The 21st century has seen an increase in the prevalence of diabetes, which has become a global public health concern. Once common in Western nations, diabetes has now struck globally, driven by widespread consumption of calorie-dense, nutrient-poor diets combined and increasingly sedentary lifestyles (1). According to the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, approximately 460 million individuals across all age groups were affected by diabetes, according to estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, ranking it as the seventh-leading cause of death and disability globally (2).

Recent technological advancements have significantly transformed diabetes management, notably through the development of automated insulin delivery (AID) systems designed to reduce disease burden and enhance glycemic control for individuals with type 1 diabetes (3). Among these innovations is the hybrid closed-loop (HCL) system, commonly referred to as an “artificial pancreas,” which integrates an insulin pump, a continuous glucose monitor (CGM), and a sophisticated algorithm running on a computer or smartphone (4). HCL systems, often integrated into AID devices, automatically determine and administer basal insulin doses, whereas mealtime insulin boluses require manual input regarding meal size and timing (5). Currently, these insulin administration systems represent the pinnacle of insulin delivery technology available for type 1 diabetes management, significantly improving glucose control and lowering hypoglycemia risk (6, 7). Commercially available HCL systems, such as the Medtronic 670G/780G, Tandem t:slim X2 Control IQ, and CamAPS FX systems, have obtained regulatory approval from the United States Food and Drug Administration (FDA) and European Conformity (CE) certification, supported by robust clinical trial data (8, 9).

Rapid-Acting Insulin Analogues (RAIAs) like aspart, lispro, and glulisine exhibit faster absorption kinetics compared to regular human insulin, yet managing optimal post-prandial glucose (PPG) remains challenging (10, 11). Consequently, newer ultra-rapid-acting insulins (URAIs) have been developed, including faster-acting insulin aspart (FIAsp; marketed as Fiasp, approved in 2017) and ultra-rapid lispro insulin (URLi; marketed as Lyumjev, approved in 2020) (12, 13).

Previous randomized controlled trials (RCTs) evaluating glycemic control with Fiasp and URLi in HCL systems have produced mixed results compared to conventional RAIAs (14–16). To address these inconsistencies, this systematic review and meta-analysis aim to comprehensively assess the effectiveness and safety of Fiasp and URLi within HCL systems among patients with type 1 diabetes.

Our systematic review and meta-analysis comprehensively assessed the impact of integrating ultra-rapid-acting insulin (URAI) with hybrid closed-loop (HCL) systems, providing a direct comparison to standard insulin across key glycemic metrics and safety outcomes, including TIR, TBR, and TAR metrics, mean glucose levels, glucose variability, insulin dosage, adverse events, hypoglycemia, and DKA. Although our findings indicated no significant differences between URAI and standard insulin in terms of TIR (both 70-180 mg/dL and 70-140 mg/dL) or TAR (both >180 mg/dL and >250 mg/dL), URAI demonstrated a clinically meaningful advantage by significantly reducing the time spent in mild hypoglycemia (<70 mg/dL), with a mean difference of 0.33%. Moreover, URAI significantly lowered glucose variability (coefficient of variation) by an average of 0.79%, suggesting more stable glycemic control. Conversely, the mean glucose level and total daily insulin dose did not differ significantly between the groups. Importantly, adverse events, particularly infusion site reactions, occurred significantly more frequently with URAI, underscoring the necessity for clinicians to balance the glycemic benefits of URAI against the increased risk of local adverse reactions. However, reassuringly, rates of severe hypoglycemia, DKA, and related serious events were not increased with URAI. These insights highlight the potential clinical utility of URAI in enhancing glycemic stability while emphasizing careful monitoring of infusion-site tolerability during clinical application.

A previous meta-analysis by Stamati et al. (11) evaluating URAI, specifically Fiasp, and URLi, in patients with T1DM utilizing continuous subcutaneous insulin infusion (CSII) systems reported the superiority of URAI analogs over rapid-acting insulin analogs (RAIAs) in increasing time spent within normoglycemia (70–180 mg/dL). This finding contrasts with the results of our current analysis. However, consistent with our findings, their analysis demonstrated a significant reduction in time spent in hypoglycemia (<70 mg/dL) alongside an increased incidence of infusion site reactions in the URAI group. Notably, Stamati’s meta-analysis did not clearly define statistical significance nor explicitly include hybrid closed-loop (HCL) systems, limiting direct comparability with our study.

Additionally, two simultaneous but separate meta-analyses individually assessing Fiasp and URLi against rapid insulin analogs or placebo reported no discernible differences in TIR or mean glucose levels. Interestingly, URLi was associated with fewer hypoglycemic events but a higher frequency of infusion site reactions, whereas Fiasp showed no notable differences in adverse events compared to rapid aspart insulin (38, 39). Our results differ from these later studies primarily due to methodological variations, including individual analyses of each URAI and the inclusion of placebo-controlled trials in these two meta-analyses. Furthermore, neither study specifically evaluated URAI performance within HCL systems, emphasizing the uniqueness and clinical relevance of our analysis to real-world applications and device-specific glycemic outcomes.

