Does Intensive Therapy Targeting Modifiable Risk Factors Prevent Diabetic Neuropathy in Adults with Type 2 Diabetes? A Systematic Review and Meta-analysis of Randomized Clinical Trials.

Authors

Alana L Sheehan, Jordan M O'Malley, Sophia Gunawan, Gregory Laynor, Andrew Nicholson, Nicholas Illenberger, Sundar Natarajan

Published in

Journal of general internal medicine. Oct 05, 2026. Epub Oct 05, 2026.

Abstract

Diabetic peripheral neuropathy (DPN) is a serious complication of type 2 diabetes (T2DM). Guidelines recommend targeting modifiable risk factors for primary prevention, but their effectiveness is unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of interventions targeting modifiable risk factors to prevent DPN in adults with T2D.
We searched PubMed, Embase, and ClinicalTrials.gov databases for RCTs published since 1980 investigating glycemia, lipids, blood pressure (BP), smoking cessation, lifestyle, and multifactorial interventions. Two reviewers independently screened articles; a third reviewer resolved disagreements. Meta-analysis used a random-effects model. Results are reported as odds ratios (ORs) with 95% confidence and prediction intervals.
From 1287 identified articles, 863 underwent title/abstract screening, with 41 full-text review, yielding nine studies with extractable data. Eight had low risk of bias (Cochrane RoB 1); one had unclear risk. The glycemic control meta-analysis (n = 5) yielded OR = 0.89 (95% CI 0.66-1.19; prediction interval 0.37-2.15; I² = 77.8%). Sensitivity analysis identified BARI-2D as the dominant heterogeneity source; its removal reduced I² to 23% and narrowed the prediction interval (0.80-1.08). This is clinically explainable: BARI-2D compared insulin-sensitizing versus insulin-providing drug strategies rather than glycemic intensity targets, in patients with coronary artery disease. The four-study analysis showed glycemic control may result in little to no difference in DPN risk (OR 0.93, 95% CI 0.85-1.02). In BARI-2D, an insulin-sensitizing strategy may reduce incident DPN independently of achieved HbA1c (0.84 (95% CI 0.71-0.99)) (low certainty). Single-study evidence suggests that BP-lowering and multifactorial interventions may reduce incident DPN (low certainty).
Glycemic intensity interventions may result in little to no difference in incident DPN risk. The BARI-2D drug class-specific finding and single-study evidence suggesting benefit from BP-lowering and multifactorial interventions warrant further rigorous research on incident DPN.

PMID:
42831957
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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