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

Intensive treatment of glycemia produced little to no difference in the risk of incident diabetic peripheral neuropathy among adults with type 2 diabetes, according to a systematic review and meta-analysis of randomized controlled trials. The review found low-certainty evidence that an insulin-sensitizing strategy may reduce neuropathy risk in the BARI-2D trial, while evidence from single studies suggested possible reductions with blood-pressure-lowering and multifactorial interventions.

The authors searched PubMed, Embase, and ClinicalTrials.gov for randomized trials published since 1980 that evaluated interventions targeting modifiable risk factors for primary prevention of diabetic peripheral neuropathy. Eligible interventions included those addressing glycemia, lipids, blood pressure, smoking cessation, lifestyle, and combinations of these factors. Two reviewers independently screened studies, with a third resolving disagreements, and a random-effects model was used for meta-analysis. The searches identified 1,287 articles, 863 underwent title and abstract screening, and 41 were assessed in full text. Nine studies provided extractable data; eight were rated as having low risk of bias under the Cochrane risk-of-bias tool, while one had unclear risk.

A meta-analysis of five glycemia-control studies estimated an odds ratio of 0.89 for incident diabetic peripheral neuropathy, with a 95% confidence interval of 0.66 to 1.19 and a prediction interval of 0.37 to 2.15. Heterogeneity was substantial, with an I² of 77.8%. Sensitivity analysis identified BARI-2D as the dominant source of heterogeneity; removing that trial reduced I² to 23% and narrowed the prediction interval to 0.80 to 1.08. The authors noted that BARI-2D compared insulin-sensitizing with insulin-providing drug strategies rather than different glycemia-intensity targets in patients with coronary artery disease. In the four-study analysis, glycemic control yielded an odds ratio of 0.93 (95% CI 0.85 to 1.02), indicating little to no difference in neuropathy risk.

Within BARI-2D, the insulin-sensitizing strategy was associated with lower odds of incident diabetic peripheral neuropathy independently of achieved HbA1c, with an odds ratio of 0.84 (95% CI 0.71 to 0.99). The authors characterized this as a low-certainty, drug-class-specific finding. Evidence that blood-pressure-lowering and multifactorial interventions may reduce incident neuropathy came from single studies and was also rated low certainty. These findings are limited by the small evidence base, substantial heterogeneity in the broader glycemic analysis, and reliance on single-study evidence for several interventions. The review concludes that further rigorous research is warranted on the prevention of incident diabetic peripheral neuropathy.

Subject of Research: Effects of interventions targeting modifiable risk factors on prevention of diabetic peripheral neuropathy in adults with type 2 diabetes

Article Title: 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

Article References: Sheehan, A. L., O’Malley, J. M., Gunawan, S., Laynor, G., Nicholson, A., Illenberger, N., & Natarajan, S. (2026). 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. Journal of General Internal Medicine. https://doi.org/10.1007/s11606-026-10801-z

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DOI: 10.1007/s11606-026-10801-z

Keywords: type 2 diabetes, diabetic peripheral neuropathy, systematic review, meta-analysis, randomized controlled trials, glycemic control, blood-pressure lowering, multifactorial intervention, BARI-2D, risk-factor modification, Does, Intensive