Metabolic changes with intermittent fasting

Abstract Background The prevalence of obesity is rising globally and effective strategies to treat obesity are needed. Intermittent fasting, a dietary intervention for weight management, has received growing interest from the general public, as well as healthcare professionals, as a form of lifestyle intervention. Methods We executed a rapid review using PUBMED database to identify systematic reviews that examined the impact of intermittent fasting on metabolic indices, published between 2011 and 2022. Results Intermittent fasting leads to weight loss of a similar magnitude to continuous energy restriction. Most of the evidence shows that intermittent fasting leads to greater fat loss as measured by fat mass (kg) or body fat percentage compared to an ad libitum diet, but fat loss attained during intermittent fasting is not significantly different to continuous energy restriction, although recent evidence shows intermittent fasting to be superior. There is mixed evidence for the impact of intermittent fasting on insulin resistance, fasting glucose and lipid profile. Some studies focused on populations of Muslim people, which showed that Ramadan fasting may lead to weight loss and improvement of metabolic parameters during fasting, although the effects are reversed when fasting is finished. Conclusions Intermittent fasting is more effective than an ad libitum dietary intake, and equally or more effective as continuous energy restriction, for weight management. However, there is inconclusive evidence on whether intermittent fasting has a clinically beneficial effect on glucose and lipid metabolism.


INTRODUCTION
Globally, between 1980 and 2019, the prevalence of obesity increased from 3.2% to 12.2% in men and from 6% to 15.7% in women. 1 Obesity can lead to various adverse health outcomes, including type 2 diabetes (T2D), heart disease and some cancers, highlighting the importance of weight management.Treating obesity is likely to be cost-effective, reducing the prevalence of associated diseases in the future. 2Until recent years, dietary interventions for weight loss have focused on continuous energy restriction (CER), with clinical guidelines recommending that people living with obesity should aim for a daily energy intake that is 600 kcal less than their total energy expenditure. 3Although this is an effective strategy for weight loss, adherence to CER has been reported to be as low as 32%. 4,5Consequently, weight maintenance is rarely sustainable in the long term.Therefore, alternative weight loss strategies are needed to provide person-centred approaches.
In recent years, intermittent fasting (IF) has been subject to growing research interest.Although definitions vary slightly, the concept of IF is energy restriction through abstaining from food for a specified amount of time, rather than CER over the course of a whole day. 6here are several variations of IF, including: − Time restricted eating (TRE): this is a fasting period of between 3 and 21 h per day (although most commonly >12 h).Ramadan diurnal intermittent fasting (RDIF) is the fasting period during Ramadan, which is practised by Muslim people from sunrise to sunset on consecutive days over a 1-month period and therefore aligns with TRE.Energy restriction is not required.− Alternate day fasting (ADF): the individual restricts their energy consumption to 25% of their daily energy requirements on 1 day, and then an ad libitum diet is followed the next day, on a repeating basis.Alternatively, a 24-h fast period for 1 day is followed by an ad libitum diet the next day, also known as periodic fasting.− Intermittent energy restriction (IER): This is a less defined duration of fasting, where the individual undertakes periods of energy restriction alternated with periods of habitual intake or minimally restricted dietary intake.

Rationale
The previous literature has suggested that IF may be a more sustainable approach to weight loss because the duration of restriction is not as prolonged. 7As the popularity of IF is increasing and interest is growing, the effectiveness of IF needs to be appraised to provide evidence-based sustainable weight loss recommendations.Hence, our aim was to synthesise the available evidence on the metabolic effects of IF from the findings of published, systematic reviews.

