The Lean Mass Hyper-responder Phenotype: Paradoxical Lipid Response to Low-Carbohydrate Diets

Introduction

The Lean Mass Hyper-responder (LMHR) phenomenon represents one of the most intriguing paradoxes in modern nutritional science. When lean, metabolically healthy individuals adopt low-carbohydrate or ketogenic diets, some develop a striking pattern of elevated LDL cholesterol, alongside protective markers such as high HDL cholesterol and very low triglycerides. This unique lipid profile challenges conventional cardiovascular risk assessment and has sparked significant scientific debate.

The Lipid Energy Model suggests this response may reflect an adaptive metabolic state rather than pathology, with the body efficiently transporting fat-based energy through the bloodstream when carbohydrates are restricted. Current research using advanced coronary imaging techniques has yielded conflicting interpretations about cardiovascular implications, creating uncertainty for clinicians and patients.

This comprehensive analysis explores the science behind this dietary response, examines emerging evidence, and offers practical considerations for those experiencing or studying this distinctive metabolic adaptation.

Overview of Carbohydrate-Restricted Diets (CRDs)

Carbohydrate-restricted diets (CRDs), including a wide range of approaches of very-low-carbohydrate diets (VLCDs) and ketogenic diets (KDs), have gained considerable attention and popularity. KDs typically restrict carbohydrate intake to less than 25–50 grams per day, inducing a metabolic state known as nutritional ketosis (read more about ketosis in The Biohacker's Guide to Ketosis).(1) These dietary strategies are used for various health objectives, including weight management, improving type 2 diabetes, and treating certain chronic conditions, such as epilepsy, where ketogenic diets have been used for over a century.(2) Emerging research also explores their potential therapeutic benefits for a broader range of neurological and mental health disorders, such as Alzheimer's disease, Parkinson's disease, and mood disorders.(3)

Despite their potential benefits, CRDs are associated with markedly varied effects on plasma lipid profiles, particularly Low-Density Lipoprotein Cholesterol (LDL-C).(4) While LDL-C is widely recognized as an essential risk factor for atherosclerotic cardiovascular disease (ASCVD), its response to a carbohydrate-restricted diet is notably heterogeneous. Some studies report significant or even extreme elevations in LDL-C following the adoption of a CRD. Conversely, other investigations show no clinically meaningful increases or even reductions in LDL-C levels. Interestingly, based on the latest meta-analysis (2025) on CRDs and dyslipidemia, CRDs significantly enhance lipid profiles and contribute to weight management in individuals with dyslipidemia.(5)

This observed heterogeneity appears to be linked to the baseline characteristics of individuals who adopt the diet. Many studies demonstrating minor or no significant increases in LDL-C have involved participants with preexisting conditions such as obesity, metabolic syndrome, or type 2 diabetes. These conditions are often associated with an adverse metabolic profile characterized by insulin resistance, typically including low High-Density Lipoprotein Cholesterol (HDL-C) and high triglycerides (TG), a pattern known as atherogenic dyslipidemia.(6)

For instance, a non-randomized study involving patients with type 2 diabetes on a very low-calorie diet (VLCD) reported only a modest mean increase in LDL-C of 11 mg/dL after two years.(7) Similarly, an isocaloric substitution of fat for carbohydrates in participants with obesity and metabolic syndrome did not raise LDL-C even with increased saturated fat intake.(8)

In striking contrast, studies involving lean, metabolically healthy individuals have reported substantial elevations in LDL-C upon adopting CRDs. An observational study comparing keto-adapted ultra-endurance runners who habitually consumed low-carbohydrate (10% of calories) versus high-carbohydrate (57% of calories) diets found significantly higher LDL-C levels in the low-carbohydrate group (161 vs. 88 mg/dL).(9) Furthermore, a crossover feeding study in lean, healthy young women showed a mean LDL-C increase of 70 mg/dL on a very low-calorie diet (VLCD) compared to a standard diet, with all participants experiencing an increase.(10)

Although the participant numbers in these studies were quite small, this pattern suggests that individuals who are lean and metabolically healthy before starting a CRD may paradoxically be more susceptible to significant diet-induced increases in LDL cholesterol.

