Does intermittent fasting reduce LDL-c?

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

Literature - Bartholomew CL, Muhlestein JB, May HT, et al. - Eur Heart J Open. 2021 Sep 3;1(2):oeab026. doi: 10.1093/ehjopen/oeab026

Introduction and methods


Although intermittent fasting can improve several lipid and lipoprotein parameters [1], it is not clear what the effect is on LDL-c. While some studies have reported that intermittent fasting increased the LDL-c level [2-4], no study has used LDL-c as the primary endpoint.

Aim of the study

The study aim was to evaluate the effect of low-frequency intermittent fasting on the levels of LDL-c and other biomarkers compared with an ad libitum diet.


In this RCT, 103 patients (aged 21–70 years) were recruited from Intermountain hospitals and clinics in the USA and from local community volunteers. They had to have modestly elevated LDL-c levels (90–189mg/dL for ages 21–39 years, or 90–159mg/dL for ages 40–70 years, or >90mg/dL in anyone who had used statins and stopped due to intolerance or contraindications), ≥1 metabolic syndrome feature or T2DM, and no chronic disease diagnoses, and they should not be taking statins (or had an indication for statin therapy) or antidiabetic medications. The participants were randomized (1:1 ratio) to intermittent fasting, which consisted of only drinking water for 24 hours twice weekly for 4 weeks and then once weekly for 22 weeks, or an ad libitum control diet (consisting of the usual food intake) for 26 weeks. The intermittent fasting group was allowed to eat ad libitum between the fasting days. The investigators anticipated a 15% drop-out rate.


The primary outcome was the change in LDL-c level from baseline to 26 weeks. Secondary outcomes (requiring prespecified Bonferroni-corrected P≤0.01) were 26-week changes in the homeostatic model assessment of insulin resistance (HOMA-IR), metabolic syndrome score (MSS), level of brain-derived neurotrophic factor (BDNF), and MicroCog general cognitive proficiency index (GCPi).

Main results

  • During the study, 12/50 subjects in the intermittent fasting arm (24.0%) and 20/53 in the control arm (37.7%) dropped out.
  • The mean (± SD) change in LDL-c level at 26 weeks did not differ between the intermittent fasting group (n=38; 0.18 ± 16.7 mg/dL) and control group (n=33; 2.48 ± 19.4 mg/dL; P=0.59). Similar results were seen at 4 and 13 weeks.
  • Intermittent fasting improved the mean (± SD) 26-week change in the 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) but not in the BDNF level (0.59 ± 2.21 vs. 0.30 ± 1.89 ng/mL; P=0.58) and MicroCog GCPi (4.14 ± 8.63 vs. 1.69 ± 5.51; P=0.17).
  • The 26-week LDL-c change was correlated with the 26-week change in the MSS (r=−0.257; P=0.031) but not with 26-week changes in the HOMA-IR (r=−0.127; P=0.29), BDNF level (r=0.102; P=0.41), or MicroCog GCPi (r=0.108; P=0.38).
  • Significant differences between the intermittent fasting and control groups were also seen for the mean (± SD) 26-week change in insulin level (–2.76 ± 2.61 vs. –0.33 ± 3.51 mIU/L; P=0.001), glucose level (–7.21 ± 9.30 vs. –2.12 ± 11.1 mg/dL; P=0.04), diastolic blood pressure (–1.7 ± 9.1 vs. –4.9 ± 11.8 mmHg; P=0.01), and HDL-c level (2.37 ± 6.20 vs. –0.39 ± 5.17 mg/dL; P=0.05).
  • The intervention did not affect participants’ body weight (intermittent fasting: –1.70 ± 4.69 kg vs. control: 0.20 ± 3.45 kg; P=0.06).
  • In the intermittent fasting group, adherence was ≥80% for 95% of the participants.


In an RCT with 71 participants with modestly elevated LDL-c levels, a low-frequency intermittent fasting regimen did not decrease LDL-c levels or improve markers of cognitive function compared with an ad libitum control diet. However, it did lower insulin resistance (as measured by the HOMA-IR) and the MSS.


1. Mirmiran P, Bahadoran Z, Gaeini Z, Moslehi N, Azizi F. Effects of Ramadan intermittent fasting on lipid and lipoprotein parameters: an updated meta-analysis. Nutr Metab Cardiovasc Dis 2019;29:906–915.

2. Trepanowski JF, Kroeger CM, Barnosky A, Klempel MC, Bhutani S, Hoddy KK, et al. Effect of alternate-day fasting on weight loss, weight maintenance, and cardioprotection among metabolically healthy obese adults: a randomized clinical trial. JAMA Intern Med 2017;177:930–938.

3. Jamshed H, Beyl RA, Della Manna DL, Yang ES, Ravussin E, Peterson CM. Early time-restricted feeding improves 24-hour glucose levels and affects markers of the circadian clock, aging, and autophagy in humans. Nutrients 2019;11:1234.

4. Wijndaele K, Beunen G, Duvigneaud N, Matton L, Duquet W, Thomis M, et al. A continuous metabolic syndrome risk score: utility for epidemiological analyses. Diabetes Care 2006;29:2329.

Find this article online at Eur Heart J Open.

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