Effect of Intermittent Fasting on Glycaemic Control in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: Type 2 diabetes mellitus (T2DM) is a severe public health issue notably impacting human life and health expenditure. It has been observed in literature that intermittent fasting (IF) addresses diabetes and its underlying cause, which benefits people with diabetes. Therefore, this study aimed to evaluate the effectiveness of IF treatment on glycaemic control in people with T2DM compared with control group. Methods: Systematic review and meta-analysis of interventional studies among patients with T2DM with glycated haemoglobin (HbA1c) as an outcome was performed. A comprehensive search of electronic databases, including PubMed, Embase and Google Scholar, for articles published before 24 April 2022, was done. Studies reporting 24 hours of complete fasting or intermittent restricted energy intake (feeding permitted for only 4–8 hours daily, with 16–20 hours of fasting) and reporting changes in HbA1c and fasting glucose levels were eligible. Meta-analysis was performed using Cochrane’s Q statistic and the I2 statistical approach. Results: Eleven studies (13 arms) measuring the effect of IF on patients’ HbA1c level were analysed. There was no statistically significant difference between IF and control groups (Standardized mean difference [SMD] -0.08, 95% confidence interval [CI] -0.20 to 0.04;p=0.19, I2=22%). Overall, seven studies on patients’ fasting blood glucose were analysed, and the meta-analysis revealed no significant difference between the two groups i.e. IF and control groups (SMD 0.06, 95% CI -0.25 to 0.38;p=0.69, I2=76%). Conclusion: IF and usual diet pattern have no difference in terms of glycaemic control. Although, IF may be used as a preventative diet pattern in the pre-diabetic population, as it works well in the long-term to achieve controlled sugar levels. Study registration: The protocol of this study was registered in The International Prospective Register of Systematic Reviews (PROSPERO) with a registration number CRD42022328528.

Type 2 diabetes mellitus (T2DM) is a severe public health issue notably impacting human life and health expenditure. Around 9.3% (463 million people) of the global population were living with diabetes in 2019, and this is projected to increase to 10.2% (578 million people) by 2030 and 10.9% (700 million people) by 2045. 1,2 Diabetes impacts functional capacity and quality of life, and ultimately causes significant morbidity and premature mortality. In 2019, diabetes was the tenth biggest cause of death worldwide, directly causing an estimated 1.5 million deaths. 3 Despite lifestyle treatments such as a healthy diet, frequent physical activity and maintaining a normal body weight being critical pillars of diabetes management, achieving persistent glycaemic control with nonpharmacological techniques is difficult. 4,5 Recent studies have investigated the benefits of intermittent fasting (IF), which involves repeatedly and purposefully interrupting or drastically reducing energy intake for a period, for people with obesity and T2DM. IF has also been suggested as a glycaemic control and weight loss strategy with additional cardio-metabolic benefits. [6][7][8][9] Although it has not yet been standardized, intermittent or short-term energy restriction through very low-calorie diets is a common IF regimen. 4,5 Time-restricted feeding, which allows for only 4-8 hours of feeding per day (16-20 hours of fasting per day), is one of the most popular IF regimens. 10,11 Other popular IF techniques include alternate-day fasting and periodic fasting, which call for a circular diet that includes fasting for 1 or 2 days per week (burning ≤25% of the required calories) and eating normally for the rest of the week. 12 The impact of IF has been observed on a range of health outcomes including risk factors for metabolic diseases, such as weight, blood pressure, waist circumference, body fat, lipid distribution and blood glucose. [15][16][17][18] Previous studies on people with T2DM have shown that IF can result in comparable weight loss and glycated haemoglobin (HbA1c) reduction as traditional dietary recommendations. [19][20][21][22] However, in some randomized crossover experiments, IF had no impact on lipid and glucose metabolism. [23][24] These findings demonstrate that IF inconsistently impacts numerous metabolic parameters. Furthermore, the small sample sizes of these studies prevent drawing of firm conclusions. Therefore, a thorough and methodical meta-analysis that includes all eligible randomized controlled trials, a large sample size, and a range of IF types is needed to ascertain the effectiveness of IF interventions on glycaemic control in people with T2DM. This comprehensive review and meta-analysis evaluates the effect of IF treatments on glycaemic control in people with T2DM.

Materials and methods
This systematic review was submitted to the International Prospective Register of Systematic Reviews and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. 25 The protocol of this study was registered (PROSPERO ID: CRD42022328528).

Databases and search strategy
This meta-analysis was done and presented in accordance with the PRISMA standards. We conducted a comprehensive search of electronic databases, including PubMed, Embase and Google Scholar, for articles published before 24 April 2022, regardless of area. In addition, the reference lists of particular articles were examined. As search terms, we used intermittent fasting, intermittent energy restriction, type 2 diabetes, HbA1c and fasting blood glucose.

