No 96: Why is Luther causing me Statin troubles?

Jan 01, 2025

Welcome to 2025!

This year, I am going to write 25 posts (one of my resolutions) and this is the start. They will be shorter, more precise and hopefully, more “readable”.

Why oh, why am I writing about statins again?

Mainly, because there is something there still niggling at me, I just feel like there are bits of the jigsaw puzzle missing.

My biases: I love eating steak and butter. I don’t like the idea that eating fat, raises your cholesterol and increases your risk of dying of a heart attack. I know we are supposed to be rational, but I can’t give up steak. I think this is probably why I dislike the whole cholesterol-statin issue. But bare with me…

No 90: The History of Diets and The Fat Heretics

No 85: using ChaptGPT to summarise Statins

No 51 - Statins - all you need to know

No 78 - A Timeline of General Practice and EBM: In Much More Detail

No 77 - The Art and Science of UK GP: A Historical Timeline

No 37 - My plan for learning the history of modern medications

No 36 - Searching for the ideal history of EBM and medications

What has Martin Luther got to do with statins, EBM and Grok?

A good question you might ask, and my second blog in a row with a religious figure (‘tis the season).

I have spent about 2.5 days this holiday reading about statins. I then tried to compile and “summarise” this reading list into a BlueSky Thread on Statin Studies.

Searching PubMed revealed over 70k papers that mention statins, >8k trials and >14k reviews. Obviously, I have not been able to read them all.

Evidence based medicine (EBM) was supposed to provide all clinicians with the skills and mindset to be able to go to the primary literature and work out if a particular treatment would work for the patient they were treating.

This was a glorious idea, but it was always going to be too lofty a goal for the overwhelmed front line clinician. So, institutions developed guidelines. These institutions found experts, who read “all” of the literature, discussed it, debated it, summarised it and presented it in an easy to use fashion for everyone else.

This “institutional-EBM” model worked relatively well, while there was trust in the institutions and trust in the experts.

However, Like the medieval Catholic church, it became possible to buy your way into heaven. Big pharma soon realised that if they funded the research, funded the Universities and the professors and the senior consultants, and the hospitals and the regulatory bodies, and the patient groups and the guideline committees. Then, it was possible to massage the guidelines in a way that meant more of their medications could be prescribed.

Martin Luther (Spectator article) is famous for his desire to rid the church of corruption. He believed that if the common people could read and understand the bible, then the teachings of the church would have to revert to their fundamentalist message and it would remove the power from the people within the church.

This belief in the lay man being able to read, analyse, debate and discuss the literature is still a core part of EBM. Occasionally, you need someone to read the guidance with scepticism and then go to the primary literature. And just like Martin Luther, sometimes this can be seen as an attack on authority and career damaging. Many clinicians who have questioned the efficacy of statins have cut their careers short or had to defend their position in court: No 90: The History of Diets and The Fat Heretics and Dr Malcom Kendrick's Libel Case Against The Mail on Sunday 2024.

I thought that there are 4 ways to approach this issue:

Just trust the institutions and follow the guidelines (When was Big Pharma ever wrong? Big Pharma - hardly ever).
Talk to an expert and ask them to list all of the major studies.
Ask Grok and Google and ChatGPT to summarise the evidence and list the key studies.
Go to PubMed and trawl the literature and list the key studies.

Below are a number of Grok answers for questions about statins and their mortality benefit:

Some of the answers are better than others and the good thing, is that Grok references each statement. This was really handy for deciding where to start on PubMed.

However, Grok seems to have a capped capacity of 25 sources when used in the free version. The problem with not being an expert, is you don’t necessarily know what is missing, but most of these answers feel like they are missing something.

Using Grok, as a start, I then went to PubMed and BlueSky to map and list what I found (BlueSky Thread on Statin Studies).

