Intermittent fasting plus early time-restricted eating in adults at risk of T2DM
Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trialLiterature - 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
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.
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.
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.
- 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).
- 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.
- 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).
- 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%).
iTRE led to greater improvements in postprandial glucose metabolism at month 6 in adults at increased risk of T2DM compared to CR or standard care. Fasting triglycerides were strongly reduced at month 2 and 6 in the iTRE group, but not in the CR or the standard care group. Weight loss was greater in the iTRE and CR group compared to the standard care group, but these reductions were lost at follow-up. This indicates that neither weight loss plans were sustainable without active counseling.