The Peter Attia Drive

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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
More.
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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.
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We discuss:
Why thyroid management is unusually complex and what the thyroid does [2:00];
Why symptoms are insufficient for diagnosis and the risks of underdiagnosis and overtreatment [9:00];
Regulation of the thyroid axis and conversion of T4 to T3 [13:30];
Reverse T3 and the metabolic effects of T3 [20:00];
Thyroid blood tests, assay limitations, and who should be tested [22:45];
Causes and mimics of hypothyroidism and the criteria for diagnosis [29:00];
Navigating subclinical hypothyroidism [34:30];
Treating hypothyroidism with T4 and T3 [37:00];
Hashimoto's disease, pregnancy, and associated autoimmune risks [42:45];
Proper timing and administration of thyroid medication [43:45];
Causes, symptoms, diagnosis, and treatment of hyperthyroidism [45:15];
Iodine excess, the risks of thyroid-support supplements, and evidence for dietary interventions [53:45];
A practical framework for evaluating and treating patients who suspect thyroid dysfunction [59:30]; and
More.
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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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