Journal of Clinical Lipidology (2022) 16, 765–768

Editorial

Elevated LDL-cholesterol levels among lean

mass hyper-responders on low-carbohydrate
ketogenic diets deserve urgent clinical
attention and further research
Background: social media, science, and lean at reducing LDL-c. The impact of these narratives on the
mass hyper-responders values, preferences, and health outcomes of the broader
population, and the LMHR community specifically, has not
It has been observed that lean individuals with low triglyc- been well researched.
erides (TG) and high HDL-cholesterol (HDL-c) may de- There is thus a significant need to tamp down hyper-
velop a marked elevation of plasma LDL-cholesterol (LDL- bole and encourage studies of the LMHR phenomenon
c) when consuming a very low-carbohydrate ketogenic diet1 . that could provide important guidance for specific patient
This phenomenon, which has been termed the lean mass populations and advance our understanding of its impact on
hyper-responder (LMHR) phenotype,1 , 2 has been widely dis- cardiometabolic health. Hence, the objectives of the present
cussed on social media networks over the past 6 years. letter are to suggest a pragmatic approach for dealing with
One Facebook page devoted to the LMHR trait now has elevated LDL-c levels in the context of ketogenic diets, to
∼9,000 members and continues to grow. Over the past sev- highlight the importance of researching the LMHR phe-
eral months, several publications1 , 3 , 4 have amplified discus- notype, and to disentangle the science from the broader
sion of the phenotype and its relevance to traditional cardio- narratives discussed above.
vascular risk profiles. There is a paucity of direct clinical
data with regard to the predictive value of elevated LDL-c
for risk of atherosclerotic cardiovascular disease (ASCVD) Calling for a prudent patient-centered clinical
in the context of a very low-carbohydrate ketogenic diet - es- approach
pecially in the LMHR phenotype.
The social media dissemination of the concept of the The LMHR phenotype, while it may be renamed or re-
LMHR has important implications for the dynamic relation- defined with emerging research, was originally defined as
ship between the public and the biomedical research com- LDL-c ≥200 mg/dl, HDL-c ≥80 mg/dl, and TG ≤70 mg/dl.2
munity. Social networks have played a prominent role for in- To understand why LMHRs have prompted such attention,
dividuals and clinicians who have supported each other in we need to recognize the magnitude of the change in LDL-
following low-carbohydrate diets during a protracted period c in this phenotype upon adopting a low-carbohydrate diet.
when guidelines have largely ignored or dissuaded their use. In a recent cohort study, the mean lipid levels in LMHRs
This alternative space for information has also been fertile were LDL-c 320 mg/dl, HDL-c 99 mg/dl and TG 47 mg/dl,
ground for questioning conventional dietary and pharmaco- with a marked difference of LDL-c compared to non-LMHRs
logical practices aimed at reducing risk of ASCVD. In fact, only appearing after adopting a carbohydrate restricted diet.1
some clinicians, researchers, and social media influencers There are even individuals who, after adopting ketogenic di-
who support low-carbohydrate diets have questioned the ets, have had increases in LDL-c from normal levels (∼100
evidence that LDL is causal for ASCVD5 , and sought to dis- mg/dl) to as high as 500-800 mg/dl, which is on par with
courage those with elevated LDL-c on a low-carbohydrate LDL-c concentrations in homozygous familial hypercholes-
diet from seeking treatment.6 This has understandably terolemia, a one-in-one-million genetic condition with dev-
drawn ire from the medical and research community who astating consequences for ASCVD7 .
are concerned that individuals may be persuaded to forego Extreme hypercholesterolemia requires a prudent clinical
lifestyle change or guideline-based medical therapy aimed approach. Given evidence that elevated levels of LDL-c

1933-2874/© 2022 National Lipid Association. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jacl.2022.10.010
766