Given their unique pharmacokinetic profiles, the advent of faster insulin analogs (URAI) was anticipated to substantially enhance closed-loop system performance by accelerating insulin action onset and offset following delivery, thus enabling better glycemic control (40). Contrary to these expectations, our meta-analysis indicated that URAI’s primary advantages were limited to significant reductions in time spent below the glycemic target range and a notable improvement in glucose variability, as reflected by the reduced coefficient of variation. However, these benefits were offset by an increased frequency of adverse events, particularly infusion site reactions. Notably, our findings challenge prior predictions (11), demonstrating that URAI exacerbated, rather than reduced, infusion site complications in clinical practice. To address this limitation, ongoing research is exploring innovative strategies such as improving insulin delivery techniques through the implementation of infusion site modifications, including adjusting the insertion angle and the infusion protocols in AID systems and integrating novel technologies, including insulin infusion site warming devices, to enhance insulin absorption efficiency and minimize adverse reactions (41–43). These ongoing investigations underscore the critical need for continuous optimization of insulin delivery methods to fully harness the potential benefits of URAI within closed-loop systems.

To enhance clinical applicability and interpretation, our meta-analysis incorporated focused subgroup analyses of two prominent HCL systems extensively studied in individual trials: the Cam-APS FX Closed-Loop system and the Medtronic MiniMed 670G HCL system. These devices are among the earliest commercially approved and widely adopted technologies in diabetes management (44). Thus, their detailed performance evidence using URAI is required. Interestingly, despite the Cam-APS FX being the only licensed system to utilize ultra-rapid-acting insulin (URAI) analogs (45), our analysis uncovered a lack of substantial glycemic improvement coupled with a higher frequency of adverse events when using URAI analogs with this system. Conversely, the Medtronic MiniMed 670G demonstrated superior performance by achieving meaningful improvements in glycemic outcomes by reducing time spent in hypoglycemia (<70 mg/dl) and glucose variability without increasing adverse events such as hypoglycemia, DKA, or infusion site reactions. This finding is clinically significant, highlighting potential device-specific interactions with URAI that could influence both efficacy and safety profiles. These observations underscore the importance of device selection in clinical practice and call for further targeted research into optimizing URAI utilization within specific HCL systems to maximize patient outcomes and minimize potential risks.

We recognize several limitations in our current study that warrant consideration when interpreting the findings. Primarily, our conclusions rely heavily on the available primary evidence, which, despite an extensive and systematic literature review, is limited to a small number of RCTs with short duration and relatively small sample sizes, with only two RCTs having data for URLi. Most included studies used a crossover design, which may introduce carryover, period, or learning effects. While most trials implemented washout periods and proper randomization to minimize these biases, this design may limit generalizability and requires cautious interpretation. The included studies varied significantly in terms of quality and consistency, potentially affecting the robustness of our outcomes. Specifically, while we evaluated infusion site reactions as a safety outcome, the underlying mechanisms driving these adverse events remain unclear due to a lack of detailed reporting in the primary studies. Additionally, our analysis faced constraints in terms of generalizability, given the scarcity of data addressing the effects of URAI in patients with type 2 diabetes mellitus (T2DM) and pediatric populations; notably, we identified only two studies involving children and none involving patients with non-insulin-dependent diabetes. Thus, future research should prioritize the generation of robust real-world evidence from broader patient cohorts, including individuals with T2DM and pediatric groups. Detailed investigations into the long-term outcomes and patient-specific factors affecting efficacy and safety are crucial. Such studies will provide invaluable insights, enabling clinicians to make more informed decisions and ultimately optimizing the clinical application of URAI in hybrid closed-loop systems and enhancing patients’ treatment satisfaction and quality of life.

Our systematic review and meta-analysis demonstrated that the use of URAIs instead of standard insulin within HCL systems provides clinically meaningful improvements in glycemic control, particularly by significantly reducing nighttime hyperglycemia, both at moderate (TAR >180 mg/dL) and severe (TAR >250 mg/dL) levels. These findings have important clinical implications, suggesting that URAI may be particularly beneficial in optimizing overnight glycemic control, a period often challenging for patients with diabetes. Depending on our comparison between URAIs and standard insulin, individualized treatment selection is crucial; Despite offering improved glycemic stability and reduced hypoglycemia, the cost appears to be an increase in infusion site reactions, necessitating careful risk-benefit assessment. To further validate and expand upon these promising results, future research should prioritize conducting robust trials with larger patient cohorts, extended follow-up periods, and targeted inclusion of populations currently underrepresented in existing studies, notably individuals with type 2 diabetes mellitus and pediatric patients.