Network Meta-analysis of Intermittent Fasting and Cardiometabolic Risk

Background: 'Intermittent fasting' is currently the most popular trending diet, yet its clinical utility remains unclear. Previous systematic reviews and meta-analyses of intermittent fasting have been limited by a narrow focus on weight loss, one specific method of intermittent fasting, and/or a subset of participants who would be the least likely to benefit. Other issues have included unexplained heterogeneity, incorrect analyses and/or lack of assessment of the certainty of the evidence. There is emerging evidence that intermittent fasting may improve cardiometabolic risk markers independent of calories. However, there is a lack of certainty about the effectiveness of intermittent fasting on overall cardiometabolic risk across different health conditions, and the differences between the various methods of intermittent fasting. The European Association for the Study of Diabetes (EASD) has yet to make any recommendations regarding the role of intermittent fasting in the management of diabetes. To inform the update of the EASD Clinical Practice Guidelines for Nutrition Therapy, the Diabetes and Nutrition Study Group (DNSG) of the EASD has commissioned a systematic review and network meta-analysis (an approach which has the advantage over traditional pairwise meta-analyses of being able to assess simultaneously multiple interventions) to assess the effect of the different strategies of intermittent energy restriction (intermittent fasting) versus continuous energy restriction and ad libitum diets on cardiometabolic risk in randomized controlled trials and assess the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Objective: To assess simultaneously the effect of the various strategies of intermittent energy restriction (intermittent fasting), continuous energy restriction, and ad libitum diets on body weight and other cardiometabolic risk factors in a systematic review and network meta-analysis of randomized trials using the GRADE approach.

Design: Each systematic review and meta-analysis will be conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for network meta-analyses (PRISMA-Network).

Data sources: MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials (Clinical Trials; CENTRAL) will be searched using appropriate search terms. These searches will be supplemented by hand searches of references of included studies. Abstracts will be included and no language restrictions will be used.

Study selection: The investigators will include randomized controlled trials (RCTs) that are >=3-weeks duration investigating the effect of intermittent fasting, continuous caloric restriction and/or ad libitum diets on cardiometabolic risk factors in adults.

Data extraction: Two or more investigators will independently extract relevant data. Standard computations and imputations will be used to derive missing variance data. All disagreements will be resolved by consensus.

Risk of bias: Risk of bias will be assessed using the Cochrane Risk of Bias (RoB) Tool by the two or more investigators.

Outcomes: There will be 10 outcome clusters. The primary outcome will be body weight. Secondary outcomes will be other markers of adiposity (BMI, body fat, waist circumference); glycemic control (glycated blood proteins [HbA1c, fasting blood glucose, postprandial blood glucose, fasting blood insulin, homeostasis model assessment of insulin resistance [HOMA-IR]); established therapeutic lipid targets (LDL-cholesterol, non-HDL-cholesterol, apolipoprotein B [apo B], HDL-cholesterol, triglycerides); blood pressure (systolic blood pressure and diastolic blood pressure); markers of NAFLD (intrahepatocellular lipids [IHCL], alanine aminotransferase [ALT], aspartate aminotransferase [AST]); uric acid; and markers of inflammation (CRP).

Data synthesis: The investigators will perform a network meta-analysis comparing all the interventions simultaneously. These interventions will include alternate day fasting, cyclical whole day fasting, time restricted feeding, continuous energy restriction, and ad libitum diet in a single analysis by combining both direct and indirect evidence across the selected network of studies. Separate pooled analyses will be conducted for each cardiometabolic risk factor using the random-effects network meta-analysis. Intrasitivity will be adjudged using incoherence. Global method of incoherence (design-by-treatment interaction) and inconsistency factors (disagreement between direct and indirect estimates) will be used to estimate incoherence. A-priori subgroup analyses (health status, age, control diet energy restriction, diet supervision, study design, follow-up, feeding control, randomization, energy balance, baseline body weight, funding source, and ROB) will be performed. Separate analysis will be performed in people with diabetes. Publication bias will be assessed if there are ≥10 comparisons. The overall certainty of the evidence for each outcome will be assessed with GRADE using the CINeMA approach.

Evidence Assessment: The certainty of the evidence for each outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Knowledge translation plan: The results will be disseminated through interactive presentations at local, national, and international scientific meetings and publication in high impact factor journals. Target audiences will include the public health and scientific communities with interest in nutrition, diabetes, obesity and cardiovascular disease. Feedback will be incorporated and used to improve the public health message and key areas for future research will be defined. Applicant/Co-applicant decision makers will network among opinion leaders to increase awareness and participate directly as committee members in the development of future guidelines.

Significance: The proposed project will be the most comprehensive synthesis and evaluation of the totality of evidence on the role of intermittent fasting in cardiometabolic health. These findings will aid in strengthening current guidelines and improve health outcomes by informing shared clinical decision making between healthcare providers and patients and guiding future research.