The purpose of this post is to inform the reader of a journal article that describes a particular subset of patients that have marked elevation in LDL-C (low-density lipoprotein cholesterol) and total cholesterol when eating a low-carbohydrate diet. This article was published in 2022.
The importance of cholesterol and specifically LDL-C in determining cardiovascular risk across patient populations has certainly been stressed in mainstream medicine. Some physicians and patients have questioned whether LDL-C is actually an important risk-factor for cardiovascular disease. I wrote a recent post on the journal article, Global effect of modifiable risk factors on cardiovascular disease and mortality, that attempted to answer this question. Notably, higher LDL-C readings did not increase mortality, but increased risk of cardiovascular events, maybe 50-60% increased risk above baseline. Let’s say that you believe these findings and the premise that LDL-C is important in cardiovascular risk. When making blanket suppositions like this, you will quickly encounter challenges if you examine data regarding sodium-glucose cotransporter 2 (SGLT-2) inhibitor medications. This class of medication prevents reabsorption of glucose at the level of the kidney. Use of these medications for diabetes mellitus type 2 (DMII) elevate LDL-C, but seemingly paradoxically, decrease cardiovascular risk. In a way, SGLT-2 inhibitor medications mimic the effects of eating a low-carbohydrate diet, but instead of reducing carbohydrate intake, these medications prevent retaining the carbohydrate intake. As a result when using SGLT-2 inhibitors, some of the body’s energy is obtained from fat-oxidation, with the production of ketones. Ketogenesis, the production of ketones, is what occurs when consuming a very low-carbohydrate or “keto” diet. When your body is using ketogenesis it is using mostly stored fat for energy, rather than energy obtained solely through glucose intake.
A low-carbohydrate diet can have myriad benefits on a host of medical problems. Probably most importantly, low-carbohydrate diet can be a cornerstone treatment for DMII. If we again look at the data from the above referenced paper, DMII results in both a massive increase in cardiovascular events and death. As a scientist and a physician, I must reconcile the potential benefit and potential harm of such a diet and apply this to patient care.
Nicholas Norwitz, David Feldman and others have noticed an interesting set of findings when eating a low-carbohydrate diet. Some lean patients have a fairly normal VLDL-C and triglyceride level, but massively increased LDL-C and total cholesterol after implementing a low-carbohydrate diet. Interestingly, in some of these patients, these laboratory findings can been reversed in a very short time window with addition of extra carbohydrates in the diet and subsequent retesting. I have listed the title of this open access journal article and hyperlink below.
Elevated LDL Cholesterol with a Carbohydrate-Restricted Diet: Evidence for a “Lean Mass Hyper-Responder” Phenotype https://doi.org/10.1093/cdn/nzab144
Now that these patients have been identified, they need to be studied to determine their cardiovascular risk. To begin with, it seems that the massive increases in LDL-C and total cholesterol will likely not be as profound in metabolically unhealthy patients that I see more commonly in my office setting, compared to those lean patients identified in the above study. Regardless, the BIG question is: does this elevated LDL-C and total cholesterol finding in those using a low-carbohydrate diet equate to increased risk of cardiovascular events and death? I am eagerly awaiting the results of a lean mass hyper-responder study that has been submitted for publication. I am aware of the framework of this study. In this study, coronary calcium scans were used to objectively compare predicted risk of cardiovascular events between a group of patients identified as lean mass hyper-responders eating a low-carbohydrate diet and a patient group that did not eat a low-carbohydrate diet with fairly “normal” LDL-C and total cholesterol readings. I am aware that this study is a small in size and will be under-powered to generalize the results across large population groups. I am also aware that a low-carbohydrate diet does not offer a pharmaceutical company the opportunity to develop a profitable patented medication. This information may be as good as it gets for now. Stay tuned. I will summarize the results of this upcoming article when it is published!