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SGLT2 inhibitors deliver broader cardiometabolic advantages than DPP-4 inhibitors when combined with insulin in poorly controlled type 2 diabetes, while preserving comparable glycemic efficacy.
As treatment priorities in type 2 diabetes mellitus (T2DM) increasingly shift beyond glucose lowering toward comprehensive cardiometabolic risk reduction, selecting the optimal add-on therapy for patients inadequately controlled on insulin remains a persistent clinical challenge. To address this therapeutic dilemma, investigators conducted the first direct comparative evaluation of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP-4i) as adjuncts to insulin therapy in patients with suboptimally controlled T2DM.
A systematic review and meta-analysis of major biomedical databases was undertaken to identify studies issued between 2015 and 2025 that examined the comparative performance of SGLT2i and DPP-4i in insulin-treated individuals with T2DM. Study eligibility was independently verified, while methodological quality and potential sources of bias were rigorously assessed via validated appraisal frameworks for randomized and observational research.
Pooled analyses were subsequently performed to compare efficacy, cardiometabolic outcomes, and treatment safety across the included evidence base. The analysis of 11 studies revealed comparable glucose-lowering efficacy between SGLT2i and DPP-4i when used as add-on therapy to insulin; however, vital differences emerged in their cardiometabolic profiles. Compared with DPP4i, SGLT2i + insulin markedly reduced body weight by 1.07 kg (mean difference [MD] −1.07 kg) and lowered systolic blood pressure by 2.91 mmHg (MD −2.91 mmHg).
Although SGLT2i therapy also exhibited greater reductions in glycated hemoglobin (HbA1c; MD −0.29%), fasting plasma glucose (MD −21.27 mg/dL), mean amplitude of glycemic excursions (MAGE; MD −1.85 mg/dL), insulin dose (MD −2.0), and triglycerides (MD −23.43 mg/dL), these differences did not reach statistical significance. Importantly, observational evidence indicated a 46% lower cardiovascular (CV) mortality with SGLT2i + insulin therapy compared with DPP4i + insulin (odds ratio [OR] 0.54).
Subgroup analyses further showed that SGLT2i achieved greater improvements in HbA1c and fasting plasma glucose among those receiving premixed insulin, particularly in studies with 24-week treatment duration, diabetes duration longer than 13 years, and baseline HbA1c ≥8%. The review also highlighted differing safety profiles. While SGLT2i offered broader cardiometabolic advantages, DPP4i illustrated a more favorable tolerability and adverse-event profile, suggesting that treatment selection must be individualized as per patient characteristics and therapeutic priorities.
To sum up, although SGLT2i and DPP4i offer comparable glucose-lowering efficacy when added to insulin, SGLT2i offer additional benefits in weight management, blood pressure reduction, and potentially CV survival. The authors noted that large, long-term randomized clinical trials are needed to substantiate the observed CV benefits and define optimal patient populations for each treatment strategy.
Primary Care Diabetes
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
Navami K.S. et al.
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