Expert insight on health, performance, longevity, critical thinking, and pursuing excellence. Dr. Peter Attia (Stanford/Hopkins/NIH-trained MD) talks with leaders in their fields.
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#409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles behind bringing new medicines to patients | Lloyd Klickstein, M.D., Ph.D.
Lloyd B. Klickstein is a physician-scientist who has spent more than 20 years at the intersection of drug discovery, healthy aging, and preventive medicine. Drawing on his experience in academic medicine, translational research, and biotechnology, Lloyd walks through the full arc of modern drug development. He explains how scientists identify an unmet medical need and decide which diseases and therapeutic targets are worth pursuing. From there, he takes us through the process of engineering a drug, testing it in animals, and navigating clinical trials and regulatory approval. Using bimagrumab as a case study, Lloyd explains the rationale for targeting myostatin and activin signaling to increase muscle mass and strength and describes how the antibody was engineered and screened. He then walks through what was learned from early clinical trials. Unexpected effects on fat mass and type 2 diabetes helped reshape bimagrumab's development as a potential treatment for obesity, including its use in combination with semaglutide. Along the way, Peter and Lloyd explore the differences among drug modalities, including biologics and small-molecule therapeutics. They discuss the roles of patents and capital allocation in drug development, along with the requirements for IND submission and GMP manufacturing. They also examine why developing a new drug takes so long and costs so much, and why identifying failures early is critical. At the end of the episode, the conversation turns to mTOR inhibition and geroprotection, as well as Lloyd's current work on a novel pharmacologic approach to cancer prevention. This episode provides a rare behind-the-scenes look at how new medicines are actually created and the scientific, regulatory, and economic decisions that determine which ideas ultimately make it to patients.
We discuss:
Lloyd's path from academic medicine to translational drug development [3:15];
Drug modalities, patents, and the economics of innovation [11:30];
Choosing sarcopenia as a target for drug development, and confronting the problem of measuring falls [23:00];
The rationale for bimagrumab: improving muscle mass and strength by targeting myostatin and activin signaling (and why follistatin failed) [36:45];
Engineering and screening the bimagrumab antibody, and the cost of developing a new drug [43:45];
From candidate antibodies to animal proof of concept (impressive muscle hypertrophy) [54:15];
Toxicology, capital allocation, and the path to an IND [1:02:45];
IND requirements, GMP manufacturing, and gray market peptides [1:14:45];
First in-human study design, patient selection, and protection of healthy volunteers [1:22:00];
Phase 1 dosing, pharmacodynamics, and global trial strategy [1:33:45];
Phase 2 lessons on muscle mass, function, and nutrition [1:43:30];
Bimagrumab's effects on fat mass and type 2 diabetes [1:50:45];
The BELIEVE trial of bimagrumab plus semaglutide [1:59:30];
Selective mTORC1 inhibition and the challenge of testing geroprotection [2:11:45];
A new pharmacologic approach to cancer prevention [2:15:45]; and
In this "Ask Me Anything" (AMA) episode, Peter takes a deep dive into thyroid health and explains why diagnosing and managing thyroid dysfunction is unusually complex. He begins with the basic biology of the thyroid gland and three commonly measured hormones—free T4, free T3, and TSH. He explains how T4 is converted to the active hormone T3 and the important functions T3 performs throughout the body. He also explains what reverse T3 is and when it may be useful to measure it. Peter then breaks down thyroid blood tests and their limitations and provides a practical framework for evaluating suspected thyroid dysfunction. He explains why symptoms alone are insufficient for diagnosis and reviews the criteria for diagnosing hypothyroidism, along with conditions that can mimic it. He also explores how hypothyroidism can be both underdiagnosed and overtreated and how to navigate subclinical hypothyroidism. Peter discusses treatment with T4 and T3, including why some patients continue to experience symptoms despite standard T4 replacement. He also explains how thyroid medications should be taken to optimize absorption. Additional topics include Hashimoto's disease, thyroid considerations during pregnancy, hyperthyroidism, the risks of excess iodine, and supplements marketed to support thyroid function. Finally, Peter offers guidance for patients who continue to feel unwell despite apparently normal thyroid tests.
If you're not a subscriber and are listening on a podcast player, you'll only be able to hear a preview of the AMA. If you're a subscriber, you can now listen to this full episode on your or our website at the . If you are not a subscriber, you can learn more about the subscriber benefits .
#407 ‒ Preventing cardiovascular and Alzheimer's disease: lowering LDL early, APOE4, and promising new therapies | Michael Davidson, M.D.
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.
Blood pressure: how to measure, manage, and treat high blood pressure (AMA #48 rebroadcast)
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];
#406 ‒ Migraine, cluster headache, and tension headache: symptoms, causes, prevention, and treatment | Brian Grosberg, M.D.
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];
#405 ‒ AMA #88: Metabolic liver health: how to assess risk, catch dysfunction early, and prevent or reverse liver disease
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.
If you're not a subscriber and are listening on a podcast player, you'll only be able to hear a preview of the AMA. If you're a subscriber, you can now listen to this full episode on your private RSS feed or our website at the . If you are not a subscriber, you can learn more about the subscriber benefits .
#404 ‒ Mental health beyond neurotransmitters: the role of hormones in psychiatry, why symptom reduction isn't enough, and the future of psychedelic therapies | Linus Abrams, M.D.
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.
