The guide

The story of cholesterol, from rabbits to the 2026 guideline

By GyroscopeUpdated November 15, 202622 sources

The idea that cholesterol causes heart disease took a century to prove, and it was nearly dropped more than once. Rabbits came first, then whole towns and countries, then a mold from a Kyoto rice shop, then a pair of Texas doctors who found the liver’s drain, then families with broken genes. Here it is in order, with what each step taught us.

A century, step by step

1. 1910 and 1913: the rabbitsAdolf Windaus found that plaques in human arteries held more than 20 times the cholesterol of healthy artery walls. Three years later the Russian pathologist Nikolai Anitschkow fed pure cholesterol to rabbits, and their arteries filled with plaque, the first time anyone had made atherosclerosis happen on purpose. Most people ignored him for decades.What we learned: cholesterol can build plaque, at least in an animal.
2. 1961: FraminghamThe US National Heart Institute followed the people of Framingham, Massachusetts. In 1961 William Kannel and colleagues reported that people with higher cholesterol at their first exam had more heart attacks in the years after, and so did people who smoked or had high blood pressure.What we learned: in people, higher cholesterol goes with more heart attacks, and it isn’t the only thing that does.
3. 1950s to 1970: Keys and the diet-heart ideaAncel Keys, a physiologist at the University of Minnesota, measured how diet changed blood cholesterol and then started the Seven Countries Study, following about 15,000 middle-aged men. Heart attacks rose in step with average cholesterol from country to country, and countries that ate more saturated fat had higher cholesterol and, 25 years on, more heart deaths.What we learned: whole populations with higher cholesterol had more heart disease, and diet moved cholesterol. Comparing countries can’t prove cause, which is why the argument didn’t end there.
4. 1972: the shortcutWilliam Friedewald and two colleagues published a formula to work out LDL from total cholesterol, HDL and triglycerides. Labs still use it.What we learned: how to get an LDL number cheaply, with errors that grow when triglycerides are high.
5. 1972 to 1987: a mold from KyotoIn the summer of 1972, Akira Endo’s team at the Japanese company Sankyo found a blue-green mold, from a rice sample bought at a grain shop in Kyoto, that blocked the body’s cholesterol factory. Its compound, compactin, was the first statin. Merck’s lovastatin became the first statin on sale in the US in September 1987.What we learned: you could switch off most of the body’s own cholesterol making with a pill.
6. 1985: the drainMichael Brown and Joseph Goldstein in Dallas found the LDL receptor, the doorway that pulls LDL out of the blood into cells, by studying people with familial hypercholesterolemia, whose receptors were missing or broken. They won the Nobel Prize in 1985.What we learned: why LDL builds up, and how a drug could lower it, by making the liver put out more receptors.
7. 1994: 4SIn the Scandinavian Simvastatin Survival Study, 4,444 people with heart disease got simvastatin or a placebo. LDL fell 35%, and over about five years 8% died on the statin against 12% on placebo.What we learned: lowering cholesterol with a drug saves lives, which settled the main argument of the 1980s.
8. 2003 and 2006: PCSK9Researchers led by Marianne Abifadel found mutations in a gene called PCSK9 that cause very high LDL. Three years later, Jonathan Cohen and Helen Hobbs found people with broken copies of the same gene, with LDL 28% lower all their lives and 88% less heart disease.What we learned: lower LDL for a lifetime protects far more than lowering it later, and PCSK9 was a target for a new drug.
9. 2007 to 2012: the HDL detourIf LDL was bad, HDL had to be good, so companies set out to raise it. Torcetrapib raised HDL 72% and killed more people than placebo. Niacin raised HDL and didn’t help in AIM-HIGH. A 2012 genetic study found that genes raising HDL didn’t lower heart attacks, while genes raising LDL did raise them.What we learned: a number linked to risk isn’t always the cause. HDL is a marker, and raising it doesn’t help.
10. 2010 and 2012: the doseThe Cholesterol Treatment Trialists pooled 26 statin trials and about 170,000 people. Each 39 mg/dL off LDL cut major events by about a fifth. A 2012 genetic study of 312,321 people found the same drop held from early life gave about three times that protection.What we learned: the benefit follows the size of the drop and the years it lasts.
11. 2015: ezetimibeIMPROVE-IT added ezetimibe, which blocks cholesterol in the gut, to a statin after heart attacks. LDL went from 70 to 54 and events fell 2 percentage points over 7 years.What we learned: lowering LDL helps even by a route other than statins, and lower than the old goals still helps.
12. 2016: the recovered diet trialsChristopher Ramsden and colleagues dug out unpublished data from the Minnesota Coronary Experiment of 1968 to 1973. Corn oil in place of animal fat lowered cholesterol 13.8% and didn’t lower deaths.What we learned: swapping in one kind of vegetable oil isn’t proven to save lives, and leaving trials unpublished distorts what we think we know.
13. 2017: PCSK9 drugs and the consensusIn FOURIER, the PCSK9 drug evolocumab took LDL from 92 to 30 on top of a statin and cut the main events 15%. The same year the European Atherosclerosis Society reviewed over 200 studies and 2 million people and concluded that LDL causes atherosclerosis.What we learned: very low LDL is safe and protective, and the causal question was settled for most researchers.
14. 2019: particles, not cholesterolA genetic study of 654,783 people found that what counted was the number of ApoB particles, whether genes lowered triglycerides or LDL.What we learned: ApoB is the sharper measure of what causes plaque.
15. 2026: goals come back, and Lp(a) is testedIn March the new US guideline brought back LDL goals, swapped in the PREVENT risk calculator and asked every adult to test Lp(a) once. In November, Lp(a)HORIZON found that cutting Lp(a) 78% with pelacarsen didn’t cut heart events in people with heart disease.What we learned: the LDL story is settled enough to set goals, and Lp(a) is still an open question.

What the story says about today

The cholesterol idea survived because it kept passing harder tests. It started with animals and populations, which can’t prove cause, and ended with genes, which are handed out at random at conception, and trials, which hand out treatment at random. HDL looked just as good in the population studies and failed both of the harder tests.

The skeptics have been right about some things. Old diet trials were left unpublished, and HDL-raising drugs were a costly mistake. Does LDL really matter? weighs their best arguments against the model, and the 10 studies that shape our view ranks the evidence.