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Apologies for getting on my #LMHR soapbox, but it's warranted - A MegaTweet 🧵 If you were following, yesterday, the topic of "hyper-responders" to #ketodiet was a topic of discussion and intrigue (as it should be) But, too often, the discussion remains shallow. The following 2 themes arise: 👉(1) Broad vilification of #ketogenic diet, rather than recognizing 'skyrocketing' LDL cholesterol levels is a minority response 👉(2) Attribution of the phenomenon to ⬆️ saturated fat intake or genetics 🧬, while overlooking pieces of the puzzle that simply don't fit well with this explanation (although butter and beef are typically excellent scapegoats) I will address each in turn, bolding what is most important and ital that which is less essential (for your reading efficiency) 👉(1) #ketogenic diets typically improve markers of cardiovascular risk, especially in those with #obesity- metabolic syndrome- insulin resistance. LDL-C levels (and ApoB) typically do not change, or even go down. Sometimes, there is a transient small rise that resolves over the course of months. We will have more on this in an upcoming paper (it will be a shocker!), but you are free to examine the RCTs by BMI category yourself. See if you can find any in which LDL-C "skyrockets" in patients with obesity or diabetes. I bet you can't find one. That said, there are some people in whom LDL-C/ApoB does 'sky-rocket' on a ketogenic diet. I will emphasize, this is a MINORITY. Nevertheless, it's not a phenomenon to be taken lightly, as we've emphasized repeatedly on social media and in publications (lipidjournal.com/article/S19…). Some cases may be due to identifiable underlaying genetic vulnerabilities, but most cases appear to be linked instead to something else... a phenotype of relatively low body fat, higher energy expenditure and - in the context of carbohydrate restriction - a lipid triad of sky-high LDL-C WITH high HDL-C and low TG. These are the lean mass hyper-responders (#LMHR). Onto point (2)... 👉(2) The easy answer to the "hyper-responder" phenomenon is to lean into the conventional explanations... "it's all the saturated fat" or "genetics." But easy isn't always right. Some considerations... If saturated fat drives the #LMHR phenomenon then (i) Why are there #LMHR on low-saturated fat high MUFA/PUFA diets? (ii) Why does eating loads of saturated fat in the context of a higher-carb diet not generate the phenotype? (Aside: A very brave and generous Twitter doc attempted this very feat by eating sticks of butter and came nowhere close to generating an LMHR lipid profile. If you can find 1 example of an individual with LDL≥200, HDL≥80, TG≤70 on a higher carb diet, let me know - please and thank you) (iii) Also, if saturated fat were the driver of the #LMHR phenotype, then Why does BMI inversely correlate with LDL-C changes on a #ketodiet? Are lean people eating more saturated fat in a dose-dependent manner (pubmed.ncbi.nlm.nih.gov/3510…). (iv-v) The saturated fat 'hypothesis' also does not explain well the LMHR lipid triad (above), and there's simply an issue of order of magnitude of effect... there's no data to suggest butter and cream are sufficient to shoot LDL from 90 to 500+ 🚨 Why this matters 🚨 Let's first emphasize the clinical importance of this topic: at population scale, high LDL-C/ApoB is associated with elevated ASCVD risk and ApoB are part of the causal pathway in ASCVD. This isn't a debate, and levels seen in #LMHR are truly astronomical, and clinically terrifying for many, if fascinating. While some may handle this topic dismissively, on both sides, there are those using #ketogenic diet for therapeutic reasons who deserve answers -- answers to both the clinical risk associated with this unusual and understudied phenomenon (*elevated LDL-C/ApoB in the context good metabolic health, without known genetic causes, and apparently driven by carbohydrate restriction) as well as answers to the fundamental mechanistic question -- what's going on inside my body? Solid answers to these questions lay beyond the boundaries of current knowledge. We can presume and hypothesize, but that's all. I've been most disappointed in those "experts" who attempt to disregard this area of study - and even go so far as to insult practitioners of #ketogenic diets (clinicians and patients) (or use vulgarities to describe the researchers pursuing this line of inquiry), while simultaneously demonstrating that they haven't taken the time to inform themselves on this topic. That's inappropriate. In summary, I have this call to action and this promise: 👉 Be curious and be respectful. If you don't know, say "I (we) don't know." 👉I promise, more research is coming... we are approaching and inflection point Some refs: Study: academic.oup.com/cdn/article… Case report: ncbi.nlm.nih.gov/pmc/article… JCL Editorial: lipidjournal.com/article/S19… LEM hypothesis (more than 'the butter did it'): mdpi.com/2218-1989/12/5/460 Encourage to share @realDaveFeldman @davidludwigmd @Lipoprotein @nationallipid & forgive any perceived 'overstepping' by this humble @harvardmed student and young PhD. Sometimes, I do find it hard to "know my place," by I like to believe my intent is positive: I have questions and want answers, and get especially passionate when I feel patients are being poorly served