We talk less of paradigms in science and medicine than we did in the 1990s. Then a ‘paradigm shift’ was a phrase not uncommonly heard in a time of rapidly changing tech and science. Think of the advent of mobile phones, personal computers, the internet and the world wide web to get a sense of what was to come.
AI is generating that same sense of change thirty years on, but this post is about the 1990s cholesterol-busting drugs called statins and the drugs which followed them. These were remedies for cardiovascular diseases that came to rule many lives over the following decades. People knew their cholesterol blood levels with numbers as familiar as their house’s street number. For instance one may hear ‘mine’s 5.5 or 7’ or whatever. Such words would not be unusual to hear at a middle class dinner party. And so a cardiovascular paradigm was born, a paradigm which is now deeply embedded into the medical profession and the general population alike. A paradigm which is collapsing.
Also in the nineties I regularly taught a class on scientific method. Classics like Karl Popper’s Conjectures and Refutations 1963; The Structure of Scientific Revolutions 1962 by Thomas S Kuhn and Paul Feyeraband’s 1975 Against Method: Outline of an Anarchistic Theory of Knowledge were foundations of the class. What has really stuck in my mind though was Kuhn’s description of the life of a prevailing scientific paradigm
He asserted that no amount of Popper-esque refutation (e.g. by experimental ‘disproof’) can unseat a powerful embedded way of looking at things, a paradigm. Instead, competing paradigms grow according to the ‘weight of confirmation’ or fade under the ‘weight of disproof’. This is illogical but as he points out we don’t live in a clean cut Popper scientific logical world of conjecture, test, refute ( or not), repeat. Life, even in science, is messier.
The point I am heading towards is that the long lived cholesterol paradigm has had its glory days of ‘confirmations’ and under the weight of refutations is fading. To the medical profession who crave scientific validation this is a sad blow as their cardiovascular remedies default to basic empiricism … if it produces a good result it’s in, otherwise it’s out.
Below is a summary of this paradigm's story.
The Beginning
Arterial plaques are fatty cholesterol-rich deposits which can block arteries and may rupture. They increase with age and start early in life. Some unfortunate individuals produce a lot of cholesterol and have extremely high blood levels of cholesterol lipoproteins and unfortunately also have massive plaque deposition. They usually died young … until the advent of miracle statin drugs which blocked cholesterol synthesis and saved their lives.
The ‘paradigm’ really gets started when these statin drugs were applied to a wider population of people with high but not pathological levels of cholesterol. And behold, in the newly formed wake of ‘big data’, positive health outcomes were evident at the population level. And so statin prescription became widespread and millions, no billions, of dollars were poured into the field of lipidology and a lot of knowledge was accumulated.
Not just Cholesterol but ‘Good’ and ‘Bad Cholesterol
It came to pass that the cholesterol-laden lipoproteins were sub-classified according to their density (how big the fatty-droplet bit was) broadly, low-density (big) and high density (small) droplets. We know these as LDL and HDL (the former are large and the latter smaller). LDL is usually ‘bad cholesterol’ and HDL ‘good cholesterol’ to help the public relate to their respective levels.
Actually these droplets circulating in the blood exist in a spectrum of sizes but only the small HDL droplets can penetrate the blood brain barrier and the brain needs a lot of cholesterol to function! Worries about reducing available cholesterol to the brain during a global epidemic of dementia meant a new Holy Grail: the trick would be to make drugs that lowered bad cholesterol and kept decent levels of good cholesterol, maybe even boost it!
At about the same time a very-bad cholesterol containing very low density lipoprotein called LPa was discovered. Billions of dollars later, drugs are developed to boost good cholesterol and others to lower bad cholesterol, and lately even to greatly reduce very-bad cholesterol(LPa). Daily, lifetime-medication with its associated profit beckoned and by the way cardiovascular disease was to be defeated.
The paradigm unravels
As the reader may have guessed some nasty shocks were coming.
Firstly, in first line ( i.e. well run, large and validated) medical trials, drugs which boosted good cholesterol whilst lowering bad cholesterol made no improvements in cardiovascular outcomes. The drugs were withdrawn not least due to unfortunate side effects.
Secondly, and shockingly to the scientists involved, lowering very bad cholesterol (LPa) which the industry was convinced was causal for plaque formation, had absolutely no effect on cardiovascular outcomes.
Finally, an awkward epidemiological fact was emerging. It is called the ‘cholesterol paradox’. For people under sixty, lower levels of cholesterol in the blood, especially the bad cholesterol (LDL) and the very bad cholesterol ( LPa) do associate with what the medical profession call a protective effect. But, above 65 yrs old, in the 64-74 group and for all of the octo- and nonagenarians the opposite is true. Low bad cholesterol is strongly associated with poor cardiovascular outcomes and vice versa. You may need to read this again.
The end of an era.
So it’s over. Drugs to prevent cardiovascular disease are now only judged on one criterion: ‘do they work?’. Gone are the mad metrics of your cholesterol numbers; gone are the theoretical scientific assumptions underpinning medical research in this area and gone is the confidence of big pharma. All that is left is a ‘suck it and see’ strategy.
It’s devastating for the scientists whose careers have been built on these sands and schadenfreude for the biochemists who were baffled from the start at the claims of the medical industry. I take some comfort though in being privileged to witness Kuhn’s philosophy of science actually happening in my own era.
Hopefully this news will trickle down to the GPs but as with all paradigms says Kuhn, they never actually disappear.
