Beyond insulin therapy: Comparing relative benefits of adding SGLT2 versus DPP4 inhibitors in poorly controlled type 2 diabetic patients: A systematic review and meta-analysis.

Abstract

This systematic review and meta-analysis directly compared the efficacy and safety of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors as insulin add-ons in patients with inadequately controlled type 2 diabetes mellitus. A comprehensive search of the Cochrane Library, Web of Science, PubMed, and Scopus was conducted for studies published between January 2015 and June 2025. Eligible studies were independently screened. Risk of bias was assessed using RevMan v5.4.1 for randomized trials and using the Risk of Bias in Non-randomized Studies of Interventions (ROBINS-I) tool for observational studies.Certainty of evidence was evaluated using GradePro. Meta-analyses were performed using RevMan v5.4.1. Eleven studies were included. SGLT2i in combination with insulin reduced body weight (MD -1.07 kg; p = 0.004) and systolic blood pressure (MD -2.91 mmHg; p = 0.01). Reductions were observed in HbA1c (MD -0.29%; p = 0.07), fasting plasma glucose (MD -21.27 mg/dL; p = 0.09), mean amplitude of glycaemic excursions (MD -1.85 mg/dL; p = 0.87), insulin dose (MD -2.0; p = 0.10), and triglycerides (MD -23.43 mg/dL; p = 0.25) with SGLT2i and insulin, but were not statistically significant. Observational evidence suggested lower cardiovascular mortality with SGLT2i plus insulin therapy (OR 0.54; p < 0.00001). Subgroup analyses demonstrated greater reductions in HbA1c and fasting plasma glucose among patients receiving premixed insulin, particularly in studies with longer treatment duration (24 weeks), longer diabetes duration (>13 years), and baseline HbA1c≥ 8%. Among insulin-treated patients with inadequately controlled T2DM, SGLT2i and DPP4i provide comparable glycaemic control; however, SGLT2i confer additional cardiometabolic benefits, particularly weight reduction and improved systolic blood pressure. Subgroup findings indicate that these benefits may be more pronounced in patients receiving premix insulin, those with higher baseline HbA1c levels, those with longer treatment duration, and those with longer diabetes duration. Although observational evidence suggests potential cardiovascular mortality reduction with SGLT2i plus insulin therapy, further large-scale randomized trials are required to confirm long-term clinical outcomes. WHAT IS KNOWN ABOUT THIS RESEARCH TOPIC?: In patients with inadequately controlled type 2 diabetes mellitus (T2DM) receiving insulin therapy, the addition of newer oral antihyperglycemic agents (OHAs), including SGLT2 inhibitors and DPP4 inhibitors, has been shown to improve glycemic control while potentially reducing insulin dose requirements and mitigating insulin-associated adverse effects such as weight gain and hypoglycemia. Previous comparative evidence has mainly been derived from indirect meta-analyses. The study by S. H. Min et al. primarily evaluated outcomes such as HbA1c, fasting plasma glucose (FPG), body weight, hypoglycaemia, and urinary tract infections. However, direct comparative studies assessing a broader range of clinical parameters in insulin-treated patients with type 2 diabetes are still limited. WHAT DOES THIS STUDY ADD AND ITS FUTURE IMPLICATIONS?: This review provides the first direct meta-analysis comparing SGLT2 inhibitors and DPP4 inhibitors as add-on therapy to insulin among inadequately controlled T2DM patients. Beyond conventional glycaemic endpoints, this review evaluates glycaemic variability (MAGE), insulin dose requirements, body mass index, blood pressure, lipid parameters, renal outcomes, and a broad range of safety events, offering a multidimensional assessment of comparative effectiveness. The findings highlight clinically meaningful differences in cardiometabolic profiles between the two drug classes, supporting more optimized and patient-centred strategies for insulin combination therapy in diabetes management.