Is isocaloric intermittent fasting superior to calorie restriction? A systematic review and meta-analysis of RCTs.

This systematic review and meta-analysis compared the effects of two dietary strategies:

**Isocaloric Intermittent Fasting (IF):** This involved various patterns of alternating periods of eating and fasting (e.g., 16/8 method, 5:2 method, alternate-day fasting) where the total weekly calorie intake was *restricted* to the same degree as the control group. The key here is "isocaloric," meaning the total calories consumed over a week were equal between the IF and CR groups.

**Isocaloric Calorie Restriction (CR):** This involved consistently reducing daily calorie intake by a certain percentage (e.g., 20-40% of usual consumption) such that the total weekly calorie intake was *equal* to that of the IF group.

The researchers aimed to determine if IF offered additional health benefits beyond those achieved solely by calorie restriction. They investigated a wide range of outcome measures, categorized as:

**Anthropometric measurements:** These relate to body size and composition, including body weight (BW), body mass index (BMI), fat mass (FM) in kilograms and percentage, lean body mass (LBM), waist circumference (WC), and hip circumference (HC).

**Adherence factors:** How well participants stuck to the diet, assessed through reported adherence and dropout rates.

**Metabolic profile:** Markers related to metabolism, such as fasting blood glucose (FBG), fasting blood insulin (FBI), hemoglobin A1c (HbA1c), Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).

**Inflammatory biomarkers and adipokines:** Substances in the blood related to inflammation and fat cell function, including C-reactive protein (CRP), Interleukin-6 (IL-6), leptin, adiponectin, and insulin-like growth factor-1 (IGF-1).

**Subjective experiences:** Self-reported hunger and fatigue.

The meta-analysis synthesized data from **20 randomized controlled trials (RCTs)**. The participants in these individual studies were **adults and elderlies** (aged 18 years or older). The inclusion criteria specified that participants were undergoing a weight loss strategy that combined IF and CR, or CR alone, and that the studies did not *solely* emphasize anthropometric measurements, implying a focus on broader health outcomes. The specific health conditions or BMI ranges of the participants in the individual RCTs would have varied, but the overall aim was to assess the effects in a general adult population interested in weight management and health improvement. The studies were conducted in various locations, as is typical for a global meta-analysis.

The specific instruments and scales used would have varied across the 20 individual RCTs included in the meta-analysis. However, the meta-analysis pooled data on the following common measures:

**Anthropometric measurements:**

* **Body Weight (BW):** Typically measured using calibrated scales.

* **Body Mass Index (BMI):** Calculated from height and weight (kg/m²).

* **Fat Mass (FM) and Lean Body Mass (LBM):** Often measured using methods like Dual-energy X-ray Absorptiometry (DXA), bioelectrical impedance analysis (BIA), or air displacement plethysmography (Bod Pod). The abstract specifies FM in kilograms and percentage, and LBM in kilograms.

* **Waist Circumference (WC) and Hip Circumference (HC):** Measured using a tape measure at standardized anatomical points.

**Metabolic profile:**

* **Fasting Blood Glucose (FBG):** Measured from blood samples after an overnight fast, typically using enzymatic assays.

* **Fasting Blood Insulin (FBI):** Measured from blood samples after an overnight fast, often using immunoassays.

* **Hemoglobin A1c (HbA1c):** Measured from blood samples, indicating average blood sugar levels over the past 2-3 months.

* **Homeostasis Model Assessment for Insulin Resistance (HOMA-IR):** A calculated index derived from FBG and FBI values, used to estimate insulin resistance.

* **Triglycerides (TG), Total Cholesterol (TC), Low-density Lipoprotein (LDL), High-density Lipoprotein (HDL):** Measured from blood samples, typically using enzymatic assays.

**Inflammatory biomarkers and adipokines:**

* **C-reactive protein (CRP):** A marker of inflammation, measured from blood samples using immunoassays.

* **Interleukin-6 (IL-6):** A pro-inflammatory cytokine, measured from blood samples using immunoassays.

* **Leptin, Adiponectin, Insulin-like Growth Factor-1 (IGF-1):** Hormones and growth factors related to metabolism and fat tissue, measured from blood samples using immunoassays.

**Subjective experiences:**

* **Hunger and Fatigue:** Typically assessed using self-report questionnaires or visual analog scales (VAS), where participants rate their feelings on a numerical scale.

**Adherence:**

* **Adherence rates:** Reported narratively from the individual studies, based on their specific criteria for successful adherence.

* **Dropouts:** The number of participants who left the study before completion, serving as an indirect indicator of adherence.

The meta-analysis focused on the "net changes in the mean ± SD" for these variables, meaning the difference in the change from baseline between the IF and CR groups.

This study was a **systematic review and meta-analysis of randomized controlled trials (RCTs)**. This design sits at the top of the evidence hierarchy for clinical questions, as it systematically synthesizes the findings of multiple high-quality studies (RCTs) to provide a more robust and precise estimate of an intervention's effect than any single study could.

**Search Strategy:**

The researchers conducted a comprehensive search across four major electronic databases: Embase, PubMed, Scopus, and Google Scholar. The initial search was performed up to February 12, 2024, and then repeated on May 2, 2024, to ensure the inclusion of the most recently published relevant articles. This thorough, multi-database search strategy minimizes the risk of missing relevant studies, which is crucial for a systematic review. The search used a broad range of keywords related to intermittent fasting, calorie restriction, various anthropometric and metabolic outcomes, and adherence, combined with terms like "isocaloric" or "equal calories" to identify studies matching their core research question.

**Inclusion and Exclusion Criteria:**

The study followed the PICO (Population, Intervention, Comparator, Outcomes) framework to define strict eligibility criteria.

**Population:** Adults and elderlies (≥18 years old).

**Intervention:** Any type of intermittent fasting (e.g., alternate-day fasting (ADF), time-restricted eating (TRE), 5:2 diet) *combined with calorie restriction*.

**Comparator:** Calorie restriction alone.

**Crucial Criterion:** Both the intervention (IF+CR) and control (CR) groups *had to be isocaloric*, meaning they consumed an equal amount of calories weekly or had an equal energy restriction percentage. This was the defining feature of this meta-analysis, aiming to isolate the effects of the *timing* of food intake (IF) from the *amount* of food intake (CR).

**Outcomes:** Anthropometric measurements, adherence, metabolic profile, inflammatory biomarkers, and adipokines.

**Study Design:** Only peer-reviewed, English-language randomized clinical trials (RCTs) were included.

**Duration:** Studies had to have an intervention duration between 3 and 12 months.

**Exclusions:** Non-randomized trials, review articles, observational studies, in vivo/in vitro studies, non-peer-reviewed articles, foreign language articles, studies shorter than 3 months, studies where participants were not aiming for weight loss with IF, studies with participants younger than 18, studies where IF was not combined with CR, and studies with considerable differences in CR between groups.

These strict criteria are vital for ensuring that the included studies are comparable and directly address the research question, particularly the "isocaloric" requirement, which is a strength of this meta-analysis compared to others that did not control for total caloric intake.

**Data Extraction:**

Two independent authors extracted relevant information from the selected articles (e.g., author, year, location, sample size, age, BMI, health condition, intervention details, calorie restriction amounts, duration, energy intake measurement method, and adherence data). This independent extraction process helps to minimize errors and biases in data collection. Any disagreements were resolved by a third author.

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