Interventions with mitochondrial-related effects in older adults with type 2 diabetes: Protocol for a systematic...

Mitochondrial dysfunction is central to type 2 diabetes mellitus (T2DM) pathogenesis, driving insulin resistance and pancreatic β-cell dysfunction. Age-related mitochondrial impairment worsens this in older adults, yet evidence on mitochondrial interventions for this group is limited. This protocol outlines a systematic review and conditional network meta-analysis of randomized controlled trials evaluating mitochondrial interventions in adults aged 60+ with T2DM.

The primary objective of this systematic review and conditional network meta-analysis (NMA) is to evaluate the comparative efficacy and safety of diverse mitochondrial-related interventions, including pharmacological agents, nutritional supplements, and lifestyle modifications, relative to placebo, standard care, or no intervention, on mitochondrial function biomarkers in adults aged 60 years or older with type 2 diabetes mellitus (T2DM). Interventions with mitochondrial effects are operationally defined as those whose primary mechanism is known to target mitochondrial pathways or those that are explicitly evaluated for their effects on direct markers of mitochondrial function in the trial. The secondary objectives are: (1) to assess the impact of these interventions on glycemic and metabolic control outcomes including glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR), body weight, and body mass index (BMI); (2) to conduct a conditional NMA to compare and rank the relative efficacy of different intervention categories if the evidence network is sufficiently connected and clinically coherent; and (3) to explore potential sources of heterogeneity (e.g., intervention duration, baseline HbA1c levels) via prespecified subgroup and sensitivity analyses.

Prepared per PRISMA-P, the review will follow PRISMA 2020 and PRISMA-NMA if applicable. Registered with PROSPERO (ID: CRD420251145356), searches will cover PubMed, Embase, Cochrane CENTRAL, Web of Science, and Scopus from inception to April 2026. Focused on T2DM, mitochondrial function/dysfunction, and interventions, age eligibility will be assessed during full-text screening. Primary analysis includes trials with participants aged 60+ or extractable data for this group; sensitivity analyses will include those with mean/median age ≥ 60. Two reviewers will handle screening, data extraction, and bias assessment using RoB 2.Analysis will focus on trials reporting mitochondrial function outcomes, categorized by biological domain, tissue source, and assay method. Glycemic control, geriatric health, and safety are secondary outcomes. Network meta-analysis will be conducted if a connected evidence network exists; otherwise, pairwise meta-analysis or narrative synthesis will be used. Random-effects models will be employed, with heterogeneity assessed via subgroup analysis and meta-regression. If significant heterogeneity persists, a Synthesis Without Meta-Analysis (SWiM) framework narrative review will be done. Evidence certainty will be appraised using GRADE and CINeMA.

Ethics approval is not required for this systematic review as the systematic review will include only previously anonymised data from primary studies. Dissemination of the findings of the final systematic review will occur through publishing in a peer-reviewed journal. PROSPERO registration number CRD420251145356.