Ketogenic diets (KDs) are increasingly used for purposes far beyond weight loss. Therapeutic carbohydrate restriction is now being employed for mental health purposes, chronic kidney disease, inflammatory bowel disease, and more. Despite the obvious benefits of carbohydrate restriction—such as weight loss, improved glycemic control, and reversal of metabolic syndrome—concerns remain regarding the potential for elevated low-density lipoprotein cholesterol (LDL-C) in people who adopt KDs. Keto is well-recognized for lowering triglycerides and raising high-density lipoprotein cholesterol (HDL-C), which is a favorable change with regard to risk for cardiovascular disease (CVD), but an elevation in LDL-C—particularly an extreme elevation—leaves many practitioners feeling uncertain about the overall risk profile.
It is imperative to come closer to answering questions regarding the impact of elevated LDL-C among individuals following a KD in order to inform treatment. If someone experiences a remarkable transformation in health—they lose weight, put type 2 diabetes into remission, resolve major depression or obsessive-compulsive disorder—should they be encouraged to abandon the diet if a profound elevation in LDL-C happens to occur alongside those improvements?
A study published in JACC: Advances seeks to move research forward toward identifying whether severe elevations in LDL-C are associated with increased atherosclerosis in lean, otherwise healthy people following KDs. This one-year prospective study followed 100 subjects classified as “lean mass hyper-responders” (LMHRs) or near-LMHRs—a population characterized by a non-overweight or obese body mass index (BMI) and a triad consisting of triglycerides ≤80 mg/dl, HDL-C ≥60 mg/dl and LDL-C ≥90 mg/dl, with the LDL-C measurement having increased substantially (≥50%) after adoption of a KD. In other words, these individuals do not have familiar hypercholesterolemia; they had normal or closer-to-normal LDL-C on a higher carbohydrate diet. (The triad for the true LMHR phenotype is slightly stricter: triglycerides ≤70 mg/dl, HDL-C ≥80 mg/dl and LDL-C ≥200 mg/dl.)
Previous research showed that, compared to matched controls, LMHRs who had followed a KD for a mean of nearly five years exhibited no greater total coronary plaque, calling into question whether an extreme elevation in LDL-C induced by carbohydrate restriction represents a risk factor for cardiovascular disease. The present study showed that over one year, there was no association between baseline LDL-C or ApoB, nor changes in these, and changes in total plaque score or non-calcified plaque volume. There were also no associations found between saturated fat intake or cumulative exposure to LDL-C while on a KD. The strongest associations found were between baseline coronary artery calcium score (CAC) and other plaque metrics, leading the researchers to say, “Plaque begets plaque but ApoB does not.”
To clarify, this study looked at a unique population: those with extreme elevations in LDL-C specifically in response to carbohydrate restriction, who are metabolically healthy based on other typical measurements. The findings may not be generalizable to metabolically unhealthy individuals, but for those who adopt a low-carb or ketogenic diet and experience significant improvements in their health along with a substantial rise in LDL-C, these and similar findings may provide some degree of reassurance that the elevation in LDL-C may not automatically indicate increased cardiovascular risk.
Evaluations of other populations have also called into question the validity of using LDL-C as an independent predictor of CVD. Research on the well-known Multi-Ethnic Study of Atherosclerosis (MESA) revealed that more than a third of subjects with LDL-C ≥190mg/dL had a zero CAC score and low risk for cardiovascular events, suggesting that even among a population of people not following low-carb diets and not classified as LMHRs, LDL-C, by itself, is a poor indicator of cardiovascular risk. Similar findings came from a 2022 study in Denmark: in individuals with LDL-C ≥190 mg/dL (considered “severely elevated”), absence of calcified and noncalcified plaque assessed via coronary computed tomography angiography (CCTA) was associated with low risk for cardiovascular events. The authors noted that owing to the high LDL-C, these subjects “are universally considered to be at high risk by guidelines,” yet the advanced screening revealed them to be low risk. Here again it’s evident that treatment should be individualized and that the concentration of cholesterol in the bloodstream is not always a reliable indicator of existing atherosclerosis, nor of future event risk.
Regardless of the type of diet an individual follows, advanced screening—such as CAC and CCTA—can help to “de-risk” and give a clearer picture as to whether or not they are candidates for lipid-lowering therapies.
More research is needed to elucidate the degree to which LDL-C may be an independent risk factor, but findings from the present study noted:
“While both LDL-C and ApoB are independent risk factors for atherosclerosis, the absolute risk associated with elevated LDL-C and ApoB is context-dependent, including the etiology of the elevations in these biomarkers as well as interactions with other risk markers. Thus, these data are consistent with the observation that high LDL-C and ApoB among a metabolically healthy population have different cardiovascular risk implications than high LDL-C among those with metabolic dysfunction, who constitute a majority proportion of the population.” (Emphasis added.)
An obvious limitation of the present study is that subjects were followed for only one year, but it employed advanced screenings. As the researchers noted, “…given the quality of modern CCTA imaging, it is generally agreed that this is sufficient to observe and quantify changes in NCPV [non-calcified plaque volume].”
It is worth noting that extreme elevations in LDL-C in response to carbohydrate restriction are rare. It appears to happen more commonly in individuals who are lean, whereas those with a BMI in the obese category are more likely to see a decrease in LDL-C, and many will see no significant change at all. Regardless of changes to LDL-C, overall cardiovascular risk profiles typically improve on low-carb and ketogenic diets. Compared to low-fat diets, low-carb diets—and very-low-carb diets, in particular—have been shown to induce greater improvements in cardiometabolic risk owing to larger decreases in triglycerides and larger increases in HDL-C. In subjects with type 2 diabetes, a KD was shown to decrease 10-year atherosclerotic cardiovascular disease (ASCVD) risk score by approximately 12%—despite a 10% increase in LDL-C. (Favorable changes included increases in HDL-C and LDL particle size, with decreases in blood pressure, LDL particle number, triglyceride-to-HDL-C ratio, and hs-CRP.)