and other apoB-containing particles play a causal role in circumference, low blood pressure, low levels of inflam-
cardiovascular disease,8 , 9 there does not, at present, appear matory markers, and high insulin sensitivity.1 , 3 As such,
to be any sound argument for withholding consideration of elevated LDL-c is, by and large, an isolated ASCVD risk
LDL-c lowering strategies in this situation. However, there factor in the LMHR phenotype.
are also clinical circumstances in which this principle may A caveat is that in large-scale epidemiological studies
not be pragmatic or patient-centered. HDL-c has a U-shaped relationship to ASCVD risk,11 , 12
There are some individuals who have adopted a ketogenic and most LMHR individuals exhibit HDL-c levels higher
diet for treatment of epilepsy10 or who have discovered that than what may be considered optimal. However, it would be
a ketogenic diet, after trial and error, was the only effective premature to draw conclusions about either a protective or
treatment for a chronic condition such as inflammatory bowel pathological role of high HDL-c in a population unlike any
disease.3 These individuals may have already attempted to that has previously been characterized in large scale epidemi-
lower LDL-c via reduction in saturated fat and/or have been ological studies. A more an in-depth discussion of the pos-
intolerant of LDL-c lowering therapies. Others, based on sible role of HDL in LMHR is discussed more extensively
their values, preferences, or other personal reasons may have elsewhere.4
decided to not change their nutrition pattern or start LDL- While most may infer that the likelihood of ASCVD risk
c lowering pharmacologic therapy. In cases where there are in LMHR is high, this has not been confirmed. It is noted that
competing medical conditions, patient-physician teams may individuals with heterozygous familial hypercholesterolemia
consider additional investigations such as hsCRP, lipopro- have substantial variation in ASCVD incidence,13 and this
tein subfractions, and functional testing, including a coronary suggests that there may be aspects of the LMHR phenotype
artery calcium (CAC) scan, coronary computed tomography that confer some degree of protection, resulting in an overall
angiography (CCTA), and/or carotid intima media thickness lower ASCVD risk than expected. Even if this probability is
(CIMT) to help determine the relative urgency of lipid low- low, it remains an unanswered inquiry worthy of investiga-
ering treatment. tion.
Thus, we advocate that individuals with elevated lev- Four unique features of the LMHR phenotype, as it has
els of LDL-c and/or apoB (both LMHRs and otherwise) been defined, are worth highlighting. First, preliminary data
work closely with their doctor to implement lifestyle changes supports that in LMHRs baseline LDL-c prior to carbohy-
and/or medical therapy directed toward lipid lowering with drate restriction is typically normal, and the phenotype can
the aim of reducing cardiovascular risk. We warn individuals largely be reversed with a reintroduction of carbohydrates to
to be cautious of the risk of accepting information regarding the diet.1 Second, the degree of LDL-c elevation is inversely
LDL-c and ASCVD risk based on shared beliefs and opin- related to BMI (possibly related to lower than average adi-
ions offered on social media. Finally, we advise that in cir- posity) across a population of persons with a low TG/HDL-c
cumstances where there are competing medical conditions, ratio1 . This raises a question about the role of adaptive lipid
weighing of treatment options should be an individual mat- energy trafficking in the genesis of this phenotype.4 Third,
ter determined by patient-physician collaboration. among LMHRs who have been tested, there are no shared
genetics with familial hypercholesterolemia1 , 3 ; so, if there
is a genetic interaction with a low-carbohydrate diet, any
A call for research and support LMHR genotype has yet to be elucidated. Fourth, the LMHR
phenotype usually presents in context of otherwise low car-
Recognition of the LMHR phenotype creates an opportu- diometabolic risk factors, such as low TG/HDL-c, low blood
nity to provide important information to LHMR patients and pressure, low waist-to-hip ratio, and high insulin sensitivity.
to identify environmental and/or metabolic influences that While the data on LMHR are as yet preliminary, and all
could add to the understanding of factors affecting lipopro- of these findings will require validation in larger studies,
tein metabolism and related ASCVD risk. As the magni- the phenomenon is of clear and pressing scientific interest
tude of diet-induced change in LDL-c seen in LMHRs is and deserves further research. The assembly of an LHMR
so marked, this group provides a unique opportunity to un- registry and biobank could provide a valuable resource to
derstand LDL-c dynamics beyond what has previously been support future clinical, genetic, and laboratory research
possible. aimed at identifying determinants and optimal management
The prevalence and cause of the proposed LMHR of the LHMR phenotype. While long-term studies aimed
phenotype are unknown. Modifying factors may include at assessing risk of clinical events would be prohibitive
conventional contributors to elevated LDL-c such as satu- due to ethical concerns, conceivably it would be acceptable
rated fat consumption, but the magnitude of the increase in to assess plaque development in shorter trials using sur-
LDL-c, together with the fact that not all LMHRs consume rogate endpoints (CAC, CCTA, CIMT) in LHMR versus
diets rich in saturated fat, suggest that other factors are non-LMHR. Acquisition of funding for such research will
likely involved. The LMHR phenotype tends to occur in likely present challenges, but data from pilot studies could
individuals with otherwise low cardiometabolic risk factors provide the basis for a more substantial proposal to NIH or
such as low TG/HDL-c ratio (by definition) and small waist other funding agencies The results would not only advance
Elevated LDL-cholesterol levels among lean mass hyper-responders on low-carbohydrate 767

scientific understanding of LHMR, but also assist clinical Acknowledgements

and public health professionals in providing appropriate
guidance for individuals with this trait. The authors would like to thank Dr. Penny M. Kris-
Etherton and Dr. John R. Guyton for their constructive and
thoughtful feedback on this editorial.

