Systematic review protocol for effectiveness and cost-effectiveness of non-surgical interventions to prevent diabetes progression in adults with prediabetes

Abstract

Introduction

Prediabetes (PD), defined by impaired glucose tolerance or impaired fasting glucose, represents a growing global health challenge, with a prevalence projected to increase substantially. PD is a critical intervention target because of its high annual progression rate (5–10%) to type 2 diabetes mellitus (T2DM) and elevated cardiovascular disease (CVD) risk. Non-surgical interventions (NSIs), particularly lifestyle modifications (LMs) and pharmacological therapies, are the cornerstone of PD management, demonstrating efficacy and cost efficiency over surgical options. However, despite LM’s ability to reduce T2DM incidence by 40–70% in trials such as the Diabetes Prevention Program, real-world implementation faces barriers, including resource intensity and complex delivery requirements, which increase upfront costs. We aim to review scientific literature reporting on the effectiveness and cost-effectiveness of NSIs for preventing the progression of PD to T2DM among adults.

Methods and analysis

A comprehensive systematic search will be conducted across major biomedical databases (PubMed, Scopus, Cochrane Library, Web of Science) for records published up to July 2024. We will include studies involving adults diagnosed with PD according to the American Diabetes Association (ADA) or WHO criteria, focusing on LM and pharmacological treatments. Observational and interventional study designs, including economic evaluations, will be considered. Primary outcome: diabetes incidence (ADA or WHO glycaemic criteria). Secondary outcomes: (1) CVD risk factors, (2) health utilities and (3) healthcare cost analyses. The protocol adheres to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines and is registered with PROSPERO (CRD42024561294). Data extraction and quality assessment will be performed by two reviewers, with discrepancies resolved by the consensus of a third reviewer. Data will be narratively synthesised; if the data allow, a meta-analysis will be conducted.

Ethics and dissemination

This systematic review was exempt from ethical approval as it involved no collection of individual patient data and posed no confidentiality risks. The findings will be shared via publication in a peer-reviewed journal or presentation at relevant conferences.

PROSPERO registration number

CRD42024561294.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This review will provide a dual assessment of non-surgical interventions, considering clinical and economic outcomes.

• Variability in intervention types and durations across studies may limit direct comparability.

• The use of simulated models for economic projections may introduce assumptions affecting the accuracy of cost-effectiveness estimates.

Introduction

Epidemiological data underscore the substantial global burden of prediabetes (PD), a condition clinically defined by either impaired glucose tolerance (IGT: 2-hour plasma glucose 140–199 mg/dL during Oral Glucose Tolerance Test or impaired fasting glucose (IFG: fasting plasma glucose (FPG) 100–125 mg/dL).¹ In 2021, approximately 9.1% of adults globally met the criteria for IGT and 5.8% met the IFG diagnostic threshold, a figure projected to continue to rise annually.²

PD represents a critical intervention target because of its high-risk trajectory, characterised by an annual progression rate of 5–10% to type 2 diabetes mellitus (T2DM) and a lifetime conversion risk exceeding 70%.³ Beyond its role in the development of T2DM, PD independently increases the risk of cardiovascular disease. Meta-analyses have shown elevated risks of both diabetes onset and adverse cardiovascular outcomes in prediabetic populations.^{4 5}

Given these significant risks, it is imperative to explore effective therapeutic strategies to manage PD, focusing on both prevention and cost efficiency. PD can be managed through lifestyle modifications (LMs), pharmacological treatments and, less commonly, surgery. Due to high costs and risks, surgical options are discouraged, making non-surgical interventions (NSIs), primarily LM and pharmacotherapy, the preferred approach (figure 1).⁶

Figure 1. Conceptual framework of non-surgical interventions in adults with prediabetes.

While randomised controlled trials (RCTs) have demonstrated the clinical effectiveness of these NSIs in reversing PD, a critical evidence gap persists regarding their economic evaluations (cost-effectiveness), limiting their appeal to healthcare payers and policymakers. Studies have confirmed that LM is the most effective NSI for managing PD.^{7 8} Despite their established efficacy, NSIs encounter substantial implementation challenges, including resource-intensive protocols and complex delivery systems that generate considerable costs. For instance, the Diabetes Prevention Program trial⁹ demonstrated that LM programmes cost approximately US$ 300–700 annually per participant, which is a higher upfront cost than metformin (US$ 100–200 annually). The high cost of T2DM care is evident, with expenses increasing from US$ 500 per PD case to US$ 13 240 annually for diagnosed T2DM patients. This substantial increase in healthcare costs highlights the role of NSIs to offer up to 50% cost savings for public health systems.¹⁰

