This meta-analysis concurrently and comprehensively evaluates the association of intermittent fasting, CER, and ad-libitum diets on cardiometabolic risk factors. Our findings showed a trivial to small reduction in body weight for all diet strategies compared with ad-libitum, and trivial reductions for ADF compared with CER, TRE, and WDF. These associations, however, were only significant among comparisons with ad-libitum diet in moderate-to-long term follow-up durations of at least 24 weeks. ADF when compared with TRE or WDF was associated with a reduction in BMI, non-high density lipoprotein cholesterol, and triglycerides. WDF only showed an improvement in total cholesterol over TRE. Additionally, all diet strategies presented similar benefits in cardiometabolic risk over an ad-libitum diet. ADF was the only intermittent fasting strategy to show an improvement in anthropometric and lipid measures when compared to CER. No benefit was observed for HbA 1c or high density lipoprotein cholesterol in any diet strategy comparison.
Comparison with other studies
While several systematic reviews and meta-analysis have been performed on intermittent fasting over the years, there are numerous limitations which restrict their overall interpretation or applicability. Previous meta-analyses either focused solely on weight loss, focused on a specific method of fasting, excluded studies with people who have comorbidities, even though this population stands to benefit the most from intermittent fasting, lacked assessment of heterogeneity, or did not assess the certainty of evidence.8910129130131 Our network meta-analysis addresses these important limitations through our comprehensive evaluation of intermittent fasting diet strategies, CER, and ad-libitum diet, on body weight and other cardiometabolic risk factors.
In our analysis, intermittent fasting strategies showed trivial to small improvements in body weight reduction, with similar improvements in other anthropometric measurements including BMI and waist circumference compared to an ad-libitum diet and little additional benefit against CER. These findings are in accordance with previously published meta-analyses.910 Cioffi and colleagues evaluated intermittent fasting, which grouped together WDF and ADF, against CER, in 11 identified trials of adults with overweight or obesity and observed no significant improvement for weight loss.9 In our network meta-analysis, ADF was the only intermittent fasting strategy to show a reduction in weight when compared with CER, perhaps due to easier adherence to ADF compared with a continuous diet strategy.11 To date, however, only three studies have directly compared intermittent fasting diets with cardiometabolic outcomes.3952102 Among patients with non-alcoholic fatty liver disease, Cai and colleagues showed that both intermittent fasting strategies were effective in weight loss and other anthropometric measures over an ad-libitum diet; however, no significant differences were observed between intermittent fasting strategies.39 Similarly, Erdem and colleagues compared anthropometric changes across a 12 week period and observed no significant difference in body weight between intermittent fasting groups (TRF and WDF).52 Among people with type 2 diabetes and obesity, Umphonsathien and colleagues’ study results showed similar improvements for glycaemic control between WDF and ADF.102 For the first time, using the network meta-analysis approach, we were able to comprehensively examine the associations between intermittent fasting strategies, accounting for both direct and indirect estimates, and observed an improvement in body weight for ADF over TRE. ADF’s greater weight loss and cardiometabolic benefits, such as reduced HOMA-IR, may reflect enhanced fat oxidation and insulin sensitivity from prolonged fasting periods; although, short trial durations probably limited larger differences compared with TRE, WDF, or CER.
While our analysis by trial duration for body weight showed similar changes in trials with less than 24 weeks duration to the network analysis of all trials, assessment of longer trial studies showed a reduction in body weight for diet interventions when compared with ad-libitum. The loss of association in the network assessment of moderate to longer term trials (≥24 weeks) may be due to an insufficient number of studies available. Additionally, while our analysis included randomised clinical trials, adherence to dietary interventions may decline over time,11 and metabolic adaptation could limit sustained weight loss in longer term trials.132 Notably, the results show that intermittent fasting may offer unique benefits primarily in the short term, whereas both intermittent fasting and CER appear to provide similar moderate-to-long term improvements over ad-libitum diets. This equivalence in sustained outcomes in the moderate-to-long term is a critical take-away for clinicians managing chronic metabolic conditions. The inclusion of three week trials, while showing early weight loss (eg, 0.5-2 kg), reflects short term feasibility rather than sustained effects, which potentially may have inflated short term benefits in the less than 24 week stratum. Additionally, the scarcity of trials of 52 weeks or longer (only five identified) precluded a separate network meta-analysis for very long term effects, limiting relevance to related to sustained long term weight loss. Future randomised clinical trials with extended follow-up are needed to assess the durability of these dietary strategies.
Moreover, as glucose, lipid, and energy metabolism are all regulated by the circadian system, eating at certain times of the day may provide benefits beyond weight loss through differences in insulin sensitive periods, beta cell responsiveness, and thermic effect of food.133 In a proof-of-concept study among men with prediabetes, a group using TRE with a morning eating window improved (insulin resistance and blood pressure) and impaired (triglycerides) cardiometabolic risk factors independent of weight loss when compared with a control group.134 While our analysis did not examine specific eating time windows, these findings were generally consistent with our results for TRE versus ad-libitum diet showing a benefit in fasting blood glucose, insulin resistance (HOMA-IR), and diastolic blood pressure. Similar benefits were evaluated in the other intermittent fasting diets, ADF and WDF, with additional benefits for total cholesterol. A meta-analysis also showed similar improvements in intermittent fasting compared with a non-intervention diet for insulin and HOMA-IR.135
The benefits between intermittent fasting and CER, and among intermittent fasting strategies, for cardiometabolic markers remain unclear. We showed that ADF improved several cardiometabolic risk factors, including non-high density lipoprotein cholesterol, triglycerides, and total cholesterol, while TRE and WDF generally did not result in additional benefits to CER. A few meta-analyses that evaluated intermittent fasting with CER showed no significant benefit for several cardiometabolic risk factors including fasting glucose,910136137 HbA 1c ,9 HOMA-IR,9 or lipid markers10136137; however, findings for high density lipoprotein cholesterol are less consistent. In a review of patients with metabolic syndrome, intermittent fasting improved high density lipoprotein cholesterol concentrations,136 while a separate analysis among individuals with type 2 diabetes and metabolic syndrome found no significant change for high density lipoprotein cholesterol.137 In our analyses, we found no significant changes in any diet comparison for high density lipoprotein cholesterol. However, comparisons between intermittent fasting showed that ADF was more effective in lowering total cholesterol and triglyceride concentrations. WDF also showed an improvement in reducing total cholesterol levels when compared with TRE. These findings were primarily based on indirect estimates, and thus, direct comparisons are not needed to confirm these associations.
The hypothesised improvement in cardiometabolic health through a fasting diet approach derives primarily from extensive animal model studies.138139140 Such studies have noted that fasting states can encourage the use of fat stores, with a preferential reduction or browning of adipose tissue mass, improved insulin sensitivity, and reduction in inflammation and oxidative stress.138 Furthermore, the notion of metabolic switching between the fed and fasted states, particularly through a TRE approach, have also shown benefits in preventing glucose intolerance and dyslipidaemia.139140 These metabolic changes, however, have not been substantiated in humans. Moreover, as determined in our network analyses, poor adherence, particularly in longer trials, pose challenges in assessing the true impact of these diet strategies on cardiometabolic health. Additional studies focused on comparing intermittent fasting strategies with focused improvement in participant adherence are needed to elucidate potential differences in dietary approaches and their impact on cardiometabolic risk factors.