Norwitz 2021: Evidence for the Lean Mass Hyper-Responder Phenotype

In 2021, Dr. Nicholas Norwitz and colleagues published the first systematic characterization of Lean Mass Hyper-Responders (LMHR)—individuals who develop dramatically elevated LDL cholesterol on carbohydrate-restricted diets while maintaining otherwise excellent metabolic markers.

Defining the Phenotype

The LMHR phenotype is defined by three simultaneous criteria:

• •LDL cholesterol ≥200 mg/dL (often 300-500+)
• •HDL cholesterol ≥80 mg/dL (exceptionally high)
• •Triglycerides ≤70 mg/dL (exceptionally low)

This triad represents a paradox: the "bad" cholesterol is very high, but the triglyceride/HDL ratio—one of the best predictors of cardiovascular risk—is extraordinarily favorable.

Study Findings

Analyzing survey data from 548 adults on carbohydrate-restricted diets, the researchers identified 100 individuals meeting LMHR criteria (18%). Key observations:

• •LMHRs had lower BMI than other ketogenic dieters
• •Baseline (pre-diet) LDL levels were similar across groups
• •The effect was dietary, not genetic—moderate carbohydrate reintroduction substantially reduced LDL

The Central Insight

Greater LDL elevation on carbohydrate-restricted diets tends to occur in the context of otherwise low cardiometabolic risk. The individuals with the most alarming LDL numbers paradoxically have the most favorable metabolic profiles by other measures.

Clinical Implications

The LMHR phenotype challenges the assumption that all LDL elevation carries equal risk. These individuals may be using LDL particles primarily for energy transport rather than driving atherosclerosis. However, long-term cardiovascular outcomes data is still needed—which motivated the subsequent KETO Trial.

Why This Matters

Understanding LMHR prevents premature discontinuation of therapeutic diets and inappropriate medicalization of what may be a healthy metabolic adaptation.