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407 ‒ Preventing cardiovascular and Alzheimer’s disease: lowering LDL early, APOE4, and more
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New research suggests statins may not protect against Alzheimer's, but a novel drug, obetropib, shows promise by targeting lipid metabolism in the brain, potentially preventing the disease in its earliest stages.
Key Insights
The 8-gram rule posits that lifetime cholesterol exposure leading to heart disease is equivalent to 200 mg/dL for 40 years, 100 mg/dL for 80 years, or 80 mg/dL for 100 years, suggesting that maintaining LDL below 80 mg/dL throughout life may prevent heart disease.
CTP inhibitors, like the drug obetropib, lower LDL by transferring cholesterol from HDL to LDL and improving LDL clearance, while also potentially raising HDL and reducing diabetes risk.
The development of CTP inhibitors faced significant setbacks, with early candidates like torcetrapib failing due to increased mortality and other CTP inhibitors failing to demonstrate a significant reduction in major adverse cardiac events (MACE).
While APOE4 gene variants significantly increase Alzheimer's risk, loss-of-function CTP mutations appear to mitigate this risk, suggesting a role for lipid metabolism in Alzheimer's pathogenesis.
Obetropib has demonstrated a significant reduction in various Alzheimer's biomarkers, including p-tau217, in patients with mild cognitive impairment (MCI), suggesting potential for disease prevention.
Omega-3 fatty acids, particularly EPA, may reduce cardiovascular risk through anti-thrombotic and anti-inflammatory effects rather than triglyceride lowering, while DHA's entry into the brain is dependent on a specific lysophosphatidylcholine (lyso-PC) form.
The "8-gram rule" and the case for early LDL lowering
Michael Davidson emphasizes a proactive approach to cardiovascular disease prevention, advocating for early intervention based on the '8-gram rule.' This principle suggests that a lifetime accumulation of 8 grams of cholesterol exposure leads to heart disease, translating to an LDL cholesterol level of 200 mg/dL for 40 years, 100 mg/dL for 80 years, or 80 mg/dL for 100 years. The core message is that maintaining LDL below 80 mg/dL throughout life could effectively prevent atherosclerotic cardiovascular disease (ASCVD). Davidson contrasts this with the mainstream approach of treating established plaque buildup or acute events, highlighting that interventions are far more effective before disease onset. He draws parallels to managing hypertension and diabetes, where treatment doesn't wait for severe complications. The challenge lies in convincing younger individuals to adopt preventive measures, often requiring genetic testing, polygenic risk scores, or imaging like coronary calcium scans to illustrate individual risk.
The turbulent history and promise of CTP inhibitors
The discussion delves into the complex development of CETP (cholesteryl ester transfer protein) inhibitors. Initially, the focus was on raising HDL cholesterol, driven by epidemiological data linking higher HDL to lower cardiovascular risk. However, early trials of CTP inhibitors like torcetrapib (Pfizer) were halted due to increased mortality, later attributed to off-target effects beyond blood pressure elevation. Subsequent CTP inhibitors, such as anacetrapib (Merck) and evacetrapib (Eli Lilly), also failed to demonstrate significant benefits in major adverse cardiac events (MACE), despite some showing promise in reducing diabetes risk. These failures were attributed to various factors, including insufficient LDL lowering, inadequate study duration, or off-target effects. The hope for the class was reignited by Merck's anacetrapib trial, which, despite its own commercial challenges, provided proof-of-concept for LDL lowering via CTP inhibition leading to cardiovascular benefit, though the magnitude was modest.
Obetropib: A potent CTP inhibitor with dual benefits
Obetropib, developed by New Amsterdam Pharma, emerges as a highly potent CTP inhibitor. Unlike earlier candidates, it achieves significant LDL lowering (40-50% as monotherapy, and even higher in combination with ezetimibe) and HDL raising (up to 150%) at low doses (5-10 mg). Crucially, obetropib has shown a reduction in MACE in early trials like Broadway, which is a critical differentiator from previous CTP inhibitors. The drug also appears to lower Lp(a) by approximately 50%, a significant risk factor for cardiovascular disease, and shows a reduction in diabetes risk, a known side effect of statins. This multifaceted profile positions obetropib as a potential companion therapy to statins, addressing statin-related liabilities like increased Lp(a) and diabetes risk, while offering substantial LDL reduction.
