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Elevated LDL-cholesterol levels among lean mass hyper-responders on low-carbohydrate ketogenic diets deserve urgent clinical attention and further research

Published:November 02, 2022DOI:https://doi.org/10.1016/j.jacl.2022.10.010

      Highlights

      • Lean mass hyper-responders exhibit extreme increases in LDL-c on ketogenic diets.
      • LDL-c increases in LMHRs are dependent on carbohydrate restriction.
      • Other cardiometabolic risk factors are normal to optimal in LMHRs.
      • A prudent clinical approach is required for managing LDL-c in LMHR patients.
      • Research is warranted to assess mechanisms and cardiovascular risk of this trait.

      Keywords

      Background: social media, science, and lean mass hyper-responders

      It has been observed that lean individuals with low triglycerides (TG) and high HDL-cholesterol (HDL-c) may develop a marked elevation of plasma LDL-cholesterol (LDL-c) when consuming a very low-carbohydrate ketogenic diet
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      . This phenomenon, which has been termed the lean mass hyper-responder (LMHR) phenotype,
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      ,

      Feldman D. Cholesterol Code. Are you a lean mass hyper-responder? https://cholesterolcode.com/are-you-a-lean-mass-hyper-responder/.

      has been widely discussed on social media networks over the past 6 years. One Facebook page devoted to the LMHR trait now has ∼9,000 members and continues to grow. Over the past several months, several publications
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      ,
      • Norwitz NG
      • Soto-Mota A
      • Feldman D
      • Parpos S
      • M B
      Case report: hypercholesterolemia "Lean Mass Hyper-Responder" phenotype presents in the context of a low saturated fat carbohydrate-restricted diet.
      ,
      • Norwitz NG
      • Soto-Mota A
      • Kaplan B
      • Ludwig DS
      • Budoff M
      • Kontush A
      • et al.
      The lipid energy model: reimagining lipoprotein function in the context of carbohydrate-restricted diets.
      have amplified discussion of the phenotype and its relevance to traditional cardiovascular 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) in the context of a very low-carbohydrate ketogenic diet - especially in the LMHR phenotype.
      The social media dissemination of the concept of the LMHR has important implications for the dynamic relationship between the public and the biomedical research community. Social networks have played a prominent role for individuals and clinicians who have supported each other in following low-carbohydrate diets during a protracted period when guidelines have largely ignored or dissuaded their use.
      This alternative space for information has also been fertile ground for questioning conventional dietary and pharmacological practices aimed at reducing risk of ASCVD. In fact, some clinicians, researchers, and social media influencers who support low-carbohydrate diets have questioned the evidence that LDL is causal for ASCVD
      • Diamond DM
      • Alabdulgader AA
      • de Lorgeril M
      • Harcombe Z
      • Kendrick M
      • Malhotra A
      • et al.
      Dietary recommendations for familial hypercholesterolaemia: an evidence-free zone.
      , and sought to discourage those with elevated LDL-c on a low-carbohydrate diet from seeking treatment.
      • Diamond DM
      • Bikman BT
      • Mason P
      Statin therapy is not warranted for a person with high LDL-cholesterol on a low-carbohydrate diet.
      This has understandably drawn ire from the medical and research community who are concerned that individuals may be persuaded to forego lifestyle change or guideline-based medical therapy aimed at reducing LDL-c. The impact of these narratives on the values, preferences, and health outcomes of the broader population, and the LMHR community specifically, has not been well researched.
      There is thus a significant need to tamp down hyperbole and encourage studies of the LMHR phenomenon that could provide important guidance for specific patient populations and advance our understanding of its impact on cardiometabolic health. Hence, the objectives of the present letter are to suggest a pragmatic approach for dealing with elevated LDL-c levels in the context of ketogenic diets, to highlight the importance of researching the LMHR phenotype, and to disentangle the science from the broader narratives discussed above.

      Calling for a prudent patient-centered clinical approach

      The LMHR phenotype, while it may be renamed or redefined with emerging research, was originally defined as LDL-c ≥200 mg/dl, HDL-c ≥80 mg/dl, and TG ≤70 mg/dl.

      Feldman D. Cholesterol Code. Are you a lean mass hyper-responder? https://cholesterolcode.com/are-you-a-lean-mass-hyper-responder/.

