AI Summary
→ WHAT IT COVERS Simon Hill and surgeon Terry Simpson examine cardiovascular disease risk, cholesterol management, and emerging therapies including oral PCSK9 inhibitors and gene-editing treatments. They analyze a contested ketogenic diet plaque study, address misinformation from health influencers, and cover superager brain health research, colorectal cancer screening, and new 2026 dyslipidemia guidelines across 113 minutes. → KEY INSIGHTS - **Superager Genetics:** A study of cognitively intact adults in their 80s found no relationship between APOE genetic variants and preserved brain function — people with APOE4 (elevated Alzheimer's risk) and APOE2 (protective variant) were equally represented. This suggests genetics is not destiny for cognitive aging. The likely drivers are blood pressure control, lipid management, Mediterranean-style diet with 250g fruit and 250g vegetables daily, exercise, and social community. - **PCSK9 Inhibitor Selection:** Repatha (evolocumab) remains the strongest choice for LDL and ApoB reduction because it carries hard cardiovascular outcomes data showing fewer heart attacks and strokes. Newer options — oral PCSK9 inhibitor Lerodalcibep, Inclisiran (siRNA mechanism), and Lerodalcibep (ambient-stable, no refrigeration required) — lower ApoB by 50–60% but currently lack equivalent outcomes trials. Those trials are expected within one year. Until then, Repatha or Praluent offer the most evidence-backed approach. - **Plaque Stabilization Target:** Driving ApoB below 50 mg/dL — achievable by combining statins, ezetimibe, and PCSK9 inhibitors — appears to shift arterial plaque from a vulnerable, lipid-rich state toward a stable, calcified state less likely to rupture. The volcano-to-dormant-mountain analogy describes this shift: the goal is not necessarily eliminating plaque but reducing its inflammatory core and fibrous cap vulnerability, which reduces myocardial infarction risk independent of lesion size. - **Keto CTA Study Red Flags:** A preprint study of 100 ketogenic diet followers with elevated LDL (near 200 mg/dL) showed 21–29% experienced rapid plaque progression, defined as greater than 1% annual increase in percentage atheroma volume. A comparable metabolically healthy cohort with LDL around 110 mg/dL showed only 3% rapid progressors. The study abstract emphasized that 15% showed regression while burying the progression data in the discussion — a framing inconsistency that misrepresents the overall findings. - **Colorectal Cancer and Diet:** Colorectal cancer incidence in younger adults has risen approximately 2% annually since the 1960s, linked to increased ultra-processed food consumption and low fiber intake — 92% of Americans fall short of adequate fiber. High red meat consumption raises colorectal cancer risk by a factor of roughly 1.3, but adding sufficient fruits and vegetables normalizes that risk back to population baseline. Colonoscopy screening starting at age 45 (covered by insurance) detects and removes precancerous polyps before they progress to cancer over 7–10 years. - **Type 1 Diabetes Gene Editing:** Vertex has demonstrated that stem cell-derived islet cells injected into the portal vein can restore insulin production in severe type 1 diabetics, though patients currently require lifelong immunosuppression. Sana Biotech used CRISPR gene editing on donor islet cells to make them immunologically invisible, eliminating the need for immunosuppression in a human subject over 14 months. Combining both approaches — lab-grown stem cell islets with gene editing — could produce a functional cure without immunosuppression within the next several years. - **2026 Dyslipidemia Guidelines:** New guidelines recommend a first lipid panel at age 19, then every five years if results are normal and no family history exists. Children with a parent carrying familial hypercholesterolemia should be screened at age two. Lp(a) testing is now recommended at least once per lifetime, as elevated Lp(a) disproportionately increases plaque vulnerability rather than just volume. PCSK9 inhibitors lower Lp(a) by 25–30%, though clinical significance remains unconfirmed pending the Horizon outcomes trial expected to report results this year. → NOTABLE MOMENT Terry Simpson describes witnessing a pattern in carnivore diet comment sections where followers report strokes and heart attacks, yet creators ignore those accounts while amplifying success stories like psoriasis remission. He points out that psoriasis is episodic by nature, making dietary attribution unreliable — a stark illustration of how selective amplification of anecdotes shapes dangerous health decisions for large audiences. 💼 SPONSORS [{"name": "Momentous", "url": "https://livemomentous.com"}, {"name": "Eight Sleep", "url": "https://8sleep.com/theproof"}, {"name": "Function Health", "url": "https://functionhealth.com/simonhill"}, {"name": "LMNT", "url": "https://drinklmnt.com/simon"}, {"name": "WHOOP", "url": "https://join.whoop.com/simon"}] 🏷️ Cardiovascular Disease, PCSK9 Inhibitors, ApoB Cholesterol, Atherosclerosis, Colorectal Cancer Screening, Type 1 Diabetes Gene Therapy, Dyslipidemia Guidelines