Describing the origins of this heterogeneity is crucial for identifying individuals who may be at risk for significant LDL-C increases when starting a carbohydrate-restricted diet.

Introducing the Lean Mass Hyper-responder (LMHR) Phenotype

With the previously introduced varied responses, a specific and particularly pronounced pattern of lipid alterations has been identified, termed the Lean Mass Hyper-responder (LMHR) phenotype. Initially observed anecdotally within online communities of CRD consumers, this phenotype was formally proposed and investigated in academic research. It is characterized by extremely high LDL-C levels that develop after adopting a CRD, paradoxically occurring alongside lipid markers typically associated with favorable cardiovascular health: very high HDL-C levels and very low triglyceride levels.(11)

Highlighting the Central Question

This unique LMHR lipid profile presents a significant clinical and scientific conundrum. Elevated LDL-C is widely considered a primary cause of the development and progression of ASCVD. Standard clinical guidelines often recommend treatment based on LDL-C levels exceeding certain thresholds.(12)

Doctors often only measure LDL-C levels to save costs for their clinics. However, the LMHR phenotype involves LDL-C elevations that occur in a specific dietary context (CRD-induced), typically in lean individuals, and are accompanied by high HDL-C and low triglycerides (TGs) – factors generally linked to a lower ASCVD risk.

This raises a critical question: Does the markedly elevated LDL-C observed in the LMHR phenotype carry the same cardiovascular risk as elevated LDL-C seen in other contexts, such as familial hypercholesterolemia or atherogenic dyslipidemia?

Answering this question is essential for providing appropriate clinical guidance, especially given the increasing adoption of CRDs for various health reasons. The LMHR phenomenon necessitates a closer examination of whether the metabolic context in which LDL-C is elevated modulates its associated risk.

Defining the Lean Mass Hyperresponder (LMHR) Phenotype

The Characteristic Lipid Triad

The LMHR phenotype is formally defined by a specific triad of lipid values measured while an individual consumes a CRD or KD. These criteria were selected based on empirical observation and the rarity of each threshold individually in the general population, as summarized in Table 1.

Note: These thresholds represent levels achieved while consuming a carbohydrate-restricted diet.

The simultaneous presence of these three lipid values distinguishes the LMHR phenotype. LDL-C levels often exceed the 200 mg/dL threshold substantially, and in some cases, can reach 500 mg/dL or higher in specific individuals.(13)

Key Associations

Research investigating individuals on CRDs has revealed strong associations between the LMHR lipid triad and specific physiological characteristics:(14-16)

Leanness: A consistent finding across studies is an inverse relationship between Body Mass Index (BMI) and the magnitude of LDL-C change experienced on a CRD. Leaner individuals tend to exhibit larger increases in LDL-C. Consequently, those who meet LMHR criteria typically have significantly lower BMI compared to individuals on CRDs who do not meet the criteria. One survey analysis reported a mean BMI of 22.0 kg/m² for LMHR respondents versus 24.6 kg/m² for non-LMHR respondents. While the term "Lean Mass" is part of the name due to this strong empirical association, it is essential to note that the formal definition relies solely on the lipid triad, not a specific BMI cutoff.
Metabolic Health: The LMHR phenotype is strongly associated with markers indicative of good metabolic health before initiating a CRD. Specifically, a low baseline ratio of triglycerides to HDL-C (TG/HDL-C), which is considered a marker of insulin sensitivity and a favorable metabolic status, predicts larger increases in LDL-C after carbohydrate restriction. Individuals who develop the LMHR profile tend to have lower triglyceride (TG) levels and higher high-density lipoprotein cholesterol (HDL-C) levels, even before starting the diet, compared to those who do not. While on a CRD, LMHR individuals maintain this favorable metabolic signature, exhibiting very low TG/HDL-C ratios (e.g., a mean of 0.5 in one study cohort), alongside their elevated LDL-C levels.
Prior LDL-C Levels: A crucial observation is that individuals who develop the LMHR phenotype generally do not have elevated LDL-C before adopting a CRD. Their pre-diet LDL-C levels are typically unremarkable and similar to those of individuals on CRDs who do not exhibit the LMHR response. For example, one study found that mean prior LDL-C levels were nearly identical between the LMHR (148 mg/dL) and non-LMHR (145 mg/dL) groups. This strongly suggests that the extreme hypercholesterolemia characteristic of LMHR is an acquired, diet-induced phenomenon in susceptible individuals rather than a preexisting condition. This functional, diet-dependent nature is a key differentiator from genetic conditions like Familial Hypercholesterolemia.

