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Intermittent fasting for cardiovascular disease risk factor reduction

Background The metabolic syndrome (MetSy), which is defined by the spectrum of obesity, insulin resistance and dyslipidaemia, is recognised as a major contributor to the overall risk of developing cardiovascular disease. Intermittent fasting (IF), which encompasses dieting plans with varying schedules of fasting, may be an effective method of reducing the burden of MetSy and the consequent cardiovascular events in the face of a worsening obesity epidemic in the contemporary society. Aims Despite the widespread public interest there is a serious lack of scientific understanding of the evidence base and the safe, optimal recommendations. This has created a level of public confusion that we endeavour to address by this narrative review of the published literature. Methods This narrative literature review summarises the current findings and suggests which regimens may be more effective and where future research in this area should be focused. Results Although the ideal regimen for IF remains unclear, there is promising evidence that alternate day fasting or modified fasting regimens, paired with or without continuous caloric restriction, may be more effective than continuous caloric restriction alone. Conclusion IF has been shown in the small number of human clinical trials discussed here to be an alternative to continuous caloric restriction in reducing the factors that contribute to the development of cardiovascular disease. Long-term randomised, controlled trials comparing continual caloric restriction and IF are required to objectively assess energy intake, energy expenditure, adherence, disease outcomes and metabolic factors.


Introduction
Excess energy consumption leading to weight gain and increased adiposity has been linked to increased rates of morbidity and mortality in western societies. 1,2 Obesity itself forms a component of MetSy, which includes the cluster of risk factors for cardiovascular disease 3 such as dyslipidaemia, increased insulin resistance and systemic hypertension. 4 Numerous trials, both in animal and human models, have demonstrated that caloric restriction and intentional weight loss can significantly reduce the deleterious impact of MetSy. [5][6][7] Epidemiological studies suggest that even modest weight loss of only 5-10 per cent can significantly reduce MetSy, leading to reductions in blood pressure, cholesterol and insulin resistance. 8,9 Long-term, this could reduce the incidence of serious health effects including cardiovascular disease, diabetes, dementia and tumour burden. 10 The health industry promotes a broad spectrum of weight loss treatments and quick-fixes of varying credibility.
However, the obesity epidemic shows no signs of slowing. In 2016 the World Health Organisation estimates that there were more than 1.9 billion overweight adults worldwide, which represents 39 per cent of adults worldwide aged 18 years and over. 11 Intermittent fasting (IF) is a weight loss strategy that involves subjecting participants to varying periods of fasting. An example of a more commonly used IF diet is alternate day fasting (ADF), which involves removing most, or all, oral intake every second day but eating as normal on alternate days. One of the perceived benefits of ADF over more traditional continual caloric restriction-type diets is that ADF only requires participants to focus on dieting every second day and therefore compliance may be improved longterm. 12 IF has gained much interest in recent years after several small cohort clinical trials highlighted its potential to accelerate weight loss and reverse MetSy. [13][14][15] It has been theorised that IF diets encourage the body to use fats for energy and initiate cellular level repairs and metabolic rejuvenation. This process may reduce cardiovascular risk factors and therefore the health benefits of IF may exceed those of simple caloric restriction. 16 This review will evaluate the clinical evidence that IF in humans is associated with a significant reduction in risk factors for cardiovascular disease and also identify subject areas where further clinical studies are needed.

Methods
Experimental studies and clinical trials on IF were collated from the PubMed and Medline databases. Studies available prior to the time of writing in March 2018 were assessed. Human studies were searched using the terms "fasting", "intermittent fasting" or "alternate day fasting" alone or in combination with "cardiovascular disease". Studies were included if they assessed 1) adult male or female patients and 2) if the end points of the study included measurement of risk factors for cardiovascular disease, such as cholesterol or body weight.
Population-based observational studies were excluded but for specific discussion where the presence of clinical trials was lacking. Studies assessing cultural fasting regimens, such as Ramadan were excluded. The outcomes of such studies have been extensively reviewed in the past. 17,18 These fasting patterns are not driven by health concerns and have generally been studied using population-based observational study designs. Following the literature search a total of 18 randomised, crossover or prospective cohort studies were identified and are discussed herein, categorised by the method of IF that was assessed.