Conclusion Nicholas G. Norwitz, PhD∗

Harvard Medical School, 25 Shattuck Street, Boston, MA
The authors of the present letter advocate that all individ- 02115, USA
uals whose LDL-c levels substantially increase on ketogenic Michael R. Mindrum, MD
diets should consider implementing lifestyle change and/or Department of Internal Medicine, Dalhousie University,
pharmacologic therapy for lowering LDL-c and ApoB. In Halifax, Nova Scotia, Canada
those circumstances where there are competing medical Philippe Giral, MD
conditions, weighing of factors should be an individual mat- Endocrinologie Métabolisme et Prévention
ter determined by patient-physician collaboration. Future Cardiovasculaire, Institut E3M et IHU Cardiométabolique
research is warranted to understand ASCVD risk in this (ICAN), Hôpital Pitié Salpêtrière, Paris, France
population as well as to understand the mechanistic determi- Anatol Kontush, PhD
nants of this phenotype. In particular, there is an urgent need Sorbonne Université, INSERM, Unité de recherche sur les
to develop an internationally recognized definition and diag- maladies cardiovasculaires, le métabolisme et la nutrition,
nostic criterion of LMHR. This should facilitate the conduct ICAN, F-75013 Paris, France
of studies for determining the origins and consequences of Adrian Soto-Mota, MD PhD
this novel phenomenon. Metabolic Diseases Research Unit, National Institute for
Medical Sciences and Nutrition Salvador Zubiran, Tlalpan,
CDMX, Mexico
Thomas R. Wood, MD
Author contributions Department of Pediatrics, University of Washington School
of Medicine, Seattle, WA 98195, USA
NGN conceptualized the editorial and served as the Dominic P. D’Agostino, PhD
project coordinator. NGN and MM jointly drafted the initial Department of Molecular Pharmacology and Physiology,
manuscript. All other authors provided significant editorial University of South Florida Morsani College of Medicine,
input and contributed meaningfully to the final draft. MB and Tampa, FL 33612, USA
RMK served equally as senior authors. Venkat S. Manubolu, MD, Matthew Budoff, MD1
Lundquist Institute at Harbor-UCLA Medical Center,
Torrance, CA 90502, USA
Ronald M. Krauss, MD1
Declaration of Competing Interest Departments of Pediatrics and Medicine, University of
California, San Francisco, CA 94143, USA
NGN is coauthor of a Mediterranean low-carbohydrate ∗
Corresponding author.
diet cookbook; he donates all royalty payments to nutrition E-mail addresses: nicholas_norwitz@hms.harvard.edu
research and education. MRM receives consulting fees (N.G. Norwitz), michael.mindrum@nshealth.ca (M.R.
for Novo Nordisk, Bausch Health, Dexcom, and editorial Mindrum), philippe.giral@aphp.fr (P. Giral),
support for Diet Doctor. TRW is a paid scientific advisor anatol.kontush@sorbonne-universite.fr (A. Kontush),
for Hintsa Performance, Thriva LLC, Sidekick Health, and adrian.sotom@incmnsz.mx (A. Soto-Mota),
Rewire Fitness, and is a founding director of the British tommyrw@uw.edu (T.R. Wood), ddagosti@usf.edu (D.P.
Society of Lifestyle Medicine. DPD is the owner of Ketone D’Agostino), venkat.manubolu@lundquist.org (V.S.
Technologies LLC, which does research consulting and Manubolu), mbudoff@lundquist.org (M. Budoff),
public speaking events. MB has grant support from General ronald.krauss@ucsf.edu (R.M. Krauss)
Electric. RMK has research support from Quest Diagnostics, 1
MB and RK served equally as senior authors.
receives a royalty from Lawrence Berkeley National Lab-
oratory for patents for ion mobility lipoprotein analysis, Received August 4, 2022
and is a scientific advisor to Virta Health and Seraphina Accepted October 24, 2022
Therapeutics. Other authors (PG, AK, ASM, VSM) declare
no conflicts.
768

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