Current reviews assess the effectiveness or cost-effectiveness of PD interventions separately; however, the lack of a combined analysis of NSIs limits value-based care implementation.^{7 8 11 12} This systematic review expands on the existing literature by evaluating the clinical effectiveness of NSIs by measuring T2DM incidence reduction, alongside the cost-effectiveness measured through incremental cost-effectiveness ratio (ICER) or cost per averted diabetes case. Additionally, it addresses real-world implementation challenges, such as attrition, adherence and acceptability of the interventions, providing a comprehensive perspective on the feasibility and value of NSIs in managing PD across diverse healthcare settings. This multifaceted approach aims to inform clinical practice and health policy decision-making.

Objectives

This systematic review aims to comprehensively evaluate NSIs for PD by:

1. Assessing their clinical effectiveness in reducing the incidence of T2DM.

2. Examining their cost-effectiveness using measures such as ICER or cost per averted diabetes case.

3. Identifying real-world implementation challenges including attrition, adherence and acceptability of the interventions.

Investigator-developed framework of intervention focus

Figure 1 presents the NSIs identified through a comprehensive literature review table 1. These interventions were categorised based on their established effectiveness in managing PD. The framework highlights both modified and non-modified factors, providing a clear representation of conventional approaches that have been proven in the literature to aid in the prevention and management of PD.

Table 1. Investigator-proposed classification framework.

Non-surgical intervention
Conventional/traditional approaches	Modified approaches
Proven pharmacological intervention Metformin, Alpha-glucosidase inhibitors Lifestyle modification (Diet, physical activity) Increased intensity Increased frequency	Community-based Behavioural therapy Digital therapeutics

Newer pharmacological agents, such as Glucagon-like Peptide-1 receptor agonists and Sodium-Glucose Transport Protein-2 inhibitors, are often associated with higher costs.

Methods and analysis

Reporting guidelines

The protocol was developed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) Protocols 2015 guidelines¹³ and registered with PROSPERO under registration number CRD42024561294. The review will be conducted following the PRISMA 2020 Statement.¹⁴ Any significant amendments to this protocol will be documented and reported in publications, alongside the review results. For each amendment, the date of the amendment, a description of the changes and the rationale for these changes will be provided.

Eligibility criteria

Studies that meet the following inclusion criteria will be included in this review:

1. Studies will include adults aged 18 years and older diagnosed with PD according to the criteria set by the American Diabetes Association or the WHO. Any accepted method for diagnosing PD will be considered, such as IFG, IGT, elevated FPG and increased glycated haemoglobin (HbA1c).

2. NSIs targeting PD include LM strategies such as dietary changes, physical activity programmes and educational initiatives, as well as pharmacological treatments.

3. Variety of study designs: observational studies (cross-sectional surveys, case-control and cohort studies) and interventional studies (including RCTs, non-RCTs, non-controlled trials and quasiexperimental studies). Economic studies cover analyses such as cost analysis, cost-effectiveness, cost-utility, cost-benefit, cost minimisation and cost consequences analyses.

4. We will focus exclusively on studies reporting T2DM incidence and cardiovascular risk factors, such as blood pressure, cholesterol, glucose levels and HbA1c. Additionally, we will incorporate economic evaluations that detail health economic outcomes, including cost and quality of life.

5. English-language peer-reviewed articles.

Animal studies, studies involving pregnant or lactating women and studies with participants who have comorbidities that may affect blood sugar levels will be excluded. Participants with a prior diagnosis of diabetes or gestational diabetes mellitus will be excluded. Additionally, studies that reported only the costs of screening or detection were not considered. The excluded study types included case reports, case series, reviews, meta-analyses, conference proceedings, posters, news articles, commentaries, editorials, practice guidelines and clinical updates. The intervention period must be a minimum of 1 year.

Outcome measure

The primary effectiveness outcome will be the incidence of T2DM. Secondary outcomes will include anthropometric measures, such as body weight (kg) and body mass index (kg/m²), which are key indicators of metabolic health and intervention effectiveness. Intermediate metabolic outcomes will include HbA1c (%), FPG (mg/dL) and insulin sensitivity (Homeostatic Model Assessment for Insulin Resistance). Cardiovascular risk will be assessed through biomarkers such as low-density lipoprotein cholesterol, blood pressure and triglycerides.

