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

Literature - Tong Teong X, Liu K, Vincent AD, et al. - Nat Med. 2023 Apr;29(4):963-972. doi: 10.1038/s41591-023-02287-7

Introduction and methods

Background

Healthy lifestyle changes such as dietary interventions and weight management reduce the risk of developing T2DM [1-2]. Intermittent fasting (IF), which is often described as days with ~30% of energy requirements interspersed with days of unrestricted eating, results in greater improvements in insulin resistance compared with calorie restriction (CR) [3-4]. However, it remains unknown whether IF improves postprandial glucose tolerance compared with CR. Time-restricted eating (TRE) with long fasting periods per day has emerged as a novel IF method, which is more in alignment with circadian rhythms, and may active several metabolic pathways [5-6].

Aim of the study

The authors compared the effects of IF plus early time-restricted eating (iTRE) with CR and standard care in adults at risk of T2DM.

-

Methods

This was an open-label, three-arm parallel group sequential RCT, with a 6-month intervention phase followed by a 12-month follow-up. A total of 209 participants (57% female, 58±10 years, 34.8 ± 4.7 kg mֿ²) were randomized to iTRE, CR or standard care (2:2:1 ratio). iTRE was defined as 30% of energy requirements consumed between 8:00 and 12:00, followed by a 20-h fasting period on three nonconsecutive days per week and unrestricted eating on other days. CR was defined as 70% of the energy requirements without time prescription. Participants in the iTRE group and CR group received meal replacements and one-on-one diet counseling during the first 6 months. After 6 months these participants had the option to continue with the previous or a modified plan. Participants in the standard care group received a weight booklet, with no further counseling. Eligible participants were aged 35-75 years, scored ≥12 on the Australian Type 2 Diabetes Risk Assessment Tool, had weight fluctuations ≤5% for more than 6 months before study entry, had no diagnosis of diabetes, and did not take medications that might affect glucose metabolism and/or weight management.

Outcomes

The primary endpoint was the change in postprandial glucose area under the curve (AUC) at 6 months. Key secondary endpoints were related to changes in glycemic, cardiovascular and liver markers, and body weight.

Main results

Glycemic control

• The improvements in glucose tolerance after a mixed-meal at month 6 were greater in the iTRE group compared to the CR group (difference in glucose AUC of -10.10 mg dl ֿ ¹min ֿ ¹; 95%CI: -14.08 to -6.11 in the iTRE group; and -3.57 mg dl ֿ ¹min ֿ ¹; 95%CI: -7.72 to 0.57 in the CR group; P=0.03). However, the effect was lost at month 18.
• A greater difference in insulin AUC after a mixed-meal at 6 months was measured in the iTRE group compared to the CR group (difference of -30.13 U mLֿ ¹ min ֿ ¹; 95%CI: -38.80 to -21.46 in the ITRE group; -16.83 U mLֿ ¹ min ֿ ¹; 95%CI: -25.6 to -8.06 in the CR group; P=0.04).
• HbA1c levels at month 6 were reduced in both the iTRE group (-0.09%; 95%CI: -0.13 to -0.06) and CR group (-0.11%; 95%CI: -0.15 to -0.07), but not in the standard care group (+0.02%; 95%CI: -0.03 to 0.07).

Cardiovascular risk

• Greater reductions in SBP at month 2 were detected in the iTRE group and the CR group compared with the standard care group (difference of -6.16 mmHg; 95%CI: -8.42 to -3.91 in iTRE; -6.25 mmHg; 95%CI: -8.67 to -3.84 in CR; -0.90 mmHg; 95%CI: -4.32 to 2.52 in standard care). Similar results were found for DBP at month 6 (difference of -5.42 mmHg; 95%CI: -6.69 to -4.15 in iTRE; -4.84 mmHg; 95%CI: -6.19 to -3.49 in CR; -2.19 mmHg; 95%CI: -4.05 to -0.33 in standard care).
• Fasting triglycerides levels at month 6 were more strongly reduced in the iTRE group vs. the CR group and the standard care group (difference of -18.41 mg dl ֿ ¹; 95%CI: -25.68 to -10.63; -2.80 mg dl ֿ ¹; 95%CI: -10.40 to 5.37; -2.49 mg dl ֿ ¹; 95%CI: -13.35 to 9.49, respectively). This effect was already present at month 2. There were no differences between groups in postprandial triglycerides.
• Total cholesterol and LDL levels at month 6 were lower in the iTRE group vs. standard care group (difference in total cholesterol was -14.55 mg dl ֿ ¹; 95%CI: -21.00 to -8.10 in iTRE vs. -0.79 mg dl ֿ ¹; 95%CI: -10.21 to 8.64 in standard care; P<0.05; difference in LDL was -13.87 mg dl ֿ ¹; 95%CI: -20.05 to -7.69 in iTRE vs. -1.52 mg dl ֿ ¹; 95%CI: -10.56 to 7.52 in standard care; P<0.05).
• There was no difference in HDL or hsCRP levels between groups.

Liver health

• Reductions in plasma β-hexosaminidase activity at month 6 were greater in iTRE compared to CR or standard care (difference of -24.70 pmol min ֿ ¹ mg ֿ ¹; 95%CI: -33.81 to -15.59 in iTRE; -8.91 pmol min ֿ ¹ mg ֿ ¹; 95%CI: -18.32 to 0.50 in CR; 4.51 pmol min ֿ ¹ mg ֿ ¹; 95%CI: -8.51 to 17.53 in standard care; P between iTRE and CR=0.02; P between iTRE and standard care <0.05).
• There was no significant difference in alanine aminotransferase or aspartate aminotransferase between groups.

Body weight and composition

• Body weight reductions at month 6 were greater in both iTRE and CR compared to standard care (difference of -7.59%; 95%CI: -8.32 to -6.82 in iTRE; -6.99%; 95%CI: -7.77 to -6.20 in CR; -2.55%; 95%CI: -3.64 to -1.46 in standard care; both P<0.05). However, these differences were abolished at month 18. There was no difference in weight reduction between the iTRE group and the CR group.
• Greater reductions in fat mass at month 6 were detected in the iTRE group and the CR group compared to the standard care group (difference of -6.19 kg; 95%CI: -7.34 to -5.03 in iTRE; -5.76 kg; 95%CI: -6.87 to -4.66 in CR; -2.48 kg; 95%CI: -4.12 to -0.83 in standard care).
• Visceral fat mass reductions at month 6 were greater in the iTRE group and the CR group compared to the standard care group (difference of -0.51 kg; 95%CI: -0.63 to -0.39 in iTRE; -0.48 kg; 95%CI: -0.60 to -0.37 in CR; -0.26 kg; 95%CI: -0.43 to -0.09 in standard care).

Safety outcomes

• Participants experienced mostly transient and mild adverse events such as flu-like symptoms and back pain. Four serious adverse events were reported, but they were not related to the intervention.
• The incidence of fatigue was higher in iTRE (56%) compared to CR (37%) and standard care (35%) over the first 6 months and during follow up.
• The incidence of constipation during the first 6 months were higher in iTRE (33%) and CR (27%) compared to standard care (5%).
• Headaches were more frequently reported during follow-up in the iTRE group (26%) and the CR group (26%) compared to the standard care group (6%).

Conclusion

References

Find this article online at Nat Med.