High LDL Cholesterol, Low Risk? Lean Mass Hyper-responder phenotype – A literature review

Abstract

Introduction:
The Lean Mass Hyper-Responder (LMHR) phenotype is a distinct lipid profile observed in individuals following carbohydrate-restrictive diets (CRDs), such as ketogenic or carnivore diets. This phenotype is characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C), high high-density lipoprotein cholesterol (HDL-C), and low triglycerides (TG). Understanding the mechanisms and clinical implications of LMHR is crucial given its potential impact on cardiovascular risk assessment.

Materials and methods:
We reviewed recent studies investigating the epidemiology, metabolic mechanisms, and clinical outcomes of the LMHR phenotype. Particular focus was given to the Lipid Energy Model hypothesis and coronary computed tomography angiography findings.

Results:
The LMHR phenotype presents with LDL-C >200 mg/dL, HDL-C >80 mg/dL, and TG <70 mg/dL, differing from classical atherogenic dyslipidemia. The Lipid Energy Model suggests that increased reliance on triglyceride-rich lipoproteins as an energy source underlies these lipid alterations. Observational data show no significant difference in plaque burden or progression between LMHR individuals and matched controls, despite elevated LDL-C levels. Results from large dietary studies present no significant correlation between CVD and following carbohydrate restriction, which further supports the hypothesis and points out the necessity of the intensive research in this field. 

Conclusions:
While elevated LDL-C traditionally indicates increased cardiovascular risk, current evidence suggests heterogeneity within the LMHR population, with no clear correlation between high LDL-C and atherosclerotic progression. Long-term prospective studies are needed to clarify the clinical significance of this phenotype and guide risk assessment in individuals on CRD.