Glucose Variability in a 26-Week Randomized Comparison of Mealtime Treatment With Rapid-Acting Insulin Versus GLP-1 Agonist in Participants With Type 2 Diabetes at High Cardiovascular Risk

Objective: A1C is associated with diabetes complications but does not reflect glycemic variability (GV), which may worsen outcomes by inducing inflammation, oxidative stress, and cardiac arrhythmias. We tested whether a glucagon-like peptide 1 agonist-based regimen can reduce GV and cardiometabolic risk markers while maintaining similar A1C levels in people with insulin-requiring type 2 diabetes and high cardiovascular risk.

Research Design And Methods: After run-in on metformin and basal-bolus insulin (BBI), 102 participants continued metformin and basal insulin and were randomized to exenatide dosing before the two largest meals (glucacon-like peptide-1 receptor agonist and insulin [GLIPULIN group]) or continuation of rapid-acting insulin analogs (BBI group). Indices of GV by continuous glucose monitoring (CGM), hypoglycemia, weight, risk markers, and cardiac arrhythmias were assessed. The primary end point was change in glucose coefficients of variation (CV) by CGM from baseline to 26 weeks.

Results: At randomization, the median A1C was 7.3% (57 mmol/mol) for GLIPULIN and 7.4% (56.3 mmol/mol) for BBI, and glucose CVs were 30.3 for BBI and 31.9 for GLIPULIN. At 26 weeks, A1C levels were similar (7.1% [54 mmol/mol] vs. 7.2% [55 mmol/mol]), whereas mean CV improved with GLIPULIN (-2.4 vs. 0.4, P = 0.047). Other GV indices followed similar nonsignificant patterns of improvement with GLIPULIN. There were no differences in hypoglycemic events during CGM or arrhythmias during electrocardiographic monitoring. On-trial changes in body weight (-4.8 kg vs. +0.7 kg, P < 0.001), alanine aminotransferase (P = 0.0002), and serum amyloid A (P = 0.023) favored GLIPULIN.

Conclusions: GLIPULIN reduced GV, weight, and some cardiometabolic risk markers while maintaining equivalent A1C levels versus BBI and might improve clinical outcomes in a larger trial.