Conclusions
This retrospective comparative study showed that people with T2D who switched from a first-generation BI to Gla-300 had lower primary and secondary HCRU than those switched to another first-generation BI or degludec. In terms of total direct costs, people who switched to Gla-300 had, in general, lower all-cause, diabetes-related and DKA-related costs compared with those switched to another first-generation BI during the follow-up period and lower DKA-related costs compared with those switched to degludec.
Microvascular complications that commonly affect people with T2D can lead to serious health issues if not managed properly.19 A retrospective cohort study that utilized electronic medical records from people with T2D from the Heart of England Foundation Trust showed that 22.6%, 20.8% and 3.1% of the study population had comorbid nephropathy, retinopathy or neuropathy, respectively.20 Consistently, in our study, people had a high proportion of microvascular complications (26.15% nephropathy, 87.5% retinopathy and 21.3% neuropathy). Moreover, reduced eGFR was observed for approximately 70% of total population prior to the index date. These findings highlight the significant burden of microvascular complications in people with T2D, indicating that our study population likely has more severe diabetes and is more prone to resource utilization than most patients with T2D.
We found that people who switched to Gla-300 had a lower HCRU rate and fewer associated costs, particularly for diabetes-related, hypoglycemia-related and DKA-related services, compared with those who switched to another first-generation BI or degludec. Notably, the Gla-300 group experienced 51%–59% fewer hypoglycemia events and 45%–55% fewer DKA events, along with shorter hospital stays for these acute complications. These are clinically meaningful differences, as both hypoglycemia and DKA are serious events associated with substantial morbidity, hospital admissions and even mortality. Fewer episodes not only reduce healthcare burden but also improve patient safety, treatment adherence and quality of life. These findings align with prior real‐world studies in the USA, showing that switching to insulin Gla‐300 reduced hypoglycemia risk and associated HCRU, supporting both clinical and economic benefits.21–23 The follow-up period in these studies (6–12 months) was shorter than the follow-up time in our study but comparable to most randomized controlled trials. Another recent US study evaluating the value and affordability of Gla-300 over a 3-year model horizon for a hypothetical one million member US health plan population using HCRU parameters from the DELIVER-2 and DELIVER-naïve studies showed economic benefits driven by reductions in HCRU and costs.24 However, market shares were projected based on clinicians’ opinions rather than real-world patient data. A systematic review on cost-effectiveness, measured by cost per quality-adjusted life year, suggested that insulin degludec may be of lower value compared with insulin glargine. Differences in costs and benefits were mainly driven by hypoglycemic event models based on systematic reviews of RCTs, which often excluded individuals at the highest risk of hypoglycemia, making severe hypoglycemia rare and the event estimates unstable.25
Our data provide real‐world evidence that switching to Gla-300 from first-generation BI is associated with reduced hypoglycemia-related and DKA-related HCRU. People in the Gla-300 group had lower rates of hypoglycemia and DKA events and shorter hospital stays for these conditions compared with those switched to an alternate first-generation or degludec. A European multicenter prospective study demonstrated that switching the BI to Gla-300 significantly enhanced metabolic control and treatment satisfaction in many people with T2D within 12 months.26 This switch reduced the risk of symptomatic and nocturnal hypoglycemia without causing weight gain.26 Insulins with a lower risk of hypoglycemia may lead to better adherence to and persistence with therapy, and potentially, to longer-term glycemic control.27 28 Although people in the Gla-300 group had fewer hypoglycemia-related and HHS-related events overall, the zero-inflated regression analysis showed that conditional on experiencing an event, the per-episode costs were higher compared with the other groups (1.7 times higher for hypoglycemia than the first-generation BI, and 2.9 times higher for HHS than the degludec). These findings may reflect greater severity or complexity of cases that did require HCRU among people in the Gla-300 group, or potential differences in how these events were managed (eg, more intensive treatment or inpatient services). These results highlight the importance of interpreting total cost alongside per-event cost, as the overall burden was still lower in the Gla-300 group due to fewer events overall. Further research is warranted to explore the drivers of higher per-episode costs in this subgroup.
Gla-300 and degludec are both long-acting insulins. In this study, HbA1c decreased by 0.57 (from 10.01 to 9.44) at 6 months’ follow-up in people of the Gla-300 compared with a 0.54 decrease (from 9.81 to 9.27) in the degludec group. In line with our study, a small retrospective comparative study (degludec: n=171, Gla-300: n=123) indicated that degludec and Gla-300 have a similar impact on HbA1c levels (0.5–0.6 reduction) after switching from other BIs in Japanese patients with T2D.29 Another retrospective comparative study among insulin-naïve patients found that Gla-300 or degludec led to comparable improvements in glycemic control and hypoglycemia rates.30 One US RWE study did report that insulin degludec led to a larger reduction in HbA1c and hypoglycemia rates compared with Gla-300 in insulin-naïve adults,31 but some methodological questions have been raised over these findings.32 While not adjusting for baseline differences between studies, we note the HbA1c changes reported in this study are broadly consistent with those reported in previous studies (0.6 to 1.8).29 30 33–35 According to a trial-level meta-analysis, Gla-300 showed similar HbA1c reduction to Gla-100, with a lower risk of hypoglycemia at night and any time of day.36
In this study, the rate of hypoglycemia and DKA events was generally lower in the Gla-300 group compared with the degludec group. As these analyses were adjusted for baseline clinical characteristics, this may suggest that people in the Gla-300 group experienced fewer diabetes-related complications than those in the degludec group, and possibly insulin Gla-300 was more effective at reducing complications compared with insulin degludec. The CONCLUDE trial showed that both insulins improved HbA1c similarly, with no significant differences in overall hypoglycemia events.37 However, nocturnal symptomatic and severe hypoglycemia rates were lower with degludec compared with Gla-300. These results are inconclusive due to the primary endpoint not being met and glucometer reliability issues. In the BRIGHT trial including insulin-naive people with uncontrolled T2D, Gla-300 and IDeg-100 (degludec insulin) provided similar glycemic control improvements, with comparable hypoglycemia incidence and rates.38 Results from clinical trials may differ from those observed in real-world settings due to controlled environments, strict protocols, strict inclusion/exclusion criteria, predefined outcomes, and shorter follow-up times. Integrating clinical trial data with RWE is essential for a comprehensive understanding of the efficacy and safety of therapeutic interventions.