METHODS
We conducted a rapid overview (an umbrella review) of systematic reviews published in the medical literature on the impact of IF on metabolic effects.When compared with full reviews, rapid reviews incur no discernible impacts on derived conclusions. 8Rapid reviews summarise the highest level of academic evidence and provide healthcare professionals with a clear summary of existing evidence. 9PUBMED was searched by one researcher (ML) to identify relevant literature published between November 2011 and November 2022.Studies were included if they were systematic reviews written in English language.Systematic reviews were chosen as they are more robust than narrative reviews, with clearly defined primary and secondary objectives, explicit methods of extraction and synthesis of the data.We included any systematic review that observed the effects of any IF dietary intervention compared to a control group, as measured by changes in body composition or metabolic indices.Body composition could include body mass index (BMI) (kg/m 2 ), weight (kg), body fat mass (kg) or fat mass as a proportion of total body weight (%).Diabetes control was measured by fasting glucose (mg/dl) and HbA1c (mmol/mol).Insulin resistance was measured by fasting insulin (mIU/ml) and HOMA-IR.Changes in lipids were measured by total cholesterol (TC) (mg/dl), triglycerides (TG) (mg/dl), low-density lipoprotein-cholesterol (LDL-C) (mg/dl) and highdensity lipoprotein-cholesterol (HDL-C) (mg/dl).Data were collected using a pre-defined framework and included the surname of first authors, publication year, study design, sample size, analysis, population, intervention/exposure and outcomes.

RESULTS
This review identified 48 systematic reviews (Table 1).
The number of included studies in each systematic review ranged from 4 to 101.The individual studies included a combination of interventional and observational studies.Nine of these reviews specifically examined the effects of fasting during Ramadan, whereas the remaining studies examined a range of conventional IF approaches.The study populations were diverse, including predominantly adults with overweight (≥25 kg/m 2 ) or obesity (≥30 kg/m 2 ), with and without associated metabolic comorbidities.The majority of populations included in Ramadan studies were healthy adults.The control diets that were used within the included systematic reviews were either CER or an ad libitum diet (consuming a normal diet which is nonrestrictive).
T A B L E 1 Included systematic reviews.

IF versus ad libitum
All reviews concluded that IF led to weight loss compared an ad libitum diet, [5][6][7] with one review reporting a reduction of initial body weight of up to 13%. 27 Themajority of studies were conducted in individuals with a BMI ≥ 25 kg/m 2 , with four reviews finding that IF was more effective for weight loss in those with a higher body weight initially.14,20,23,29 Conversely, one study found a significant reduction in body weight in lean and overweight but not among individuals with obesity.21 Two studies found no change in weight in lean and metabolically healthy participants.22,25 BMI decreased after IF compared to an ad libitum diet in 13 out of 14 reviews.[5][6]11,18,19,23,[25][26][27][31][32][33][34][35][36][37][38][39] In terms of BMI change, five reviews compared IF to CER, finding no significant difference between the two interventions.11,25,27,38,39

Fat mass
Changes in fat mass following IF compared to control diets (CER or ad libitum) varied between reviews, with the majority of studies supporting that IF significantly reduces fat loss compared to an ad libitum diet, but no difference between IF and CER diets.

IF versus ad libitum
Seventeen reviews reported the effects of IF on fat mass compared to an ad libitum diet.The study populations were highly heterogenous across various BMI categories.Some studies included healthy adults, whereas others included adults with metabolic diseases.[23]26,29 One metaanalysis showed a directional reduction in reduced FM in IF but this was not statistically significant (p = 0.151). 16he remaining three studies showed inconclusive results, 13,24,40 although, no studies found IF to increase fat mass.

IF versus CER
37,39 Three meta-analyses of interventional trials (randomised and non-randomised) stated that IF results in higher levels of fat mass loss than CER, with a mean difference range from −0.66 kg to −3.31 kg. 5,18,31hese three reviews predominantly investigated the ADF form of IF, whereas the other nine reviews included various IF types.Further studies are needed to determine whether ADF is superior to other forms of IF with respect to achieving greater levels of fat mass loss than CER.

Insulin resistance and diabetes control
Twenty-eight reviews reported changes in fasting glucose, insulin, HbA1c and insulin resistance, with mixed results.

