#384 - Special episode — Obicetrapib: The CETP inhibitor with cardiovascular benefits and potential Alzheimer's prevention

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Mar 16, 2026

A deep look at obicetrapib and why this CETP inhibitor has revived interest in a once-failed drug class. A concise history of prior CETP trials and what made them stumble. Clear breakdowns of how CETP alters HDL, LDL, ApoB, and Lp(a). Emerging Alzheimer’s biomarker signals, especially in APOE4 carriers, and what trials like BROADWAY are showing.

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INSIGHT

Why First Generation CETP Drugs Failed

Early CETP inhibitors failed for two main reasons: off-target toxicities or insufficient ApoB/LDL lowering despite large HDL increases.
Torcetrapib raised blood pressure (off-target) while dalcetrapib barely lowered ApoB, explaining prior program abandonments.

INSIGHT

Obicetrapib Strongly Lowers LDL And ApoB

Obicetrapib produced very large LDL-C and ApoB reductions on top of maximal therapy in phase 2 trials (ROSE, OCEAN, ROSE2).
Results showed ~50% additional LDL-C lowering with statin ± ezetimibe and up to >60% when combined with both.

INSIGHT

Broadway Shows LDL, ApoB, And Lp(a) Improvements

In the BROADWAY trial, adding 10 mg daily obicetrapib to maximal therapy reduced LDL by ~30% at 3 months and ApoB by 16%.
HDL rose ~125% and Lp(a) fell by about one-third, suggesting meaningful effects on difficult-to-modify lipoproteins.

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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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