Comparative Effectiveness of GLP-1 RAs, SGLT2 Inhibitors, and Metformin in Type 2 Diabetes

Abstract

Background: Insulin-sparing therapies are central to contemporary type 2 diabetes (T2D) care,

yet comparative HbAIc effects across GLP-1 receptor agonists (GLP-1 RAs), SGLT2 inhibitors,

and metformin remain variably reported.

Methods: Following PRISMA 2020, we searched major databases (January 2010—February 2025) for randomized and real-world studies in adults with T2D reporting baseline and change in HbA Ic.

Arm-level data were pooled as mean differences (MD, %) using random-effects models;

heterogeneity was assessed with Q and P. Prespecified analyses included class-level pooling,

duration and baseline-HbA Ic subgroups, dose-response, and sensitivity checks.

Results: Fifteen studies met criteria for qualitative and quantitative synthesis. GLP-1 RAs

achieved greater HbAIc reduction than active comparators (pooled MD =~ -0.53%, 95% CI = — 0.65 to —0.42; moderate heterogeneity). SGLT2 inhibitors lowered HbAIc versus placebo (pooled

MD = —0.52%, 95% Cl ~ —0.61 to —0.43; moderate heterogeneity) with dose-dependent and

durable effects. Metformin extended-release and immediate-release were glycaemically equivalent over 24 weeks. A pragmatic head-to-head study suggested semaglutide reduced HbA 1c more than dapagliflozin, especially in insulin-deficient phenotypes, but variance was insufficient for pooling. Sensitivity analyses (RCT-only, exclusion of open-label/higher-risk studies, fixed-effects) supported the main findings.

Conclusions: Among insulin-sparing options, GLP-1 RAs provide the largest HbA1Ic reduction,

SGLT2 inhibitors offer durable, moderate benefit versus placebo, and metformin XR is non-

inferior to IR with better tolerability. Early phenotype-guided signals favor GLP-1 RAs in insulin- deficient patients.