Triple oral therapy combining metformin, SGLT-2 and DPP-4 inhibitors versus dual therapy in type 2 diabetes mellitus: A systematic review and meta-analysis

Clinical Snapshot

Key Findings

• P Value: P = 0.005 for HbA1c reduction

• Effect Size: Moderate effect size favouring triple therapy

• Primary Outcome: HbA1c reduction: SMD -0.54 (95% CI: -0.92 to -0.16)

• Nnt Or Sensitivity: RR 2.02 for achieving HbA1c <7% (95% CI: 1.55-2.63)

• Confidence Interval: 95% CI excludes null for primary outcome

Clinical Application

All medications PBS-listed in Australia, though triple therapy increases pill burden and cost Aligns with RACGP diabetes guidelines for stepwise intensification. PBS subsidises all three drug classes. TGA-approved combinations available. Consider in patients failing dual therapy before insulin initiation Australian adults with T2DM requiring intensification beyond dual therapy

Abstract

BACKGROUND: Triple oral therapy combining metformin, sodium-glucose cotransporter 2 inhibitor, and a dipeptidyl peptidase-4 inhibitor has been proposed as a synergistic approach to intensify glycemic control in patients with type 2 diabetes mellitus. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of triple therapy compared to dual therapy (metformin plus either sodium-glucose cotransporter 2 or dipeptidyl peptidase-4 inhibitor). METHODS: Following preferred reporting items for systematic review and meta-analysis guidelines, we searched PubMed, Embase, Scopus, and Web of Science through January 2026. Studies included randomized controlled trials comparing triple versus dual therapy in adults with type 2 diabetes mellitus. Outcomes included hemoglobin A1c (HbA1c), fasting plasma glucose, body weight, achievement of HbA1c < 7%, and adverse events (AEs). Pooled standardized mean differences (SMDs) and risk ratios (RRs) were calculated using random-effects models. RESULTS: Eight studies encompassing 2606 participants were included. Findings indicate triple therapy significantly reduced HbA1c levels compared to dual therapy, with a SMD of - 0.54 (95% confidence interval [CI]: -0.92 to -0.16; P = .005). Triple therapy resulted in greater reduction in fasting plasma glucose, with an SMD of -0.30 (95% CI: -0.62 to 0.01; P = .06). Patients on triple therapy were more likely to achieve HbA1c levels below 7% (RR: 2.02; 95% CI: 1.55-2.63; P < .0001). Weight reduction was modest, with an SMD: -0.14 (95% CI: -0.22 to -0.07; P = .0002). No significant differences were found in total AEs (RR = 0.97; P = .69) or hypoglycemia (RR = 1.32; P = .32), although there was higher discontinuation due to AEs (RR = 2.62; P = .03). CONCLUSION: Triple therapy offers superior glycemic control over dual therapy without major safety trade-offs, though tolerability may affect long-term adherence.

References

1. 1.Malik, A. F., Kashish, F., Shivani, F., Kumar, S., Kumari, V., Haseeb, A., Mujtaba, A., Raheem, A., Ali, S. M. S., Saleh, U., & Ahmad, T. K. F. (2026). Triple oral therapy combining metformin, SGLT-2 and DPP-4 inhibitors versus dual therapy in type 2 diabetes mellitus: A systematic review and meta-analysis. Medicine, Article 0000000000049050. https://doi.org/10.1097/MD.0000000000049050