Diets · Metabolic & Cardiometabolic
lean mass hyper-responder phenotype causes coronary atherosclerosis progression
In plain terms: Does very high cholesterol on low-carb diets still clog arteries?
Insufficient Diets 🔬 Includes disconfirming⚠️ Includes retracted (not counted)
RefutedContestedStrong support
consensus score -0.11
⚖️ Thin evidence — read the needle loosely. The score shows which way the studies lean, but there are too few independent, high-quality ones to place it firmly. Expect this to move as better evidence arrives.
Unknown for this specific group — nobody has yet followed these people's arteries in a sound study, and the one trial that claimed to was retracted in 2026. Everywhere else, high "bad" cholesterol causes plaque however it got high, and nothing shows this pattern is exempt. Measure ApoB; do not assume it is benign.
📅 Last reviewed: 2026-07-14 ⓘ
Evidence ladder
How far up the ladder this claim has climbed. A high consensus on a low rung means "consistent so far," not "proven in people."
Top evidence so far: Population patterns (Observational)
MechanismIn-vitroAnimalObservationalRCTMeta-analysis
How the studies fall
0 support 4 contradict 0 tested null 5 mixed · 9 sources, 1 independent group · 1 retracted, not counted
What the evidence shows
Whether the extreme LDL/ApoB of the LMHR phenotype causes coronary plaque is UNRESOLVED and the honest crux. The general ApoB->atherosclerosis causal chain is rock-solid, but LMHR-specific outcome data are thin and conflicted.
The evidence (14)
| Source | Grade | Stance | Quality | Finding |
|---|---|---|---|---|
| Houttu V, Grefhorst A, Cohn DM, Levels JHM, Roeters van Lennep J, Stroes ESG, Groen AK, Tromp TR 2023 · Nutrients | observational | mixed | low | Critical review: high-fat low-carb diets can induce severe FH-mimicking LDL elevations; cautions these warrant clinical attention given LDL-ASCVD causality. |
| Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, Kahn J, Afonso L, Williams KA, Flack JM 2012 · J Am Coll Cardiol | observational | mixed | high | [GENERAL-POPULATION evidence, extrapolated — does not test the LMHR phenotype specifically; establishes LDL causality broadly but not whether LMHR are an exception] Mendelian randomization: lifelong lower LDL via LDL-lowering alleles gave ~3x the CHD risk reduction per mmol/L vs late statin therapy; cumulative-exposure causality. |
| Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL 2017 · European Heart Journal | observational | mixed | moderate | [GENERAL-POPULATION evidence, extrapolated — does not test the LMHR phenotype specifically; establishes LDL causality broadly but not whether LMHR are an exception] EAS consensus: genetic, epidemiologic & RCT evidence that LDL causally drives ASCVD in a log-linear, cumulative-exposure manner (supports premise LMHR LDL is atherogenic). |
| Soffer DE, Marston NA, Maki KC, Jacobson TA, Bittner VA, Peña JM, Thanassoulis G, Martin SS, Kirkpatrick CF, Virani SS, Dixon DL, Ballantyne CM, Remaley AT 2024 · J Clin Lipidology | observational | mixed | high | NLA Expert Clinical Consensus: 'provides an overview of the physiologic and clinical considerations regarding the role of apolipoprotein B (apoB) measurement ... based on the available scientific evidence and expert opinion'; 'ApoB has been shown to be superior to LDL-C in risk assessment'. No own data and no LMHR-specific content — review, zero weight. |
| Norwitz NG, Feldman D, Soto-Mota A 2026 · Diseases | observational | contradicts | low | Case report (n=1): LDL ~700 for 7y, no coronary atherosclerosis reported |
| Budoff M, Manubolu VS, Kinninger A, Norwitz NG, Feldman D, Wood TR, Fialkow J, Cury R, Feldman T, Nasir K 2024 · JACC Adv | observational | contradicts | low | Coronary CT in 80 lean-mass-hyper-responder adults (LDL-C ≥190, HDL-C ≥60, triglycerides ≤80 mg/dL) on a ketogenic diet a mean 4.7 years, matched 1:1 to 80 Miami Heart controls. Calcium score 0 (0-56) vs 1 (0-49), P = 0.520; plaque score 0 (0-2) vs 1 (0-4), P = 0.245; 'There was no significant correlation between plaque burden ... and LDL-C level in the fully matched group (r = 0.12, P = 0.29)'. In the 35 meeting strict criteria, calcium 0 vs 0, P = 0.849. Plaque measured once, not progression: no repeat scan, median plaque 0 in both arms, and 33% of controls on lipid-lowering drugs. |
| LMHR-plaque-2026 2026 · (preprint) | observational | contradicts | low | Over one year, LMHR participants showed only MODEST, HETEROGENEOUS non-calcified plaque progression (median 5.6 mm3) - weaker and more variable than a clean 'high LDL causes plaque' effect. Preprint; same LMHR cohort family as the retracted KETO-CTA (grouped, not double-counted). |
| Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJP, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Honda S, Shishikura D, Scherer DJ, Borgman M, Brennan DM, Wolski K, Nissen SE 2018 · J Am Coll Cardiol | RCT | mixed | high | [GENERAL-POPULATION evidence, extrapolated — does not test the LMHR phenotype specifically; establishes LDL causality broadly but not whether LMHR are an exception] Evolocumab substudy: very low LDL-C shifted plaque toward regression/stabilized composition; reinforces causal LDL->coronary plaque link underpinning the LMHR concern. |
| Nicholls SJ, Puri R, Anderson T, Ballantyne CM, Cho L, Kastelein JJ, Koenig W, Somaratne R, Kassahun H, Yang J, Wasserman SM, Scott R, Ungi I, Podolec J, Ophuis AO, Cornel JH, Borgman M, Brennan DM, Nissen SE 2016 · JAMA | RCT | mixed | high | [GENERAL-POPULATION evidence, extrapolated — does not test the LMHR phenotype specifically; establishes LDL causality broadly but not whether LMHR are an exception] GLAGOV RCT/IVUS: incremental LDL-C lowering with evolocumab caused coronary atheroma regression proportional to achieved LDL; LDL drives plaque progression. |
| Norwitz NG, Soto-Mota A, Feldman D, Parpos S, Budoff M 2022 · Front Endocrinol | observational | contradicts | low | Single case report (n=1), not a cohort: a 26-year-old man with the lean-mass-hyper-responder lipid triad on a ketogenic diet, LDL-C peak 545 mg/dl (HDL-C 94, TG 58), exposed to 'LDL-C ~400–550 for ~2.5 years'. One coronary CT angiogram, against 'a prior CAC of 0', showed 'No plaque or stenosis was observed in any vessels CAD-RADS = 0'. Lp(a) was 109-168 mg/dl. The authors state 'two and half years is insufficient for any measurable atherosclerotic plaque to precipitate' is a reasonable reading, and that the case is not generalizable. |
| Norwitz NG, Mindrum MR, Giral P, Kontush A, Soto-Mota A, Wood TR, D'Agostino DP, Manubolu VS, Budoff M, Krauss RM 2022 · J Clin Lipidol | observational | mixed | low | LMHR-network letter: flags markedly elevated LDL in LMHR as deserving urgent attention/further research; acknowledges outcome data lacking. |
| Soto-Mota A, Norwitz NG, ... Budoff M 2025 · JACC Adv (RETRACTED 2026) | observational | mixed | low | RETRACTED in 2026: the authors and editors state “concerns were raised regarding the methodology in this article, which effect the reliability of the data” and “the identified errors are too great to be corrected with a corrigendum.” Single-arm 1-year CT-angiography follow-up of 100 lean ketogenic-diet responders (mean LDL-C 254 mg/dL, BMI 22.5). Plaque did progress — median change 18.9 mm3 (IQR 9.3–47.0) — yet “neither total exposure nor changes in baseline levels of ApoB and LDL-C were associated with changes in plaque”; baseline plaque was. No comparator group. ⚠️ RETRACTED — not counted |
| Glavinovic T, Thanassoulis G, de Graaf J, Couture P, Hegele RA, Sniderman AD 2022 · J Am Heart Assoc | observational | mixed | low | Narrative review: 'This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk'. General apoB physiology; no LMHR-specific data (existing relevance_note already says off-topic for the phenotype). Review — zero weight. |
| Borén J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, Daemen MJ, Demer LL, Hegele RA, Nicholls SJ, Nordestgaard BG, Watts GF, Bruckert E, Fazio S, Ference BA, Graham I, Horton JD, Landmesser U, Laufs U, Masana L, Pasterkamp G, Raal FJ, Ray KK, Schunkert H, Taskinen MR, van de Sluis B, Wiklund O, Tokgozoglu L, Catapano AL, Ginsberg HN 2020 · European Heart Journal | observational | mixed | moderate | EAS consensus statement (JATS review-article), no own data: 'Extensive evidence on the pathophysiology of ASCVD presented here supplements and extends our earlier review on the causality of LDL based on epidemiological, GWAS, and Mendelian randomization studies, as well as controlled intervention trials'. General-population LDL causality; never tests the LMHR phenotype. Review — zero weight. |
Considered, not graded (2)
Sources we looked at but did not score, and why. Radical transparency includes what we set aside.
- Norwegian research-news restating KETO-CTA 18.8mm3 figure (2025) Non-independent
- High LDL Low Risk? LMHR commentary, Quality in Sport (2025) Below methodology floor
Disagree, or know a study we missed?
We grade by evidence, not opinions. The way to weigh in is to point us to a study we haven't cited (check the evidence table above first), or to flag a problem with one we have. Every submission is reviewed; if it holds up, the grade updates and shows in Science Changes Its Mind.
Opens a short form. You'll sign in with Google so submissions are tied to a real account — we don't display your identity, and we only accept a link we can verify (PubMed, DOI, ClinicalTrials.gov).
Educational only, not medical advice. Grades and scores reflect published evidence weighted by study design and quality; see the methodology.