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Here's a detailed systematic review protocol following the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols) 2015 guidelines. You'll need to fill in specific details for authors, affiliations, and the PROSPERO registration number once submitted.

Protocol Title: The Efficacy and Safety of Exercise Interventions for Glycemic Control and Cardiometabolic Health in Adults with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis Protocol

Version Number: 1.0
Date of Protocol: October 26, 2023

Registration: This systematic review protocol has been registered with PROSPERO (International Prospective Register of Systematic Reviews). The registration number will be [PROSPERO Registration Number: CRDxxxxxx] upon acceptance.

1. Administrative Information

1a. Identification

• Review Question: What is the efficacy and safety of structured exercise interventions on glycemic control, cardiometabolic markers, body composition, and quality of life in adults with Type 2 Diabetes Mellitus?


• Review Team:


• [Author Name 1], [Affiliation 1], [Email 1] (e.g., Primary Reviewer, Methodology Lead)


• [Author Name 2], [Affiliation 2], [Email 2] (e.g., Data Extraction, Risk of Bias Assessment)


• [Author Name 3], [Affiliation 3], [Email 3] (e.g., Search Strategy, Statistical Analysis)


• [Author Name 4], [Affiliation 4], [Email 4] (e.g., Clinical Expertise, Manuscript Preparation)


• Corresponding Author: [Author Name], [Email Address]

• Source of Funding: [e.g., No specific funding was received for this systematic review protocol. / This review is supported by [Grant Name/Number] from [Funding Body].]


• Role of Funder: [e.g., The funder has no role in the study design, data collection, analysis, interpretation, or manuscript writing. / The funder played a role in [specify].]

• [e.g., The authors declare no conflicts of interest. / Author X has received lecture fees from Y company, etc. Be transparent.]

2. Introduction

2a. Background and Rationale

Type 2 Diabetes Mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia resulting from insulin resistance and/or impaired insulin secretion. Globally, T2DM represents a significant public health challenge, with its prevalence steadily rising. The disease is associated with a range of microvascular and macrovascular complications, including nephropathy, retinopathy, neuropathy, cardiovascular disease, and stroke, leading to increased morbidity, mortality, and healthcare costs.

Current management guidelines for T2DM emphasize lifestyle modifications, including dietary changes and regular physical activity, alongside pharmacological interventions. Exercise is a cornerstone of T2DM management due to its numerous physiological benefits. These benefits include improved insulin sensitivity, enhanced glucose uptake by muscle cells, reduced systemic inflammation, improved lipid profiles, lower blood pressure, favorable changes in body composition, and enhanced cardiovascular fitness. Exercise can be broadly categorized into aerobic training, resistance training, combined training, and high-intensity interval training (HIIT), each potentially offering distinct advantages for individuals with T2DM.

While numerous systematic reviews and meta-analyses have explored the effects of exercise on T2DM, the evidence base is continually expanding with new studies. Furthermore, existing reviews often focus on specific exercise modalities or a limited set of outcomes, or may not incorporate the most recent high-quality evidence. There is a need for a comprehensive, up-to-date synthesis that examines a broad range of structured exercise interventions against usual care or no-exercise controls, evaluating their efficacy across key glycemic, cardiometabolic, anthropometric, fitness, and quality of life outcomes, while also assessing their safety profile.

This systematic review aims to provide a comprehensive and robust summary of the current evidence on the effects of various structured exercise interventions on adults with T2DM. By systematically identifying, appraising, and synthesizing the findings of high-quality randomized controlled trials (RCTs), we seek to inform clinical practice, guide future research, and ultimately contribute to improved health outcomes for individuals living with T2DM.

2b. Objectives

The primary objective of this systematic review and meta-analysis is to evaluate the efficacy of structured exercise interventions on glycemic control, as measured by glycated hemoglobin (HbA1c), in adults with Type 2 Diabetes Mellitus.

Secondary objectives include assessing the effects of structured exercise interventions on:

• Other markers of glycemic control: fasting plasma glucose (FPG), fasting insulin, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR).


• Cardiometabolic risk factors: lipid profiles (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides), systolic blood pressure (SBP), diastolic blood pressure (DBP).


• Body composition: body weight, body mass index (BMI), waist circumference, body fat percentage.


• Physical fitness: maximal oxygen uptake (VO2max) or other objective measures of cardiorespiratory fitness.


• Health-related quality of life (HRQoL).


• Safety: incidence and type of adverse events.

• Type of exercise intervention (e.g., aerobic, resistance, combined, HIIT).


• Intensity, frequency, and duration of exercise.


• Supervision status (supervised vs. unsupervised).


• Duration of the intervention.


• Baseline characteristics of participants (e.g., age, sex, diabetes duration, baseline HbA1c, BMI).

