Ultra-Rapid Lispro or Fast-Acting Aspart Compared to Standard Insulin Lispro and Aspart Using Closed-Loop Insulin Therapy: A Systematic Review and Meta-Analysis of Randomized Control Trials

Mohamed Rakab¹Rahma Mogahed Rateb²Hatem Basel Elsalakawi¹Bashar M Al Zoubi³Abubakar Nazir⁴Mutaz Moath Abu-Laila⁵Abdelrahman Sherif Ghanem¹Alaa Maamoun¹Mohab Mattar⁶Basma Ataallah⁷Brian T Layden^8,9Abeer M. Mahmoud^10,8*

• ¹Faculty of Medicine, Mansoura University, Mansoura, Dakahlia, Egypt
• ²Faculty of Medicine, Assiut University, Assiut, Asyut, Egypt
• ³Faculty of Medicine, Hashemite University, Zarqa, Zarqa, Jordan
• ⁴King Edward Medical University, Lahore, Punjab, Pakistan
• ⁵Yarmouk University, Irbid, Irbid, Jordan
• ⁶Faculty of Medicine, Zagazig University, Zagazig, Al Sharqia, Egypt
• ⁷Houston Methodist Hospital, Houston, Texas, United States
• ⁸Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States
• ⁹Jesse Brown VA Medical Center, United States Department of Veterans Affairs, Chicago, Illinois, United States
• ¹⁰Department of Kinesiology and Nutrition, College of Applied Health Sciences, University of Illinois at Chicago, Chicago, Illinois, United States

Background: Ultra-rapid-acting insulin (URAI) improves glycemic control by reducing variability; however, optimal strategies for its use, especially within hybrid closed-loop (HCL) insulin delivery systems, remain unclear.This meta-analysis assesses the efficacy and safety of combining URAI with HCL systems in maintaining the euglycemic range and reducing glycemic excursions. Methods: We systematically searched PubMed, Scopus, Cochrane Library, Web of Science, and related article citations for relevant studies. Outcomes assessed included time in range (TIR), time below range (TBR), and time above range (TAR) during overall 24-hour periods, daytime, nighttime, postprandial, and post-exercise periods, as well as adverse events. Dichotomous outcomes were summarized using risk ratios (RR), and continuous outcomes were pooled using mean differences (MD) presented with 95% confidence intervals (CI). Results: URAI showed a modest, statistically non-significant improvement in TIR (70-180 mg/dL) compared to standard insulin (MD 0.87%, 95% CI [-0.21 to 1.85], P = 0.12). Importantly, glycemic variability significantly improved with URAI, as demonstrated by reductions in the coefficient of variation (CV) (MD -0.78%, 95% CI [-1.44 to -0.12], P = 0.02). The combination of URAI with HCL systems significantly reduced hypoglycemia (TBR <70 mg/dL: MD -0.32%, 95% CI [-0.56 to -0.13], P = 0.002). However, overall reductions in TAR >250 mg/dL and TAR >180 mg/dL were statistically non-significant.The integration of URAI with HCL demonstrates encouraging improvements in glycemic outcomes, notably reduced glucose variability and nighttime hypoglycemia risk. However, further research with larger sample sizes is essential to confirm these benefits and establish broader clinical recommendations.