Limited head-to-head studies compare established glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4is), and sodium-glucose co-transporter-2 inhibitors (SGLT-2is) to insulin in the management of uncontrolled type 2 diabetes mellitus (T2DM). This systematic review and meta-analysis evaluated the efficacy and safety of traditional GLP-1 RAs, DPP-4is, and SGLT-2is compared with insulin. Comprehensive searches were conducted in the Cochrane Database, PubMed, MEDLINE, ClinicalTrials.gov, and EMBASE for publications from January 2010 to June 2022, with an additional search extended through June 2025 to capture newly published studies. Randomized controlled trials (RCTs) comparing insulin with established GLP-1 RAs, DPP-4is, or SGLT-2is were included. Thirteen trials involving 5,807 participants were identified. Nine trials compared GLP-1 RAs to insulin, four compared DPP-4is to insulin, and one examined SGLT-2i combined with DPP-4i versus insulin. Compared with insulin, traditional non-insulin agents were associated with greater reductions in hemoglobin A1c (HbA1c) (mean difference (MD) = -0.27, 95% confidence interval (CI) -0.5 to -0.03), body weight (MD = -3.27, 95% CI -4.16 to -2.38), and systolic blood pressure (MD = -3.55, 95% CI -4.92 to -2.17). Insulin use carried a higher relative risk of hypoglycemia (risk ratio (RR) = 2.24, 95% CI 1.88-2.67). Subgroup analyses showed that GLP-1 RAs were superior to insulin in reducing HbA1c and hypoglycemic events, whereas DPP-4is achieved similar glycemic control with improved safety profiles. These findings suggest that established GLP-1 RAs, DPP-4is, and SGLT-2is offer superior or comparable efficacy with better safety than insulin in insulin-naïve patients with uncontrolled T2DM.
