Dietary guidelines continue to recommend restricting intake of saturated fats. This recommendation is based largely on the observation that saturated fats can raise levels of TC, thereby putatively increasing the risk of CHD.

TC matters less for CHD than how cholesterol is packaged into transport particles. LDL is one class of transport particles, with different implications for CHD depending on particle size and density.

Small-dense LDL is more susceptible to oxidation and is pro-atherogenic,19, 20, 21 pro- thrombotic,22–25 and pro-inflammatory.26 Conversely large buoyant LDL is resistant to oxidation and my even be anti-atherogenic.144

Eating saturated fat can decreases small-dense LDL and increases large buoyant LDL.30

But saturated fat is a diverse class of compounds, with different implications for lipid profiles and CHD risk depending on the type of fatty acids the fats contains. The SFA, palmitate, raises levels of LDL; the SFA, stearate, does not. Stearate and laurate reduce the TC/HDLratio.33

Importantly, people eat foods, not isolated fatty acids, and the mix of fatty acids and other food components matters. Some food sources of SFAs may increase the risk of CHD (e.g., processed meats) but other may have no effect or even decrease the risk (e.g. dairy foods).

Meta-analyses of randomized trials do not demonstrate a clear role for saturated fat in increasing all-cause mortality or CHD mortality.97, 99

Saturated fats have played some role in the human diet for the last 2.6 million years. Conversely, added sugars have only played a significant role in the last few hundred years. In the modern era of ultra-processed foods, dietary sources of saturated fats are also often dietary sources of sugar.

When sugar replace saturated fats, the result can be unfavorable effects on lipid profiles: TC tends to increase,40, 41 HDL tends to drop12,42, 43 and triglycerides tend to rise12,45, 46

High sugar diets are associated with impaired glucose tolerance, insulin resistance, elevated uric acid level, and altered platelet function47, 52–54—abnormalities that can be reversed when reverting to a diet low in sugar.54, 55

Sugar-related hyperglycemia is associated with pro-inflammatory and prothrombotic glycated LDL, and sugar-related hyperinsulinemia is associated with smooth muscle cell proliferation,56–58 lipogenesis,59 dyslipidemia,60 inflammation, oxidative stress, and increased platelet adhesiveness.61–63

Some sugars may be more problematic than others with regard to CHD risk: fructose, and fructose-containing sweeteners (e.g. sucrose or high-fructose corn syrup) may present greater risk for CHD than glucose (alone or as starch).55, 64, 74 Fructose, as compared to glucose, increases oxidized low-density lipoprotein (oxLDL);74 which likely leads to endothelial cell dysfunction/apoptosis, foam cell formation, abnormal vascular tone and blood flow, inflammation, increased cell adhesion molecule expression, pro-clotting, and increased intracellular oxidative stress.75 Additionally, fructose increases the levels of advanced glycation end products76, 77—which, may lead to dysfunctional macrophages entering the arterial wall and contribute to atherosclerosis.78 Oxidative stress, reactive oxygen species forming in the heart and aorta, and lipid peroxidation may also play a role in fructose-induced adverse cardiac effects.79, 80

Feeding sucrose to rats causes the development of atheroma, the degree to which depends on the amount of sucrose (not fat) in the diet.91 Humans that develop ischemic heart disease have been found to eat more sugar, not more fat.138

Sugar seems to act as both a predisposing factor for heart disease (e.g. through inflammatory, thrombotic, oxidative, and hormonal pathways), and a precipitating factor (e.g. through an increase in myocardial oxygen demand, cardiac sympathetic nerve activity, and platelet adhesiveness).47, 89, 90

Replacing saturated fats with sugars increases the risk of non-fatal MI 108, 109 A diet high in added sugars has been found to cause a 3-fold increased risk of death due to cardiovascular disease.135

Dietary guidelines should shift focus away from reducing saturated fat, and from replacing saturated fat with carbohydrates, especially when these carbohydrates are refined. To reduce the burden of CHD, guidelines should focus particularly on reducing intake of concentrated sugars, specifically the fructose-containing sugars added by industry like sucrose and high-fructose corn syrup.