Distinguishing LMHR from Atherogenic Dyslipidemia and Familial Hypercholesterolemia (FH)

Understanding the unique context of LMHR requires distinguishing it from other conditions characterized by abnormal lipid profiles, particularly atherogenic dyslipidemia associated with metabolic syndrome and the genetic disorder Familial Hypercholesterolemia (FH).

Atherogenic Dyslipidemia

This common lipid abnormality, often seen with obesity, insulin resistance, metabolic syndrome and type 2 diabetes, typically presents with high triglycerides (e.g., >150 mg/dL), low HDL-C (e.g., <40 mg/dL in men, <50 mg/dL in women), and often a predominance of small, dense LDL (sdLDL) particles. LDL-C levels in atherogenic dyslipidemia may be normal or only mildly elevated. The LMHR profile is essentially the inverse of this pattern, featuring low triglycerides (TGs) and high high-density lipoprotein cholesterol (HDL-C) alongside markedly elevated low-density lipoprotein cholesterol (LDL-C). This fundamental difference in accompanying lipid markers (HDL-C, TG) suggests potentially different underlying pathophysiology and possibly different associated risks.(17-18)

Familial Hypercholesterolemia (FH): FH is an inherited genetic disorder most commonly caused by mutations affecting the LDL receptor pathway, leading to impaired clearance of LDL particles from the blood. This results in lifelong exposure to very high LDL-C levels, often exceeding 190 mg/dL and sometimes reaching levels above 400-600 mg/dL, particularly in homozygous forms. This chronic exposure significantly accelerates atherosclerosis, leading to a massively increased risk of premature ASCVD, sometimes manifesting even in childhood. While LDL-C levels in LMHR may overlap with those seen in FH, several key distinctions exist:(19-20)

Etiology: LMHR is diet-induced, specifically by CRDs in susceptible individuals, whereas FH is genetic.
Reversibility: The LMHR phenotype, characterized by high LDL-C, is typically reversible when dietary carbohydrates are reintroduced. FH requires lifelong management, usually including pharmacotherapy; diet alone cannot normalize LDL-C levels.
Accompanying Lipids: LMHR is defined by a triad that includes high HDL-C and low TGs. In FH, HDL-C and TGs are often within the normal range, although variations occur.
Genetics: Individuals with the LMHR phenotype who have undergone genetic testing have generally not shown mutations typically associated with familial hypercholesterolemia (FH).
Clinical Context: Concerns have been raised about potentially misdiagnosing individuals with LMHR as having FH or vice versa, highlighting the importance of distinguishing between these conditions for appropriate management and risk assessment.

Table 2 provides a comparative overview of these lipid profiles (see below).

Note: Direct data on LDL particle size distribution, specifically well-characterized in LMHR cohorts, are limited in the provided sources, and some conflicting evidence exists.

Exploring Underlying Mechanisms: The Lipid Energy Model (LEM)

Detailed Explanation of LEM

The Lipid Energy Model (LEM) has been proposed to explain the paradoxical lipid changes observed in the LMHR phenotype. This model offers a physiological framework suggesting that the LMHR profile arises not from pathology but from an adaptation to altered energy metabolism under specific conditions.

The core premise of LEM is that lean (low body fat) and insulin-sensitive individuals who adopt a CRD strict enough to deplete liver glycogen stores significantly force a major metabolic shift toward using fat as the primary energy source.(21)

Image: The Lipid Energy Model.

Source: Norwitz, N. G., Soto-Mota, A., Kaplan, B., Ludwig, D. S., Budoff, M., Kontush, A., & Feldman, D. (2022). The lipid energy model: reimagining lipoprotein function in the context of carbohydrate-restricted diets. Metabolites, 12(5), 460.