To support the review’s focus on both effectiveness and cost-effectiveness, the number needed to treat (NNT) will be calculated for studies that report T2DM incidence. Additionally, costeffectiveness will be assessed based on the cost per quality-adjusted life year (QALY) gained and incremental cost-effectiveness ratio (ICER). For studies reporting T2DM incidence, the cost per case of diabetes prevention will also be estimated to provide a comprehensive evaluation of economic value.

Setting and time frame

Studies conducted in healthcare settings, community-based settings and workplace settings will be included. The intervention period must be a minimum of 1 year for inclusion.

Information sources

The primary literature search will be conducted on 1 August 2025, using a structured approach across major electronic databases, including PubMed, Cochrane Library, Scopus and Web of Science. Each database will be searched from inception for relevant studies. Manual searches of reference lists from the included studies, relevant reviews, national clinical practice guidelines and other pertinent documents will also be performed. To ensure comprehensive coverage, content experts and prolific authors in the field will be contacted for further insights and potential unpublished data.

Search strategy development

A systematic search strategy was developed based on three key concepts derived from a comprehensive review of the search methodologies.

1. Adult with PD.

2. Non-surgical approaches to PD management.

3. Clinical and economic outcomes.

• Search terms and methodology.

1. Relevant Medical Subject Headings (MeSH) and controlled vocabularies were identified and validated using PubMed.

2. Both free-text and MeSH terms were combined using Boolean operators (‘OR’ within each concept, ‘AND’ between concepts).

3. Truncations and wildcards were used to capture variations in terminology.

4. The search strategy was initially designed for PubMed and will be adapted for databases without MeSH support (see online supplemental tables S1-S4).

5. Two research team members will independently peer-review the strategy to ensure its comprehensiveness and accuracy.

Patient and public involvement

Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

Data extraction and management

Data management

Identified records will be managed using the EndNote reference manager, which will allow for the identification and removal of duplicates. The screening process will be conducted using the software Rayyan (free version), which facilitates reviewers during screening. Data extraction and risk of bias assessment for the included studies will be performed using a Microsoft Excel spreadsheet.

Data extraction

Using a two-step approach, two reviewers will screen the studies. The initial step will involve screening titles and abstracts, followed by a second step of reviewing the full text of the retrieved studies. In cases where the reviewers do not reach an agreement on study selection, discussions will continue until consensus is reached. If necessary, a senior team member will act as an arbitrator, and a decision will be made. Additional records will be identified by searching the reference lists of retained articles. The screening process for article inclusion in the systematic review will be thoroughly documented following the PRISMA 2020 flow diagram.¹⁵ This diagram visually represents the steps of identification and screening, detailing the reasons for exclusion where applicable (table 2).

Table 2. Data to be extracted: study characteristics, participant details, intervention details, outcome measures, statistical methods and main finding.

Study characteristics	Participant characteristics	Intervention details	Outcomes measure	Statistical methods	Main finding
Title	Gender	Non-surgical (lifestyle, drug therapy)	Primary (diabetes incidence, glucose levels)	Relative risk, OR, or HR on disease progression	Summary of key outcomes from the study
Authors	Age	Duration and frequency	Secondary (weight reduction, blood pressure, lipid profile)	Absolute risk reduction/increase
Year of publication	Ethnicity	Specific components (diet, exercise, medication)	Time points of outcome assessment	P value, confidence intervals
Study design	Baseline health status	Comparison group	Follow-up and adherence (duration, dropout)	P value, confidence intervals
Setting	Family history			Cost associated with intervention
Sample size	Criteria for prediabetes			Cost per quality adjusted life year gained
Country				Cost per case of diabetes prevented
Study objective				Incremental cost-effectiveness ratio

Risk of bias assessment

The quality of the included studies will be assessed by one reviewer (CFS) and verified by a second reviewer (CHN) using appropriate tools. For economic evaluations, the reporting quality will be evaluated using the Consolidated Health Economic Evaluation Reporting Standards statement.¹⁶ RCTs will be assessed using the Risk of Bias 2.0 tool,¹⁷ while non-randomised studies will be evaluated using the ROBINS-I tool.¹⁸ Any disagreements will be resolved by consensus or by consulting a third reviewer (LCM).

Data synthesis

The PRISMA 2020 flow chart will be employed to document the number of studies identified during the search process, along with those excluded and included based on the outlined eligibility criteria. Study characteristics will be summarised using tables and narrative descriptions according to population, intervention, comparators, outcomes and study types (PICOS) (Refer format in tables3 4). Additionally, the study findings will be grouped by type of intervention, comparator and outcomes.

Table 3. Study characteristic and summary of evidence on effectiveness of NSIs.

