Interpreting a lipid profile can be quite daunting. With new studies indicating that total cholesterol values cannot be used alone to understand heart disease risk, how should a lipid profile really be analysed?
What does the Lipid Profile measure?
A standard fasting blood test for lipids includes values for total cholesterol, HDL cholesterol, LDL/VLDL cholesterol, and triglycerides.
Let’s understand what each of these means.
Cholesterol is a fat-like substance that helps build cells and make hormones. It is made in the liver, but we also get it from animal-based foods like meat, eggs, dairy, and poultry. Normally, when dietary cholesterol increases, the liver produces less. This balance works in people with healthy metabolism but may not function properly in people with diabetes or genetic issues. Total cholesterol (TC) increases when either LDL or HDL or both go up.
Triglycerides (TG) are the fats that circulate in the blood and are stored in fat cells.
Lipoproteins are like vehicles that carry triglycerides and cholesterol through the bloodstream. The main types you see in your report are HDL, LDL, and VLDL.
HDL stands for high-density lipoprotein. It’s often called the “good” cholesterol because it carries cholesterol away from your organs and back to the liver for removal. Higher HDL levels are linked to lower heart disease risk. That’s why TC/HDL and LDL/HDL cholesterol ratios are used as important risk indicators.
LDL (low-density lipoprotein) and VLDL (very low-density lipoprotein) mainly deliver cholesterol and triglycerides from the liver to the rest of the body. These are the ones that can get stuck in your arteries and are commonly referred to as “bad” cholesterol.
But before labelling them as bad, it’s essential to understand their structure and how they impact disease risk.
Lipoprotein = lipid + protein
Different types of lipoproteins carry different proportions of triglycerides and cholesterol. VLDL particles carry more triglycerides, while LDL particles carry more cholesterol. In the bloodstream, VLDL eventually becomes LDL.
Particle size
VLDL particles are larger than LDL particles.
People who eat high-carbohydrate diets often have larger, triglyceride-rich VLDL1 particles. People who eat lower carbohydrates and more fat tend to have smaller VLDL2 particles, which contain more cholesterol and less triglyceride. (1)
If triglyceride levels are high, VLDL is more likely to become small, dense LDL. These smaller particles are more likely to clog arteries. (2)
So, when triglycerides are high, the risk of atherosclerosis (plaque build-up) increases. Lower triglycerides are linked with larger, less dangerous LDL particles.
Small, dense LDL is more likely to cause artery damage because it doesn’t bind well to receptors and stays in circulation longer, where it’s prone to oxidation. (14)
In patients with insulin resistance and abdominal obesity, HDL types also change. They tend to have more small, dense HDL (HDL3) and fewer large HDL particles (HDL2). This pattern is associated with progression of cardiovascular disease. Studies show that low HDL2 and high HDL3 levels are linked to higher heart disease risk. (1)
Particle number
The key protein found in VLDL and LDL is called Apolipoprotein B (ApoB or ApoB100).
LDL values in your report show how much cholesterol is being carried (the passenger), not how many particles (the vehicles) are doing the carrying. That’s why it’s considered an indirect risk marker.
ApoB can be measured but is not usually included in routine lipid tests. Research now shows that ApoB is a more accurate way to assess heart disease risk than total cholesterol or LDL alone. It reflects the number of Non-HDL cholesterol in your blood.
ApoB covers LDL, IDL (intermediate-density lipoproteins), VLDL, and Lp (a), because each of these has one ApoB100 molecule. Measuring ApoB gives better predictions of cardiovascular risk.
According to the National Lipid Association, ApoB levels should be below 90 mg/dL for general patients and below 80 mg/dL for those at very high risk. (2)
The more vehicles on the road, the higher the chance of a traffic jam. Having more cholesterol (passengers) isn’t necessarily a problem if there are fewer vehicles to carry it.
Discordance and genetic variants
High triglycerides are often linked with small, dense LDL and high ApoB levels.
But sometimes, people with high triglycerides may have normal ApoB, and vice versa. In such cases, ApoB gives a clearer picture of how many atherogenic particles are in circulation. (15)
In individuals with ApoB mutations, the liver struggles to release VLDL, which may result in fatty liver (steatosis). The type of particles produced depends on the mutation—some produce small particles with low triglycerides, others produce fewer particles but with high triglyceride content. Each results in a different type of abnormal lipid profile. (1)
If your LDL is high but ApoB is normal (called discordance), your risk is likely lower. However, when ApoB is high despite normal LDL, the risk of artery disease goes up. (3)
The Friedewald equation may miscalculate LDL
Most labs use the Friedewald formula to estimate LDL cholesterol. But if triglycerides are very low (like on low-carb diets), this method can overestimate LDL levels.
This was first noticed in a 2001 case, where a person with low TG and high TC had inaccurately high LDL using the formula. Direct measurement gave a lower, more accurate LDL value. (6)
Risk factors that accelerate atherosclerosis
There are many factors that contribute to artery plaque buildup, and LDL is just one of them. In fact, lipid levels during pregnancy may influence heart risk in children. Babies born to mothers with high cholesterol can have fatty streaks in their arteries from birth. (11)
These are major contributors to atherosclerosis:
A. Oxidative stress and inflammation
When LDL gets oxidized, it triggers the build-up of cholesterol inside immune cells (macrophages), forming foam cells that are the start of artery plaque. Normal LDL doesn’t cause this problem unless it’s been modified by oxidation.
