Higher LDLs with Low Carbs?

As increasing numbers of people adopt low-carb and ketogenic diets, new data are emerging that raise intriguing questions about the effects of these ways of eating on long-term cardiometabolic health. A paper published recently in The American Journal of Clinical Nutrition sheds new light on the phenomenon of increased LDL-cholesterol among a subset of people who adopt low-carbohydrate diets.

The effect of low-carb diets on a standard lipid profile are somewhat predictable: triglycerides decrease, HDL-C increases, and the pattern of LDL particles shifts in favor of increased large, buoyant particles and decreased small, dense particles – a shift to “pattern A” from “pattern B,” with pattern A believed to be less atherogenic. However, the effect of carbohydrate restriction on LDL-C varies. While most people who follow a low-carb diet experience a decrease in LDL-C, some experience an increase, and a small subset – a group referred to as “hyper-responders” – experience a very large increase.

It was previously believed that an increase in saturated fat intake was responsible for the rise in LDL-C on a low-carb diet, and therefore, patients in the hyper-responder category were counseled to reduce saturated fat and emphasize foods higher in mono- and polyunsaturated fats, along with increasing fiber intake in an effort to decrease LDL-C. However, this new paper suggests that it’s not the composition of dietary fat, but rather, an individual’s BMI, that determines whether they are more or less likely to exhibit increased LDL-C in conjunction with carbohydrate restriction.

The paper was a meta-analysis of 41 trials with 1379 participants and a mean intervention duration of just over 19 weeks. Subjects with a lower body mass index (BMI) at baseline were found to show increases in LDL-C while those with a higher BMI showed decreases:

This may not be a new phenomenon, but it is becoming more prevalent as low-carb and ketogenic diets become more popular. Although the ketogenic diet originated a century ago as a treatment for epilepsy, the most common reasons people adopt low-carb diets today include weight loss and managing type 2 diabetes, so the majority of people eating this way fall in the higher BMI categories and thus are more likely to experience a decrease in LDL-C or a neutral effect. It’s only of late that greater numbers of people at the lower end of the body weight spectrum have been adopting low-carb diets, so this “lean-mass hyper-responder” phenotype was identified only recently.

At the present time, the question remains whether this increase in LDL-C is something that warrants pharmaceutical intervention and/or a dietary change toward increased carb intake, or whether it may be a non-harmful artifact common to leaner individuals following low-carb diets. Research is ongoing to determine whether an increase in LDL-C, independent of any other factor, is inherently dangerous for cardiovascular health, particularly in the context of a low-carb diet, which typically improves a host of other risk factors, such as blood glucose, insulin sensitivity, hypertension, body weight, and inflammation.

Previous research has identified numerous individuals who, despite having LDL-C ≥190 mg/dL, were found to have zero arterial calcification and be at low risk for cardiovascular events, raising interesting questions about the purported causal link between elevated LDL-C and CVD – a link that has been controversial for years.

Research is currently underway to study lean-mass hyper-responders to see if their substantially increased LDL-C causes or accelerates atherosclerotic plaque buildup. Findings published at the end of 2023 suggested that this is not the case. Compared to subjects from the Miami Heart Study matched for multiple factors (age, gender, race, diabetes, hyperlipidemia, hypertension, and past smoking), lean-mass hyper-responders following a ketogenic diet showed no significant difference in coronary artery calcium score and there was no relationship between LDL-C elevation and plaque burden.

It is important to note that familial hypercholesterolemia was ruled out among the lean-mass hyper-responders. These individuals had normal LDL-C levels prior to adopting a ketogenic diet; the dramatic elevation in LDL-C coincided with carbohydrate restriction. This phenomenon was described in detail in a paper using the phrase, “the Lipid Energy Model,” which explored the biochemical and metabolic mechanisms that may explain why the LDL-C elevation occurs, particularly among leaner people.

As more research is conducted, we may get closer to understanding the implications of elevated LDL-C in the context of low-carb and ketogenic diets, and whether it is cause for concern, or whether our fundamental understanding of lipid trafficking and the relationship between cholesterol and cardiovascular disease may need further examination.