Randomized controlled trial of once-per-week intermittent fasting for health improvement: the WONDERFUL trial

Abstract

Aims: Low-density lipoprotein cholesterol (LDL-C) predicts heart disease onset and may be reduced by intermittent fasting. Some studies, though, reported that fasting increased LDL-C; however, no study evaluated LDL-C as the primary endpoint. This randomized controlled trial evaluated the effect of low-frequency intermittent fasting on LDL-C and other biomarkers.

Methods and results: Adults aged 21-70 years were enrolled who were not taking a statin, had modestly elevated LDL-C, had ≥1 metabolic syndrome feature or type 2 diabetes, and were not taking anti-diabetic medication (N = 103). Water-only 24-h fasting was performed twice weekly for 4 weeks and then once weekly for 22 weeks; controls ate ad libitum. The primary outcome was 26-week LDL-C change score. Secondary outcomes (requiring P ≤ 0.01) were 26-week changes in homeostatic model assessment of insulin resistance (HOMA-IR), Metabolic Syndrome Score (MSS), brain-derived neurotrophic factor (BDNF), and MicroCog general cognitive proficiency index (GCPi). Intermittent fasting (n = 50) and control (n = 53) subjects were, respectively, aged 49.3 ± 12.0 and 47.0 ± 9.8 years, predominantly female (66.0% and 67.9%), and overweight (103 ± 24 and 100 ± 21 kg) and had modest LDL-C elevation (124 ± 19 and 128 ± 20 mg/dL). Drop-outs (n = 12 fasting, n = 20 control) provided an evaluable sample of n = 71 (n = 38 fasting, n = 33 control). Intermittent fasting did not change LDL-C (0.2 ± 16.7 mg/dL) vs. control (2.5 ± 19.4 mg/dL; P = 0.59), but it improved HOMA-IR (-0.75 ± 0.79 vs. -0.10 ± 1.06; P = 0.004) and MSS (-0.34 ± 4.72 vs. 0.31 ± 1.98, P = 0.006). BDNF (P = 0.58), GCPi (P = 0.17), and weight (-1.7 ± 4.7 kg vs. 0.2 ± 3.5 kg, P = 0.06) were unchanged.

Conclusions: A low-frequency intermittent fasting regimen did not reduce LDL-C or improve cognitive function but significantly reduced both HOMA-IR and MSS.

Trial registration: clinicaltrials.gov, NCT02770313.

Keywords: Cholesterol; Cognitive function; Insulin resistance; Metabolic syndrome; Pre-diabetes; Therapeutic fasting.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Graphical Abstract

Figure 1

CONSORT diagram. Of the 1824 potential subjects, 21.6% became aware of the study due to advertising, among whom 68.0% (n = 70) were randomized. The other 78.4% of the potential subjects were patients identified through historical electronic health record data who were sent an invitation letter, among whom 32.0% (n = 33) were randomized.

Figure 2

Mean low-density lipoprotein cholesterol in the intermittent fasting and ad libitum control arms of the trial at each of the four study visits. No differences between randomization groups were found in the change scores (P = 0.59 at 26 weeks) or differences in means across the four timepoints (P = 0.11).

Figure 3

Mean results for the intermittent fasting and ad libitum control arms at each of the four study visits for: (A) homeostatic model assessment of insulin resistance, (B) metabolic syndrome score, (C) brain-derived neurotrophic factor, and (D) the MicroCog GCPi Score. Differences were found between randomization groups for the change scores of homeostatic model assessment of insulin resistance (P = 0.004 at 26 weeks) and metabolic syndrome score (P = 0.006 at 26 weeks) and for the differences in means across the four timepoints for homeostatic model assessment of insulin resistance (P = 0.007). Values are means and whiskers are 95% confidence intervals of the means. Data are drawn from all subjects at each time point, thus simple subtraction of means will not necessarily provide the change score values in Table 2. GCPi was only measured at baseline and week 26 (see Methods).