Ezetimibe

Selective NPC1L1 inhibitor that blocks intestinal cholesterol absorption — the only mechanistically distinct lipid-lowering option you can stack cleanly on top of a statin to get an extra 15-25% LDL drop. Best-evidenced in IMPROVE-IT (n=18,144 ACS, ~6% relative CV event reduction adding ezetimibe to simvastatin) and RACING 2022 (combo with low-dose statin non-inferior to high-dose statin alone with fewer adverse events). For Dylan: NOT-RELEVANT default — 20yo, lean, no known lipid issues. Revisit once June 2026 bloodwork lands; if he turns out to be a "lean reactor" (high LDL/ApoB despite lean habits, driven by intestinal hyperabsorption rather than overproduction) ezetimibe is mechanistically the exact right tool and would jump to STRONG-CANDIDATE or PRIMARY-PICK.

Ezetimibe selectively inhibits Niemann-Pick C1-Like 1 (NPC1L1), a sterol transporter densely expressed on the apical brush border of jejunal enterocytes (and to a lesser extent on hepatocyte canalicular membranes).

The cholesterol absorption pathway in plain English:

1. Dietary cholesterol (~300-500 mg/day) and biliary cholesterol (~800-1200 mg/day reabsorbed) sit in the intestinal lumen as micelles.
2. NPC1L1 at the enterocyte brush border grabs cholesterol from the micelle and pulls it into the cell.
3. Inside the enterocyte, cholesterol is esterified by ACAT2 and packaged into chylomicrons.
4. Chylomicrons enter lymphatics → systemic circulation → liver.
5. The liver senses arriving cholesterol and downregulates its own LDL receptor expression. More LDL stays in blood.

Ezetimibe blocks step 2. Cholesterol absorption drops by ~50-65%. The liver gets less cholesterol delivered, so it upregulates LDL receptors to scavenge LDL from blood — net effect ~15-25% LDL-C reduction as monotherapy.

Why ezetimibe stacks synergistically with statins:

• Statins inhibit HMG-CoA reductase → block hepatic cholesterol synthesis.
• The body compensates by upregulating NPC1L1 and absorbing more dietary cholesterol.
• Adding ezetimibe blocks that compensation → captures another 15-20% LDL drop on top of statin baseline.
• This is mechanism-level synergy, not just additive — it is why ezetimibe + low-dose statin often beats high-dose statin alone (RACING 2022).

The "lean reactor" / hyperabsorber phenotype:

• Cholesterol homeostasis is governed by two arms: hepatic synthesis (statin target) and intestinal absorption (ezetimibe target).
• Some people are "high-absorbers" — they pull a disproportionate share of cholesterol from the gut and produce relatively less. Often lean, often endurance-athletes, often on low-saturated-fat diets, sometimes with elevated LDL despite "doing everything right."
• Markers: elevated serum sitosterol and campesterol (plant sterols absorbed via the same NPC1L1 pathway) are surrogates for high cholesterol absorption.
• High-absorbers respond better to ezetimibe and relatively less to statins.
• Conversely, "high-synthesizers" (often metabolically driven, insulin-resistant phenotypes) respond more to statins.
• This is a real, clinically relevant axis. If Dylan turns out to have unexpectedly high LDL/ApoB on June bloodwork despite being a 20yo lean MMA athlete on a clean diet, the lean-reactor / hyperabsorber phenotype is one of the leading explanations and ezetimibe is the matched intervention.

Familial hypercholesterolemia (FH):

• Heterozygous FH affects ~1:250 people; LDL-receptor or PCSK9 or ApoB mutations cause lifelong elevated LDL-C from birth.
• 23andMe + Promethease can flag known FH-causing SNPs (LDLR, APOB, PCSK9 variants) — relevant for Dylan once results land.
• Ezetimibe is standard add-on therapy in FH alongside statin and (for severe cases) PCSK9 inhibitors.