3. Methods

This systematic review protocol has been developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) 2015 statement.

3a. Eligibility Criteria

• Study Design: Only randomized controlled trials (RCTs) will be included.


• Participants (P): Adults (≥18 years old) diagnosed with Type 2 Diabetes Mellitus, irrespective of gender, ethnicity, or geographical location. Studies including participants with Type 1 Diabetes Mellitus or gestational diabetes will be excluded.


• Intervention (I): Any structured exercise intervention (e.g., aerobic training, resistance training, combined aerobic and resistance training, high-intensity interval training (HIIT), flexibility, balance training, or combinations thereof). The exercise intervention must be planned and systematic, with clearly defined parameters (e.g., frequency, intensity, duration, type).


• Comparator (C): Usual care, standard diabetes education, no exercise, or minimal physical activity advice. Studies comparing different types or doses of exercise interventions against each other (e.g., aerobic vs. resistance) will be excluded unless one arm also serves as a true control group.


• Outcomes (O): Studies must report at least one of the following outcomes:


• Primary Outcome: Glycated hemoglobin (HbA1c, reported in %).


• Secondary Outcomes: Fasting plasma glucose (FPG), fasting insulin, HOMA-IR, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, systolic blood pressure (SBP), diastolic blood pressure (DBP), body weight, body mass index (BMI), waist circumference, body fat percentage, VO2max or other objective fitness measures, health-related quality of life scores, and adverse events.


• Language: Studies published in English will be included.


• Publication Status: No restrictions on publication date. Both published and unpublished (e.g., conference abstracts, theses where sufficient data is available) studies will be considered, if accessible and peer-reviewed.

A comprehensive search will be conducted across the following electronic databases from their inception to the present date:

• PubMed/MEDLINE


• Embase


• Cochrane Central Register of Controlled Trials (CENTRAL)


• Web of Science (Core Collection)


• Scopus

• ClinicalTrials.gov


• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP)

3c. Search Strategy

The search strategy will be developed in consultation with a medical librarian and will be tailored for each database using a combination of Medical Subject Headings (MeSH) terms, Emtree terms, and keywords related to Type 2 Diabetes Mellitus and exercise interventions. Boolean operators (AND, OR) will be used to combine terms. The search will not be limited by date.

Example Search Strategy for PubMed/MEDLINE:

• Diabetes Mellitus, Type 2:


• "Diabetes Mellitus, Type 2"[Mesh] OR "Diabetes, Type 2"[tiab] OR "Noninsulin-Dependent Diabetes Mellitus"[tiab] OR "NIDDM"[tiab] OR "Adult-Onset Diabetes"[tiab]


• Exercise/Physical Activity:


• "Exercise"[Mesh] OR "Physical Activity"[Mesh] OR "Exercise Therapy"[Mesh] OR "Resistance Training"[Mesh] OR "High-Intensity Interval Training"[tiab] OR "HIIT"[tiab] OR "Aerobic Training"[tiab] OR "Strength Training"[tiab] OR "Physical Training"[tiab] OR "Exercise Program"[tiab] OR "Physical Exercise"[tiab] OR "Workout"[tiab]


• Study Design:


• "Randomized Controlled Trial"[pt] OR "Controlled Clinical Trial"[pt] OR "Randomized Controlled Trials as Topic"[Mesh] OR "Random Allocation"[Mesh] OR "Double-Blind Method"[Mesh] OR "Single-Blind Method"[Mesh] OR "RCT"[tiab] OR "Randomly Assigned"[tiab]


• Combine:


• (#1) AND (#2) AND (#3)

3d. Study Selection Process

Following the database searches, all identified citations will be imported into a reference management software (e.g., EndNote, Covidence). Duplicate records will be removed.
Two independent reviewers will then screen the titles and abstracts against the eligibility criteria. Studies deemed potentially relevant by at least one reviewer will proceed to full-text review.
Full-text articles will be retrieved and independently assessed for eligibility by two reviewers. Any disagreements between reviewers at both the title/abstract and full-text screening stages will be resolved through discussion or, if necessary, by a third independent reviewer.
Reasons for exclusion of full-text articles will be documented. A PRISMA flow diagram will illustrate the study selection process.

3e. Data Collection Process

Two independent reviewers will extract data from the included studies using a standardized, pre-piloted data extraction form. The form will be piloted on a small subset of studies (e.g., 2-3 studies) and refined as needed to ensure consistency and completeness. Any discrepancies will be resolved by discussion or adjudication by a third reviewer.
If essential data are missing from a study, the reviewers will attempt to contact the corresponding authors to request the information.

3f. Data Items

The following data will be extracted from each eligible study:

• Study Characteristics:


• Author(s), year of publication, country of study, funding source.


• Study design (e.g., parallel, crossover).


• Setting (e.g., hospital, community).