Adipose tissue releases increased amounts of non-esterified fatty acids (NEFAs) into circulation. The liver takes up these NEFAs and re-esterifies them into triglycerides, rather than storing them as might occur in states of energy excess or insulin resistance, such as non-alcoholic fatty liver disease. These triglycerides are then packaged into Very Low-Density Lipoprotein (VLDL) particles and exported from the liver into the bloodstream.

According to LEM, this VLDL export serves as a crucial mechanism for trafficking energy in the form of triglycerides from the liver to peripheral tissues, such as skeletal muscle, cardiac muscle, or adipose tissue, in storage and release cycles when carbohydrate availability is low.

Once in circulation, these triglyceride-rich VLDL particles encounter the enzyme Lipoprotein Lipase (LPL) located on the capillary endothelium of peripheral tissues. LEM posits that in the LMHR context, LPL activity is robust, leading to efficient hydrolysis of triglycerides within VLDL particles. This process releases fatty acids for uptake and utilization by surrounding tissues, meeting their energy demands.

The efficient removal of triglycerides from VLDL transforms these particles first into Intermediate-Density Lipoproteins (IDL) and subsequently into Low-Density Lipoproteins (LDL). LEM proposes that the high rate of VLDL production, turnover and lipolysis results in an increased number of LDL particles circulating in the blood, consequently leading to the high measured LDL-C levels characteristic of LMHR.

Simultaneously, during lipolysis of VLDL, surface components (phospholipids, free cholesterol, some apolipoproteins) become redundant and are transferred to acceptor particles, primarily involving apolipoprotein A-I (ApoA-I). This leads to the formation and maturation of High-Density Lipoprotein (HDL) particles, which explains the elevated HDL-C levels observed in LMHR.(22)

Finally, the efficient uptake of triglycerides by peripheral tissues through LPL activity results in low levels of triglycerides remaining in the circulation.

Image: High HDL is a result and cause of efficient lipoprotein lipase-mediated triglyceride-rich lipoprotein metabolism, and vice versa.

Source: Norwitz, N. G., Soto-Mota, A., Kaplan, B., Ludwig, D. S., Budoff, M., Kontush, A., & Feldman, D. (2022). The lipid energy model: reimagining lipoprotein function in the context of carbohydrate-restricted diets. Metabolites, 12(5), 460.

Therefore, LEM provides a unified mechanistic hypothesis explaining the entire LMHR lipid triad (high LDL-C, high HDL-C, low TG) as a consequence of increased flux through the VLDL energy transport pathway driven by the metabolic demands of carbohydrate restriction in lean, insulin-sensitive individuals.

This perspective reframes high LDL-C not as a result of impaired clearance (as in familial hypercholesterolemia, or FH) but as a marker of a high-throughput physiological energy delivery system.

Supporting Evidence

Carbohydrate Reintroduction

A key prediction of LEM is that restoring dietary carbohydrate intake should reverse the LMHR phenotype. Replenishing liver glycogen stores would decrease the need for extensive VLDL-mediated fat transport for systemic energy, which in turn would reduce VLDL production and lower LDL particle numbers and LDL-C levels. This prediction is supported by case series and experimental settings. Moderate reintroduction of carbohydrates has been shown to produce marked decreases in LDL-C in individuals exhibiting the LMHR profile.(23)

The "Oreo Cookie Experiment" by Norwitz, N.(2024) is a striking demonstration involving a single LMHR subject on a stable ketogenic diet who added 12 Oreo cookies (providing approximately 100g of carbohydrates daily) to their diet for 16 days. His LDL-C level plummeted from a baseline of 384 mg/dL to 111 mg/dL (a 71% reduction), bringing it into the normal range. The fact that this dramatic effect occurred using processed food high in simple carbohydrates, often considered unhealthy, underscores LEM's emphasis on carbohydrate availability as the primary regulator, rather than the quality or source of carbohydrates. This suggests that simply signaling carbohydrate sufficiency to the liver is enough to downregulate the VLDL export pathway, which is responsible for high LDL-C.(24)