Polyunsaturated fats (PUFAs) in LDL oxidize more easily than monounsaturated fats (MUFAs). (12). So the type of fats/oils in the diet matter.
Antioxidants & HDL can help protect LDL.
- Antioxidants in the body like glutathione, uric acid, ferritin, transferrin
- Dietary antioxidants like vitamin E, C, carotenoids, and flavonoids
HDL prevents foam cell formation by promoting cholesterol removal from the macrophage. HDL-associated enzymes like PON-1 and apolipoproteins like ApoA-I and ApoE are also protective.
B. Endothelial (blood vessel wall) injury
Long-term stress on blood vessels (like from high blood pressure or poor lipid control) damages the vessel walls. This allows more LDL particles to stick and penetrate the wall. ApoB-rich particles are especially prone to binding with the artery wall. (13)
Maintaining healthy blood vessel lining is essential to preventing atherosclerosis.
What increases ApoB levels?
ApoB can go up due to:
- Genetics
- Being overweight
- Insulin resistance
- Alcohol
- Poor fat metabolism (2)
Some people have a strong response to saturated fat because of their genes. They may produce more ApoB or more small, dense LDL (phenotype B). (10)
Generally those with high ApoB often consume too many saturated fats and carbohydrates. (3)
When you eat more carbs than needed, your liver converts the extra into triglycerides. This can raise both triglycerides and ApoB—especially if the diet is high in both carbs and fat. (4)
Alcohol has a similar effect.
LDL rises on low-carb/ketogenic diets: Is it bad? This is common and not necessarily harmful.
Cholesterol and ketones are made through related biochemical pathways. It is possible that during ketone production, some cholesterol production is likely to be pushed up. (5)
In low-carb diets, your body increases fat burning and ketone production. This can also lead to a slight increase in cholesterol production.
In athletes who follow low-carb diets with high energy needs, this may increase their circulating cholesterol levels. (5)
However, studies show this increase is mostly in large LDL particles (LDL1), which are less harmful. Small, dense LDL and ApoB don’t change much. (2)
Also, both HDL and total cholesterol may go up on keto diets, but the LDL/HDL ratio improves, which lowers heart risk. Saturated fat is known to increase LDL and HDL.
Overall, HDL increases and triglycerides decrease, while LDL may increase slightly or stay the same. The LDL particles become larger, and the number of particles often goes down. (2)
All good things!
A groundbreaking prospective study showed that LDL was not associated with heart disease or plaque progression in a subset of 100 people known as Lean Mass Hyper-Responders. They were following the ketogenic diet for at least 2 years with an average LDL level above 200 mg/dl. Imaging studies like the CT angiogram and calcium score were done at baseline and 1 year later.
Who are Lean Mass Hyper-Responders?
These are individuals who may have higher LDL levels after following a ketogenic diet but they are metabolically healthy based on factors like higher HDL, and lower triglycerides.
Typically these individuals lose total body fat on the diet, specially visceral fat and have lower insulin levels, maintaining their lean mass.
The proposed mechanism called the lipid energy model. (16)
On the ketogenic diet, when fat stores are mobilised and fat burning is enhanced in the liver, triglycerides reduce with higher HDL levels and larger sized LDL particles as explained above.
Who’s the real culprit—saturated fat or carbohydrates?
In most people, reducing saturated fat doesn’t reduce small LDL particles.
Did you know that the saturated fat you eat is not the exactly the same saturated fat in your blood circulation? It tends to track more closely with dietary carbohydrate intake. (7)
Recent evidence shows that circulating saturated fats (especially even-chain types like palmitate) are linked with higher disease risk, but these levels are more influenced by carbohydrate intake than by eating saturated fat. (7)
Carbohydrates, especially from sources like alcohol, sugary drinks, and starchy foods, increase blood levels of these fats. In contrast, foods like meat and butter have less of this impact. (8)
Switching to a high-carb, low-fat diet may lower LDL but it increases triglycerides, ApoB and may also lower HDL. (3)
All bad things!
Diet-heart hypothesis
The belief that saturated fat causes heart disease by raising cholesterol is known as the diet-heart hypothesis. It’s been around for over 60 years.
Most public health guidelines still recommend reducing saturated fat to protect heart health.
But in the past decade, many independent scientific reviews have found no clear link between saturated fat and heart attacks, strokes, or death. (17)
The PURE study followed people from 18 countries over 7 years. It found no connection between saturated fat and heart risk. In fact, it showed:
- Lower total deaths
- Lower stroke risk
- Better outcomes in people eating more saturated fat
Other studies and reviews since 2010 support these findings. (9)
Takeaway
Testing for Apo B, calculating ratios such as TC/HDL(Castelli Risk Index-I), LDL/HDL(Castelli Risk Index-II), TG/HDL, the atherogenic index and coefficient (Non HDL/HDL) may be better ways to assess risk while interpreting the lipid profile.
Total cholesterol and LDL levels cannot measure your risk alone. If the physician is still worried about your levels, you may benefit from cardiac imaging before dismissing the diet and/or considering statin therapy.
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