PCSK9 discovery and mechanism

Heart disease is the leading cause of death worldwide, but it’s also one of medicine’s biggest success stories. Since the 1950s, the risk of dying from cardiovascular disease has fallen dramatically, thanks to public health efforts, emergency care, medical innovation, and surgeries.

In this episode, Jacob and Saloni explore the cholesterol revolution: from statins discovered in fungi to new drugs that cut LDL cholesterol by 60% and last for months, driven by breakthroughs in genetics, monoclonal antibodies, RNA therapies, and modern medicinal chemistry. They talk about how cholesterol travels through the bloodstream, how it causes atherosclerosis and heart disease, and why it took nearly a century for scientists to form the consensus that lowering cholesterol saves lives.

Hard Drugs is a podcast from Works in Progress and Coefficient Giving about medical innovation presented by Saloni Dattani and Jacob Trefethen.

You can watch or listen on YouTube, Spotify, or Apple Podcasts.

Chapters: 
0:00:00 Introduction
13:35 The decline in heart disease mortality
31:02 Surprising facts about cholesterol
55:40 The lipid hypothesis: 7 lines of evidence for the harms of LDL cholesterol
1:22:15 How cholesterol works
1:30:40 The discovery of statins
1:48:44 Should everyone be on statins?
1:57:10 PCSK9 drugs and beyond
2:22:56 Summary 

Saloni’s substack newsletter: https://www.scientificdiscovery.dev/

Jacob’s blog: https://blog.jacobtrefethen.com/ 

Acknowledgements:

• Aria Babu, editor at Works in Progress
• Graham Bessellieu, video editor
• Abhishaike Mahajan, cover art
• Atalanta Arden-Miller, art direction
• David Hackett, composer

Works in Progress & Coefficient Giving

Correction: In the episode, Saloni makes an error in converting the number of heartbeats per lifetime. It is roughly 2.5 billion beats, not a trillion.

Books

• Daniel Steinberg (2007) The Cholesterol Wars.
• Jie Jack Li (2009) Triumph of the Heart: The Story of Statins.

Blog posts

• James Stein (2025) Lipid and lipoprotein basics series. https://jamesstein18.substack.com/p/part-i-lipid-and-lipoprotein-basics 

Articles

• Akira Endo (2017) Discovery and Development of Statins https://doi.org/10.1177/1934578X1701200801 
• Joseph L Goldstein, Michael S Brown (2010) History of discovery: The LDL receptor. https://pmc.ncbi.nlm.nih.gov/articles/PMC2740366/ 
• Patty W. Siri-Tarino and Ronald M. Krauss (2016) The early years of lipoprotein research: from discovery to clinical application https://pubmed.ncbi.nlm.nih.gov/27474223/ 
• Eun Ji Kim and Anthony S. Wierzbicki (2020) The history of proprotein convertase subtilisin kexin-9 inhibitors and their role in the treatment of cardiovascular disease https://pubmed.ncbi.nlm.nih.gov/32537117/ 
• Patrick W. Siri-Tarino et al. (2010) Saturated fat, carbohydrate, and cardiovascular disease. https://www.pnas.org/doi/10.1073/pnas.94.9.4312
• Saloni Dattani (2025) Death rates from cardiovascular disease have fallen dramatically — what were the breakthroughs behind this? https://ourworldindata.org/cardiovascular-deaths-decline
• Cholesterol Treatment Trialists’ (CTT) Collaboration (2010) Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. https://doi.org/10.1016/S0140-6736(10)61350-5
• E. J. Mills et al. (2011) Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. https://pubmed.ncbi.nlm.nih.gov/20934984/
• Julia Brandts and Kausik K. Ray (2023) Novel and future lipid-modulating therapies for the prevention of cardiovascular disease.  https://www.nature.com/articles/s41569-023-00860-8

Videos

• Ninja Nerd (2018) Lipoprotein metabolism https://www.youtube.com/watch?v=wQY0xpwqPfQ