GLP1-RA versus metformin as first-line therapy for achieving glycemic control and risk-factor management - a one-year nationwide cohort study

Abstract Background Glucagon-like peptide 1 receptor agonist (GLP1-RA) reduces cardiovascular events in patients with long standing diabetes. We hypothesized that treatment early during diabetes could be beneficial. Purpose The aim was to compare one-year effects of GLP1-RA and metformin as first-line glucose-lowering therapy on glycemic control, adherence, kidney function, and cholesterol levels. Methods Using the Danish nationwide registers, we included all first-line users of monotherapy with GLP1-RA or metformin between 2018-2021, who had information on glycated hemoglobin (HbA1c) maximum one year prior to baseline and a measured HbA1c level above 41 mmol/mol. The outcomes were one-year change in HbA1c category, adherence to therapy, avoidance of add-on glucose lowering drugs, as well as absolute change in HbA1c, creatinine, and cholesterol levels. Targeted likelihood maximum estimation with ensemble Superlearning was used to estimate the average treatment effects. Results A total of 40,987 individuals were included, of which 870 were prescribed GLP1-RA and 40,117 were prescribed metformin. After adjusting for age, sex, income, education, degree of urbanization, baseline HbA1c levels, comorbidities, and concomitant medication, GLP1-RA users had an one-year absolute decrease in HbA1c (ATE: -3.84 mmol/mol, 95% CI: -5.36;.-2.33), and HDL (ATE: -0.03 mmol/L, 95% CI: -0.06;-0.01), an absolute increase in creatinine (ATE: 2.89 μmol/L, 95% CI: 0.07;4.82), and no difference in low-density lipoprotein cholesterol (ATE: 0.11 mmol/L 95% CI: -0.03;0.24), total lipoprotein cholesterol (ATE: 0.13 mmol/L 95% CI: -0.03;0.29), triglycerides (ATE: 0.02 mmol/L 95% CI: -0.25;0.30), non-adherence (RR: 1.05 95% CI: 0.75;1.46), and add-on therapy (RR: 1.04 95% CI: 0.75;1.44), compared to metformin users. Conclusion First line use of GLP1-RA was associated with a clear one-year reduction of HbA1c and a very small increase in creatinine. Future studies are needed to show whether this translates to a clinical benefit.