      To understand why LMHRs have prompted such attention, we need to recognize the magnitude of the change in LDL-c in this phenotype upon adopting a low-carbohydrate diet. In a recent cohort study, the mean lipid levels in LMHRs were LDL-c 320 mg/dl, HDL-c 99 mg/dl and TG 47 mg/dl, with a marked difference of LDL-c compared to non-LMHRs only appearing after adopting a carbohydrate restricted diet.
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      There are even individuals who, after adopting ketogenic diets, have had increases in LDL-c from normal levels (∼100 mg/dl) to as high as 500-800 mg/dl, which is on par with LDL-c concentrations in homozygous familial hypercholesterolemia, a one-in-one-million genetic condition with devastating consequences for ASCVD
      • Goldstein JL
      • Brown MS.
      The LDL receptor.
      .
      Extreme hypercholesterolemia requires a prudent clinical approach. Given evidence that elevated levels of LDL-c and other apoB-containing particles play a causal role in cardiovascular disease,
      • Zuber V
      • Gill D
      • Ala-Korpela M
      • Langenberg C
      • Butterworth A
      • Bottolo L
      • et al.
      High-throughput multivariable Mendelian randomization analysis prioritizes apolipoprotein B as key lipid risk factor for coronary artery disease.
      ,
      • Boren J
      • Chapman MJ
      • Krauss RM
      • Packard CJ
      • Bentzon JF
      • Binder CJ
      • et al.
      Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel.
      there does not, at present, appear to be any sound argument for withholding consideration of LDL-c lowering strategies in this situation. However, there are also clinical circumstances in which this principle may not be pragmatic or patient-centered.
      There are some individuals who have adopted a ketogenic diet for treatment of epilepsy
      • Martin-McGill KJ
      • Bresnahan R
      • Levy RG
      • PN Cooper
      Ketogenic diets for drug-resistant epilepsy.
      or who have discovered that a ketogenic diet, after trial and error, was the only effective treatment for a chronic condition such as inflammatory bowel disease.
      • Norwitz NG
      • Soto-Mota A
      • Feldman D
      • Parpos S
      • M B
      Case report: hypercholesterolemia "Lean Mass Hyper-Responder" phenotype presents in the context of a low saturated fat carbohydrate-restricted diet.
      These individuals may have already attempted to lower LDL-c via reduction in saturated fat and/or have been intolerant of LDL-c lowering therapies. Others, based on their values, preferences, or other personal reasons may have decided to not change their nutrition pattern or start LDL-c lowering pharmacologic therapy. In cases where there are competing medical conditions, patient-physician teams may consider additional investigations such as hsCRP, lipoprotein subfractions, and functional testing, including a coronary artery calcium (CAC) scan, coronary computed tomography angiography (CCTA), and/or carotid intima media thickness (CIMT) to help determine the relative urgency of lipid lowering treatment.
      Thus, we advocate that individuals with elevated levels of LDL-c and/or apoB (both LMHRs and otherwise) work closely with their doctor to implement lifestyle changes and/or medical therapy directed toward lipid lowering with the aim of reducing cardiovascular risk. We warn individuals to be cautious of the risk of accepting information regarding LDL-c and ASCVD risk based on shared beliefs and opinions offered on social media. Finally, we advise that in circumstances where there are competing medical conditions, weighing of treatment options should be an individual matter determined by patient-physician collaboration.

