Reference
Budoff MJ, Manubolu VS, Kinninger A, et al. Carbohydrate restriction-induced elevations in LDL-cholesterol and atherosclerosis: the KETO trial. JACC Adv. 2024;3(8):101109.
Study Objective
The objective of this study was to evaluate coronary artery plaque burden in individuals exhibiting the lean mass hyper-responder (LMHR) lipid phenotype or near-LMHR lipid phenotype with low-density lipoprotein cholesterol (LDL-C) ≥ 190 mg/dL and compare that to matched controls with lower LDL-C from the Miami Heart (MiHeart) Study.
Key Takeaway
The understanding of risk level imparted by elevated LDL-C in different metabolic states continues to evolve, and more research is needed to help clinicians determine whether lipid-lowering treatment is necessary in all cohorts.
Design
Matched cohort study
Participants
The ketogenic diet (KETO) cohort consisted of 80 individuals, aged 55.5 ± 7.9 years, who were: following a ketogenic diet for an average of 4.7 years; exhibiting a carbohydrate restriction–induced LDL-C ≥ 190 mg/dL, high-density lipoprotein cholesterol (HDL-C) ≥ 60 mg/dL, and triglyceride levels ≤ 80 mg/dL; and without familial hypercholesterolemia. Investigators compared these individuals 1:1 with 80 subjects, aged 55.5 ± 7.4 years, from the MiHeart cohort. They also matched subjects for gender, race, hyperlipidemia, hypertension, and smoking status.
Investigators also included a subgroup analysis of 35 individuals with LDL-C ≥ 200 mg/dL, HDL-C ≥ 80 mg/dL, and triglycerides ≤ 70 mg/dL. These individuals met the full criteria for LMHR status.
Study Parameters Assessed
Investigators compared coronary plaque burden between cohorts, using coronary artery calcium (CAC) scans and coronary computed tomography angiography (CCTA). They then correlated LDL-C levels to these plaque levels.
Primary Outcome Measure
Coronary plaque burden. Specifically, researchers sought to investigate whether the otherwise metabolically healthy individuals, maintaining the LMHR or near-LMHR phenotype for an average of 4.7 years, exhibited different coronary plaque burden compared to individuals matched 1:1 from the population-based MiHeart cohort.
Key Findings
Multivariable regression analysis revealed no difference in CAC and CCTA measurements, after adjustment for body mass index (BMI) and age, between KETO and MiHeart subjects.
- Median CAC was 0 (interquartile range [IQR]: 0–56) for KETO subjects and 1 for MiHeart subjects (IQR: 0–49; P=0.520).
- Median CCTA total stenosis score (TSS), total plaque score (TPS), and segment involvement score (SIS) were 0 for KETO subjects and 1 for MiHeart subjects, and investigators noted no differences between groups (P>0.20).
A subset of 35 KETO subjects met all 3 strict criteria for LMHR status (LDL-C ≥ 200 mg/dL, HDL-C ≥ 80 mg/dL, and triglycerides ≤ 70 mg/dL). These KETO subjects also exhibited a median CAC score of 0 (IQR: 0–47), while the matched MiHeart subjects had a CAC score of 0 as well (IQR: 0–23). Median TSS, TPS, and SIS were all 0 for subjects in each cohort.
There was no significant correlation between plaque burden (as measured by TPS) and LDL-C level in the fully matched KETO group or subgroup.
Transparency
The Citizen Science Foundation funded the study. The authors reported no disclosures relevant to the contents of the study.
Practice Implications & Limitations
Since the ketogenic diet is a fairly popular choice amongst the lay public and is also not infrequently prescribed by health practitioners, studying the safety of following it long-term is warranted. One key area of concern is cardiovascular risk if/when an individual following the diet sees a substantial rise in their LDL-C.
Some might question the necessity of evaluating the risk of elevated LDL-C when evidence supporting its cardiovascular impacts is already well-established.1
However, lean mass hyper-responders have a unique phenotype and may also display a lack of correlation between LDL-C and plaque burden, at least relative to the typical study subjects involved when investigators are assessing how plaque burden correlates to LDL-C. So, assuming that LDL-C imparts risk in people displaying LMHR characteristics that is similar to what is already understood, may be premature.