#403 ‒ Peptides: separating scientific promise from marketing hype
In this episode, Peter returns to the topic of peptides, offering a clear and accessible guide to a field surrounded by both genuine scientific promise and widespread misinformation. Peptides are increasingly marketed for everything from injury recovery and muscle growth to longevity and improved appearance, often with claims that extend far beyond the available evidence. Rather than promoting or dismissing peptides as a category, Peter presents a practical framework for evaluating any peptide: what it is, how it is supposed to work, and where the science is strong, weak, or simply absent. He then applies this framework to a specific example before examining the risks of gray-market products, concerns about sourcing and quality, and where the field may be headed—ultimately helping listeners distinguish legitimate therapies from hope that has been packaged and sold without sufficient evidence.
We discuss:
What peptides are and why they must be evaluated individually [3:15];
A five-question framework for evaluating peptides and other drugs [5:30];
A three-tier system for classifying the scientific evidence behind peptides [10:00];
Evaluating BPC-157: unclear mechanisms, absent human evidence, and unknown risks [14:00];
Why BPC-157's expanding claims do not indicate a broad mechanism [20:45];
CJC-1295: biological activity versus meaningful clinical benefit [23:30];
#402 ‒ NMR blood analysis: how heart disease risk, insulin resistance, inflammation, and mortality risk can be assessed from a single blood sample | Jim Otvos, Ph.D.
Jim Otvos is a biophysical chemist who pioneered the use of nuclear magnetic resonance (NMR) spectroscopy to measure lipoprotein particles and developed the first FDA-cleared method for directly quantifying LDL particle number (LDL-P), a technology that has since expanded to provide broader insights into metabolic health, inflammation, insulin resistance, and mortality risk. In this episode, Jim recounts the unlikely story of transforming a flawed cancer test into a new way of measuring lipoproteins, explains what standard cholesterol tests can miss and why LDL-P and apoB can inform treatment decisions beyond LDL cholesterol alone, and dispels the misconception that large, "fluffy" LDL particles are benign. He also explores how NMR can reveal insulin resistance before blood sugar rises, GlycA as a marker of chronic low-grade inflammation, and the metabolic vulnerability index (MVX) as a potential measure of frailty, resilience, and mortality risk across the lifespan. Finally, Jim explains why NMR diagnostics remain underused despite the wealth of information they can extract from a single blood test.
We discuss:
How investigating a flawed 1986 cancer test led to the development of NMR (nuclear magnetic resonance) lipoprotein testing [3:30];
How standard lipid panels measure cholesterol and triglycerides, and why LDL cholesterol is estimated rather than directly measured [15:15];
#401 ‒ How curiosity transforms medicine: extraordinary discoveries that changed modern healthcare
In this episode of The Drive, Peter explores how seemingly obscure basic science discoveries have laid the foundation for some of the most important medical breakthroughs of the past half century. Rather than focusing on the clinical applications of modern therapies, he traces the fascinating stories behind the scientists, experiments, and unexpected discoveries that ultimately led to transformative drug classes, revealing how groundbreaking advances often emerge from research with no obvious clinical goal. Through these historical case studies, Peter provides a new perspective on the unpredictable path of medical innovation and makes the case for why investing in basic scientific research remains essential for driving the next generation of life-changing therapies.
We discuss:
The discovery of green fluorescent protein (GFP): how curiosity about glowing jellyfish transformed modern biology [2:30];
Why basic research and nature's biological innovations are the foundation of medical progress [10:45];
The discovery of statins: how fungi provided the blueprint for cholesterol-lowering drugs [15:15];
From snake venom to ACE inhibitors: the discovery of a cornerstone therapy for cardiovascular disease [21:00];
From Yellowstone hot springs to PCR: how Thermus aquaticus transformed modern biology and medicine [28:00];
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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
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
How NMR spectroscopy measures lipoprotein particle size and concentration [20:30];
Why LDL particle number matters more than particle size, and why large, "fluffy" LDL is not benign [28:45];
Discordance between LDL cholesterol and LDL particle number: which measure better reflects cardiovascular risk? [36:30];
How metabolic syndrome and lipid-lowering treatment contribute to the discordance between LDL-C and LDL-P, and the value of particle number for managing risk [45:30];
Using the NMR-derived LP-IR score to detect insulin resistance and predict type 2 diabetes before glucose rises [51:15];
The development, commercialization, and uncertain future of the Vantera NMR Analyzer and NMR-based diagnostics [1:04:45];
The analytical efficiency of NMR testing and the data-driven development of the Metabolic
Vulnerability Index (MVX) [1:16:00];
GlycA as an NMR-derived marker of systemic inflammation: its discovery, biological basis, and advantages over hs-CRP [1:25:45];
Developing the Metabolic Vulnerability Index (MVX): biomarkers of inflammation, malnutrition, muscle wasting, and mortality risk [1:34:00];
What MVX can tell us about longevity and mortality [1:44:15];
How MVX may reveal metabolic frailty and predict premature mortality decades in advance in young, healthy adults [1:50:30];
Potential applications of MVX for predicting treatment response, surgical resilience, and clinical trial outcomes, and the barriers to broader use [2:00:00];
ApoB versus LDL-P: their clinical similarities, the additional information provided by NMR, and barriers to broader adoption [2:07:30];
Interpreting the effects of the CETP inhibitor, obicetrapib, on LDL-P, apoB, and small HDL particles [2:13:00];
The future of NMR diagnostics and MVX: translating scientific potential into broader clinical use [2:20:45]; and