Inverse BMI Association

LEM aligns well with the consistent observation that leanness (lower BMI) is associated with larger increases in LDL-C on CRDs. The model posits that individuals with lower body fat reserves and potentially more readily depleted glycogen stores rely more heavily on this VLDL-mediated energy transport system when carbohydrates are restricted. This greater reliance translates into increased VLDL flux and, consequently, higher LDL-C levels than individuals with higher body fat stores.(25)

Role of Dietary Fat

Evidence supporting this comes from a detailed case report of an LMHR individual (identified as LM) who developed extremely high LDL-C levels (peaking at 545 mg/dL) while consuming a ketogenic diet specifically designed to be low in saturated fat and high in unsaturated fats. During periods when his LDL-C was highest, his dietary fat profile was reported to be over 80% unsaturated. Furthermore, his longitudinal data suggested that changes in his LDL-C levels were more closely and inversely associated with changes in his body weight and BMI than with variations in his saturated fat intake. A 6-10 lbs increase in body weight was associated with a drop in LDL-C of over 100 mg/dL.(26)

This observation aligns with LEM's prediction that increased body fat may reduce reliance on VLDL transport, thereby lowering LDL-C, and suggests that for this individual, changes in body composition were a more dominant factor than saturated fat intake. A meta-analysis also found that low BMI (<25 kg/m²) was a much stronger predictor of LDL-C increases on CRDs than high saturated fat intake.(27)

However, this does not imply that dietary fat composition is entirely irrelevant. As mentioned, the type and amount of fat and protein consumed as compensatory calories when restricting carbohydrates might influence lipid profiles, particularly triglyceride levels. While the core LMHR phenomenon of high LDL-C driven by VLDL flux might be primarily regulated by carbohydrate availability and leanness according to LEM, specific dietary choices regarding fat sources could still modulate aspects of the overall lipid profile.

Cardiovascular Risk Conundrum in LMHR

Does the "unhealthy" signal from LDL-C/ApoB outweigh the "healthy" signals from HDL-C, TGs, and overall metabolic status, or does the favorable metabolic context mitigate the risk typically associated with such high LDL levels?

Insights from LDL Particle Characteristics

The potential atherogenicity of LDL particles is influenced not only by their concentration (LDL-C) and number (ApoB, LDL-P) but also by their physical and chemical characteristics, particularly size and density.

General Concepts

The pool of LDL particles in circulation is heterogeneous. Smaller, denser LDL (sdLDL) particles are widely considered more atherogenic per particle than larger, more buoyant LDL particles.

Several factors contribute to this increased atherogenicity:(28)

sdLDL particles may more readily penetrate the arterial intima (inner wall)
They exhibit prolonged residence time in circulation due to reduced affinity for the LDL receptor
And they show increased susceptibility to oxidative modification

These changes enhance their uptake by macrophages in the artery wall, contributing to foam cell formation and plaque development. A predominance of sdLDL particles (often called LDL Pattern B) is a key feature of atherogenic dyslipidemia, typically associated with high triglycerides and low HDL-C and often linked to insulin resistance. Conversely, larger, buoyant LDL particles (Pattern A) are considered less atherogenic.(29)

Apolipoprotein B (ApoB) provides a direct measure of the total number of atherogenic lipoprotein particles (VLDL, IDL, LDL, Lp(a)) because each particle contains exactly one molecule of ApoB. Many experts consider ApoB or LDL particle number (LDL-P) superior predictors of ASCVD risk compared to LDL-C, particularly in situations where LDL-C may be discordant with particle number, such as in individuals with high triglycerides or very low LDL-C levels.(30)

LMHR Context

Given that the LMHR phenotype is characterized by low triglycerides and high HDL-C (the opposite of atherogenic dyslipidemia), one might intuitively hypothesize that the elevated LDL particles in LMHR individuals are predominantly of the larger, buoyant (Pattern A) type, which may make them less atherogenic. However, direct and comprehensive data on LDL subfractions and particle size/density, specifically within well-defined LMHR cohorts, are scarce in the provided research materials.

