A systematic review and meta‐analysis of the relative benefit of dual versus single oral hypoglycaemic therapy following diagnosis with type 2 diabetes ( T2D )

Abstract Introduction Achieving and sustaining target glycated haemoglobin (HbA1c) levels is fundamental in the management of type 2 diabetes (T2D). We here aimed to assess whether initial dual oral therapy outperforms monotherapy in reaching glycaemic targets in patients with treatment‐naive or early‐stage T2D. Methods This systematic review and meta‐analysis were registered with PROSPERO (CRD420251111096). Parallel‐group randomised controlled trials with a duration of at least 12 weeks were identified through searches of PubMed and the Cochrane Library spanning 2005 to 2025. Data at the trial arm level, including baseline and endpoint HbA1c values, were extracted for seven predefined comparisons and combined using a random‐effects inverse‐variance meta‐analysis in R version 4.3.1 (meta package). The primary outcome was the proportion of treatment arms achieving an HbA1c level of ≤7.5% (58 mmol/mol). Secondary outcomes included the proportions achieving HbA1c levels of ≤7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol), as well as mean differences in HbA1c levels. Results A total of 20 trials, encompassing 37 treatment arms, were analysed. Dual combination therapy consistently demonstrated superior efficacy compared to monotherapy. The proportion of patients achieving HbA1c levels of ≤7.5% (58 mmol/mol) was 86% with initial dual therapy versus 82% with initial monotherapy (odds ratio OR 1.33, 95% confidence interval CI 1.20–1.47, p = 0.002). At the more stringent threshold of ≤7.0% (53 mmol/mol), the rates were 69% versus 64% (OR 1.27, p = 0.003), and at ≤6.5% (48 mmol/mol), 42% versus 39% (OR 1.18, p = 0.056). When comparing initial dual therapy to metformin monotherapy, the respective achievement rates were 86% versus 81% (OR 1.41, p = 0.001) for a target of ≤7.0% (53 mmol/mol). The combination of metformin with a sodium–glucose cotransporter 2 inhibitor (SGLT2‐i) resulted in 88% reaching ≤7.5% (58 mmol/mol), compared to 81% with metformin alone (OR 1.55, p ≤ 0.001), a difference significant across all thresholds. Dual therapy containing SGLT‐2i achieved 87% at ≤7.5% (58 mmol/mol), compared with 82% with all monotherapies (OR 1.43, p ≤ 0.001). SGLT‐2i monotherapy itself led to 89% reaching the target, compared with 81% with metformin (OR 1.73, p ≤ 0.001). No significant difference in outcome was observed between dual and monotherapy involving SGLT2‐is (OR 0.87, p = 0.480). The pooled final HbA1c values were 6.7% (50 mmol/mol) for dual therapy and 7.9% (63 mmol/mol) for monotherapy, corresponding to a mean difference of –0.45% (95% CI −0.60 to −0.25, p ≤ 0.001). Heterogeneity among studies was low to moderate ( I 2 25%–50%), and results remained consistent after excluding rosiglitazone arms. Conclusions Initial dual therapy, particularly combining metformin with an SGLT2‐i, results in superior achievement of HbA1c targets across various thresholds compared to monotherapy. SGLT2‐i alone surpasses metformin alone in efficacy. Adding a second agent to SGLT2‐i did not provide additional glucose‐lowering benefit to SGLT2‐i monotherapy. Early initiation of SGLT2‐i monotherapy or combination therapy should be considered upon diagnosis of T2D.