Alternate day fasting
As defined previously, ADF involves consuming heavily reduced or no calories on fasting days with ad libitum or modest calorie-controlled diet on alternate days. Currently, there are only a small number of human clinical trials that have assessed the effectiveness of ADF in reducing risk factors for cardiovascular disease in Table 1.
Haldberg et al. 19  ] to undergo ADF for a period of 15 days. Over this short period it was noted that insulin sensitivity, and therefore whole-body glucose uptake, significantly increased [6.3±0.6 to 7.3±0.3mg/kg/min, p=0.03]. A similar study by Soeters et al. 20 also took eight healthy, young men and performed a comparison between simple calorie restriction and ADF using a two week crossover method. However this study failed to show any significant difference between the two dieting methods in terms of whole-body glucose, lipid or protein metabolism.
It is worth noting that both studies above had significant limitations in that subject sizes were small, participants were not overweight and the study durations were short.
A more recent study by Varady et al. 15 took 32 participants with a normal to overweight BMI (20-29kg/m 2 ) and randomised them to either an ADF diet or no dieting over a 12 week period. On reduced intake days participants were allowed to consume up to 25 per cent of recommended daily requirements. Compared to the control group, those on the ADF diet had significantly reduced CRP [p<0.01], increased adiponectin [p<0.01], reduced leptin [p=0.03] and reduced triglyceride levels [p=0.01]. LDL particle size was increased, but LDL and HDL levels were not significantly different between the two groups. Weight loss was also greater in the ADF group, with an average weight loss of 5.2±0.9 kg (6.5±1.0 per cent) relative to the control group. Although the sample size is small, this study suggested that ADF was an effective method of weight loss and was also potentially cardio protective.
Four further small studies 13,14,21,22 enrolled overweight participants and placed them on an ADF diet over an [8][9][10][11][12] week period. These studies demonstrated that body weight, total cholesterol, LDL-C and triglycerides were significantly decreased compared to baseline. These findings support those of Varady et al. 15 Although they did not directly assess the effect of ADF on reducing risk of CVD, Klempel et al. 23 noted the important finding that on the feeding days of an ADF diet participants appetite and calorie consumption did not increase compared to baseline. On the feed day, subjects consumed on average only 95 per cent ± 6 per cent of their calculated daily energy requirements. Hunger on the fasting days also decreased during the 10 week period [p<0.05]. The possibility of hyperphagia on feed days and high levels of hunger on fasting days has been a criticism of ADF diets previously. 24 Unfortunately most published studies on ADF, such as those mentioned previously, do not directly compare outcomes to a calorie-restricted control group. At least one study 25 has acknowledged this limitation by randomising subjects to either an ADF diet or a calorie restricted diet for eight weeks. Volunteers in the ADF group consumed zero calories on fasting days but could eat ad libitum on alternate days, while the calorie restricted group was limited to approximately 20 per cent of usual daily energy requirements. At the conclusion of this study there was no significant difference in weight loss, lipid profile and insulin sensitivity between the two groups. Importantly, there was no increased risk of rebound weight gain in the ADF group at twenty four weeks follow-up after completing the intervention. Although the sample size in the study was small [n=26], the findings suggest that ADF dieting may at least be as effective as simple daily caloric restriction.
The small number of quality human trials on ADF dieting generally favour ADF as an effective method for not only weight loss but also as a means of reducing risk factors for MetSy. Decreasing cholesterol, body weight and insulin resistance should also decrease individual risk for cardiovascular disease, but this has not yet been directly observed.

