Duration-Dependent Ketone Body Responses to Fasting: A Systematic Review, Meta-Analysis, and Meta-Regression

Prolonged fasting with no caloric intake induces a metabolic shift characterized by increased fat oxidation and ketone production. However, the magnitude of circulating ketone responses and their dependence on fasting duration have not been quantitatively synthesized. This systematic review and meta-analysis evaluated the effects of water-only fasting and other prolonged fasting protocols involving complete caloric abstinence on circulating ketone biomarkers and examined whether fasting duration moderates these responses. PubMed, Web of Science, and Scopus were searched for human studies published between 2000 and 2025. Eligible studies reported pre–post measurements of β-hydroxybutyrate (BHB), acetoacetate, or total plasma ketones following water-only or other non-caloric fasting protocols. Random-effects meta-analyses were performed using Hedges’ g. Duration effects were assessed through subgroup analyses (≤3 days vs. >3 days) and random-effects meta-regression with study-level cluster-robust standard errors. Thirty studies providing 44 effect sizes were included. Fasting significantly increased BHB (g = 2.794), total plasma ketones (g = 3.260), and acetoacetate (g = 1.731). Greater elevations in BHB and total plasma ketones were observed with fasting durations exceeding three days. Meta-regression indicated significant positive associations between fasting duration and responses for BHB and total plasma ketones, whereas no significant association was detected for acetoacetate. Despite substantial heterogeneity for BHB and total plasma ketones, sensitivity analyses supported the robustness of the pooled effects. Small-study effects were detected for BHB, whereas funnel-plot asymmetry for total plasma ketones was considered exploratory because of the limited number of studies. Water-only fasting and other prolonged fasting protocols involving complete caloric abstinence are associated with marked increases in circulating ketone bodies, with a clear duration-dependent pattern observed particularly for BHB and total plasma ketones.