One critical commentary pointed to a randomized controlled trial in young, lean women (a population susceptible to marked LDL-C increases on CRDs) that found a CRD led to a deleterious lipid profile, including increases in ApoB and specifically small, dense LDL particles, challenging the assumption that LDL particles in this context are necessarily benign.(31-32)

Furthermore, the KETO-CTA trial reported a high mean baseline ApoB level of 185 mg/dL in its LMHR/near-LMHR cohort, confirming the presence of many ApoB-containing particles, regardless of their size distribution.(33)

Therefore, while the metabolic milieu of low TG and high HDL might favor larger LDL, concrete evidence confirming a predominantly benign LDL particle profile in LMHR is lacking, and some data suggest otherwise. The high ApoB levels indicate a high atherogenic particle burden.

Evidence from Imaging Studies

Initial Case Reports: One LMHR individual with LDL-C peaking at 545 mg/dL on a low-saturated-fat ketogenic diet showed no detectable coronary plaque after two years (in computed tomographic angiogram).(34)
KETO Trial: Compared 80 individuals meeting LMHR/near-LMHR criteria (mean LDL-C 272 mg/dL) with 80 matched controls (mean LDL-C 123 mg/dL). Found no statistically significant difference in coronary plaque burden despite nearly 5 years of exposure to much higher LDL-C levels.(35) See image below.
KETOCTA Trial: Followed 100 LMHR/near-LMHR individuals for one year. The published conclusion stated that neither baseline levels of ApoB/LDL-C nor changes in these levels were associated with the progression of coronary plaque.(36) However, he study didn’t test whether elevated LDL-C and ApoB cause plaque—it tested whether continuing to live with already high levels predicted more plaque over just one more year.

LMHR Theory Critique: Key Points from Gene Food (mygenefood.com)

But as is the case with every new theory, particularly on a such hot and contradictory topic, there will be critique and hopefully, further objective discussion.(37)

Below, is a short summary of the critique:

Gene Food's critique of the Lean Mass Hyper-Responder (LMHR) theory reveals how Dave Feldman's Lipid Energy Model fails to explain why lean individuals develop extremely high LDL cholesterol on low-carb diets. Most incriminating is the KETOCTA study, conducted by Feldman's team, which inadvertently showed alarming plaque progression (18.8 mm³ increase in soft plaque) and new plaque development in 9% of participants within just one year—rates 3-5 times higher than seen in high-risk populations. The critique highlights how the model violates fundamental principles of cholesterol homeostasis and mass balance while ignoring more plausible explanations like genetic variants affecting absorption (ABCG5/8), synthesis (APOE), or clearance (LDLR). Ironically, Feldman's own position paper acknowledges LDL's causal role in heart disease, making his suggestion that LMHRs might be exceptions particularly dangerous when conventional lipid science and now his study data indicate these individuals face significant cardiovascular risk.

Clinical Considerations and Research Frontiers

Current State of Clinical Guidance

A significant challenge arises from the fact that major cardiovascular disease prevention guidelines, such as those implicitly referenced from the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS), currently lack specific recommendations tailored to managing the LMHR phenotype.

These guidelines generally emphasize lowering LDL-C as a primary target for ASCVD prevention and often recommend initiating pharmacotherapy (typically statins) when LDL-C levels exceed certain thresholds, such as 190 mg/dL, particularly in primary prevention settings.

Individuals exhibiting the LMHR phenotype frequently surpass these LDL-C thresholds, placing them in a category where medication is typically considered under standard guidelines.

However, the applicability of these general recommendations to the unique LMHR context remains highly uncertain and subject to ongoing debate.

High HDL-C, low triglycerides (TGs), good insulin sensitivity, and the diet-induced, reversible nature of high LDL-C complicate the direct application of guidelines developed primarily from populations with different underlying pathophysiology, such as familial hypercholesterolemia (FH) and atherogenic dyslipidemia.

N.b. Some analyses suggest that statin therapy may not be warranted in individuals on a low-carbohydrate diet with elevated LDL-C if they have achieved a low TG/HDL ratio, arguing that LDL-C is an ineffective predictor of CVD risk in this specific context. This creates a clinical dilemma for patients and healthcare providers when managing individuals who develop the LMHR profile.(38)

Potential Management Strategies Based on Mechanistic Understanding

Given the lack of definitive guidelines and ongoing uncertainty about risk, management approaches for LMHR individuals currently rely on clinical judgment informed by mechanistic understanding and available evidence.

