Low-carb diets like keto have surged in popularity, fueling stories of weight loss and offering relief for various health struggles. However, a high-fat, low-carb approach can sometimes lead to elevated LDL cholesterol levels, raising concerns about heart health. This article delves into the fascinating world of Lean Mass Hyperresponders (LMHRs), a group whose cholesterol reacts uniquely to ketogenic diets.
LMHRs, typically lean individuals, exhibit extreme cholesterol responses to low-carb diets, sometimes seeing LDL levels skyrocket. Yet, their lipid profiles often present a paradox: high LDL coupled with high HDL and low triglycerides. What explains this intriguing phenomenon? We’ll explore the science behind LMHRs, examining the research and insights that shed light on this distinctive metabolic response.
This article will cover the definition of LMHRs, predictors of LDL spikes, self-dietary experiments that revealed surprising insights, the Lipid Energy Model (LEM), and the Keto trial that examines the cardiovascular risk that comes with high LDL in LMHRs.
Who are Lean Mass Hyper Responders?
The term “lean mass hyperresponders” was coined by Dave Feldman, following his own experience with skyrocketing LDL cholesterol on a ketogenic diet. He noticed that despite the elevated LDL, his other health markers remained favorable, and genetic testing ruled out familial hypercholesterolemia.
Feldman’s experience wasn’t isolated. Studies have shown that normal-weight individuals on low-carb, high-fat diets often experience similar LDL spikes, ranging from 5% to over 100%. Even ultra-endurance athletes, known for their metabolic health, are not immune. In 2020, Feldman launched the “Cholesterol Super Survey,” gathering data from 903 participants to identify others with similar experiences.
His analysis revealed a trend: LDL surges were most pronounced in lean and physically fit individuals consuming an average of 27 grams of carbohydrates daily. This led him to propose the LMHR criteria: LDL ≥ 200 mg/dL (5.17 mmol/L), HDL ≥ 80 mg/dL (2.07 mmol/L), and triglycerides ≤ 70 mg/dL (0.79 mmol/L).
Feldman’s work gained the attention of Nicholas G. Norwitz, who also identified as an LMHR. Together with other researchers, they formally characterized the LMHR phenotype in a 2021 study titled “Elevated LDL Cholesterol with a Carbohydrate-Restricted Diet: Evidence for a ‘Lean Mass Hyper-Responder’ Phenotype.”
What Predicts LDL Spikes on Low-Carb Diets?
Norwitz and his team analyzed Feldman’s dataset to identify factors driving LDL increases. They found two key predictors:
- Body Mass Index (BMI): Individuals with a BMI under 26 kg/m^2 experienced the largest LDL spikes.
- Triglyceride-to-HDL Ratio (TG/HDL): A lower TG/HDL ratio before starting the diet was linked to more dramatic LDL elevations.
Participants with the lowest BMI and TG/HDL ratios saw median LDL increases of 135 mg/dL, compared to just 35 mg/dL in those with higher ratios.
The results of this study suggest that a large elevation in LDL cholesterol on a [low-carb diet] is more likely to occur in people who are lean and metabolically healthy. Low TG/HDL cholesterol ratio prior to consumption of a current [low-carb diet] and low BMI were strongly associated with a larger LDL cholesterol increase.
Essentially, being lean and metabolically healthy (low triglycerides and high HDL at baseline) predisposes individuals to significant LDL responses on low-carb diets.
Self-dietary experiments, surprising insights
Feldman and Norwitz, both LMHRs, conducted self-experiments to understand how dietary tweaks impacted their cholesterol levels. Their meticulous experiments yielded counterintuitive insights:
- Calorie deficits raised LDL, calorie surplus lowers it: Feldman found that cutting calories on a low-carb diet sent his LDL soaring, while a calorie surplus brought it down.
- Saturated fats didn’t raise LDLs more than unsaturated fats: One LMHR subject saw lower LDL levels on a diet emphasizing saturated fats compared to one rich in unsaturated fats.
- Carbs reintroduction outperforms statins in LDL reduction: Norwitz’s LDL plummeted by 71% in just 16 days by adding 12 Oreos to his daily diet, a more significant reduction than he achieved with six months on statins.
These findings suggest that LMHRs may have unique metabolic dynamics compared to individuals on conventional diets. Drawing on these insights, Norwitz and colleagues proposed the Lipid Energy Model (LEM) to explain the unique lipid patterns observed in this group.
The Lipid Energy Model
The LEM posits that when carbohydrates are scarce, the body relies on fat for energy, impacting the lipid transport system and leading to the distinctive LMHR lipid profile (↑ LDL, ↑ HDL, ↓ triglycerides).