Time-restricted feeding
IF diets that utilise time-restricted feeding (TRF) usually involve participants forgoing nutrition during a specific portion of the day, or missing one or two of their three main daily meals 26 in Table 2.
Two human studies 27,28 assessed the impact of TRF by taking normal weight volunteers and restricting oral intake to one evening meal over eight weeks. Subjects then completed an 11 week wash-out period and resumed three meals/day. The researchers found that glucose tolerance, as measured by an oral glucose tolerance test, was significantly impaired [p<0.05] while consuming one meal per day, as compared to three meals per day. Whilst fat mass was decreased [mean 2.1kg], blood pressure, total cholesterol and LDL-c were all significantly increased. Subjects consuming one meal per day demonstrated a total cholesterol, LDL-C, and HDL-C 11.7 per cent, 16.8 per cent, and 8.4 per cent higher on average, respectively, compared to when eating three meals per day.
These two studies suggested that restricting subjects to one meal per day worsened risk factors for CVD. It was noted, however, that the single meal that was provided consisted of the same number of calories as the 3 meal per day eating plan. It was proposed that reducing the calories within the one meal may have led to more favourable health outcomes.
Hunger in those following the 1 meal per day plan was rated as high in the two previous studies, indicating that compliance long-term may be poor. 27,28 An alternative to this strict diet is a two meal/day TRF diet. However, one study 29 demonstrated that, similar to omitting breakfast and lunch, omitting breakfast alone was also associated with increased LDL-C in healthy volunteers, when followed over a two week period [mean change -0.08mmol/L in full diet, +0.20mmol/L in TRF, p=0.001].
The question remained regarding whether the same effects would be seen in overweight individuals. Chowdhury et al. 30 took 23 overweight individuals and randomised them to either three meals per day or two meals per day with breakfast excluded. Calorie restriction was not enforced. After 6 weeks there was no significant difference in any of the measured risk factors for cardiovascular disease, including body weight, total cholesterol, LDL-C, HDL-C and triglycerides. The only significant finding in this regard was that, insulin sensitivity, as measured by an oral glucose tolerance test, was decreased in the two meal per day cohort [p=0.05].
Of particular interest is a similar study 31  This suggested that overall risk for CVD may be increased in this group.
Conversely, in patients with T2DM, a short two week trial where volunteers omitted their morning meal led to significant weight loss [mean 1.4kg, p=0.009], as well as a favourable reduction in fasting glucose levels [mean change -6.10%].32 However, volunteers in the two meal/day plan also consumed approximately 15 per cent fewer calories compared to when eating regular meals so this may account for both of these findings.
There is a sparsity of randomised human trials assessing the metabolic effects of omitting breakfast. However, the studies discussed here and the observational studies currently published, [33][34][35][36][37][38] indicate that it is unlikely to be beneficial and furthermore may worsen risk factors for CVD, such as hypercholesterolemia.

Modified fasting regimens
Modified fasting regimens (MFR), or periodic very low calorie diets, are IF diets where 1-5 days per week are allocated as days with strictly reduced, or absent, calorie consumption Table 3. An early human trial 39

Conclusion
The development of cardiovascular disease is a leading cause of death worldwide. IF has been shown in the small number of human clinical trials discussed here to be an alternative to continuous caloric restriction in reducing the factors that contribute to the development of cardiovascular disease. Although the ideal regimen for IF remains unclear, there is promising evidence that ADF or MFR, paired with or without continuous caloric restriction, may be more effective than continuous caloric restriction alone in achieving this target. Unfortunately there is limited data linking IF directly with disease outcomes, such as cardiovascular disease, diabetes or cancer. Large population, long-term, randomised studies will be required to effectively assess these outcomes.
The patient adherence and long-term safety data for IF requires further human studies. Few trials have analysed these important factors beyond six months of follow-up. A diet that is too difficult to adhere to and reduces a patients' perceived quality of life is unlikely to be a worthy alternative long-term. Long-term randomised, controlled trials comparing continual caloric restriction and IF are required to objectively assess energy intake, energy expenditure, adherence, disease outcomes and metabolic factors.

men and women, normal weight
In TRF -reduced fat mass, increased total cholesterol and LCL-C Farshchi et al. 29 TRF -breakfast omitted.

women, normal weight
In TRF -higher fasting total and LCL-C, impaired insulin sensitivity. Chowdhury et al. 30 TRF-breakfast omitted vs. normal diet.

men and women, obese
Insulin sensitivity increased with breakfast compared to fasting Geliebter et al. 31 TRF -breakfast omitted vs. normal diet.

overweight men and women
In TRF -reduced body, increased total cholesterol