OBJECTIVES: To grade the evidence from published meta-analyses of randomized clinical trials (RCTs) that assessed the association of ketogenic diets (KD), ketogenic low-carbohydrate high-fat diet (K-LCHF), and very low-calorie KD (VLCKD) with health outcomes.

METHODS: PubMed, EMBASE, Epistemonikos, and Cochrane database of systematic reviews were searched up to May 20, 2022. Meta-analyses of RCTs of KD were included. Meta-analyses were re-performed using a random-effects model. The quality of evidence per association provided in meta-analyses was rated by the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) criteria as high, moderate, low, and very low.

RESULTS: We included 16 meta-analyses comprising 67 RCTs (median [interquartile range, IQR] sample size of 52 [20-115] participants and follow-up period of 3 [2-12] months) and 113 unique associations. There were 52 statistically significant associations (46%) of which four associations were supported by high-quality evidence (reduced triglyceride (n=2), seizure frequency (n=1) and increased low-density lipoprotein cholesterol (LDL-C) (n=1)) and four associations supported by moderate-quality evidence (decrease in body weight, respiratory exchange ratio (RER), hemoglobin A1c, and increased total cholesterol). The remaining associations were supported by very low (28 associations) to low (18 associations) quality evidence. In overweight or obese adults, VLCKD was significantly associated with improvement in anthropometric and cardiometabolic outcomes without worsening muscle mass, LDL-C, and total cholesterol. K-LCHF was associated with not only reduced body weight and body fat percentage but also reduced muscle mass in healthy participants.

CONCLUSIONS: This umbrella review found beneficial associations of KD supported by moderate to high-quality evidence on seizure and several cardiometabolic parameters. However, KD was associated with a clinically meaningful increase in LDL-C. Clinical trials with long-term follow-up are warranted to investigate whether the short-term effects of KD will translate to beneficial effects on clinical outcomes such as cardiovascular events and mortality.