The Peter Attia Drive

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Michael Davidson is a world-renowned cardiologist, lipidologist, and the founding CEO of NewAmsterdam Pharma. He begins this episode by sharing how his family history shaped his interest in lipidology and primary prevention. He explains why prevention should focus on causal drivers of disease rather than near-term risk and examines the causal relationship between LDL and atherosclerotic cardiovascular disease. Michael then traces the complicated history of CETP inhibitors—from the original rationale that raising HDL would reduce cardiovascular risk to the failures of torcetrapib, dalcetrapib, and evacetrapib—and explains how lessons from these trials ultimately led to the development of obicetrapib. He reviews the phase 2 and phase 3 trials of obicetrapib, its effects on LDL-C, apoB, LDL particle number, and Lp(a), the ongoing cardiovascular outcomes trial, and where the drug could fit alongside statins and other lipid-lowering therapies. Peter and Michael discuss the relationship between statins and diabetes risk, then turn to the potential role of obicetrapib in Alzheimer's disease prevention, exploring the genetics of APOE4 and CETP, cholesterol metabolism within the brain, and emerging biomarker data. Finally, Peter and Michael explore the benefits of omega-3 fatty acids and the challenge of delivering DHA to the brain, as well as ongoing work on klotho in preparation for clinical trials. They discuss the potential for AI to transform clinical trials and the scientific and financial challenges of developing new therapies for cardiovascular and neurodegenerative disease.
We discuss:
Michael's path to lipidology, and his passion for primary prevention [3:30];
Reframing prevention around causal drivers rather than time horizon [9:30];
What CETP inhibition does, the evolutionary biology of CETP, the HDL-raising rationale, and Pfizer's torcetrapib failure [15:00];
Why raising HDL is thought to be beneficial, a quick review of the functions of HDL, and how this connects to torcetrapib [24:00];
The graveyard of CETP inhibitors: Roche's dalcetrapib, Lilly's evacetrapib, and Merck's REVEAL trial [27:15];
The causality of LDL in cardiovascular disease [34:30];
Reviving obicetrapib at NewAmsterdam, and confirming the benefit is LDL lowering: the TULIP data, the abandoned statin-intolerance path, and the Mendelian randomization verdict on HDL [37:30];
Phase 2 and phase 3 trials of obicetrapib—ROSE, BROOKLYN, BROADWAY, and TANDEM—and the PREVAIL outcomes trial, with the European and US approval paths [44:45];
Discordance among LDL-C, LDL-P, and apoB with CETP inhibition, and obicetrapib's Lp(a)-lowering effect [50:30];
Where obicetrapib fits in the lipid-lowering toolkit, the case against high-dose statins, and the problem of drug pricing [57:30];
The case for obicetrapib in Alzheimer's: the APOE4 and CETP genetics, the animal models, and funding Alzheimer's research [1:03:45];
Brain cholesterol metabolism and the APOE4 mechanism: the blood-brain barrier, astrocyte cholesterol efflux, the amyloid-tau cascade, the role of HDL, and why statins don't cause Alzheimer's disease [1:08:00];
The biomarker evidence: the CSF pilot study, Alzheimer's as a disease of middle age, the pharma graveyard problem, and the p-tau 217 results from BROADWAY [1:17:45];
Whether obicetrapib translates into clinical benefit for Alzheimer's disease: the risk of fooling yourself, the persistence of the amyloid dogma, ARIA in APOE4 homozygotes, and the next prevention trial [1:28:00];
Fish oil, EPA, and DHA: the cardiovascular trials and the challenge of delivering DHA to the brain [1:32:00];
Two open problems: using AI to reform clinical trials, and the statin–diabetes signal [1:41:15];
What it takes to develop a drug, the biotech investment landscape, and the klotho program [1:48:15];
Closing reflections: what to do if you carry APOE4, balancing motivation against over-testing, and the need for multiple therapies [1:55:15]; and
More.
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In this "Ask Me Anything" (AMA) episode, Peter delves into the critical subject of blood pressure, which is one of the three primary causes of atherosclerosis, along with high apoB and smoking. He begins by unraveling the nature of high blood pressure, its prevalence, and why it often goes undiagnosed. Peter describes in detail the proper way to accurately measure blood pressure and what determines a diagnosis. Next, Peter discusses the actionable steps one can take in response to high blood pressure, shedding light on the extent to which factors like weight loss, exercise, and nutrition can make an impact. He also explores the pharmacological options available and offers valuable insights on how to approach them.
