Open Letter to the Editor – Journal of Clinical Lipidology

On October 30th, the Journal of Clinical Lipidology published Ketogenic diets, not for everyone. It details five cases where lipid levels were substantially altered after patients adopted a low carb diet. Moreover, the case series specifically identifies us, “The Cholesterol Code Team” and points to examples of statements we have on the website.

In contrast, within a general population, there is no shortage of information available on the internet for the public. The Cholesterol Code Team, led by a software engineer and entrepreneur, created a Facebook group for ‘lean mass hyper-responders.’16 The Cholesterol Code Team defines hyper-responders as those “who have a very dramatic increase in their cholesterol after adopting a low-carb diet.”35 Furthermore, “the increase can be anywhere from 50% to 100% or more of original, prediet cholesterol numbers.”35 The Cholesterol Code Team claims ‘we do not know’ whether having high LDL-C on a low-carbohydrate diet is dangerous; it further presents a number of ‘good reasons’ why LDL-C could be so high.35 These include that the “body is transporting more fat for energy to cells due to being on a high-fat diet.”35 Given the weight such statements could have on a significant number of individuals seeking guidance on the internet, it is important to identify and advise patients with similar presentations.

Let me first say that I am and continue to be optimistic for a productive dialog on this crucial subject. Throughout the last five years I’ve sought to share our research and data with the National Lipid Association in particular. I’ve reached out to several prominent leaders both via email and social media. Siobhan and I have attended NLA conferences and took the opportunity to network further.

Their reluctance is understandable given the internet provides a great deal of demonstrably bad information. With that said, this case series seemed an especially appropriate moment to establish our nuanced position and likewise emphasize the research and data informing us. Thus, we drafted a Letter to the Editor within their requirements (450 words) and submitted it.

The editor objected to the phrasing in the second paragraph and whether it could relate back to two of the citations in that context (I can’t speak more to that as this was a private exchange, but I think Siobhan and I felt it was a fair point and were grateful for the feedback). So we sent back an edit to that paragraph that we felt accomplished this and even further emphasized the uncertainty (see final edit below). But we were told the letter remains rejected.

Thus, I’m going to provide this as an Open Letter to the Editor.

Re: Ketogenic diets, not for everyone

To the Editor,

In “Ketogenic diets, not for everyone”, Ira J. Goldberg, et al describes several cases of hypercholesterolemia developing after adopting a low carb, high fat diet. This phenomenon of “hyper-responders” is of interest given its apparent frequency within the low carb community, although studies documenting this occurrence have had varying levels of consistency.[1][2][3][4]

Regardless of which diet is adopted, we agree hypertriglyceridemia is of concern as was detailed in the first case. However, there are many low carb dieters who observe a “triad” of higher LDL-C, high HDL-C and low triglycerides, such as many in the “Lean Mass Hyper-responder” (LMHR) Facebook group discussed. There are studies on non-FH populations that stratify for this triad and find a low association with heart disease. While these studies show lower LDL-C as a marginal improvement, both variations alongside high HDL-C and low triglycerides associate with lower risk.[5][6] However, it should be emphasized we’ve found no studies looking at this triad in cases where LDL-C reaches levels described in the case series.

The paper quotes from our FAQ page, where we state higher LDL-C resulting from a low carb lifestyle may reflect the body “transporting more fat for energy to cells due to being on a high-fat diet.”[7] More specifically, we propose higher LDL-C in this context could be a result of greater synthesis, secretion, and turnover of triglyceride-rich VLDL particles.

To be sure, this “Lipid Energy Model” is a hypothesis, which we emphasize in the same paragraph, and we hope to have a paper out soon discussing it in detail. But there are existing studies that provide evidence to support this perspective. Long-term fasting results in fat adaptation[8], and in healthy lean humans this presents with a rise in serum ketone and cholesterol levels.[9][10][11] Similarly, research on hibernating animals, both in laboratory settings and in the wild, has documented the presence of hypercholesterolemia.[12][13][14][15] Other studies suggest greater reliance on VLDL trafficking during fasted distance traveling in migratory birds.[16][17]

It’s worth emphasizing we frequently state our “cautious optimism” regarding this triad, given existing data mentioned above, but that it is by no means definitive and that further study is crucial. Moreover, we regularly provide information regarding dietary methods of lowering total and LDL cholesterol in a low carb context.

As a number of LMHRs refuse both pharmacological and dietary lipid lowering interventions, interest in studying this profile is substantial. Given these concerns, we’ve successfully crowd-funded a study in partnership with a major research center and will be submitting for IRB approval shortly. Several tests, such as Computed Tomography Angiogram (CTA) will be used to determine the development of atherosclerosis in individuals at both baseline and follow up after one year. We hope this new data will help advance our understanding of risk for this novel phenotype.