Exploring obetropib's potential in Alzheimer's disease
A compelling aspect of obetropib's potential lies in its hypothesized role in preventing Alzheimer's disease. This is supported by genomic data showing that loss-of-function mutations in the CETP gene significantly mitigate the increased Alzheimer's risk associated with the APOE4 genotype. Animal studies further suggest that inhibiting CETP can improve cognitive function in models of dementia. Early pilot studies with obetropib in individuals with mild cognitive impairment (MCI) and at least one APOE4 allele have shown promising results, including a reduction in specific Alzheimer's biomarkers like p-tau217 and 24/27-hydroxycholesterols in cerebrospinal fluid (CSF). This suggests obetropib might intervene in brain lipid metabolism, which is heavily implicated in Alzheimer's pathogenesis, particularly in APOE4 carriers who have impaired cholesterol clearance in the brain.
The complexity of HDL and its role in brain health
While historically HDL was considered a marker of cardiovascular protection, its exact role and the significance of its raising have become more nuanced. The discussion highlights that not all HDL is equal, and certain genetic factors can lead to high HDL that is dysfunctional or even associated with increased risk. For instance, APOE4 carriers often have metabolically favorable lipid profiles (high HDL, low LDL) due to genetic variations, but this doesn't negate their Alzheimer's risk. Obetropib's ability to raise HDL may be beneficial by increasing reverse cholesterol transport and delivering antioxidants to the brain, potentially counteracting the impaired lipid metabolism seen in APOE4 individuals. However, the mechanism by which HDL interfaces with brain health and cholesterol clearance remains an area of active research.
Omega-3 fatty acids: distinct roles for EPA and DHA
The conversation touches upon omega-3 fatty acids, distinguishing between EPA and DHA. While EPA has shown cardiovascular benefits, potentially through anti-thrombotic and anti-inflammatory mechanisms rather than triglyceride lowering, DHA is crucial for brain health due to its abundance in neuronal membranes. However, DHA's passage across the blood-brain barrier is limited and appears to preferentially occur in a lysophosphatidylcholine (lyso-PC) form. Current DHA supplements may not effectively deliver sufficient amounts to the brain, especially for individuals with APOE4 variants who may have impaired DHA uptake. The development of lyso-PC forms of DHA supplements is anticipated to enhance brain delivery and potentially offer cognitive benefits.
Biomarkers and the future of Alzheimer's diagnosis and treatment
The dialogue emphasizes the evolving landscape of Alzheimer's biomarkers, particularly p-tau217, which shows strong correlation with amyloid burden and predicts disease progression. These blood-based biomarkers are becoming increasingly accurate, potentially offering a less invasive and costly alternative to PET scans. While p-tau217 is not yet a standalone endpoint for regulatory approval, its predictive power is significant. The hope is that these biomarkers could facilitate earlier diagnosis and intervention, moving beyond treating established dementia to preventing its onset, a strategy that has proven challenging in Alzheimer's drug development due to the long, preclinical disease course.
Statin-associated risks and the push for combination therapy
The conversation acknowledges that while statins are cornerstone therapies for cardiovascular disease, they are associated with a slight increase in the risk of type 2 diabetes and insulin resistance. Obetropib's profile, which shows a reduction in diabetes risk and improvement in insulin sensitivity, makes it an attractive complement to statins. Furthermore, the discussion highlights that high-dose statins may not offer significantly greater benefits than moderate doses but carry increased risks, including potential liver enzyme elevation. This supports the strategy of using combination therapies like statins with drugs like obetropib or ezetimibe to achieve LDL goals more effectively and safely, potentially allowing for lower statin doses.
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Dr. Michael Davidson is a cardiologist and lipidologist, a professor who runs the lipid clinic at the University of Chicago. His passion for prevention stemmed from his father's death at age 47 from a heart attack, which occurred when Davidson was 16. This personal experience, coupled with his own abnormal lipids and family history, drove his early involvement in lipid research and clinical trials.
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Mentioned in this video
Host of The Drive podcast and discusses his family history of heart disease as a motivator for his work.
Cardiologist and lipidologist, professor at University of Chicago, and guest on The Drive podcast. His father died of a heart attack at 47, which motivated his career in lipidology and prevention.
A past guest on The Drive podcast, familiar with lipidology.
Credited with repositioning the argument for prevention to focus on causal drivers of disease rather than just short-term risk metrics.
Colleague of Michael Davidson, a past guest on The Drive podcast, and co-founder of New Amsterdam Pharmaceuticals, involved in the development of Obicetrapib.
Where Michael Davidson runs the lipid clinic as a professor.
Their primary prevention guidelines are considered not very effective and don't emphasize early intervention for elevated LDL as much as Michael Davidson would advocate.
A Canadian university where a PhD researcher has done work on CETP and animal models of Alzheimer's.
A large-scale biomedical database being used to study the implications of discordance between lipid biomarkers.