      A call for research and support

      Recognition of the LMHR phenotype creates an opportunity to provide important information to LHMR patients and to identify environmental and/or metabolic influences that could add to the understanding of factors affecting lipoprotein metabolism and related ASCVD risk. As the magnitude of diet-induced change in LDL-c seen in LMHRs is so marked, this group provides a unique opportunity to understand LDL-c dynamics beyond what has previously been possible.
      The prevalence and cause of the proposed LMHR phenotype are unknown. Modifying factors may include conventional contributors to elevated LDL-c such as saturated fat consumption, but the magnitude of the increase in LDL-c, together with the fact that not all LMHRs consume diets rich in saturated fat, suggest that other factors are likely involved. The LMHR phenotype tends to occur in individuals with otherwise low cardiometabolic risk factors such as low TG/HDL-c ratio (by definition) and small waist circumference, low blood pressure, low levels of inflammatory markers, and high insulin sensitivity.
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      ,
      • Norwitz NG
      • Soto-Mota A
      • Feldman D
      • Parpos S
      • M B
      Case report: hypercholesterolemia "Lean Mass Hyper-Responder" phenotype presents in the context of a low saturated fat carbohydrate-restricted diet.
      As such, elevated LDL-c is, by and large, an isolated ASCVD risk factor in the LMHR phenotype.
      A caveat is that in large-scale epidemiological studies HDL-c has a U-shaped relationship to ASCVD risk,
      • Madsen CM
      • Varbo A
      • BG Nordestgaard
      Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies.
      ,
      • Ko DT
      • Alter DA
      • Guo H
      • Koh M
      • Lau G
      • Austin PC
      • et al.
      High-density lipoprotein cholesterol and cause-specific mortality in individuals without previous cardiovascular conditions: the CANHEART study.
      and most LMHR individuals exhibit HDL-c levels higher than what may be considered optimal. However, it would be premature to draw conclusions about either a protective or pathological role of high HDL-c in a population unlike any that has previously been characterized in large scale epidemiological studies. A more an in-depth discussion of the possible role of HDL in LMHR is discussed more extensively elsewhere.
      • Norwitz NG
      • Soto-Mota A
      • Kaplan B
      • Ludwig DS
      • Budoff M
      • Kontush A
      • et al.
      The lipid energy model: reimagining lipoprotein function in the context of carbohydrate-restricted diets.
      While most may infer that the likelihood of ASCVD risk in LMHR is high, this has not been confirmed. It is noted that individuals with heterozygous familial hypercholesterolemia have substantial variation in ASCVD incidence,
      • McGowan MP
      • Hosseini Dehkordi SH
      • Moriarty PM
      • Duell PB
      Diagnosis and treatment of heterozygous familial hypercholesterolemia.
      and this suggests that there may be aspects of the LMHR phenotype that confer some degree of protection, resulting in an overall lower ASCVD risk than expected. Even if this probability is low, it remains an unanswered inquiry worthy of investigation.
      Four unique features of the LMHR phenotype, as it has been defined, are worth highlighting. First, preliminary data supports that in LMHRs baseline LDL-c prior to carbohydrate restriction is typically normal, and the phenotype can largely be reversed with a reintroduction of carbohydrates to the diet.
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      Second, the degree of LDL-c elevation is inversely related to BMI (possibly related to lower than average adiposity) across a population of persons with a low TG/HDL-c ratio
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      . This raises a question about the role of adaptive lipid energy trafficking in the genesis of this phenotype.
      • Norwitz NG
      • Soto-Mota A
      • Kaplan B
      • Ludwig DS
      • Budoff M
      • Kontush A
      • et al.
      The lipid energy model: reimagining lipoprotein function in the context of carbohydrate-restricted diets.
      Third, among LMHRs who have been tested, there are no shared genetics with familial hypercholesterolemia
      • Norwitz NG
      • Feldman D
      • Soto-Mota A
      • Kalayjian T
      • DS L
      Elevated LDL-cholesterol with a carbohydrate-restricted diet: evidence for a ‘lean mass hyper-responder’ phenotype.
      ,
      • Norwitz NG
      • Soto-Mota A
      • Feldman D
      • Parpos S
      • M B
      Case report: hypercholesterolemia "Lean Mass Hyper-Responder" phenotype presents in the context of a low saturated fat carbohydrate-restricted diet.
      ; so, if there is a genetic interaction with a low-carbohydrate diet, any LMHR genotype has yet to be elucidated. Fourth, the LMHR phenotype usually presents in context of otherwise low cardiometabolic risk factors, such as low TG/HDL-c, low blood pressure, low waist-to-hip ratio, and high insulin sensitivity.
      While the data on LMHR are as yet preliminary, and all of these findings will require validation in larger studies, the phenomenon is of clear and pressing scientific interest and deserves further research. The assembly of an LHMR registry and biobank could provide a valuable resource to support future clinical, genetic, and laboratory research aimed at identifying determinants and optimal management of the LHMR phenotype. While long-term studies aimed at assessing risk of clinical events would be prohibitive due to ethical concerns, conceivably it would be acceptable to assess plaque development in shorter trials using surrogate endpoints (CAC, CCTA, CIMT) in LHMR versus non-LMHR. Acquisition of funding for such research will likely present challenges, but data from pilot studies could provide the basis for a more substantial proposal to NIH or other funding agencies The results would not only advance scientific understanding of LHMR, but also assist clinical and public health professionals in providing appropriate guidance for individuals with this trait.

      Conclusion

      The authors of the present letter advocate that all individuals whose LDL-c levels substantially increase on ketogenic diets should consider implementing lifestyle change and/or pharmacologic therapy for lowering LDL-c and ApoB. In those circumstances where there are competing medical conditions, weighing of factors should be an individual matter determined by patient-physician collaboration. Future research is warranted to understand ASCVD risk in this population as well as to understand the mechanistic determinants of this phenotype. In particular, there is an urgent need to develop an internationally recognized definition and diagnostic criterion of LMHR. This should facilitate the conduct of studies for determining the origins and consequences of this novel phenomenon.

      Author contributions

      NGN conceptualized the editorial and served as the project coordinator. NGN and MM jointly drafted the initial manuscript. All other authors provided significant editorial input and contributed meaningfully to the final draft. MB and RMK served equally as senior authors.

      Funding statement

      Open access was funded through the Citizen Science Foundation by joint contributions from the private donations of Dave Feldman, Nicholas Norwitz as well as generous contributions by 46 members of the LMHR Facebook group. Of note, the paper was written independent and without influence of that funding, which was collected after editorial acceptance.

      Declaration of Competing Interest

      NGN is coauthor of a Mediterranean low-carbohydrate diet cookbook; he donates all royalty payments to nutrition research and education. MRM receives consulting fees for Novo Nordisk, Bausch Health, Dexcom, and editorial support for Diet Doctor. TRW is a paid scientific advisor for Hintsa Performance, Thriva LLC, Sidekick Health, and Rewire Fitness, and is a founding director of the British Society of Lifestyle Medicine. DPD is the owner of Ketone Technologies LLC, which does research consulting and public speaking events. MB has grant support from General Electric. RMK has research support from Quest Diagnostics, receives a royalty from Lawrence Berkeley National Laboratory for patents for ion mobility lipoprotein analysis, and is a scientific advisor to Virta Health and Seraphina Therapeutics. Other authors (PG, AK, ASM, VSM) declare no conflicts.

      Acknowledgements

      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.

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