Rethinking LDL-Cholesterol: Is Lower Always Better for Heart Health?

For years, low-density lipoprotein cholesterol (LDL-C) has been considered the main culprit in heart disease. The common belief is that high levels of LDL-C clog up arteries, leading to heart attacks and strokes. This idea has driven medical experts to focus on lowering LDL-C as much as possible, often using medications like statins.

However, as I’ve mentioned in previous articles, LDL-C is not always the reliable marker it’s made out to be (1,2).  Recent research, including a study published last autumn in the Journal of the American College of Cardiology (JACC), supports this evolving perspective, especially in people following ketogenic diets (3).

Some people on ketogenic diets, known as Lean Mass Hyper-Responders (LMHRs), often see a substantial increase in their LDL-C levels, which can cause considerable concern. As a result, the LMHR trait has become a hot topic among experts, drawing significant interest in the health and nutrition community. There’s even a dedicated Facebook group with over 13,000 members where individuals share their experiences and explore the latest insights about this unique profile.

What the JACC Study Revealed

The JACC study specifically examined LMHRs—individuals who experience substantial increases in LDL-C, sometimes doubling or more, when following a high-fat, low-carbohydrate diet. Despite these elevated LDL-C levels, the study found no significant increase in markers of atherosclerosis, such as coronary artery calcium scores or coronary plaque burden.

This disconnect between LDL-C levels and actual measures of atherosclerosis suggests that high LDL-C may not always be as harmful as traditionally thought. This may be especially true within the context of a ketogenic diet that improves other metabolic parameters, such as HDL cholesterol, triglycerides, and markers of inflammation. These findings challenge the simplistic narrative that elevated LDL-C invariably leads to increased cardiovascular risk.

Revisiting LDL-C: Not All Increases Are Equal  

LDL-C is commonly referred to as “bad cholesterol” due to its association with an increased risk of atherosclerotic heart disease (4). Traditionally, LDL particles are thought to infiltrate the arterial wall, oxidize, and trigger inflammation, leading to plaque formation. This view has been reinforced by numerous studies linking high LDL-C to cardiovascular events, supporting the widespread practice of lowering LDL-C as much as possible. However, as I’ve pointed out before, this approach oversimplifies the complex role of LDL-C and overlooks important nuances, such as the variation in LDL particle size and type.

LMHRs often see an increase in larger, buoyant LDL particles, which are considered less atherogenic compared to smaller, denser LDL particles more closely linked to cardiovascular risk. Therefore, not all LDL elevations carry the same implications for heart health, suggesting that focusing solely on LDL-C levels may be an incomplete and sometimes misleading approach.

The Ketogenic Diet and LMHRs: A Contradictory Case 

The ketogenic diet, characterized by high fat, moderate protein, and very low carbohydrate intake, has gained popularity for its benefits in weight loss, blood sugar control, and overall metabolic health. Despite the fact that LMHRs experience significant increases in LDL-C when on this diet, the JACC study and similar research indicate that these increases do not necessarily translate into greater atherosclerosis risk.

The observation that LMHRs do not show increased levels of coronary artery calcium or other arterial plaque markers calls into question the reliability of LDL-C as a universal predictor of cardiovascular disease, particularly in unique metabolic situations like those seen with a ketogenic diet. Moreover, even with elevated LDL-C levels, LMHRs often display favorable cardiovascular markers, such as high HDL-C and low triglycerides, which suggest a lower cardiovascular risk than might be expected. (5).

The Flaws in Calculated LDL-C as a Marker 

Calculated LDL-C, usually derived using the Friedewald equation, is a standard measure in clinical practice but has significant limitations. It can be inaccurate in individuals with high triglycerides or low LDL-C levels and does not account for differences in LDL particle size, density, or number—factors crucial to assessing cardiovascular risk.

Moreover, LDL-C calculations do not differentiate between small, dense LDL particles, which are more prone to oxidation and more atherogenic, and larger, buoyant particles that are less harmful. This lack of specificity can lead to misleading conclusions about an individual’s cardiovascular risk, particularly in those with atypical lipid profiles, such as LMHRs on ketogenic diets. I’ve highlighted these flaws before, as relying solely on LDL-C can give a skewed picture of true cardiovascular risk.

Critiquing the “Lower is Always Better”

The assumption that lowering LDL-C is universally beneficial has driven much of the current approach to cardiovascular risk management. This perspective is largely influenced by studies showing that statins, which lower LDL-C, reduce cardiovascular events. However, the benefits of statins may stem from their anti-inflammatory effects and other mechanisms, not solely from LDL-C reduction. This suggests that the link between LDL-C and heart disease is more complex than sometimes suggested by medical experts.

Focusing on LDL-C reduction without considering other factors like inflammation, insulin resistance, and overall metabolic health could overlook key drivers of cardiovascular disease. For instance, ketogenic diets are known to improve insulin sensitivity and reduce systemic inflammation, both critical factors in cardiovascular risk.

Understanding the Gap: A Need for a More Nuanced Approach

The findings from the JACC study highlight a significant gap in our understanding of LDL-C’s role in cardiovascular health. They challenge the conventional wisdom that LDL-C must always be lowered and suggest that a more nuanced approach is necessary. Future research should focus on the quality of LDL particles, their context within broader metabolic health, and the interaction between various other risk factors.

Supporting this broader perspective, Nordestgaard and Varbo (2014) emphasized that cardiovascular risk cannot be fully captured by LDL-C levels alone without considering other factors such as triglycerides and HDL-C. They argue for a comprehensive approach to lipid assessment, reinforcing the idea that focusing solely on LDL-C can lead to over-treatment or misinterpretation of risk, particularly in individuals with unique metabolic profiles like LMHRs (6).

The JACC study and similar research bring to light several critical questions about the relationship between LDL-C and cardiovascular health:

1. Are All LDL Particles Created Equal?
   LDL particles vary in size, density, and composition. Smaller, denser LDL particles are considered more atherogenic than larger, buoyant ones because they are more likely to penetrate the arterial wall and become oxidized (7). Hyper responders to ketogenic diets often have an increase in larger, less dense LDL particles, which may be less harmful than smaller particles. This distinction in LDL particle types is vital, as not all LDL elevations pose the same atherogenic risk.
2. The Role of Inflammation and Insulin Sensitivity
   A critical aspect of atherosclerosis is not merely the presence of LDL-C, but the inflammatory response it induces. The ketogenic diet has been shown to reduce systemic inflammation and improve insulin sensitivity, both of which are key factors in atherosclerosis development (8). Hyper-responders on ketogenic diets may benefit from these anti-inflammatory effects, potentially offsetting the risks associated with elevated LDL-C levels. This raises the question of whether the metabolic context in which LDL-C rises matters more than the LDL-C levels themselves.
3. Genetic and Lifestyle Factors
   Genetic predisposition plays a significant role in how individuals respond to diets, including ketogenic diets. Some-hyper responders may have genetic variants that influence LDL particle size, cholesterol metabolism, or other factors that protect against atherosclerosis despite high LDL-C levels. Additionally, lifestyle factors like exercise, smoking, and overall diet quality can significantly impact cardiovascular risk, independent of LDL-C levels.

Conclusion