We discuss:
Blood pressure and other risk factors for cardiovascular disease [2:30];
Defining blood pressure and the purpose and meaning of a blood pressure measurement [5:45];
The implications of high blood pressure and the importance of maintaining an optimal level [10:30];
The importance of accurate measurements of blood pressure and how Peter approaches the care of patients at the very top range of "normal" [21:45];
The prevalence of high blood pressure—a hidden epidemic? [24:30];
The consequences of high blood pressure on cardiovascular health, brain health, kidneys, and more [24:45];
Low blood pressure: symptoms and consequences [35:30];
How to properly measure blood pressure [37:45];
Daily variance in blood pressure and the transient changes in blood pressure during exercise [48:00];
Primary hypertension vs. secondary hypertension: what to look for [51:45];
Lifestyle factors impacting blood pressure: weight loss, exercise, and sodium [57:45];
Impact of insulin resistance and type 2 diabetes on blood pressure [1:04:45];
How sleep impacts blood pressure [1:06:45];
Pharmacologic options for managing blood pressure [1:08:00]; and
More.
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Brian Grosberg is a world-renowned headache specialist who joins Peter to provide a master class on the diagnosis and treatment of headache disorders. In this episode, Brian explains the distinction between primary and secondary headaches and breaks down the defining features of the "big three" primary headache types (migraine, cluster, and tension headache)—highlighting how often they are misdiagnosed and how they are treated. He explores the epidemiology of headaches, describing migraine as an invisible disease affecting about 12% of the population, disproportionately affecting women, while cluster headaches more often affect men. He discusses the major gap between demand for headache care and available specialists, and he offers advice on when to see a physician. Brian dives into the multifactorial nature and pathophysiology of migraine, including genetic and hormonal influences, neurovascular changes, and inflammatory signaling, and connects these mechanisms to modern therapies. Throughout the conversation, he emphasizes the individualized nature of headache disorders and the importance of a detailed headache diary. Brian shares practical strategies for treating headaches including lifestyle changes, medications, and neuromodulation devices.
We discuss:
Brian's interest in headaches and how Peter met Brian [2:15];
Differentiating the types of headaches: primary versus secondary headache and tension versus migraine headache [7:30];
The epidemiology and burden of migraine, its disproportionate affect on women, and the shortage of headache specialists [20:00];
Genetic susceptibility to migraine and the role of hormones [24:45];
Migraine triggers, the impact of hormones, and the importance of a headache diary [31:15];
The phases of a migraine: premonitory symptoms, aura, the headache itself, and the postdrome [38:15];
Tension headaches: symptoms, causes, and prevalence [41:45];
Cluster headaches: extreme pain, distinctive symptoms, and frequent misdiagnosis as a sinus infection or allergies [43:15];
Lifestyle interventions to prevent headaches [51:15];
Pharmacological treatments to prevent headaches [1:05:00];
What's known about the pathophysiology of migraines: neurovascular changes, release of neuropeptides, and inflammatory response [1:14:45];
CGRP antagonists for the treatment of migraines: large monoclonal antibodies and gepants [1:20:15];
Use of calcium channel blockers and Botox to treat cluster headache and migraine [1:28:30];
Drugs for the acute treatment of migraines [1:32:30];
Treatment of migraines with electrical stimulation devices [1:40:00];
Use of THC or cannabis to treat headaches [1:44:00];
What Brian wants people to know about headaches [1:45:45];
Brian's advice on when to see a doctor about headaches and how to prepare for that visit [1:49:15]; and
More.
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In this "Ask Me Anything" (AMA) episode, Peter takes a deep dive into the liver and its central role in metabolic health. He explains why the liver can serve as a "canary in the coal mine" for metabolic dysfunction and explores how insulin resistance, visceral fat, alcohol consumption, genetics, and hormones contribute to liver disease, along with how increasing muscle mass can benefit liver health. Peter provides a framework for understanding the progression of liver disease, highlighting which stages are reversible and why early detection matters. He explains why normal liver enzymes can provide false reassurance, which labs he uses to assess liver health, and the tools available for detecting fibrosis and more advanced disease. Peter then breaks down the interventions that can meaningfully improve liver health once risk or disease is identified, ranging from diet and exercise to GLP-1–based therapies and other medications. Finally, he examines popular claims around liver "detoxification" and supplements, separating what is supported by evidence from what is unlikely to meaningfully improve liver health.
