Ketogenic Diet Associated with Increased Serum Lipids, 2-fold Greater Risk of MACE

Regular consumption of a low carbohydrate, high-fat diet (LCHF) was associated with elevated LDL-C and apolipoprotein B (ApoB) levels as well as with a 2-fold heightened risk for incident major adverse cardiovascular events (MACE), according to findings of a prospective, population based cohort study presented at American College of Cardiology’s (ACC) Annual Scientific Session Together with the World Congress of Cardiology.

The popular ketogenic, or "keto" diet has purported health benefits in a variety of conditions, including epilepsy, obesity, and even glycemic control for diabetes, according to lead study author Iulia Iatan, MD, PhD, attending physician-scientist at the Healthy Heart Program Prevention Clinic, St. Paul’s Hospital and University of British Columbia’s Centre for Heart Lung Innovation in Vancouver, Canada.

However, research on the consumption of low amounts of carbohydrate, typically 10% of total daily calories, and protein intake between 20% and 30%, with 60% to 80% of daily calories derived from fat, has found the LCHF dietary pattern in some people can either trigger or exacerbate hypercholesterolemia, added Iatan in an ACC statement.

Data are limited on the impact of a LCHF diet on the overall lipid profile and on hard cardiovascular endpoints, Iatan continued. “To our knowledge, our study is one of the first to examine the association between this type of dietary pattern and cardiovascular outcomes.”

“To our knowledge, our study is one of the first to examine the association between this type of dietary pattern and cardiovascular outcomes.”

The researchers tapped the UK Biobank database to identify adults aged 40 to 69 years recruited between 2006 and 2010. Based on responses to a 24-hour dietary intake questionnaire completed by participants upon biobank enrollment, the investigators identified those whose diet met the study's definition of LCHF: daily intake of carbohydrates <100g and/or <25% of total daily energy intake and fat >45% of total daily energy intake. A standard diet, for comparison, was defined as one that did not meet the LCHF criteria.

A total of 305 participants were identified as following the keto dietary regimen. The cohort had a mean age of 54 years, 73% were women and the majority were White. Each individual on a LCHF diet was age- and sex-matched to individuals on a standard diet (n=1220) in a 1:4 ratio.

Iatan and team established the study's primary endpoint of interest as the impact of a keto-style diet on serum lipid levels. The study's secondary endpoint was incident MACE, defined as a composite outcome of angina, MI, coronary artery disease, ischemic stroke, peripheral artery disease, and coronary and carotid revascularization.

FINDINGS

The investigators found that, compared with participants consuming a standard diet, those following the LCHF pattern had significantly elevated levels of some lipids and ketone bodies:

• LDL cholesterol (3.8 vs. 3.64 mmol/L; P=.004)
• ApoB (1.09 vs. 1.04 g/L; P<.001)
• Total cholesterol (6.08 vs. 5.85 mmol/L; P=.002)
• 3-hydroxybutyrate (0.14 vs. 0.06 mmol/L; P<.001)
• Acetone (0.02 vs. 0.01 mmol/L; P<.001)
• Acetoacetate (0.02 vs. 0.01 mmol/L; P<.001)

In contrast, the researchers reported lower levels of lipoprotein(a) (39.43 vs. 46.13 nmol/L; P=.041) and triglycerides (1.34 vs. 1.53 mmol/L; P=.001) in the keto-diet group vs the standard diet group.

After a mean follow-up period of 11.8 years, analysis of data for the secondary composite outcome, incident MACE, found the rate more than 2 times higher among those following the LCHF vs the standard diet (9.8% vs. 4.3%; adjusted HR, 2.18; 95% CI, 1.39–3.43; P<.001); this analysis was completed after multivariable adjustment for presence of diabetes, hypertension, smoking, and BMI.

In a subgroup analysis with participants stratified by LDL-C level, the risk of MACE among keto-style diet followers who had an LCL-C of ≥5 mmol/L was nearly 7-fold greater compared with those who followed a standard diet and had an LDL level of <3.5 mmol/L (HR = 6.68; 95% CI, 2.62-17.09; P<.001), according to the study. Amont participants eating a standard diet who had an LDL-C level ≥5 mmol/L, the HR was 1.90 (95% CI 0.64-5.69).

“Among the participants on an LCHF diet, we found that those with the highest levels of LDL cholesterol were at the highest risk for a cardiovascular event,” Iatan said. “Our findings suggest that people who are considering going on an LCHF diet should be aware that doing so could lead to an increase in their levels of LDL cholesterol. Before starting this dietary pattern, they should consult a health care provider. While on the diet, it is recommended they have their cholesterol levels monitored and should try to address other risk factors for heart disease or stroke, such as diabetes, high blood pressure, physical inactivity, and smoking.”

The study’s findings also suggest that not everyone responds to an LCHF diet in the same way. “One of our next steps,” adds Iatan, “will be to try to identify specific characteristics or genetic markers that can predict how someone will respond to this type of diet.”

Authors note one study limitation is that participants provided dietary information at only one point in time. Moreover, self-reports of food consumption can be inaccurate, although this questionnaire has been extensively validated, they said.

Abstract: Iatan I, Huang K, Vikulova D, Brunham L. Association of a low-carbohydrate high fat (ketogenic) diet with plasma lipid levels and cardiovascular risk in a population-based cohort. Abstract presented at the 2023 American College of Cardiology’s Annual Scientific Session Together with the World Congress of Cardiology; March 4-6. 2023; New Orleans, LA.