Contemporary Initial Glucose-Lowering Strategies for Type 2 Diabetes: A Systematic Review and Bayesian Network...

To compare contemporary initial glucose-lowering strategies in adults with type 2 diabetes who were treatment-naïve or had completed adequate washout.

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.

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.

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.

PROSPERO: CRD420251178714.