[1] Creighton, B.C., Hyde, P.N., Maresh, C.M., Kraemer, W.J., Phinney, S.D., Volek, J.S., 2018. Paradox of hypercholesterolaemia in highly trained, keto-adapted athletes. BMJ Open Sport & Exercise Medicine 4, e000429. https://doi.org/10.1136/bmjsem-2018-000429

[2] Bhanpuri, N.H., Hallberg, S.J., Williams, P.T., McKenzie, A.L., Ballard, K.D., Campbell, W.W., McCarter, J.P., Phinney, S.D., Volek, J.S., 2018. Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. Cardiovascular Diabetology 17, 56. https://doi.org/10.1186/s12933-018-0698-8

[3] Dashti, H.M., Al-Zaid, N.S., Mathew, T.C., Al-Mousawi, M., Talib, H., Asfar, S.K., Behbahani, A.I., 2006. Long term effects of ketogenic diet in obese subjects with high cholesterol level. Mol Cell Biochem 286, 1–9. https://doi.org/10.1007/s11010-005-9001-x

[4] Yancy, W.S., Olsen, M.K., Guyton, J.R., Bakst, R.P., Westman, E.C., 2004. A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial. Ann Intern Med 140, 769–777. https://doi.org/10.7326/0003-4819-140-10-200405180-00006

[5] Bartlett Jacquelaine, Predazzi Irene M., Williams Scott M., Bush William S., Kim Yeunjung, Havas Stephen, Toth Peter P., Fazio Sergio, Miller Michael, 2016. Is Isolated Low High-Density Lipoprotein Cholesterol a Cardiovascular Disease Risk Factor? Circulation: Cardiovascular Quality and Outcomes 9, 206–212. https://doi.org/10.1161/CIRCOUTCOMES.115.002436

[6] Jeppesen, J., Hein, H.O., Suadicani, P., Gyntelberg, F., 2001. Low triglycerides-high high-density lipoprotein cholesterol and risk of ischemic heart disease. Arch Intern Med 161, 361–366. https://doi.org/10.1001/archinte.161.3.361

[7] Hyper-Responder FAQ, 2016. CholesterolCode. URL https://cholesterolcode.com/hyper-responder-faq/ (accessed 11.5.20).

[8] Carlson, M.G., Snead, W.L., Campbell, P.J., 1994. Fuel and energy metabolism in fasting humans. Am J Clin Nutr 60, 29–36.

https://doi.org/10.1093/ajcn/60.1.29

[9] Sävendahl, L., Underwood, L.E., 1999. Fasting increases serum total cholesterol, LDL cholesterol and apolipoprotein B in healthy, nonobese humans. J Nutr 129, 2005–2008. https://doi.org/10.1093/jn/129.11.2005

[10] Kartin, B.L., Man, E.B., Winkler, A.W., Peters, J.P., 1944. BLOOD KETONES AND SERUM LIPIDS IN STARVATION AND WATER DEPRIVATION. J Clin Invest 23, 824–835. https://doi.org/10.1172/JCI101556

[11] Browning, J.D., Horton, J.D., 2010. Fasting reduces plasma proprotein convertase, subtilisin/kexin type 9 and cholesterol biosynthesis in humans. J Lipid Res 51, 3359–3363. https://doi.org/10.1194/jlr.P009860

[12] Arinell, K., Sahdo, B., Evans, A.L., Arnemo, J.M., Baandrup, U., Fröbert, O., 2012. Brown bears (Ursus arctos) seem resistant to atherosclerosis despite highly elevated plasma lipids during hibernation and active state. Clin Transl Sci 5, 269–272. https://doi.org/10.1111/j.1752-8062.2011.00370.x

[13] Kolomiytseva, I.K., 2011. Lipids in mammalian hibernation and artificial hypobiosis. Biochemistry (Mosc) 76, 1291–1299. https://doi.org/10.1134/S0006297911120029

[14] Chauhan, V., Sheikh, A., Chauhan, A., Tsiouris, J., Malik, M., Vaughan, M., 2002. Changes during hibernation in different phospholipid and free and esterified cholesterol serum levels in black bears. Biochimie 84, 1031–1034. https://doi.org/10.1016/s0300-9084(02)00006-8

[15] Russom, J.M., Guba, G.R., Sanchez, D., Tam, C.F., Lopez, G.A., Garcia, R.E., 1992. Plasma lipoprotein cholesterol concentrations in the golden-mantled ground squirrel (Spermophilus lateralis): a comparison between pre-hibernators and hibernators. Comp Biochem Physiol B 102, 573–578. https://doi.org/10.1016/0305-0491(92)90049-w

[16] Jenni-Eiermann, S., Jenni, L., 1992. High Plasma Triglyceride Levels in Small Birds during Migratory Flight: A New Pathway for Fuel Supply during Endurance Locomotion at Very High Mass-Specific Metabolic Rates? Physiological Zoology 65, 112–123. https://doi.org/10.1086/physzool.65.1.30158242