From fats to fuel and the lipid transport system
Dietary fats are broken down into fatty acids, bundled into triglycerides, and packaged into lipoproteins for transport through the lymphatic system and bloodstream.
As lipoproteins circulate, enzymes break down triglycerides to release fatty acids, which muscles use for fuel. Excess fatty acids are stored in fat cells for later use.
Very low-density lipoproteins (VLDLs) transport triglycerides from the liver. As they circulate and offload triglycerides, they transform into low-density lipoproteins (LDLs), which are remnants with mostly cholesterol. High-density lipoproteins (HDLs) remove excess cholesterol from the bloodstream and facilitate triglyceride metabolism.
How LEM connects the dots
The LEM explains that when the body relies on fat for fuel, the liver takes up more fatty acids, produces more triglycerides, and releases them through VLDLs. This leads to higher LDL (as VLDLs convert to LDLs), higher HDL (to facilitate surface component transfer), and lower triglycerides (due to rapid breakdown for energy).
This effect may be most pronounced in lean, insulin-sensitive individuals with high energy demands due to greater metabolic flexibility. Norwitz et al. suggest this distinctive lipid profile may be an adaptive response to prolonged low-carb diets. This begs the question: does high LDL cholesterol in LMHRs signal cardiovascular danger?
The Keto trial
The 2024 study, “Carbohydrate Restriction-Induced Elevations in LDL-Cholesterol and Atherosclerosis,” sought to answer whether the distinctive lipid profile of LMHRs signals cardiovascular danger.
The study compared 80 participants on long-term low-carb diets (average 4.7 years) with LMHR lipid profiles to a matched cohort from the Miami Heart (MiHeart) study, which had significantly lower LDL levels. Coronary artery plaque was assessed using Coronary Artery Calcium (CAC) scoring and Coronary Computed Tomography Angiography (CCTA).
Despite significantly higher LDL cholesterol levels in the KETO group (mean LDL of 272 ± 91 mg/dL vs. 123 ± 38 mg/dL in the MiHeart group), more than half (55%) of KETO participants had a CAC score of 0, indicating no detectable calcified plaque. None displayed signs of total plaque accumulation or significant artery narrowing.
The study concluded that coronary plaque in metabolically healthy individuals with carbohydrate-restriction-induced LDL-C ≥190 mg/dL is not greater than in a matched cohort with much lower LDL-C levels.
In essence, high LDL cholesterol wasn’t associated with more arterial plaque buildup in metabolically healthy individuals following a long-term low-carb diet, compared to peers with lower LDL levels.
Limitations
It’s important to acknowledge the limitations of LMHR research:
- Small Sample Size
Most LMHR studies have been based on small observational studies. The “Keto Trial,” while the largest to date, only included 80 LMHR individuals. Small sample sizes limit generalizability and statistical power, making it harder to identify trends and confirm the reliability of results. For example, the “Keto Trial” consisted of 90% of Caucasian subjects. So, we can’t be certain whether LMHR phenotypes manifest similarly across different ethnicities or genetic backgrounds.
- Weak study design
Despite its name, “the keto trial” is not a clinical trial but a cross-sectional study, which only collects data at one point in time. Atherosclerosis takes time to develop, so long-term tracking is needed to assess the long-term health effects of LMHR lipid profiles.
- Potential Confounders
Most LMHR studies haven’t accounted for crucial factors like genetics, dietary composition (e.g., saturated vs. unsaturated fats), exercise habits, and overall health behaviors, which can independently influence cholesterol levels and health outcomes. If such differences aren’t accounted for, it becomes difficult to determine whether the LMHR phenotype itself is responsible for the observed outcomes or if other factors are at play.
Putting things into perspective
Lean Mass Hyper-Responders (LMHRs) are individuals whose LDL cholesterol levels spike significantly after adopting a low-carb diet, accompanied by high HDL and low triglycerides. This may be an adaptive response to prolonged carbohydrate restriction in lean, metabolically healthy individuals with high energy demands.
While the concept is intriguing, the current evidence is insufficient to confirm the existence of LMHRs as a distinct group with unique metabolic traits. One key limitation of existing LMHR studies is the failure to account for critical factors like genetics, the type of fats consumed (saturated vs. unsaturated), exercise habits, and overall health behaviors.
Further questions linger about the health implications of this phenomenon. Does elevated LDL in LMHRs carry long-term cardiovascular risks? Or is it a benign byproduct of metabolic adaptation?
Ultimately, even if LMHRs represent a rare metabolic phenotype, adaptation does not automatically mean safety. More robust research is needed to clarify whether this metabolic pattern is harmless or poses long-term risks.