Research indicates that insulin resistance is closely linked to inflammatory responses, which play a crucial role in the development of conditions like T2D.39–41 Inflammatory markers such as cytokines and chemokines can interfere with insulin signaling pathways, leading to insulin resistance.42 By reducing inflammation, BIs can improve insulin sensitivity and enhance glucose uptake by cells.43 By mitigating inflammation, BIs may help preserve beta-cell function and improve endogenous insulin production. Additionally, they can manage other metabolic disturbances, such as dyslipidemia and atherosclerosis, which are common in T2D and associated with inflammation, leading to better overall metabolic control.43 44 Understanding and managing inflammation are crucial for optimizing the effectiveness of BI in type 2 diabetes treatment. The findings of this study may be partly related to insulin’s impact on inflammation markers; however, more research is needed to fully understand these mechanisms.
Once weekly administered BIs represent a significant innovation in the pharmacological management of T2D. They appear to be at least equally efficient in glycemic management and as safe as once-daily injections for people with T2D.45 46 Continuous glucose monitoring (CGM) metrics are crucial for managing diabetes, especially when using once-weekly BI analogs.47 Recent studies have shown that CGM-based metrics such as time in range, time above range, and time below range are comparable between once-weekly insulin and once-daily BI analogues.48 Further research is required to evaluate the cost-effectiveness of these treatments.
The results of the study should be interpreted considering certain limitations due to its retrospective real‐world design. First, only high-cost drug treatments are recorded in HES; therefore, treatment for T2D with non-high-cost drugs in hospitals is not captured. Additionally, ambulance call-out and societal costs are not available in HES, potentially underestimating HCRU and the costs associated with diabetes-related short-term complications. The study’s short timescale also limits consideration of long-term effects of insulin treatment at primary and secondary HCRU. Despite these limitations, HES data play a pivotal role in shaping healthcare policies, improving patient care and advancing medical knowledge. Second, because not all general practitioners in CPRD overlap with secondary care settings in HES, the data are limited to CPRD. Additionally, HES is limited to England, which affects the sample size and generalizability of results to other UK nations and countries with similar populations. The findings may not be directly applicable to other healthcare systems with different cost structures, insulin-prescribing patterns or reimbursement policies. However, CPRD-HES studies are considered high standard for secondary data research.11 12 Third, the IPTW method assumes that all relevant confounders are measured and included in the propensity score model. If important confounders are unmeasured, bias may still occur. To assess the robustness of our findings, we conducted several diagnostic checks. We evaluated covariate balance using SMDs, all of which were <0.1 after weighting, indicating strong balance. We also examined the distribution of weights and applied weight truncation at the 1st and 99th percentiles to minimize the influence of extreme weights. These analyses showed consistent results, suggesting that our findings are robust to model specification and relatively insensitive to moderate unmeasured confounding. Nevertheless, we acknowledge this limitation and recommend cautious interpretation of the results. Moreover, as an observational study with possible residual confounding, this research cannot establish causality, unlike randomized controlled trials. The shorter follow-up period in the Gla-300 and degludec groups compared with the first-generation BI group may introduce bias and affect conclusions about long-term effectiveness and cost savings. While adjusted analyses mitigate this to some extent, the longer follow-up in the first-generation BI group could inflate HCRU and cost differences. Additionally, the observed changes in clinical outcomes may be due to uncontrolled confounders or may be limited to patients with high event frequency. Fourth, the study used secondary data sources recorded for non-research purposes, with inherent limitations such as data availability (eg, no data on the reason for the switch), potential misclassification, HRG-based HCRU costs, which are average costs of providing a specific type of care, instead of a sum of costs for individual procedures/diagnoses. The validity and completeness of individual patient records cannot be assessed due to the nature of electronic health records. Finally, the study did not evaluate the progression of long-term diabetes complications, which should be a focus of future research.
In conclusion, this study showed that people with T2D in the UK transitioning to Gla-300 had a lower rate of hypoglycemia and DKA events and HCRU than those in first-generation BI, which could result in significant cost savings for NHS, and that within second-generation BI, insulin Gla-300 may offer economic advantages over degludec. However, given the limitations of the study, additional research is necessary to substantiate these results.
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