Author (year)	Country/study (duration)	Population (mean/median)	Diagnosis references (Standard)	Intervention/control (sample size)	Diabetes incidence HR (95% CI)	Metabolic and anthropometric outcome
Study 1
Study 2
Study 3

NSI, non-surgical intervention.

Table 4. Study characteristic on included cost-effectiveness of NSIs.

Author (years)	Perspective	Population	Study type	Study approach	Intervention	Comparator	Time horizon (years)	Discount (%)	Currency (years)
Study 1
Study 2
Study 3

NSI, non-surgical intervention.

A narrative synthesis was conducted to describe the main characteristics, methods and findings of the included studies, with particular emphasis on the effectiveness of the NSIs. We will pool the results if the data are homogeneous in terms of PICOS, and a meta-analysis will be conducted using JASP software. Summary effects, such as HRs for categorical data or mean differences for continuous data, will be calculated. Forest plots will be used to visually present the meta-analysis results.

Cost-effectiveness studies were synthesised separately, focusing on cost per participant, cost per diabetes case prevented and overall cost-benefit, to provide insights into the clinical and economic outcomes of the interventions.

Subgroup and sensitivity analysis

Statistical heterogeneity will be assessed using the I² statistic. A random-effects model will be applied if the I² value exceeds 50%; otherwise, a narrative synthesis will be conducted. In cases of significant variability among studies, subgroup analyses will be performed based on factors such as age, sex, body weight, intervention type, study design and outcome measures. The effectiveness of the NSIs will also be analysed for each specific intervention. Sensitivity analyses will be conducted to evaluate the robustness of the findings. Additionally, potential reporting bias for specific outcomes will be assessed using funnel plots and Egger’s tests.

Publication bias

To address publication bias, this review will employ statistical methods, such as funnel plots and Egger’s test, to visually and quantitatively assess the asymmetry in the data. We will focus on published studies from peer-reviewed journals and consider only those that meet the inclusion criteria. This approach will help ensure that the review provides a balanced and comprehensive analysis that reflects the best available evidence.

Assessment of level of evidence

To ensure reliable and transparent evidence, we will use the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to weigh the strength of the overall evidence and assess the level of confidence in the cumulative evidence.¹⁹ The GRADE approach evaluates the certainty of the body of evidence for relevant outcomes, categorising them into four levels: ‘high,’ ‘moderate,’ ‘low’ and ‘very low.’ Each outcome will be assessed across five domains: ‘risk of bias’, ‘inconsistency’, ‘indirectness’, ‘imprecision’ and ‘publication bias.’ Following the guidelines in the Cochrane Handbook, we will present our findings using a summary of findings table.²⁰ This method allows for a systematic assessment of the level of evidence, providing a clear understanding of the confidence that can be placed in the cumulative evidence.

Ethics and dissemination

This systematic review was exempt from ethical approval as it involved no collection of individual patient data and posed no confidentiality risks. The findings will be shared via publication in a peer-reviewed journal or presentation at relevant conferences.

Discussion

Potential implications of the review

PD represents a critical window for intervention to delay the progression to T2DM and improve cardiovascular risk. The exploration of NSIs is particularly pertinent, given the rising global incidence of PD and the consequent burden on healthcare systems. Current trends in obesity and aging further exacerbate this issue, as both factors are strongly linked to an increased risk of developing T2DM.

Previous studies have demonstrated that LMs, such as diet and exercise, and pharmacological treatments can effectively reduce the risk of developing T2DM.^{7 8 11 12} However, there is a paucity of comprehensive evaluations that simultaneously consider the clinical effectiveness and economic implications of these interventions.

This systematic review aims to fill this gap by providing a holistic assessment of NSIs, including their impact on delaying the onset of diabetes, improving cardiovascular risk factors and reducing healthcare costs. Furthermore, this review addresses the heterogeneity in intervention types, duration and intensity, offering insights into the most effective strategies tailored to different demographic and risk profiles, particularly focusing on populations with high obesity rates and older adults.

By synthesising evidence from RCTs and economic evaluations and incorporating these into the decision analytical model, this review will inform policymakers, clinicians and stakeholders on optimal resource allocation and intervention strategies to curb the diabetes epidemic.

Limitations and strengths

The search strategy used in this systematic review may be subject to several limitations. These include database limitations, where certain databases or sources may not be covered by the search, potentially omitting relevant studies from the review. Additionally, the search strategy was constrained by the terms, keywords and date range used, which may have limited the comprehensiveness of the search. An important methodological limitation is the potential for language bias, as our inclusion criteria were restricted to English-language publications. This may have resulted in the exclusion of non-English studies, potentially affecting the comprehensiveness of our findings.