Protocol
Intermittent fasting (5:2 / alternate-day energy restriction)
Randomized trials show 5:2 and alternate-day fasting lower body weight and cardiometabolic markers against no intervention, and that is replicated The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away..
Grade C: human trials exist, but they are small, mixed or not yet repeated. This is not a finding that it does not work. How to read a grade →
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How this letter has changedLatest: October 2026 · Corrected.
The ref said 'Grade C on consistent RCT Randomized controlled trial: people are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. evidence limited to cardiometabolic surrogates', which under the site's rule describes a B. The letter is C because against daily calorie restriction the fasting pattern adds nothing, and the record now says so with the trials: Trepanowski 2017 (PMID PubMed ID: the permanent number the US National Library of Medicine gives a published paper. Each one links to that paper's record on PubMed. 28459931), one year, weight loss equal to daily restriction, LDL 11.5 mg/dL higher and 38 percent dropout in the fasting arm; Schübel 2018 (PMID 30475957), HELENA, 50 weeks, equivalent not superior; Semnani-Azad 2025 (PMID 40533200), 99 trials, an edge only in short trials; Garegnani 2026 (PMID 41692034), Cochrane, little to no difference from regular dietary advice. Cioffi 2018 (PMID 30583725) is stated as pooling 8 to 24 week trials only. Kord Varkaneh 2022 (PMID 35958257) is relabeled as a small open trial in fatty liver disease against usual diet, with its null lipid and glycemic results. Letter unchanged.PMID 28459931 PMID 30475957 PMID 40533200 PMID 41692034 PMID 30583725 PMID 35958257
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This protocol covers fasting patterns such as eating very little two days a week or every other day. Compared with doing nothing, these patterns lower weight and some health markers. But compared with simply eating a little less every day, they work about the same. So the fasting pattern itself adds nothing beyond eating fewer calories.
Randomized trials show 5:2 and alternate-day fasting lower body weight and cardiometabolic markers against no intervention, and that is replicated. The reason this is C and not B is the comparator: against daily calorie restriction the fasting pattern adds nothing. In the largest one-year alternate-day fasting trial, weight loss matched daily restriction, LDL cholesterol was 11.5 mg/dL higher at 12 months and dropout was highest in the fasting arm (38 percent); in the 50-week HELENA 5:2 trial, 5:2 was equivalent and not superior to daily restriction; a 2025 network meta-analysis of 99 trials found all fasting and restriction strategies beat an unrestricted diet, with alternate-day fasting showing a small edge over restriction only in trials under 24 weeks; and a 2026 Cochrane review found little to no difference from regular dietary advice in weight loss or quality of life over up to 12 months. The benefit is calorie restriction, not the timing. Surrogate endpoints A lab value or measurement used in place of the outcome that matters, such as LDL cholesterol standing in for heart attacks. Moving a surrogate does not always move the outcome. throughout; no trial reports a clinical outcome. This is distinct from time-restricted eating, which is graded separately.
Why this gradeGrade C, small or unreplicated trials. The reasoning, and what the grade does not cover.
Grade C. Against no intervention, 5:2 and alternate-day fasting lower weight and surrogates in replicated randomized trials, which on its own would read as B. The letter is C because the graded question is the fasting pattern, and against daily calorie restriction it adds nothing: Trepanowski 2017 (PMID 28459931) and HELENA (PMID 30475957) found equivalence at one year, the 2025 network meta-analysis (PMID 40533200) found an edge only in short trials, and the 2026 Cochrane review (PMID 41692034) found little to no difference from regular dietary advice. The longest trial also recorded an LDL rise and the highest dropout in the fasting arm.
WHAT THIS GRADE DOES NOT COVERtime-restricted eating, graded separately; any clinical outcome, which no trial reports; and fatty liver disease, where one small open trial against usual diet is a clinical population.
A grade describes the human evidence for a named use. It is not advice, and it is not a judgment on any individual prescription. How the letters are decided →
The evidence, in fullSix papers, each linked to its PubMed record.
Cioffi et al. (J Transl Med, 2018; PMID 30583725): meta-analysis of randomized trials of 8 to 24 weeks; intermittent and continuous energy restriction produced comparable weight loss and metabolic change, with a slight fasting-insulin difference of uncertain relevance; short trials only. Trepanowski et al. (JAMA Intern Med, 2017; PMID 28459931): 100 obese adults randomized for one year to alternate-day fasting, daily calorie restriction or no intervention; weight loss 6.0 percent with fasting and 5.3 percent with restriction against control, no difference between them; dropout 38 percent in the fasting arm against 29 and 26 percent; LDL cholesterol 11.5 mg/dL higher with fasting than restriction at 12 months; no difference in blood pressure, glucose, insulin or CRP; an author holds a book advance on the diet. Schübel et al. (Am J Clin Nutr, 2018; PMID 30475957): HELENA, 150 overweight or obese adults randomized to 5:2, continuous restriction or control for 50 weeks; weight loss 5.2 percent with 5:2 and 4.9 percent with restriction against 1.7 percent for control, no difference between the two; equivalent, not superior. Semnani-Azad et al. (BMJ, 2025; PMID 40533200): network meta-analysis of 99 randomized trials, 6,582 adults; every fasting and restriction strategy lowered weight against an unrestricted diet; alternate-day fasting showed a 1.29 kg edge over continuous restriction, present only in trials under 24 weeks. Garegnani et al. (Cochrane Database Syst Rev, 2026; PMID 41692034): 22 randomized trials, 1,995 adults with overweight or obesity; against regular dietary advice, intermittent fasting may make little to no difference to percentage weight loss (0.33 percent) or quality of life over up to 12 months; no trial reported diabetes status or a clinical outcome. Kord Varkaneh et al. (Front Nutr, 2022; PMID 35958257): small open single-center 12-week trial of 5:2 against usual diet in 44 analyzed patients with non-alcoholic fatty liver disease, a clinical population; weight, liver indices and inflammatory markers improved, with no change in LDL, total cholesterol, fasting glucose, insulin or HOMA-IR; it does not test fasting against calorie restriction. Grade C: replicated surrogate benefit against no intervention, no advantage over daily calorie restriction, a lipid and dropout signal in the longest trial, and no clinical endpoint The outcome a trial measures to decide whether the treatment worked, such as heart attacks, blood pressure or a symptom score..
Body weight and waist circumference weekly. Fasting glucose, insulin, and lipid panel at baseline and 12 weeks. Caloric intake on fasting days (500-600 kcal) should be logged: non-compliance is the most common failure mode. Compensatory overeating on non-fasting days, measured as total weekly caloric intake.
Evidence notes: randomized trial, meta-analysis
Endpoint graded: Weight and cardiometabolic markers, compared with daily calorie restriction (surrogate)
Last reviewed: July 2026
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("intermittent fasting"[tiab] OR "alternate day fasting"[tiab] OR "alternate-day fasting"[tiab] OR "intermittent energy restriction"[tiab]) AND (randomized controlled trial[pt] OR meta-analysis[pt])Grades move when new trials publish. A free monthly email lists every grade EBL moved, with the reason and the trial behind it: the sign-up is on the Evidence Log →