Comparing Glucagon-like peptide-1 receptor agonists versus metformin in drug-naive patients: A nationwide cohort study

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are increasingly being prescribed in drug-naive patients. We aimed to contrast add-on therapy, adherence, and changes in biomarkers, 1 year after treatment initiation with GLP-1 RA or metformin.

METHODS: Using Danish nationwide registers, we included incident GLP-1 RA or metformin users from 2018 to 2021 with glycated hemoglobin (HbA1c) ≥ 42 mmol/mol. GLP-1 RA initiators were matched to metformin initiators in a ratio of 1:1 to assess outcomes in prediabetes and diabetes. Main outcomes analyzed were 1-year risk of add-on glucose-lowering medication and 1-year risk of nonadherence. One-year risks were estimated with multiple logistic regression and standardized. Multiple linear regression was used to estimate the average differences in biomarker changes.

RESULTS: In total, 1778 individuals initiating GLP-1 RA and metformin were included. After standardizing for various factors, GLP-1 RA compared with metformin was associated with reduced 1-year risk of add-on glucose-lowering treatment in patients with prediabetes (1-year risk ratio [RR]: 0.27, 95% confidence interval [CI]: 0.10-0.44) and diabetes (RR: 0.67, 95% CI: 0.37-0.98). GLP-1 RA was associated with higher 1-year risk of nonadherence among patients with prediabetes (RR: 1.60, 95% CI: 1.45-1.75), but no difference in patients with diabetes (RR: 0.88, 95% CI: 0.70-1.06). Compared to metformin, GLP-1 RA was associated with greater HbA1c reduction (prediabetes: -2.59 mmol/mol 95% CI: -3.10 to -2.09, diabetes: -3.79 mmol/mol, 95% CI: -5.28 to -2.30).

CONCLUSIONS: GLP-1 RA was associated with a reduced risk of additional glucose-lowering medication, achieving better glycated hemoglobin control overall. However, among patients with prediabetes, metformin was associated with better adherence.