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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.
Malik et al. (Fri,) studied this question.