Incretin-based injectable strategies versus intensified insulin for treatment intensification and simplification in type 2 diabetes: a systematic review and meta-analysis

Purpose Prandial insulin intensification in Type 2 Diabetes (T2D) improves glycaemia but increases regimen complexity, weight gain, and hypoglycaemia risk. Our aim was to evaluate if Incretin-based injectable strategies offer a lower-burden alternative across intensification and simplification pathways. Methods PubMed/MEDLINE, CENTRAL, Scopus, and ClinicalTrials.gov were searched to November 2025 for Randomised Controlled Trials (RCT) comparing incretin-based injectable regimens with intensified insulin strategies in adults with T2D. Primary outcomes were HbA1c change and trial-defined hypoglycaemia. Secondary outcomes included body weight, HbA1c target achievement, severe hypoglycaemia, insulin dose, gastrointestinal adverse events, and adverse-event withdrawals. Random or fixed-effects models were applied where appropriate, with subgroup analyses by regimen and by intensification versus simplification design. Results Eighteen RCTs were included. Incretin-based regimens significantly reduced HbA1c as compared to intensified insulin (MD -0.19%, 95% CI: -0.34 to -0.05, P = 0.01) and also increased HbA1c target achievement (RR 1.27, 95% CI: 1.05 to 1.54, P = 0.01). Effects differed by regimen and design: tirzepatide produced the largest HbA1c reduction, fixed-ratio or once-weekly combination regimens showed similar HbA1c efficacy, and simplification trials generally preserved glycaemic control. Incretin-based regimens decreased trial-defined hypoglycaemia (RR 0.48, 95% CI: 0.35 to 0.66, P = 0.00001), severe hypoglycaemia (RR 0.32, 95% CI: 0.19 to 0.51, P = 0.00001), and body weight (MD -4.65 kg, 95% CI: -5.85 to -3.44, P = 0.00001). Gastrointestinal adverse events were more frequent with incretin-based regimens. Conclusion Incretin-based injectable strategies are a favourable alternative to intensified insulin when hypoglycaemia, weight gain, and treatment burden are priorities, but benefits differ between intensification and simplification settings.