Inclusion and exclusion criteria
We selected articles that met the following standards: (1)

Risk of bias assessment
Using the updated Cochrane risk of bias assessment tool for randomized trials, 26 two independent reviewers assessed the likelihood of bias in trials based on the outcomes (HbA1c or fasting glucose). The Cochrane Handbook for Systematic Reviews categorizes the risk of bias for each domain as low, high or unclear based on the signal questions for each item.

Data analysis
The mean difference between before and after IF implementation and their respective 95% confidence intervals (CIs) were used to evaluate the effects of IF on HbA1c. To measure trial heterogeneity, Cochrane's Q statistic and the I 2 statistical approach were applied. A random-effect meta-analysis model was used if the pertinent p value was less than 0.05 and I 2 was higher than 50%. Otherwise, a fixed-effect model was chosen.
For each outcome, funnel plots depicting effect sizes versus standard errors were constructed and visually evaluated to assess the probability of bias. For statistical analysis, we used RevMan 5.4 software (Cochrane, London, UK).

Outcome measures
Glycaemic control (glycated haemoglobin and fasting blood glucose levels)  Figure 4).
Four studies included participants >60 years of age and nine studies included those ≤60 years of age. When analysed by patient age, the reported change in the HbA1c levels of IF and control groups was statistically significant (SMD -0.20, 95% CI -0.39 to -0.01;p=0.04, I 2 =24%; Figure 5).

Fasting blood sugar levels
One study monitored FBG after 6 months, and six studies monitored FBG at ≤6 months. When the >6 months study was excluded from analysis, there was still no significant difference between the FBG values of the IF and control groups (SMD 0.09, 95% CI -0.30 to 0.47;p=0.65, I 2 =80%; Figure 6).
Similarly, one study had participants over the age of 60 years, and the remaining six had participants aged ≤60 years. When the >60 years of age study was excluded, there was no significant difference in the FBG values of the IF and control groups (SMD -0.09, 95% CI -0.23 to 0.05;p=0.20, I 2 =0%; Figure 6).

Publication bias
The funnel plot illustrating the effect of IF on glycaemic control demonstrates a pattern that is nearly symmetric (Figure 7 and 8), which suggests that the findings were less likely to be influenced by publication bias.

Discussion
IF has gained recognition as a method to improve metabolic health.
In IF, eating habits are based on eating very few or no calories during periods from 12 hours to many days, while following a regular routine. An imbalance in the levels of adiponectin and leptin is a factor in the altered metabolism that increases the risk of developing T2DM. 37 In one study, significant reductions in HbA1c and weight were reported for almost all patients. 19 Also, there were no side effects noted among the patients on IF. Similarly, another meta-analysis also reported the positive   [27][28][29]33,34 Another meta-analysis has also concluded that there was no significant impact of IF on patients' HbA1c levels, although IF may be useful in preventing metabolic disorders. 40 These results are in line with the present meta-analysis, which reports no significant difference in glycaemic control between patients using IF versus another intervention. 42,43 Our meta-analysis on performing sensitivity analysis  Pooled analysis of the studies included in our meta-analysis showed no significant reduction in patients' FBG levels following IF. On the contrary, a study where IF was followed for 12 months reported significant reductions in fasting insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) levels in the alternate-day fasting group. 44 Similarly, another systematic review found that IF reduces participants' FBG levels. 41 Studies have also reported that insulin decreases because of increased insulin sensitivity and, hence, decrease fasting and postprandial blood glucose in patients with diabetes. 40,44 A few studies comment that IF and continuous energy restrictions have equal benefits in achieving long-term weight and glycaemic control. 19,40,42,44 The IF diet differs from the ketogenic or low-calorie diet in that it does not restrict carbohydrate intake; therefore, the direct effect on blood glucose levels in the short-term is unknown. Yet, IF is certainly beneficial in regulating blood glucose levels during fasting. IF can enhance insulin sensitivity in the long-term and therefore needs to be practised by patients with diabetes. Moreover, it is important to follow standard guidelines while practicing any dietary restrictions to avoid serious adverse effects.
There were some limitations on this analysis. First, there is heterogeneity among the studies and dietary interventions, with the treatment duration likely being the primary source of heterogeneity. As a result, the randomeffects models were used in this analysis for merging, and sensitivity analyses were carried out in accordance with potential sources. Second, there were only a small number of randomized controlled trials that met the inclusion criteria, and sample sizes were small. It was also difficult to reach a firm conclusion about how IF affected glycaemic control, because the intervention duration ranged from 8 weeks to 12 months. Additionally, it was not possible to determine whether IF was safe for patients with T2DM who were taking insulin in our analyses, which is particularly important.

Conclusion
IF and usual diet pattern have no difference in terms of glycaemic control. Although, IF might be used as a preventative diet pattern in the pre-diabetic population, as it works well in the long-term to achieve controlled sugar levels. It is clearly evident from our meta-analysis that IF alone does not reduce blood glucose levels in patients with diabetes.
Further clinical trials are required with uniform or standard IF intervention to study its impact in depth. ❑