IF versus ad libitum
When compared with an ad libitum diet, 10 reviews found fasting glucose to be significantly reduced during IF, 10,16,21,22,24,29,30,[40][41][42] whereas nine reviews found that there was no significant difference compared to an ad libitum diet. 5,6,13,17,20,25,26,28,37All seven reviews that reported HbA1c levels found no significant difference between IF and control groups. 5,14,21,25,29,30,37Four of these reviews did not include any participants with T2D and therefore most participants did not have any glucose abnormalities at baseline. 30Two out of three reviews that included participants with T2D showed a trend towards decreasing HbA1c that did not meet statistical significance. 14,37welve reviews analysed fasting insulin levels in IF versus an ad libitum diet.The number of reviews that identified no difference 13,20,24,26,28,42 was equal to the number of reviews that identified an improvement compared to control. 6,15,25,29,30,40Similarly to effects on insulin levels, evidence on insulin resistance in the IF group compared to ad libitum groups was inconclusive.Six reviews reported a significant reduction in insulin resistance, 6,21,29,30,41,42 four reviews found no difference 13,17,24,28 and one review had mixed results with an isolated study showing a decrease in insulin sensitivity. 20

IF versus CER
37,38 These reviews included 212 studies and were conducted on predominantly individuals with overweight or obesity.Across 11 reviews, 17 studies included participants with T2D.The remaining review that included participants with T2D did not specify a count. 26en reviews found no difference in fasting glucose between IF and CER.One review found mixed results attributed to the heterogeneity of studies. 4One review found evidence of significantly lower fasting glucose levels in the IF cohort compared to CER (−0.78 mmol/l vs. −0.47mmol/l, p < 0.05), although this was based on a single study. 27he evidence for differences in fasting insulin between the two groups is mixed.Five reviews found no significant differences between the two groups. 19,26,27,32,38Ezzati et al. 4 found inconsistent results across different IF variations.One meta-analysis found a significant effect of IER compared to CER on insulin levels (WMD = −3.66pmol/l, 95% confidence interval = −9.12 to −0.19, p = 0.041), although only 182 participants were included in this analysis. 18No differences were found in HbA1c 4,26,27,32,33,37,38 and HOMA-IR 26,32 between IF and CER.
Overall, the results of IF versus ad libitum are varied; therefore, it is hard to draw a robust conclusion regarding the effects of IF on fasting glucose, HbA1c, insulin resistance and insulin levels.Conversely, in IF versus CER, the results are more consistent in showing no difference between the two groups.It is important to highlight that most studies were undertaken in populations without T2D and therefore significant changes in these indices may not be expected.

IF versus ad libitum
Change in lipids (TC, TG, LDL-C and HDL-C) was only a secondary outcome measure in many of the reviews, with mixed results.TC levels varied between reviews, with some showing a significant reduction in TC in IF diets compared to an ad libitum diet.However, other reviews reported an increase in TC or no difference.Similarly, the effects of IF on TG levels and LDL-C are mixed, with some reviews finding a reduction, others no change and some an increase.Eight reviews found an increase in either LDL-C or TG, which is potentially concerning given the risk of dyslipidaemia in people with overweight or obesity. 7,13,15,20,28,35,40,42inally, of the 14 reviews observing HDL levels, 11 showed no effect on these during IF.Two reviews found a possible reduction in HDL following IF.They were both conducted in individuals with T2D or another metabolic disorder. 28,30One review identified a study that found a temporary rise in morning HDL following an overnight fast, although this result should be interpreted with caution because of the study's small sample size (n = 11). 43

IF versus CER
2,38 There was one exception where one review found CER to be superior to IF with respect to reducing total cholesterol and triglycerides, but equivalent with respect to reducing LDL. 44verall, no substantial conclusions can be drawn as a result of the inconclusive evidence on the outcomes of IF diets on lipid profiles.This could be because of inadequate power in the underlying primary studies, resulting in the inability to detect any difference.However, CER and IF diets appear to have a similar effect on lipid profiles.