One key area of concern is cardiovascular risk if/when an individual following the diet sees a substantial rise in their LDL-C.
What makes the LMHR lipid profile unique is that people who have such elevated LDL-C, unrelated to familial hypercholesterolemia syndromes, do not typically exhibit low triglycerides and high HDL-C levels, a combination that correlates with lower CVD risk.2 They are also seldom particularly fit and metabolically healthy otherwise. However, when they follow a high-quality ketogenic diet, especially while also implementing other health-promoting lifestyle factors such as adequate exercise and sufficient sleep, this phenotype may manifest at a relatively frequent rate.3
Therefore, it is warranted to assess whether risk is different for these people, both to help inform health practitioners as to how best to advise them long term and, on a more fundamental level, as a means of further understanding of the process of atherosclerosis and the role LDL-C plays in it.
Right or wrong, more than ever, people are looking to the internet to help themselves solve their health problems. One of the most common forms of chosen intervention is dietary, and ketogenic, low-carb, and carnivore diets, all of which can lead to the LMHR phenotype, are quite popular options.
It also seems that people questioning conventional medical wisdom—with the cholesterol theory of heart disease being one of the most frequently called into question—is also at an all-time high. People are turning their skepticism into action in droves and choosing to continue their ketogenic and low-carb diets even in the face of massively elevated LDL-C levels, despite direct advice from their doctors to choose another option and/or to pursue lipid-lowering therapies to reduce their apparent risk.
If the LMHR subset of these people proves over time not to exhibit the expected risk for atherosclerosis typically observed with LDL-C in high ranges, this would be very useful information. Not only might it put clinicians’ minds at ease when an LMHR patient shows elevated numbers, but it might also provide another option for dietary intervention that could be both effective and safe, while allowing for a wider array of choices to satisfy some individuals with different tastes, needs, and preferences.
Limitations
Despite all the reasons cited above that allow for some cautious optimism and despite the findings in the present study under review that also look promising at this early stage, our enthusiasm should remain tempered until more is known for a number of reasons. Here are some of the key limitations of this study:
Sample Size and Duration
The study included 80 individuals on a ketogenic diet and with elevated LDL-C who were matched with 80 controls. While this method can provide valuable data, a larger sample size and longer follow-up period would offer more robust conclusions.
Participant Selection
The study focused on lean, metabolically healthy people with a very specific lipid profile and often a lifestyle of above-average healthfulness.
Control Group
The control group came from the Miami Heart cohort, which does not perfectly match the ketogenic diet/LMHR group in multiple areas, potentially confounding the results.
Lack of Clinical Outcomes
The study did not report hard clinical endpoints such as cardiovascular events or mortality, which are crucial for determining long-term safety of the diet followed.
Lack of Generalizability
The study focused on LMHR individuals who experience significant LDL-C elevations on a ketogenic diet while remaining metabolically healthy. This specific phenotype may not be representative of the general population adopting ketogenic diets.
Context
The study doesn’t fully account for other metabolic factors that could influence cardiovascular risk. The ketogenic diet’s effects on inflammation, insulin sensitivity, and other markers might play a role in modifying the impact of elevated LDL-C.
Long-Term Effects
While the study provides valuable short-term data (mean 4.7 years on the diet), the long-term cardiovascular effects of sustained high LDL-C in this context remain uncertain.
Dietary Composition
The investigators did not detail the specific composition of the ketogenic diets participants followed, and different food choices might have varying impacts on cardiovascular health.
Lifestyle Factors
The study may not fully account for other lifestyle factors that could influence cardiovascular health, such as exercise habits or stress levels.
In conclusion, while the KETO trial provides intriguing data, challenging some conventional wisdom about LDL-C and cardiovascular risk, further research is absolutely necessary before any conclusions can be reached. The study’s focus on a very unique and specific phenotype (LMHR) and the study’s relatively short duration are key reasons to cautiously interpret the results at this stage.
Your Conflict of Interest Disclosure
None.