• Duration of follow-up.


• Participant Characteristics:


• Total number of participants randomized and analyzed in each arm.


• Age (mean ± SD), sex (% female).


• Baseline BMI (mean ± SD).


• Duration of diabetes (mean ± SD).


• Baseline HbA1c (mean ± SD).


• Other relevant comorbidities or medications.


• Intervention Characteristics:


• Detailed description of the exercise intervention (type, frequency per week, duration per session, intensity, total weekly duration).


• Supervision status (supervised, unsupervised, mixed).


• Comparator group details (e.g., usual care, education).


• Outcome Data:


• Mean and standard deviation (SD) or standard error (SE) for all primary and secondary outcomes at baseline and post-intervention (or change from baseline).


• Number of participants analyzed for each outcome in each group.


• Units of measurement for all outcomes.


• Information on adverse events (number, type, severity) in both intervention and control groups.

The methodological quality and risk of bias of each included RCT will be independently assessed by two reviewers using the Cochrane Risk of Bias 2.0 (RoB 2.0) tool for randomized trials. This tool assesses bias across five domains:

• Bias arising from the randomization process.


• Bias due to deviations from intended interventions.


• Bias due to missing outcome data.


• Bias in measurement of the outcome.


• Bias in selection of the reported result.

3h. Data Synthesis

Qualitative Synthesis:
A narrative synthesis will be conducted for all included studies, summarizing key characteristics, intervention details, and reported outcomes. If meta-analysis is not possible due to excessive heterogeneity, insufficient data, or disparate outcome reporting, a detailed descriptive summary of the findings will be provided.

Quantitative Synthesis (Meta-analysis):
If sufficient data are available from at least two comparable studies, quantitative meta-analysis will be performed using Review Manager (RevMan) software (version 5.4, Cochrane Training) or R statistical software with the 'meta' package.

• Effect Measures: For continuous outcomes, mean differences (MD) will be used when outcomes are measured on the same scale (e.g., HbA1c in %). Standardized Mean Differences (SMD) will be used when outcomes are measured using different scales or units (e.g., different HRQoL questionnaires). For adverse events, relative risks (RR) or odds ratios (OR) will be calculated for dichotomous outcomes.


• Statistical Model: A random-effects model will be used for all meta-analyses, considering the anticipated clinical and methodological heterogeneity across studies.


• Heterogeneity Assessment: Statistical heterogeneity will be assessed using the Chi-squared test (with a p-value < 0.10 indicating significant heterogeneity) and the I² statistic (I² < 25% for low heterogeneity, 25-50% for moderate, 50-75% for substantial, and > 75% for considerable heterogeneity).


• Subgroup Analysis: Pre-specified subgroup analyses will be conducted where sufficient data allow, to explore potential sources of heterogeneity, as outlined in the "Exploratory Objectives" section (e.g., by exercise type, intervention duration, supervision, baseline HbA1c).


• Sensitivity Analysis: Sensitivity analyses will be performed to assess the robustness of the findings. These may include:


• Excluding studies deemed to have an overall high risk of bias.


• Excluding studies with very short intervention durations (e.g., < 8 weeks).


• Excluding studies where data were imputed or obtained through author contact.


• Publication Bias: Publication bias will be assessed using funnel plots visually for outcomes with at least 10 studies. Egger's test will be performed if appropriate. Asymmetry in the funnel plot or a statistically significant Egger's test may indicate publication bias.

The certainty of the evidence for each primary and key secondary outcome will be assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. This framework considers five domains: risk of bias, inconsistency (heterogeneity), indirectness, imprecision (sample size, confidence intervals), and publication bias. The certainty of evidence will be rated as high, moderate, low, or very low.

4. Ethics and Dissemination

4a. Ethics Approval

Ethical approval is not required for this systematic review as it will synthesize data from previously published or publicly available studies and will not involve human participants or directly collect primary data.

4b. Dissemination

The findings of this systematic review and meta-analysis will be published in a peer-reviewed scientific journal. The results will also be disseminated through presentations at relevant national and international conferences. The full PROSPERO registration details will be included in the final publication.

5. Amendments

Any amendments made to this protocol after PROSPERO registration will be clearly documented with the date of amendment, a description of the change, and the rationale for the change, and will be updated in the PROSPERO registry.

6. References

• Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647.


• Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.4 (updated August 2023). Cochrane, 2023. Available from www.training.cochrane.org/handbook.

Appendix 1: Example PubMed Search Strategy

(This would be a more detailed, final version of the search strategy described in 3c, ready to be run in PubMed. You'd include the actual date range of the search once executed)

This detailed protocol provides a robust framework for your systematic review. Remember to submit it to PROSPERO before you begin your actual data extraction and analysis to maintain its integrity as a prospective registration. Good luck!