Finding Stability for Unstable Glucose Free

Hypoglycemia remains one of the most significant challenges in achieving near-normal glucose management for people with type 1 diabetes (T1D) (1). Recurrent hypoglycemia can lead to impaired awareness of hypoglycemia (IAH), a condition characterized by diminished counterregulatory hormonal response that increases the risk of severe hypoglycemic events (SHE). SHE are life-threatening episodes requiring third-party assistance due to loss of consciousness and seizures (2). IAH affects approximately 40% of people who have T1D and is associated with three- to sixfold increased risk of SHE (3,4). Therefore, severe hypoglycemia remains a major clinical challenge, particularly for those with IAH.

The standard of care (SOC) for people who have T1D with SHE includes continuous subcutaneous insulin infusion (CSII), continuous glucose monitoring (CGM), and structured education on hypoglycemia prevention. While SOC supports improved glycemic management and reduced hypoglycemia-related risks, a subset of people still experience recurrent SHE despite these interventions. For such individuals, islet transplantation provides an alternative treatment strategy that restores endogenous insulin secretion, improves glycemic management, and significantly reduces SHE. While insulin independence may not be permanent, even people requiring exogenous insulin after transplant experience substantial metabolic benefits, including improved counterregulatory hormone responses and marked reduction in SHE with enhanced quality of life (5,6). Current clinical practice guidelines recommend islet transplantation for people with T1D who continue to experience SHE despite optimal SOC (7). Compared with SOC, the main limitations of islet transplantation are accessibility to allogeneic islets and the need for immunosuppression.

As detailed in this issue of Diabetes Care, recent study by Rickels et al. (8) compared the efficacy and safety of islet transplantation with those of SOC using data from the Collaborative Islet Transplant Registry (CITR) and the T1D Exchange (T1DX) Registry. The study assessed the primary outcome of achieving HbA_1c <7.0% while remaining free of SHE among people with T1D and a history of hypoglycemia-induced seizures or loss of consciousness. Optimal SOC included CSII for approximately half of the participants. To date, limited data exist comparing islet transplantation to SOC, and existing studies are of short duration (9). Major strengths of this study are its long-term follow-up, large cohort size, and comparison with a well-characterized SOC population, including data on renal function.

The findings demonstrate the clear superiority of islet transplantation in achieving the primary end point, albeit at the cost of more rapid decline in kidney function. Notably, renal function decline was partially attributed to improved glycemic management, which reduces hyperfiltration in diabetic kidney disease. Up to 80% of transplant recipients achieved target glycemic management without experiencing SHE, whereas only one-third of patients receiving SOC met the same criteria. Importantly, these benefits were sustained over the entire 5-year follow-up period, underscoring the durability of islet transplantation’s effects. The present findings support current clinical practice recommendations that advocate for islet transplantation in individuals who remain at high risk for SHE despite optimal SOC. It also confirms that restoring endogenous insulin secretion is the most reliable approach to achieving near-normal glycemia without increasing the risk of hypoglycemia.

However, some limitations should be acknowledged when translating these findings to clinical practice. First, the T1DX cohort did not receive a standardized intervention specifically designed to treat SHE; rather, they were observed over 5 years while receiving SOC. Although the use of CSII increased over time, no CGM usage data were provided. Second, SOC has evolved significantly in recent years with the introduction of automated insulin delivery (AID) systems and advanced CGM technologies. Since the T1DX group was studied before 2017, many participants did not have access to these technological advancements, raising questions of whether more recent SOC strategies might yield better outcomes. In particular, CGM with predictive alarms and AID systems can significantly reduce hypoglycemia risk (10–12). Both clinical trials and real-world data demonstrate improved time in range without increasing the risk of hypoglycemia-related morbidity, including SHE (13,14). However, it remains unclear whether these systems effectively reduce SHE risk in highly susceptible individuals. A significantly lower rate of SHE has been reported in both children and adults who use AID systems compared with historical data (15), but other observational studies, also using T1DX Registry data, suggest that 15–16.6% of people continue to experience SHE, with IAH persisting in one-third of cases regardless of insulin delivery method (16,17). These findings highlight the need for additional long-term, interventional studies to determine whether AID technology can match the efficacy of islet transplantation in preventing SHE among high-risk patients.

Despite its benefits, islet transplantation is associated with several risks, primarily due to lifelong immunosuppressive therapy. A key concern is kidney function decline, although the authors’ data suggest that the steepest decline in estimated glomerular filtration rate (eGFR) occurs within the first year after transplant, largely attributable to glycemic optimization reversing renal hyperfiltration. Subsequent eGFR decline stabilizes (−2.7 mL/min/1.73 m²). The SOC cohort’s reported annual eGFR decline (−0.6 mL/min/1.73 m²) appears lower than that reported in the literature, potentially overestimating differences between groups (18). Data on albuminuria could provide further insight, but it was not studied. Notably, previous findings show an initial 20% eGFR drop after transplant followed by stabilization and reversibility upon calcineurin inhibitor withdrawal, suggesting that some renal effects are reversible and mediated by arteriolar vasoconstriction (19).

While SOC does not entail the risks of immunosuppressive therapy, it requires strict adherence to insulin therapy and diabetes technology. The ability and willingness to incorporate technology into everyday life remains challenging (20). CGM adoption is high (>90%), yet only around 50% of people with T1D use AID systems (16). Real-world data emphasize the importance of ongoing education and support for optimal technology use, as only half of AID users achieve glycemic targets (12,14,21). For some individuals, managing diabetes technology can be burdensome, leading to suboptimal adherence and increased SHE risk. For these patients, islet transplantation offers a viable treatment option, as supported by the current study. Moreover, studies have shown that transplant recipients experience significant improvements in psychological well-being, confidence in daily activities, and overall quality of life due to elimination of SHE (5). These factors must be weighed alongside the risks of immunosuppression when considering islet transplantation.

The cost-effectiveness of islet transplantation versus SOC is an additional factor in health care decision-making. Islet transplantation is expensive, requiring specialized procedures and lifelong immunosuppression, and has limited donor availability, further driving expenses. However, for people with frequent, costly hospitalizations due to SHE, islet transplantation may be a cost-effective intervention in the long term. Conversely, SOC, particularly with AID systems and CGM technology, also involves substantial expenses. The cost of insulin, monitoring devices, and diabetes-related complications can be significant over a patient’s lifetime. Ensuring affordability and insurance coverage for advanced diabetes technologies remains a challenge. Ethical considerations, including organ allocation and equitable access to transplantation, further complicate decision-making.

Both islet transplantation and advanced diabetes technology offer distinct benefits for managing severe hypoglycemia in people with T1D (Fig. 1). The choice between these approaches should be individualized, taking into account clinical, psychological, and economic factors through a multidisciplinary approach. Collaboration among endocrinologists, transplant specialists, and diabetes educators is essential to guide people with T1D toward the most suitable treatment based on their unique needs and risk profiles. Notably, when presented with a hypothetical choice, people with T1D often express a strong preference for cell therapy, driven by the potential to reduce or even eliminate the daily burden of diabetes management. Future advancements, including stem cell–derived islets, improved immunosuppressive strategies, and next-generation diabetes technologies, may further redefine the balance between these treatment options.