The Lipid Hypothesis
Total cholesterol (total-C) was one of earliest risk factors identified for coronary heart disease (CHD) and formed the basis of the lipid hypothesis, which is that “measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease” . Later research identified the total-C:HDL-C ratio to be the measure of blood lipids most predictive of CHD, being twice as informative as total-C* . With this information the original lipid hypothesis should be modified to ‘measures used to lower the plasma total-C:HDL-C ratio in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease’. Or simply put, a hypothesis that in a population: ↓ total-C:HDL-C >> ↓ CHD
* It really shouldn’t be surprising that total-C is far from being the most predictive of CHD, as total-C includes HDL-C which is inversely associated with CHD
** Using the total-C:HDL-C ratio or non-HDL-C:HDL-C ratio avoids the issues of (1) calculating LDL-C; and (2) ignoring cholesterol in other Apo B containing lipoproteins such as IDL and VLDL
The Diet Heart Hypothesis
The lipid hypothesis logically led to figuring out how to reduce cholesterol* through diet and drugs as a means of reducing CHD. The fatty acid composition of the diet was identified early as having a major influence on cholesterol and led to the Keys equation**, which predicted the change in total-C based on changes in SFA and PUFA intake .
The knowledge that dietary factors affect cholesterol levels led to the diet heart hypothesis (or diet heart question as it’s sometimes called ), which takes many forms***, but the one driven by Keys and more commonly tested in future clinical trials is that: by reducing cholesterol, decreasing intake of SFA and increasing intake of PUFA (higher PUFA:SFA ratio) would be expected to reduce CHD.
When cholestyramine (a cholesterol lowering drug – bile acid sequestrant) first appeared successful in clinical trials for CHD the results were often generalised to cholesterol lowering diets and used evidence in support of the diet heart hypothesis. But the results shouldn’t be generalised to another drug, yet alone a dietary interventions   . Each target of the lipid hypothesis has to be tested in its own right.
Fortunately there has been further research on the diet heart hypothesis: associations between intakes of SFA, MUFA and PUFA with CHD have been explored in many observational studies and the diet heart hypothesis has been tested in several clinical trials, although often quite poorly.
* Different people will use total-C, LDL-C or total-C:HDL-C, etc
** Δ total-C (mg/dl) = 2.74 Δ SFA (%) – 1.31 Δ PUFA (%). Note that dietary cholesterol isn’t considered a factor in the equation “Such low-fat diets usually contain less cholesterol and animal proteins, but the change in the serum-cholesterol level in man does not depend on this fact” 
*** May also include total fat and/or dietary cholesterol, but neither of these originated from Keys.
**** The diet heart hypothesis was initially about total-C because that’s all that could be measured. This explains why MUFA wasn’t a factor in the Keys equation because even though MUFA also reduces LDL-C and total-C:HDL-C, it doesn’t reduce total-C . With the total-C:HDL-C ratio being the most predictive measure of blood lipids for CHD, the diet heart hypothesis should be concerned with total-C:HDL-C rather than total-C
A Problem with Mechanisms
The diet heart hypothesis is not an unreasonable hypothesis, but like any other hypothesis it needs to be tested. Relying on mechanisms or risk factors as surrogate measures of CHD (or other hard endpoints) is a leap of faith that the incidence of CHD will be consistent in that direction. Unfortunately the majority the conventional dietary advice stops there, simply stating that SFA increases LDL-C and that higher LDL-C increases the risk of CHD, then either implying or just outright saying ‘therefore SFA increases the risk CHD’.
For the above to be correct it assumes either that ‘SFA only increases LDL-C*’ or that ‘LDL-C is the only risk factor for CHD’. However, SFA, PUFA, etc may affect the incidence of CHD independent of cholesterol for better or worse, and without testing you wouldn’t know. There are good examples where the results of clinical trials were contrary to risk factors and mechanisms:
- Carnitine increases TMAO and TMAO is associated with CHD , but carnitine supplementation reduces CHD events and total mortality  (post)
- CETP increases total-C:HDL-C, but torcetrapib, a CETP inhibitor, significantly increased CHD events and total mortality in clinical trials 
So far the discussion has been on the effects of single nutrients/chemicals, but it gets more complex when discussing food as food is comprised of many nutrients and other chemicals, that each has their own effects, not to mention nutrient interactions. For example: does meat increase CHD because of SFA (or something else like Neu5gc), or decrease CHD due to carnitine? This isn't to say that mechanisms and risk factors are useless. It's just that it's important to test things and not make assumptions
* Whether it’s LDL-C or total-C:HDL-C, etc the point is still the same. I originally used LDL-C in this section because most conventional dietary advice focusses on LDL-C
** See Just Kale Me
** See Just Kale Me
A Problem with Blood Lipids
A further problem with relying on blood lipids as risk factors is that reducing cholesterol may reduce CHD events and CHD mortality, but may not reduce total mortality. For example, a meta-analysis found the relationship between total-C and total mortality followed a U-shaped curve such that both high and low total-C was associated with higher total mortality . That being said, there are probably many confounding variables in this type of research, such as low total-C being the result of disease or statin use in secondary prevention. But it’s important to remember that cholesterol has many beneficial functions and lowering cholesterol too far will probably impair some of those functions.
* Cholesterol is essential to life, but this fact shouldn’t be used as an argument that it’s not capable of promoting pathology. For example: SOCS3 is essential to life but is one of the major signalling molecules responsible for leptin resistance.