consultqd.clevelandclinic.org/statin-intolerance-and-new-lipid-lowering-treatments (ODYSSEY ALTERNATIVE trial results showing ~45% LDL reduction) �
Cleveland Clinic

6. Guidelines & consensus statements:
https://www.jacc.org/doi/10.1016/j.jacc.2022.07.006 �
JACC
NIH/NLM cholesterol management guideline overview including non-statin substitutions:
https://www.ncbi.nlm.nih.gov/books/NBK305897/ �