Mentioned in the context of drug pricing, where pricing too low can lead to lack of formulary inclusion due to absence of rebating profits.
Regulates drug approval, known for not accepting per-protocol analysis and having a strict view on statin intolerance as an indication.
Early trials in the late 1970s and 1980s that Michael Davidson was involved with, related to lipid research.
One of the studies using a fibrate that showed a modest benefit by raising HDL slightly.
The ongoing outcome study for Obicetrapib, designed to show cardiovascular benefits on top of statins in a high-risk ASCVD population. Expected to read out this year or next.
A trial combining Obicetrapib with Ezetimibe, resulting in approximately 50% LDL lowering.
A triglyceride trial with a fibrate (pemafibrate) that showed no benefit, similar to the STRENGTH trial.
Provided early data suggesting a high HDL was protective against heart disease, influencing the focus on HDL raising therapies.
A study that showed Niacin on top of statins did not lower cardiovascular events, although some analysis suggested a benefit from LDL lowering.
Trial for Repatha (PCSK9 inhibitor), a chronic stable population (not acute coronary syndrome), showing benefit at two years.
A large phase 3 trial for Obicetrapib in ASCVD patients, showing a 35% LDL lowering and a 21% reduction in MACE over one year.
One of the studies using a fibrate that showed a modest benefit by raising HDL slightly.
An early study showing Niacin alone could lower cardiovascular events in the pre-statin era.
A large outcome study by Merck with a CETP inhibitor, which demonstrated that LDL lowering with CETP inhibition can translate into cardiovascular benefit, though the drug itself was not commercialized.
A phase 2 study that showed Obicetrapib achieved 45-50% LDL lowering as monotherapy and higher in combination with ezetimibe.
A GLP-1 trial that did not show improvement in cognition or effect on p-tau217 for Alzheimer's.
An outcome study for a DHA and EPA combination, which did not work overall, possibly due to the DHA component or the corn oil placebo.
A study that showed Niacin on top of statins did not lower cardiovascular events.
A phase 2 study led by John Kastelein, showing that Obicetrapib achieved 45% LDL lowering.
A study of Ashkenazi Jews aged 100 or older, which found CTP loss of function to be the most common gene and associated with mitigated Alzheimer's risk in APOE4 carriers.
A trial for pure EPA that showed cardiovascular benefit, though the mineral oil placebo might have inflated the observed effect.
Trial for Praluent (PCSK9 inhibitor) where benefit was observed after two years, even in patients with already low LDL.
A phase 3 trial for an anti-sense oligonucleotide that lowers Lp(a), expected to be released this year, but faced challenges due to a lower-than-expected event rate.
A GLP-1 trial that did not show improvement in cognition or effect on p-tau217 for Alzheimer's.
Michael Davidson conducted research on omega-3 fatty acids for lipid effects and was among the first to use fish oil capsules to treat lipid disorders.
An older drug used to lower lipids, which Michael Davidson took himself before statins became available, but has side effects and did not show outcome benefits when added to statins.
An omega-3 fatty acid that has anti-thrombotic and anti-inflammatory effects and was shown to reduce cardiovascular events in the REDUCE-IT trial.
Used as a placebo in the REDUCE-IT trial, but might have increased inflammatory signaling and affected statin absorption, potentially tilting the results.
The preferred substrate for DHA to cross the blood-brain barrier. New formulations are coming to market to deliver DHA to the brain more effectively.
A class of drugs whose trials (EVOKE and EVOKE Plus) showed no improvement in cognition or effect on p-tau217 for Alzheimer's.
Used as a placebo in the STRENGTH trial.
An omega-3 fatty acid primarily found in the brain, with potential health values, but supplementing with it doesn't always show cognitive benefits due to blood-brain barrier transport issues.
A class of drugs that inhibit cholesterol synthesis, leading to lower LDL. Michael Davidson was involved in early statin trials and started taking them early due to family history.
A CETP inhibitor developed by New Amsterdam Pharmaceuticals that potently lowers LDL and raises HDL, and is being studied for cardiovascular and Alzheimer's disease prevention.
An early CETP inhibitor developed by Pfizer, which was stopped due to increased mortality from off-target effects, specifically increased aldosterone and steroid production.
A statin that Pfizer combined with Torcetrapib in a clinical trial.
A class of drugs used in some early studies to raise HDL and show some heart disease benefit.
A well-known LDL-lowering drug (Zetia) that demonstrated benefit only after two years in similar acute coronary syndrome trials, suggesting the importance of trial duration.
A fibrate used in the PROMINENT study, which failed to show cardiovascular benefit in a triglyceride-lowering trial.
