Abstract 25: Glycemic variability of oral semaglutide versus empagliflozin: A post hoc analysis of PIONEER 2

Glycemic variability is associated with markers of microvascular and macrovascular complications and impacts quality of life in patients with type 2 diabetes. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to both improve HbA1c concentration and reduce glycemic variability in patients with type 2 diabetes. GLP-1RAs increase insulin secretion and suppress glucagon in a glucose-dependent manner, which may partly explain their ability to reduce glycemic variability. However, it is not clear if HbA1c influences the effect of GLP-1RAs on glycemic variability. Oral semaglutide, the first GLP-1RA available as an oral formulation, is effective at reducing HbA1c vs a range of comparators, but its effect on glycemic variability needs to be understood. Therefore, we have assessed the change in glycemic variability and its possible relationship with HbA1c in a 52-week randomized, open-label trial (PIONEER 2) comparing oral semaglutide with the sodium-glucose co-transporter-2 (SGLT2) inhibitor empagliflozin in patients with type 2 diabetes uncontrolled on metformin. The seven-point self-measured blood glucose profile (7-point SMBG) was assessed at baseline and at weeks 26 and 52 in the PIONEER 2 trial. The standard deviation (SD) of the measurements in the 7-point SMBG profile was used as a measure of glycemic variability. An additional post-hoc mediation analysis was performed to explore the indirect effect of HbA1c concentration on the direct relationship between treatment and glycemic variability (the SD of the 7-point SMBG) at weeks 26 and 52. The results showed that the SD of the 7-point SMBG at baseline for the once-daily oral semaglutide 14 mg (N=411) and empagliflozin 25 mg (N=410) treatment arms was 2.06 and 2.05 mmol/l, respectively. The change from baseline in the SD of the 7-point SMBG in the oral semaglutide and empagliflozin arms was -0.67 and -0.44 mmol/l, respectively, at week 26, and -0.69 and -0.49 mmol/l, respectively, at week 52. The treatment differences (95% CI) for the SD of the 7-point SMBG for oral semaglutide vs empagliflozin at weeks 26 and 52 were -0.23 (-0.33, -0.12; p<0.0001) and -0.20 (-0.31, -0.09; p=0.0003) mmol/l, respectively. The mediation analysis showed that the indirect effect of HbA1c accounted for -0.06 (-0.10, -0.02; p=0.0029) and -0.03 (-0.06, 0.00; p=0.08) mmol/l of the treatment difference for the SD of the 7-point SMBG at weeks 26 and 52, respectively. In conclusion the oral semaglutide significantly reduces glycemic variability, as assessed by the SD of the 7-point SMBG, compared with empagliflozin, and most of this effect was not explained by an indirect effect of HbA1c. Clinical Trial Registration Number: NCT02863328