#255 – Why you might be a lean mass hyper-responder if you go keto but have high cholesterol | Dave Feldman, Dr. Nick Norwitz & Dr. Dominic D’Agostino

Episode introduction

Show Notes

A lean mass hyper-responder is someone with high LDL and HDL cholesterol and low triglycerides. They are often lean and healthy people who present with strange and alarming lipid numbers after going on the ketogenic diet. Dave Feldman, Dr. Nick Norwitz & Dr. Dominic D’Agostino discuss the LMHR phenotype, whether it’s a concern, whether it’s rare, the Oreo vs statin study, how exercise levels might play a role, and why more research is needed.

Helpful links

Key Takeaways

4:29 — What is the lean mass hyper-responder phenotype?

Lean mass hyper-responders, or LMHRs, are a phenotype with a triad of unusual lipid numbers: high low-density lipoprotein (LDL) cholesterol, high high-density lipoprotein cholesterol, and low triglycerides.

I’m Dave Feldman, and many of you probably already know my story by now. I did not at all mean to get into this research. What happened was I went on a low-carb diet in 2015, saw my lipids jump through the roof, and I became obsessed with trying to understand why that happened, particularly given my other first-degree relatives had also gone on a low-carb diet and did not see their cholesterol levels go sky high. I then started doing a number of experiments, was blogging about it; it garnered more and more interest. I started to do presentations on it. And those were the beginnings of what we now call the lipid energy model. And that ultimately then led to recognition of this phenotype that it’s not just about the high LDL; it’s also about the high HDL cholesterol and the low triglycerides, this triad. And that led to identifying this phenotype lean mass hyper-responders that have this triad at extreme levels. And from there, beyond just wanting to develop this model, I wanted to also see if we could study lean mass hyper-responders and that led to the development of the Citizen Science Foundation.

8:32 — Often the LMHR phenotype gets noticed when someone goes low carb

The ketogenic diet is a popular choice for aiding with chronic illnesses. However, some people may experience a surprising shift in lipid numbers after going keto, depending on many factors that researchers are still trying to elucidate.

Along the way, at the end of college and at the beginning of my PhD, I started suffering from inflammatory bowel disease, which ended up being very debilitating—ICU-level care, palliative care. And out of desperation, I started trying things that were outside the scope of Western medicine. I had the greatest admiration for Western medicine; it’s what I wanted to do with my life, but it wasn’t helping so I got desperate. And like a lot of people, when you’re desperate you’re just going to try whatever. And I ended up stumbling across the ketogenic diet, which worked wonders for my inflammatory bowel disease. But lo and behold, something happened—same thing happened to Dave, same thing that’s happened to thousands of other people—which was, to my dismay, my LDL cholesterol went through the roof to absurdly high levels that I didn’t think could exist before.

19:02 — The Oreo cookie study garnered attention for the LMHR phenotype

The Oreo cookie study showed that adding carbohydrates back into the diet of someone who is LMHR lowered LDL cholesterol more so than a statin did.

I tested the lipid energy model publicly and prospectively. So I announced I was doing this before I did it. The test was to test if Oreo cookies could lower my cholesterol. We’ll get into the mechanism of why we thought that would work. But I thought it should work based on understanding of the model and the physiology behind the lean mass hyper-responders. But I wanted to take it a step further than just  eating some Oreos and saying, “Oh, my LDL went down.”  wanted to make it a controlled study, and the control I thought that was appropriate was statin therapy.”

25:32 — Understanding the mechanisms of the LMHR

Why would going on a ketogenic diet potentially lead to lipid numbers consistent with the LMHR phenotype.

The model, which we can go into in a little bit more detail. . . But basically is that when you’re lean, insulin sensitive, and you go low carb, you switch from carb burning to fat burning. And as that process ensues, free fatty acids go up. As your fat cells are spilling out these free fatty acids, some of them get taken up and get repackaged into triglycerides, a stored form of fat, and put into these big spheres, these VLDLs, very low-density lipoprotein. Those get shipped out of the liver and then turned over at your fat cells and your muscle cells by a protein called lipoprotein lipase. This turnover process is what generates the triad we’ve been talking about, the triad that defines lean mass hyper-responders: the high LDL, the high HDL, and low triglycerides.

40:04 — Exercise levels likely play a role in LMHR

In LMHR, exercise seems to drive LDL higher, but more research is needed.

I thought to do a sub study within where I could plant everything and then just change one variable, which is what I went from 10,000 steps per day to 20,000 steps per day. What happened? My LDL jumped by 50 milligrams per deciliter.

51:26 — The alarming LDL levels in LMHR prompted research

More research is needed to determine any concerns with LMHR. On one hand, they are lean and generally healthy, but on the other hand their LDL levels raise red flags.

We’re saying lean mass hyper-responders are unique because they’re healthy and they have this one outstanding variable. And early on in this process, they were like, “But they’re basically going to drop dead . . .”  Our LDLs went up and we’re like, “We’ve got to figure this out or we’re going to go shopping for our headstones.”

59:25 — The “gym hypothesis” will be important for further research

The question is whether LHMR is a rare phenomenon or common under specific diet and exercise conditions.

We know many different people who speculate that this is still a rare oddity and that probably there’s some genetic abnormality about myself and Nick and others who have seen this, because what they would say if they were here in the room is they would say, “But not everybody who goes on a low-carb diet sees this lean mass hyper-responder phenotype. In fact, here’s this friend of mine who’s lean and who tells me that they’re on a ketogenic diet. They don’t see that.” And what I always say is, “Well, give me a group of people who’ve never been lean mass hyper-responders.”

1:10:48 — An open and respectful dialogue is needed on the topic

The LMHR phenotype is a controversial topic but one that needs further research and attention.

Nick and I  have been very proactive. We’ve been getting more and more proactive than ever before, especially coming into this year and wanting to have a productive dialogue with other big names. Like you’re saying, if they’re big names and they can’t fully wrap their head around this physiology and perhaps they want to have a respectful conversation with us on this, we could not be more forthright in our invitation . . . As far as a wealth of data, you can’t get more engrossed in the data than Nick and I. We’re absolutely obsessed and we’re swimming in it.

1:33:47 — The importance of additional research

Ketogenic diets have proven therapeutic for many conditions, including epilepsy. More research is needed to understand LMHR phenotype and any risks or benefits because otherwise the lipid numbers could present a barrier for people who use the ketogenic diet to help manage conditions.

It really is about removing a barrier to implementation of ketogenic diets for a lot of use cases, because this remains the boogeyman. And until we solve it, understand what’s the driver of heterogeneity and what are the actual consequences in terms of risk, it’s going to remain a boogeyman across all fields and all use cases in which ketogenic diets could be therapeutic. So this isn’t just for cardiovascular risk. It’s about epilepsy. It’s about IBD. It’s about kidney disease. It’s about every disease, mental health. It’s about every disease that a ketogenic diet could touch.