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We discuss:
Why the liver is the "canary in the coal mine" for metabolic dysfunction, and an overview of what the liver does [2:00];
The relationship between the liver and blood sugar control [6:30];
A framework for understanding how metabolic disease affects the liver [9:15];
Chronic caloric surplus and insulin resistance as drivers of liver disease [11:00];
Liver diseases that result from metabolic dysfunction and the difference between steatosis and fibrosis [15:15];
How visceral fat affects liver health [20:00];
The importance of lifestyle interventions for liver and metabolic health: resistance training, not drinking calories, and the impact of fructose [22:00];
Why alcohol-associated liver disease is more common than we give it credit for [26:30];
Genetic and hormonal risks for liver disease [31:45];
Labs that objectively measure liver health and the FIB-4 score [35:30];
FibroScan: non-invasive imaging of the liver [44:30];
The resiliency of the liver: an organ that can heal itself [47:00];
Fibrosis staging and its impact on mortality and cancer risk [49:15];
Interventions for someone with MASLD: weight loss and GLP-1s [52:00];
Other medications used to treat metabolic liver disease [57:00];
The role of exercise in treating metabolic liver disease: caloric deficit and building muscle [59:45];
The myth of liver detoxes and cleanses, and a few supplements that may benefit the liver [1:01:15];
A practical summary: how to assess your risk and the levers that reverse the disease [1:08:00]; and
More.
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In this episode, Peter sits down with Dr. Linus Abrams, a psychiatrist with nearly 35 years of clinical experience specializing in mood disorders and psychopharmacology, to explore how our understanding of mental health is evolving beyond the traditional neurotransmitter model. After decades in practice, Linus began questioning many of the assumptions underlying modern psychiatry, leading him to investigate how hormones, metabolism, inflammation, circadian biology, and the endocrine system shape mood and cognition. Together, Peter and Linus examine why psychiatric care should aim not only to reduce symptoms but also to restore the full human experience. They discuss how psychiatric medications work, where they fall short, and why distinguishing bipolar disorder from unipolar depression is essential for effective treatment. The conversation also explores the growing mental health burden of social isolationn associated with digital devices and social media, along with the biological factors—nutrition, exercise, sleep, and chronic stress—that influence resilience and distress tolerance. Linus explains the powerful roles of estrogen, progesterone, testosterone, and thyroid hormone in regulating mood and cognition across the lifespan. Finally, Peter and Linus review the promise and limitations of ketamine and psychedelic therapies, and why the future of psychiatry may lie in integrating neuroscience, endocrinology, and whole-body physiology to better understand, diagnose, and treat mental illness.
We discuss:
Linus's passion for understanding his patients and going beyond traditional psychiatry [2:45];
A short primer on the different classes of drugs used in psychiatry [12:45];
Evaluation of a patient with bipolar disorder [26:00];
An evolutionary perspective on depression [33:30];
Changes in the modern world triggering mental health problems [41:00];
An evolutionary perspective on insomnia [48:15];
Peter's window analogy to understand distress tolerance and irritability [49:45];
The impact of foundational biological factors on psychiatry: nutrition, exercise, sleep, and endocrinology [52:30];
The effect of estradiol on neurotransmitters in the brain [58:15];
Options for increasing testosterone in men, and why clomiphene is inferior to exogenous testosterone [1:11:00];
The rapid drop in progesterone is linked to both premenstrual dysphoric disorder (PMDD) and postpartum depression [1:14:30];
Treatment of postpartum depression [1:18:00];
Hypothyroidism presenting as depression: how Linus makes the diagnosis and what he uses for treatment [1:26:00];
The link between hyperarousal and chronically elevated cortisol [1:39:30];
A case where the menopause transition uncovers bipolar disorder [1:44:15];
Ketamine as a tool to treat recalcitrant depression, and concerns about its recreational use [1:49:15];
Case study: an Alzheimer's patient who improved after psilocybin, and why Linus is cautious about drawing conclusions from it [1:55:15];
Peter's experience with psychedelics, and the myth that estrogen is bad for men [2:00:30];
The therapeutic potential of psychedelics in psychiatry [2:11:00]; and
More.
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