[17] M, R., R, S., Mr, G., 1999. Seasonal and diel transitions in physiology and behavior in the migratory dark-eyed junco. Comp Biochem Physiol A Mol Integr Physiol 122, 385–397. https://doi.org/10.1016/s1095-6433(99)00013-6

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Ellie M
Ellie M
1 month ago

Keep up the great work that you are doing, Dave and Siobhan. I do hope that your crowd-funded study produces eye-opening results. It is a huge struggle, but well worth the efforts. I had a carotid artery ultrasound this past summer and an angiogram this past October. Both tests showed some plaque, but not enough to be of concern. I plan on following up with these tests in the future to see if the results change…I, with a carotid test every year and an angiogram test every 3-4 years. have been following a Keto diet for 1 year and 1 month now and feel great. I am a LMHR and have entered my tests results on your comments page. I am still calculating my macros and caloric intake during my 3-day fat-increase/caloric increase prior to my test: LIPOPROTEIN FRACTIONATION, NMR WITH LIPID PANEL (TRIGLYCERIDES/HDL-C). I will update those number for you shortly. Thank you.

Siobhan Huggins
Admin
1 month ago
Reply to  Ellie M

Thanks for the support, Ellie, and for sharing back data. It’s always appreciated 🙂

Peter
Peter
1 month ago

Hi Dave, what reason did the Journal give for the letter remaining rejected?

Siobhan Huggins
Admin
1 month ago
Reply to  Peter

There hasn’t been further clarification given on that, only that the decision stands.

Ed
Ed
1 month ago

It’s disappointing that the JCL does not seem to want to engage with you; hopefully that will, in time, change. It might take the publication of the results from your study before that happens, though.

Seems like staying the course is the order of the day…

Colleen
Colleen
1 month ago

My hypothesis is that the Journal feels threatened by this wave of citizen science. Until the last century or so, citizen science was the norm, or at least common, not locked away and limited to elites in select institutions. The internet has brought a new wave of citizen science, including doctors and scientists obtaining ideas outside their institutions, peers, and journals, in addition to engineers who could not possibly add to the subject of lipidology. So, the Journal has lost control in reporting the flow of new information. Another perceived threat to the journal is that the work by the Cholesterol Code Team is highlighting the fact that the LDL-is-bad hypothesis was made upon very shaky ground. It was observed (1) within the context of a high carb diet and (2) in a sick population (see work of Joseph Kraft), and without understanding how each of those facts may have affected LDL. What if many of the Journal’s underlying precepts are wrong? Flawed? Or at best, only apply in the context of a metabolically-broken-high-carb ingester? There are so many areas now applying a ketogenic approach for therapy, may one of those other areas in medicine will lead the charge pointing out that LDL-is-bad is wrong when the triad applies. In today’s (Nov. 24) Meat Rx podcast with Dom D’Agostino he lists some of those research applications. Even he waffles a bit on whether LDL is bad, probably because this is a peril he has had to sidestep in his research. But I see revision of the LDL-is-bad as only a matter of time. Because when radiologists want to put patients on a ketogenic diet because it quickly cures fatty liver, some group in medical research, but perhaps outside cardiology, will want to research the LDL-is-bad issue. The problem with the Journal and other cardio communities, heart disease has a long progression, and hard to measure quick “cures” like in fatty liver or type 2 diabetes. Also, better to die of heart disease in your 90s then something else in your 70s-80s.

KEEP UP THE GREAT WORK!!

PS, I know you focus on LMHR, but I think there is a continuum between LMHR, and those with high HDL, “normal” LDL and low triglycerides, with LDL ranging everywhere in between. I am usually near LMHR but not quite that high with LDL, but always high HDL and low trigs.

Siobhan Huggins
Admin
1 month ago
Reply to  Colleen

RE: spectrum between LMHR and other profiles, I definitely agree. Even within the same individual I’ve seen levels vary pretty substantially depending on how hard they’re pulling the three main levels (leanness, activity, and fat reliance). I’ve seen people close to the profile with HDL slightly below cutoff (e.g. standard hyper-responders), or LDL slightly below cutoff (could be for a variety of reasons), etc. All of this makes sense if thinking from the energy model perspective, of course!

Sebastian
Sebastian
1 month ago

One of the patient had their cholesterol return to normal after treatment with ezetimibe. Wouldn’t that mean that their elevated cholesterol was from hyperabsorption rather than hyper-synthesis?

Siobhan Huggins
Admin
1 month ago
Reply to  Sebastian

I think they were presenting a variety of cases. E.g. another was possibly partially genetic in nature, prior history of hypothyroidism, etc. Although I can’t speak for them, it appears to be a mix of cases, with potentially a mix of contributing factors as well.

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