The Key Statin Studies:

WOSCOPS (West of Scotland Coronary Prevention Study), JUPITER, KAPS, ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial - Lipid-Lowering Arm), AFCAPS/TexCAPS, ASTEROID, AVIATOR, CTT Collaborators, ALLHAT-LLT, MEGA, Framingham Heart Study, The St Francies Heart Study, Treat to new Targets (TNT) study, PROVE-IT TIMI, REVERSAL trial, CARDS, ORION, HOPE, IMPROVE-IT, PolyPars, TIPs-3, EURIKA, STAREE, CorCal, The BMJ review on endpoint postponement.

https://bsky.app/profile/jakemat91.bsky.social/post/3lekg2fdk4224

https://bsky.app/profile/jakemat91.bsky.social/post/3leltp2y5hk2z

https://bsky.app/profile/jakemat91.bsky.social/post/3lelwisa3o22s

https://www.cochrane.org/CD004816/VASC_statins-primary-prevention-cardiovascular-disease

Each of the above studies has been referenced in the thread links above, and most of these studies has published multiple papers.

As a geek interested in EBM and the history of medicine, for me this was very satisfying. Like stamp collecting. However, unless someone funds me to do a PhD on this topic, there is probably no way that I would be able to read and analyse all of these in depth to the degree required to really be an expert on the data.

However, I would recommend that students and clinicians interested in EBM and statins, should start with these key papers first and then dive deeper in the literature.

Conclusion

A couple of thoughts that I will hopefully come back to one day:

These studies, seem to suggest there is no benefit of a statin over the age of 75 or when someone has less than 3 years to live. Should we be stopping these statins at age 75 in primary care?

Most of these studies range from 1 to 7 years, yet we start a statin with the aim of someone continuing it preferably for 2 decades or more. Should we stop them after 5 years?

WOSCOPS claims that 5 years of statin treatment had benefits that last 20 years. So, again, should we stop at 5 years or continue?

Most of these trials focus on western men age 45 to 75. Most of the main are nearer to 60. Significant numbers in the trials have diabetes and smoke. In each trial, hundreds die within the 2 year trial period (give or take a few years). But life expectancy in most western countries is >80. So, are the people dying in these trials “normal” people?

Almost all of the papers I read through reported a significant reduction in MACE (heart attacks + other stuff) but only a few reported an all-cause mortality benefit that was significant. So, are these statins really prolonging life in most people?

Why do we not screen people for raised CRP, raised trops and BNP? Many of these studies report that primary prevention was more beneficial in people with these raised biomarkers, than in people with raised LDL alone. But, we don’t do these tests? We also don’t do CAC scans on people, yet many of these studies suggest that statins are more beneficial in people with a raised CAC score and almost of no use in a patient with a 0 CAC score.

Statins seem to reduce LDL by 20% to 50%. They reduce markers of inflammation in some studies by a similar amount. They reduce MACE by 10-20% and all-cause mortality less than this. Inclisiran also reduces LDL by a large percentage but doesn’t seem to reduce all-cause mortality by much. To me, this suggests that other factors in the multi-factorial process are probably more important than the LDL. For example, blood sugar levels (diabetic status), smoking, genetics (family history), pollutants, infections, blood pressure etc.

Last point, there are a large number of “whistle blowers” who have pushed back on the cholesterol-hypothesis and statin efficacy. Most of these people seem to be frontline staff or scientists, not associated with pharma companies. We know the cholesterol hypothesis was based on data by Ancel Keys that was “massaged” to put it bluntly. So, on one side you have Big Pharma, mountains of studies and reviews and evidence. On the other side you have lone-wolf critics with cherry-picked studies. And yet, I still don’t know if I am fully persuaded either way.

STAREE and CorCal are ongoing studies and I found a few others with less catchy titles that are looking into statin prescribing in older populations and the more frail. I look forward to seeing their results. I really hope they do improve the mortality and quality of life for these patients.

As always, thank you for reading and I look forward to hearing your thoughts.

MediCurious

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