A pure EPA drug used in the REDUCE-IT trial that showed cardiovascular benefit.
A PCSK9 inhibitor that showed benefit in outcome trials at about two years, but struggled with its initial launch, leading to the deprioritization of Obicetrapib by Amgen.
An LDL-lowering drug that is not expensive in its branded form and is much easier to take than bile acid sequestrants.
A CETP inhibitor from Lilly that was safe and showed good LDL lowering and HDL raising, but its trial was stopped early for futility, possibly due to insufficient duration.
Another PCSK9 inhibitor whose outcome study (ODYSSEY) showed separation of lines after two years for patients with LDL below 100.
A class of injectable drugs mentioned as showing benefit at about two years in trials and whose oral versions are upcoming.
An anti-amyloid antibody that showed a high correlation between improvement in cognition and reduction in p-tau217.
Mentioned as an example of an FDA-approved drug whose exact mechanism of action is not fully known.
A weak LDL-lowering drug mentioned as being very expensive and difficult to justify its use in clinic due to cost and limited efficacy.
Mentioned as an example of an FDA-approved drug whose exact mechanism of action is not fully known.
The focus of prevention efforts, with a debate on how aggressively it should be prevented, especially in younger individuals.
A causal driver of ASCVD; lowering it early in life is emphasized for primordial prevention, with evidence from genomics suggesting lifelong low LDL prevents heart disease.
A risk factor mentioned, with advanced plaque analysis used to assess its levels, now known to be a causal risk factor.
A method used to establish causality in observational studies, confirming LDL's causal relationship to ASCVD.
A mechanism of action for drugs that transfer cholesterol from HDL to LDL; blocking it raises HDL and lowers LDL, showing promise in cardiovascular and Alzheimer's prevention.
A cholesterol metabolite that can cross the blood-brain barrier, and its levels were reduced in CSF in a pilot study of Obicetrapib, indicating target engagement.
A gene/protein with genomic validation for protecting against Alzheimer's disease (especially in APOE4 carriers) and animal data showing improved cognition, currently being developed into a therapeutic.
Another cholesterol metabolite that can cross the blood-brain barrier, and its levels were reduced in CSF in a pilot study of Obicetrapib, indicating target engagement.
Another tau biomarker for Alzheimer's disease, correlating with amyloid in the brain and predicting disease progression. Obicetrapib improved this biomarker.
A genetic risk factor for Alzheimer's disease, with homozygous E4 carriers having a significantly increased risk and earlier onset. CETP loss of function can mitigate this risk.
A biomarker for Alzheimer's disease, highly correlated with amyloid in the brain and predictive of disease progression. Obicetrapib showed a reduction in p-tau217.
A later-stage inflammatory biomarker for neurodegeneration, which also improved with Obicetrapib.
A newly discovered transporter across the blood-brain barrier specifically for the lysopc form of DHA, crucial for DHA delivery to the brain.
Discussed as a potential tool to revolutionize clinical trials by speeding them up and reducing costs, possibly by analyzing compliance and streamlining data collection.
A biomarker for Alzheimer's disease, the ratio of amyloid-beta peptides 42 to 40, which improved with Obicetrapib treatment.
Used in conjunction with genetic testing to assess an individual's higher risk for conditions like heart disease.
An imaging test that can detect plaque analysis in individuals of appropriate age to assess cardiovascular risk.
A test that measures p-tau217 with a beta 42/40 ratio, used in some biomarker analyses.
An example of a direct-to-consumer model that is starting to change the drug pricing and reimbursement system.
A company for which Michael Davidson is the CEO, manufacturing Obicetrapib, a CETP inhibitor.
Developed Torcetrapib, an early CETP inhibitor, which failed in clinical trials due to serious side effects.
Acquired Obicetrapib but shelved it due to struggles with the launch of Repatha, before New Amsterdam Pharmaceuticals acquired it.
A company that provides the standard assay (Quanterix SIMOA) for p-tau217 measurement.
Owns Liposcience, a company known for its reliable NMR assay for LDLP.
Developed Evacetrapib, a CETP inhibitor, whose trial was stopped early due to corporate financial issues and an early futility analysis.
A company that developed a reliable NMR assay for measuring LDLP, now owned by LabCorp.
A Chinese company that successfully manufactured Klotho, which was previously difficult to produce.
Developed a CETP inhibitor that saved the class by demonstrating LDL lowering and cardiovascular benefit in a large outcome study, despite the drug not making it to market due to pharmacokinetic issues.
A company (presumably a biotech startup) that will be conducting studies with lysopc DHA to demonstrate its transport across the blood-brain barrier.
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