Knife Down
"Knife Down" is what a surgeon says in the OR when she puts her scalpel down so no one gets hurt — and it’s the mission here: put the knife down, long before anyone needs to use it.
Knife Down is a podcast about how to actually invest in your health so you can live longer, stronger, and with less time in doctors’ offices. The core focus is the world’s leading cause of death—cardiovascular disease—and what to do about it before it shows up as a catastrophe.
Hosted by a vascular surgeon on a mission to put herself out of business, the show translates cutting-edge science on prevention, metabolic health, and longevity into real-world strategies you can use in clinic or at your kitchen table. Expect evidence, nuance, and zero wellness hype—plus the occasional dark joke about the state of modern medicine.
Knife Down
New Drugs Cut Lp(a) Over 90%...Will They Prevent Heart Attacks?
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In this video, we explore the exciting pipeline of drugs targeting lipoprotein a and its implications for cardiovascular disease prevention. We'll examine how these cholesterol drugs are designed to work, including those utilizing sirna technology, and discuss the reasons for both enthusiasm and caution regarding this medical breakthrough. This discussion aims to clarify the current landscape of new treatments and what questions still need answers.
Here’s what I cover:
- The strategy for lowering Lp(a): stop production vs block assembly (it’s basically all in the liver)
- The late-stage / headline agents and trials:
- Pelacarsen (ASO) — Lp(a)HORIZON
- Olpasiran (siRNA) — OCEAN(a)
- Lepodisiran (siRNA)— ACCLAIM-Lp(a) (enrolling)
- Zerlasiran / SLN360 (siRNA) — development in flux
- Muvalaplin (oral assembly inhibitor)— KRAKEN (phase 2)
- Why I’m genuinely hopeful: plasmapheresis is a “proof-of-concept” that lowering Lp(a) *might* reduce events (with important confounders)
- Why I’m still skeptical until outcomes data lands: the graveyard of “should-have-worked” drugs (CETP inhibitors, canakinumab—great biomarker/endpoint signals, messy real-world tradeoffs)
- My 5-question framework for evaluating any new cardiometabolic drug the moment it hits the market:
1. What problem does it actually solve—and how big is the benefit?
2. How strong/unbiased is the evidence (and do we have outcomes)?
3. Who is the right target (and who wasn’t in the trial)?
4. What are the tradeoffs (side effects, cost, duration, unknowns)?
5. Would I take it? Would I give it to my mom—under what conditions?
References:
Lp(a) HORIZON Phase 2 - DOI: 10.1056/NEJMoa1905239
OCEAN(a) Phase 2: DOI: 10.1056/NEJMoa2211023
ALPACA Phase 2: DOI: 10.1056/NEJMoa2415818
Zerlasiran Phase 2: doi:10.1001/jama.2024.21957
KRAKEN Phase 2: doi:10.1001/jama.2024.24017
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🧬 About Dr. Lily Johnston
Dr. Johnston is a double board-certified vascular and general surgeon in San Diego, specializing in metabolic and cardiovascular prevention. She’s the founder of CorSight Health and a passionate advocate for reimagining how medicine approaches chronic disease.
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