CVD Risk from Ketogenic Diets

By Michael H. Crawford, MD, Editor

SYNOPSIS: A recent analysis of the UK Biobank data found that subjects on a low-carbohydrate, high-fat diet had higher levels of low-density lipoprotein cholesterol and apolipoprotein B, and an increase in incident major adverse cardiovascular events over a 12-year follow-up than subjects on a standard diet.

SOURCE: Iatan I, Huang K, Vikulova D, et al. Association of a low-carbohydrate high-fat diet with plasma lipid levels and cardiovascular risk. JACC Adv 2024; Jun 3. https://doi.org/10.1016/j.jacadv.2024.100924

Low-carbohydrate (LC), high-fat (HF) diets, such as the ketogenic diet, have gained in popularity because of their positive effects on glycemic control, weight reduction, and subjective well-being. However, because of the observation that there can be considerable increases in low-density lipoprotein (LDL) cholesterol (C) on these diets, concern has risen about their effect on the risk of developing atherosclerotic cardiovascular disease (ASCVD) and major adverse cardiovascular events (MACE). Thus, these investigators from the University of British Columbia studied a population-based cohort from the UK Biobank (UKBB) to investigate the association between LCHF diets with serum lipid levels and MACE.

UKBB is a prospective, observational study of more than 500,000 subjects aged 40 to 69 years in the United Kingdom from 2006 to 2010 with ongoing follow-up. Participants who completed one or more dietary questionnaires in 2011-2012 were recruited. Those who were taking lipid-lowering therapy or were missing baseline LDL-C levels and dietary questionnaires were excluded. Included were those who met criteria for an LCHF diet or a standard diet (SD). Each LCHF participant was age- and sex-matched 1:4 to individuals on a SD. MACE was defined as the occurrence of unstable angina, myocardial infarction, ischemic stroke, peripheral arterial disease, and coronary or carotid revascularization.

The study cohort consisted of 305 subjects on a LCHF diet and 1,220 age- and sex-matched subjects on a SD (mean age 53 years, 72% women). LCHF subjects were more likely to have diabetes compared to SD subjects (4.9% vs. 1.7%; P = 0.001) and obesity (26% vs. 20%; P = 0.012). LDL-C and apolipoprotein B levels were significantly increased in the LCHF vs. SD group (P < 0.001), and 11% of LCHF and 6.2% of SD individuals demonstrated severe hypercholesterolemia (LDL-C > 5 mmol/L; P < 0.001). Interestingly, lipoprotein (a) and triglycerides were lower on the LCHF diet. After 12 years of follow-up, 9.8% of LCHF vs 4.3% of SD participants experienced a MACE (P < 0.001). This difference remained significant after adjustment for cardiovascular risk factors (hazard ratio, 2.18; 95% confidence interval, 1.39-3.43; P < 0.001). The authors concluded that a LCHF diet was associated with a significant increase in serum LDL-C and apolipoprotein B levels, and incident MACE.

COMMENTARY

Ketogenic diets have become increasingly popular not only because of appetite suppression and, consequently, weight and glycemic control, but also because of perceived subjective benefits on energy, endurance, and mental clarity. LCHF diets usually limit carbohydrate intake to ≤ 50 g/day or ≤ 10% of daily caloric intake with > 70% of total daily energy intake from fat, which typically induces ketosis. Also, the fats consumed usually are from animals and are high in saturated fats.

Naturally, there has been growing concern about the effect of LCHF diets on atherogenic lipoproteins. Thus, this study from the UKBB is of interest. It confirmed that the incidence of severe elevations in LDL-C are almost two times higher on the LCHF diet and that this increase in LDL-C was most marked in those with a genetic predisposition to hypercholesterolemia. A major strength of the UKBB study is that it the first to demonstrate the effect of the LCHF diet on ASCVD outcomes. Our fears were justified, since MACE were more frequent in those on the LCHF diet compared to a SD, which was defined as everything that was not LCHF.

There are weaknesses to the UKBB study. Since it is observational, we cannot confidently condemn the LCHF diet as the cause of the higher incidence of MACE. There may be residual confounders not measured. Since the diet questionnaire was only done once at baseline, we do not know if the diet was continued for the duration of the study. However, in a subgroup with a second questionnaire confirming continuation of the LCHF diet, the results were similar. Also, since there were more people with diabetes in the LCHF group, this may have skewed the results, but removing them did not change the results either.

UKBB participants usually are healthier, more likely white and British, so the results may not apply to those of other races or ethnicities. Finally, diet was self-reported and no confirmatory investigations were done. Despite these limitations, there has to be concern that the LCHF diet is not a good long-term solution to weight and glycemic control.