Contemporary Initial Glucose‐Lowering Strategies for Type 2 Diabetes: A Systematic Review and Bayesian Network Meta‐Analysis

AIMS: To compare contemporary initial glucose-lowering strategies in adults with type 2 diabetes who were treatment-naïve or had completed adequate washout. MATERIALS AND METHODS: We searched MEDLINE, Embase and the Cochrane Library from inception to 20 September 2025 for randomized trials comparing sodium-glucose cotransporter 2 inhibitor (SGLT2i) monotherapy, glucagon-like peptide-1 receptor agonist (GLP-1 RA) or dual incretin agonist monotherapy, SGLT2i plus metformin or placebo. Two reviewers independently selected studies and verified extracted data. Bayesian random-effects network meta-analysis was used. RESULTS: Twenty randomized trials with 8947 participants were included; all were at low risk of bias. Compared with placebo, SGLT2i plus metformin produced the largest HbA1c reduction (mean difference [MD] -1.36%, 95% credible interval [CrI] -1.91 to -0.82), followed by GLP-1 RA or dual incretin agonist monotherapy (MD -1.25%, 95% CrI -1.68 to -0.83) and SGLT2i monotherapy (MD -0.76%, 95% CrI -1.10 to -0.41). Achievement of HbA1c < 7% and fasting plasma glucose reduction showed a similar pattern. GLP-1 RA or dual incretin agonist monotherapy produced the greatest body weight percentage reduction (MD -4.74%, 95% CrI -6.71 to -2.90). Active-treatment comparisons were indirect, and baseline HbA1c was higher in the SGLT2i plus metformin node. Certainty of evidence was low or very low across key comparisons. CONCLUSIONS: SGLT2i plus metformin and GLP-1 RA or dual incretin agonist therapy are both reasonable contemporary initial glucose-lowering strategies for type 2 diabetes. Selection between these strategies should take into consideration phenotype, treatment priorities, tolerability, cost, access and patient preference. TRIAL REGISTRATION: PROSPERO: CRD420251178714.