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Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial

Nature Medicine volume 29, pages 963–972 (2023)Cite this article

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Abstract

Intermittent fasting appears an equivalent alternative to calorie restriction (CR) to improve health in humans. However, few trials have considered applying meal timing during the ‘fasting’ day, which may be a limitation. We developed a novel intermittent fasting plus early time-restricted eating (iTRE) approach. Adults (N = 209, 58 ± 10 years, 34.8 ± 4.7 kg m−2) at increased risk of developing type 2 diabetes were randomized to one of three groups (2:2:1): iTRE (30% energy requirements between 0800 and 1200 hours and followed by a 20-h fasting period on three nonconsecutive days per week, and ad libitum eating on other days); CR (70% of energy requirements daily, without time prescription); or standard care (weight loss booklet). This open-label, parallel group, three-arm randomized controlled trial provided nutritional support to participants in the iTRE and CR arms for 6 months, with an additional 12-month follow-up. The primary outcome was change in glucose area under the curve in response to a mixed-meal tolerance test at month 6 in iTRE versus CR. Glucose tolerance was improved to a greater extent in iTRE compared with CR (−10.10 (95% confidence interval −14.08, −6.11) versus −3.57 (95% confidence interval −7.72, 0.57) mg dl−1 min−1; P = 0.03) at month 6, but these differences were lost at month 18. Adverse events were transient and generally mild. Reports of fatigue were higher in iTRE versus CR and standard care, whereas reports of constipation and headache were higher in iTRE and CR versus standard care. In conclusion, incorporating advice for meal timing with prolonged fasting led to greater improvements in postprandial glucose metabolism in adults at increased risk of developing type 2 diabetes. ClinicalTrials.gov identifier NCT03689608.

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Fig. 1
Fig. 2: Postprandial responses to mixed-meal tolerance test.

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Data availability

Anonymized data from this study are available on request from the corresponding author for 36 months from date of publication with a full research plan for academic use only. The data are not publicly available as they contain information that could compromise research participant consent.

Code availability

No unique software or computational code was created for this study.

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Acknowledgements

This work was supported by the National Health and Medical Research Council Project Grant (APP1143092). X.T.T. was supported by an Australian Government Research Training Program Scholarship from The University of Adelaide. This work was supported by a Diabetes Australia Research Program Grant (Y21G-SART) awarded to T.J.S., J.B. and L.K.H. The funder had no role in the design of this study and the interpretation of the study results. We thank all the trial participants.

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Authors and Affiliations

  1. Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia

    Xiao Tong Teong, Kai Liu, Andrew D. Vincent, Julien Bensalem, Bo Liu, Lijun Zhao, Christine Feinle-Bisset, Gary A. Wittert, Amy T. Hutchison & Leonie K. Heilbronn

  2. Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia

    Xiao Tong Teong, Kai Liu, Andrew D. Vincent, Julien Bensalem, Bo Liu, Kathryn J. Hattersley, Lijun Zhao, Timothy J. Sargeant, Gary A. Wittert, Amy T. Hutchison & Leonie K. Heilbronn

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Contributions

L.K.H., A.T.H., C.F.-B., A.D.V. and G.A.W. designed the study. A.D.V. wrote the statistical analysis plan, performed randomization and statistical analysis. X.T.T., K.L., B.L., L.Z. and A.T.H. collected the blood samples. G.A.W. provided clinical support and supervision. X.T.T., K.L., A.D.V. and L.K.H. analyzed the data. J.B., K.J.H. and T.J.S. measured the β-hexosaminidase activity. All authors critically revised the draft and approved the final manuscript. L.K.H. had full access to the data and had primary responsibility for the final publication.

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Correspondence to Leonie K. Heilbronn.

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Nature Medicine thanks Jonathan Little, Krista Varady, Luke Ouma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Jennifer Sargent, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Comparisons of (a) iTRE vs CR, and (b) iTRE + CR vs SC for joint change in postprandial glucose (mg/dL/min) and HbA1c (%).

Points indicate prior (blue), posterior (red) and observed means (black). The ellipses indicate 95% central prior (blue) and posterior (red) probabilities. We note that our prior belief was for a correlation of 0.7 in change of the two outcomes, which was not observed. iTRE, intermittent time-restricted diet at 70% of calculated energy requirements; CR, calorie restriction diet at 70% of calculated daily energy requirements; SC: standard care diet.

Extended Data Fig. 2 Weight loss (kg) relative to baseline.

Presented are means and 95% CIs (calculated as \(\overline x \pm 1.96\,{{{\mathrm{SEM}}}}\)) of the non-fasting weight change by group during each face to face check-in visit. Treatment group trajectories were compared using linear mixed effects regression assuming piecewise linear effects assumed for the interventions over two time periods: month 0–6 and month 7–18, and both random intercepts and slopes for individuals. iTRE, intermittent time-restricted diet at 70% of calculated energy requirements; CR, calorie restriction diet at 70% of calculated daily energy requirements; SC: standard care diet.

Extended Data Fig. 3 Weight loss percentage from baseline to month 6 in iTRE (a), CR (b), SC (c).

iTRE, intermittent time-restricted diet at 70% of calculated energy requirements; CR, calorie restriction diet at 70% of calculated daily energy requirements; SC: standard care diet.

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Teong, X.T., Liu, K., Vincent, A.D. et al. Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial. Nat Med 29, 963–972 (2023). https://doi.org/10.1038/s41591-023-02287-7

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