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In this special episode, Peter takes a deep dive into obicetrapib, an investigational drug that has captured his attention and renewed interest in an entire class of therapies known as CETP inhibitors. He explains what obicetrapib is and how it works, revisits the history of CETP inhibitors and why earlier versions of these drugs failed—sometimes dramatically—and breaks down the key clinical trials designed to evaluate their impact on cardiovascular risk. Peter examines how obicetrapib influences major lipid biomarkers, including LDL cholesterol and lipoprotein(a) [Lp(a)], and discusses emerging evidence from a study that explored the drug's effects on Alzheimer's-related blood biomarkers. He also highlights intriguing findings in individuals carrying the APOE4 allele and reflects on what these early results may mean for both cardiovascular disease prevention and potential implications for Alzheimer's risk, as well as how he is thinking about this therapy in the context of caring for his own patients.

We discuss:

• Introducing obicetrapib: CETP inhibitor history, lipid biology, and early Alzheimer's biomarker signals in APOE4 carriers [2:15];
• CETP biology explained: lipoproteins, reverse cholesterol transport, and how CETP inhibition alters HDL and LDL particles [5:15];
• The early CETP inhibitor story: why raising HDL cholesterol alone failed to deliver cardiovascular protection [13:45];
• The rise and fall of early CETP inhibitors: torcetrapib, dalcetrapib, evacetrapib, and anacetrapib [18:30];
• Why obicetrapib may succeed where earlier CETP inhibitors failed [23:30];
• The BROADWAY trial: obicetrapib's effects on LDL, ApoB, Lp(a), and residual cardiovascular risk [26:00];
• Brain lipid metabolism and APOE4: how CETP inhibition may influence cholesterol transport in Alzheimer's disease [30:45];
• Findings from the substudy of the BROADWAY trial which looked at changes in biomarkers of Alzheimer's disease [40:00];
• Interpreting the BROADWAY Alzheimer's biomarker results: limitations, cautious optimism, and the need for a dedicated prevention trial [46:45];
• Why Peter is optimistic about obicetrapib: cardiovascular benefits, Lp(a) reduction, and the path toward approval [50:00]; and
• More.

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Layne Norton is a nutrition scientist and accomplished power athlete,who returns to The Drive for a conversation that departs from the show's usual format. In this episode, Layne presents the evidence-based case that seed oils are not uniquely harmful under isocaloric conditions, while Peter steelmans the strongest versions of the opposing argument that seed oils are inherently harmful. They examine how scientific bias and evidence are evaluated, revisit the historical randomized controlled trials that shaped the seed oil controversy, and explore the mechanistic biology underlying LDL oxidation and atherosclerosis. Along the way, Layne unpacks the chemistry and processing of modern seed oils, assesses evolutionary and ancestral nutrition arguments, clarifies the relationship between seed oils, ultra-processed foods, and contemporary dietary patterns, and situates these questions within the larger context of lifestyle factors that drive cardiometabolic health. Layne concludes by offering practical considerations around dietary fats, cooking oils, and real-world food choices.

We discuss:

• The idea behind this episode, biases, and evidence-based thinking [5:15];
• The four core arguments behind claims that seed oils are harmful [12:30];
• The Minnesota Coronary Experiment (MCE) [14:30];
• The differences among saturated, monounsaturated, polyunsaturated, and trans fats, and why those differences matter for cardiovascular disease [18:30];
• Missing trans fat data as a confounder in the Minnesota Coronary Experiment, other limitations of that study, and the challenge detecting meaningful differences in hard outcomes through nutrition research [24:00];
• The Sydney Diet Heart Study (SDHS): an attempt to address the "duration problem" by enrolling a much higher-risk population [28:30];
• Debating whether evidence from randomized trials supports the idea that seed oils are uniquely harmful once major confounders are removed [34:00];
• The Rose Corn Oil trial: an often-cited study used to argue against polyunsaturated fats [36:30];
• Three studies where replacing saturated fat with polyunsaturated fat produced different results than earlier trials [41:30];
• Layne's explanation for why the evidence is pointing towards cardiovascular risk reduction when substituting polyunsaturated fat for saturated fat [47:30];
• What Mendelian randomization says about the causal role of LDL cholesterol in ASCVD [56:45];
• The compounding effects of life-long exposure to high LDL cholesterol [1:06:45];
• Does the linoleic acid (omega-6) content of seed oils cause inflammation? [1:13:45];
• Does the linoleic acid (omega-6) content of seed oils increase oxidized LDL? [1:19:30];
• Layne's analogy to explain why lower LDL particle number outweighs higher per-particle oxidation risk when comparing polyunsaturated fats to saturated fats [1:26:15];
• The role of oxidized LDL in CVD: exploring differences in a diet high in polyunsaturated fat (seed oils) versus high in saturated fat [1:28:00];
• Examining whether industrial processing and solvent extraction of seed oils—especially residual hexane—could plausibly cause long-term harm [1:34:00];
• The evolutionary and "ancestral diet" argument against seed oils [1:40:45];
• Weighing concerns about industrial processing of seed oils against the totality of metabolic and cardiovascular evidence [1:47:30];
• Practical considerations around dietary fats, cooking oils, and real-world food choices [1:50:00];
• Comparing the health impact of seed oils with that of caloric intake and activity levels, and how to prioritize interventions [2:00:15];
• More.

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