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The cholesterol wars are over. LDL won. New guidelines. Four landmark trials. An oral PCSK9 inhibitor that matches injectables. And data proving we should be treating patients we currently aren't. Here's everything clinicians need to know. 🧵
1/ The 2026 ACC/AHA Guideline just retired 10-year-old guidance and brought back something crucial: explicit LDL-C numeric targets. Not "treat to benefit." Treat to a number. <55 mg/dL for most established ASCVD. <70 for high-risk primary prevention. Eleven societies signed off.
2/ Ez-PAVE just answered a question cardiology has avoided for years: Is <55 mg/dL actually BETTER than <70 mg/dL in secondary prevention? 3,048 patients. Head-to-head RCT. The answer: 10 mg/dL difference in achieved LDL → 33% reduction in MACE. NNT ~32 over 3 years. For a target adjustment.
3/ VESALIUS-CV changed who deserves a PCSK9 inhibitor. 3,655 diabetic patients. No MI. No stroke. No known significant atherosclerosis. Evolocumab vs. placebo. 4.8 years. Result: 31% reduction in MACE. Mortality signal HR 0.76 (exploratory). PCSK9 inhibitors are not rescue therapy. They are prevention.
4/ CORALreef Lipids: the world's first oral PCSK9 inhibitor to pass Phase 3. Enlicitide decanoate: 57% LDL reduction on top of statin. Same as injectables. Fewer than 1% of ASCVD patients in the US are on an injectable PCSK9 inhibitor. An oral agent with placebo-level safety could change that.
5/ CORALreef AddOn (presented at ACC.26): Head-to-head vs. bempedoic acid, ezetimibe, and both combined. Enlicitide at 56 days: → 64.6% LDL reduction → 78.2% reached <55 mg/dL Best oral alternative (BA + EZE): 20% reached target. And comparators increased Lp(a). Enlicitide reduced it 26%.
6/ On statin denialism: "LDL is just a surrogate." Ference 2017: I² = 0% across seven mechanistically distinct LDL-lowering approaches. Identical risk reduction per mmol/L regardless of drug. The effect tracks the LDL. Not the drug. FOURIER confirmed it. ODYSSEY confirmed it. Ez-PAVE confirmed it.
7/ 6 things to do after reading the 2026 guidelines: 1. Measure Lp(a) — once, in every adult (Class I) 2. ASCVD + LDL ≥55 on statin → add something, now 3. High-risk diabetic, primary prevention → VESALIUS-CV changed your calculus 4. CAC score reluctant patients 5. ACS admission → start or intensify before discharge 6. Start early. Biology compounds. Every year untreated is one you can't undo.
8/ I covered all of it in this week's Substance Over Noise: → 2026 ACC/AHA guideline breakdown → Ez-PAVE full trial review → VESALIUS-CV subgroup analysis → CORALreef Lipids + AddOn → How to answer every statin denialist argument <a target="_blank" href="https://substance-over-noise.beehiiv.com/p/the-cholesterol-wars-are-over-ldl-won" color="blue">substance-over-noise.beehiiv.com/p/the-choleste…</a>