Ramadan
Nine reviews described the effects of RDIF and found that weight was significantly reduced during this period (ranging from −1.02 kg and −1.34 kg).6][47] However, some reviews also highlighted that weight significantly increased after followup once fasting ended, resulting in an overall non-significant decrease in weight. 45,46,48Weight loss was also seen more predominantly in those with overweight or obesity pre-Ramadan. 45,46Fat mass was shown to significantly decrease during Ramadan; however, this also became non-significant after follow-up. 46everal reviews have assessed the impact of RDIF on metabolic parameters with variable results.Jahrami et al. 49 suggested that RDIF decreased TG and increased HDL-C.Another review concurred with an improvement in lipoprotein parameters, particularly HDL-C. 50Two reviews stated that definitive answers were lacking on the impact of RDIF on glucometabolic and lipoprotein markers. 47,51verall, RDIF causes reductions in weight, fat mass and BMI.However, this is not maintained, such that, although Ramadan may offer positive metabolic effects in the short term, strategies are needed to ensure maintenance after this period.

DISCUSSION
Overall, IF is more likely to lead to significant weight loss and a decrease in BMI compared to an ad libitum diet.Weight loss and fat loss are more pronounced in those with overweight or obesity compared to normal weight controls.This rapid review evidences that IF and CER have comparable weight loss results; however, new evidence is emerging that in some cases IF may be more effective. 52Therefore, IF could be recommended by practitioners as an alternative diet strategy for those who find CER difficult to maintain.Most studies found some reduction in fat mass and none found an increase; therefore, those wishing to reduce fat mass could undertake IF.Notably, a reduction in adiposity did not directly translate into an improvement in metabolic blood makers, with no clear effect of IF on lipid profiles and insulin levels, similar to a lack of clear effect of CER diet on these parameters.In all cases, initiation of IF needs to be discussed with a healthcare professional to provide a safe and supported approach to dietary intervention, ideally by a registered dietician.
The mechanism through which IF results in beneficial effects remains unclear.It is proposed that it is not only through a reduction in caloric intake, but also through the alignment with the circadian rhythm.Previous data suggest that disruption of the circadian rhythm is associated with the development of metabolic diseases and that humans (as well as other organisms) have evolved to optimise physiological processes by aligning with an endogenous circadian clock. 53Interestingly, RDIF directly opposes the circadian rhythm as fasting occurs during daytime hours.
Nevertheless, Ramadan fasting can lead to reduced weight, BMI and fat mass; however, these effects may not be sustained after Ramadan finishes.Direct comparison of RDIF with other IF diets is not possible for several reasons.First, the duration of fasting changes every few days on account of the lunar calendar.Second, Ramadan is undertaken worldwide in different countries, climates and seasons, which also impacts the duration of the fast.Finally, given the religious significance of Ramadan, all of the studies are observational and many do not have controls.Consequently, many confounders are not accounted for.
Many of the reviews included in this overview had several limitations.Few reviews examined outcomes beyond 6 months.Moreover, the reviews included in the present study examined different regimes of IF and did not compare different types of IF.Some reviews included both randomised and non-randomised studies, and thus the effect of confounders could not be eliminated.The heterogeneity of interventions precluded meta-analysis for most systematic reviews.Populations studied varied, with some reviews looking at healthy adults and some examining obese people living with T2D, which could explain varying outcomes between the reviews.No reviews commented on the potential of metabolic derangement of acute swing in metabolic indices that could follow if an individual alternated between IF and excessive food intake.
Future research should focus on providing long-term data on metabolic effects and their maintenance.These studies should be accompanied by an analysis of subgroup differences such as gender, age, ethnicity and distinct metabolic diseases.Furthermore, data on adherence, tolerance, dropout rates and sustainability of IF is needed.

Implications for public health and clinical practice
The worldwide obesity epidemic necessitates identifying effective dietary strategies.Many individuals find the current gold standard CER hard to maintain and fit around daily life.IF might be more favourable because of its emphasis on a restricting eating window and not calories.IF has similar, if not superior, metabolic effects to that of CER in the short-term (under 6 months) 52 ; therefore, when recommending dietary regimes to patients, IF could be offered as an alternative method for those who struggle to maintain CER.Evidence is needed for the long-term effects of IF.
Overall, the reviewed evidence suggests IF regimes consistently resulted in weight loss.The duration of interventions ranged from 1 to 104 weeks.
LANGE ET AL.