Are New Ultra-Rapid-Acting Insulins Associated with Improved Glycemic Control and Reduced Hypoglycemia in Comparison to Conventional Rapid-Acting Insulins for Individuals with Type 1 and Type 2 Diabetes? A Systematic Review and Meta-Analysis.

Introduction: This study aimed to compare efficacy and safety of ultra-rapid-acting insulin analogs (URAIs; faster aspart [FAsp], ultra-rapid lispro [URLi], and technosphere insulin [TI]) with rapid-acting insulin analogs (RAI) in individuals with type 1 (T1D) or type 2 diabetes (T2D). Methods: Searching for randomized control trial comparing the effects of URAI versus RAI that lasted at least 12 weeks, we initially selected 15 studies for analysis. Three studies involving TI were excluded due to a high degree of heterogeneity. The final meta-analysis included only 12 studies with either FAsp or URLi. Results: Mealtime URAI significantly reduced overall early 1 h postprandial glycemia in individuals with T1D (-20.230 mg/dL [95% confidence interval, 95% CI -24.040 to -16.421]; P  < 0.001; I 2  = 33.42%) and those with T2D (-9.138 mg/dL [95% CI -12.612 to -5.663]; P  < 0.001; I 2  = 0%). However, the significant reduction in 2 h postprandial glucose remained only in individuals with T1D (-17.620 mg/dL [95% CI -26.047 to -9.193]; P  < 0.001; I 2  = 65.88%). These benefits were lost when URAI was administered postmeal. At 24-26 weeks, there was no significant difference in HbA1c between groups, but at 52 weeks, a slight reduction in HbA1c with mealtime URAI was observed (-0.080% [95% CI -0.147 to -0.013]; P  = 0.019; I 2  = 0%). No difference in weight or the rate of severe or confirmed hypoglycemia was observed. Only individuals with T1D showed a small, but significant increase in early 1-h hypoglycemia with URAI (1.468 [95% CI 1.235 to 1.747]; P  < 0.001; I 2  = 0%). Conclusion: Mealtime URAI improves 1 and 2 h postprandial glycemic control compared to RAI without increasing hypoglycemia or weight gain.