Potential strategies include

Monitoring: Prudent clinical practice involves regularly monitoring the complete lipid profile (LDL-C, HDL-C, triglycerides, ApoB, Lp(a), Ox-LDL, LDL-P) along with other relevant cardiovascular risk factors, such as blood pressure, glucose metabolism and markers of inflammation.

Dietary Modification -> Carbohydrate Reintroduction: Based on LEM and empirical evidence, increasing dietary carbohydrate intake is the most direct and effective known method to reverse the LMHR phenotype and lower LDL-C levels. This offers a potent non-pharmacological lever for LDL-C reduction if deemed clinically necessary or desired by the patient. The required amount and type of carbohydrate may vary from person to person.(39)

Fat/Protein Consideration: According to LEM, while it may not be the primary driver of LDL-C elevation itself, a careful assessment of the type and amount of dietary fat and protein consumed may be relevant, particularly if triglyceride levels are unexpectedly high and fine-tuning of the overall lipid profile is attempted.(40)

Body Weight Adjustment: The inverse relationship between BMI or body weight and LDL-C observed in one case study of LMHR suggests that a modest increase in body weight (becoming less lean) may lower LDL-C levels. However, the deliberate pursuit of weight gain as a strategy to lower LDL-C has unknown broader health implications and cannot generally be recommended based on the current limited evidence.(41)

Pharmacological Intervention: The role and net benefit of lipid-lowering medications, such as statins, in the LMHR population are unknown. While statins effectively lower LDL-C via mechanisms distinct from dietary carbohydrate modulation (primarily upregulating LDL receptor activity), their impact on overall cardiovascular outcomes, specifically within the unique metabolic milieu of LMHR, is not established. Decisions regarding pharmacotherapy require careful consideration of an individual's overall risk profile, the uncertainty surrounding LMHR risk, patient preferences, and potential side effects of the medication.(42-43)

Current ambiguities emphasize the urgent need for further rigorous scientific investigation, including long-term outcome studies, mechanistic studies and intervention trials.

Personalized Risk Assessment

Without definitive data and specific guidelines, a personalized approach to cardiovascular risk assessment in individuals exhibiting the LMHR phenotype is warranted.

This approach should integrate multiple factors beyond the standard lipid panel:

Advanced Lipid Testing: Measuring ApoB concentration provides a direct count of atherogenic particles and is considered essential by many experts. LDL particle number (LDL-P) and potentially LDL subfraction analysis might offer additional insights, although their specific utility in LMHR requires further validation. Lipoprotein(a) [Lp(a)] measurement is also important as an independent genetic risk factor.
Metabolic and Inflammatory Markers: Assessing markers of insulin sensitivity (e.g., fasting glucose, insulin, HbA1c, HOMA-IR) and inflammation (e.g., hs-CRP) helps characterize the overall metabolic context.
Direct Atherosclerosis Imaging: Given the potential discordance between lipid levels and plaque burden suggested by the KETO trial and the KETOCTA finding that baseline plaque predicts progression, direct imaging of coronary arteries using CAC scoring or CCTA may be particularly valuable. These tools help quantify the existing atherosclerotic burden and inform management decisions by identifying individuals with subclinical disease who may require more aggressive intervention, despite the ongoing debate about the inherent risk of the LMHR lipid profile itself.

Conclusion

The LMHR phenotype represents a distinct, paradoxical lipid profile characterized by markedly elevated LDL-C, concurrently with high HDL-C and low triglycerides. This pattern predominantly emerges in lean individuals with favorable baseline metabolic health who follow carbohydrate-restricted diets.

The central issue surrounding LMHR is uncertainty regarding its associated cardiovascular risk. While initial cross-sectional imaging data suggested LMHR might not increase coronary plaque burden, recent longitudinal data have become highly controversial, with some analyses suggesting potentially rapid progression of non-calcified plaque in a subset of participants.

The LMHR phenomenon challenges conventional interpretations of lipid biomarkers and highlights the importance of considering a broader metabolic context when assessing cardiovascular risk.

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The Lean Mass Hyper-responder Phenotype: Paradoxical Lipid Response to Low-Carbohydrate Diets

Introduction

Overview of Carbohydrate-Restricted Diets (CRDs)