Simultaneous pancreas–kidney transplantation (SPKT) is a consolidated therapeutic option for patients with diabetes mellitus and end-stage renal disease (ESRD) who are eligible for pancreas transplantation [1–3]. By replacing both organs simultaneously, SPKT provides restoration of renal function together with endogenous insulin secretion, offering the potential for insulin independence and durable metabolic control [4–7]. Kidney transplantation alone (KTA) remains the most common approach worldwide due to its broader applicability, lower surgical complexity, and higher availability of organs, but it does not address the underlying diabetes or its long-term complications [8]. The theoretical advantages of SPKT extend beyond kidney graft survival and patient longevity [9]. Normalization of glycaemic control after successful pancreas transplantation improves HbA1c and reduces glycaemic variability, thereby decreasing the risk of acute metabolic decompensation and potentially preventing or slowing the progression of microvascular and macrovascular complications of diabetes [10–15]. Several observational studies have suggested that SPKT recipients achieve superior metabolic outcomes and quality of life compared with patients undergoing KTA, who remain insulin-dependent and often face suboptimal glucose control despite advances in medical therapy [16]. Despite these potential benefits, the impact of SPKT on hard clinical outcomes has been debated. Some registry-based analyses and single-centre reports have described lower mortality and cardiovascular events among SPKT recipients [17–22], particularly in type 1 diabetes [23, 24], while others have failed to confirm a survival advantage once differences in baseline risk profiles are accounted for [25–30]. Moreover, SPKT carries higher perioperative morbidity, increased immunosuppression, and greater risk of early complications, raising concerns about the overall balance of risks and benefits [31–33]. In the recent era, with improvements in surgical techniques [34–36], perioperative care [37–40], immunosuppressive strategies [41–43], and diabetes management [44], it remains unclear whether the historical advantages of SPKT over KTA persist in real-world practice. Importantly, while survival and graft outcomes are critical endpoints, the ability of SPKT to provide superior long-term glycaemic control represents a distinctive and clinically meaningful outcome that may translate into downstream benefits for patients. Large-scale real-world data may help clarify these uncertainties. TriNetX, a federated network of healthcare organizations, aggregates longitudinal electronic health records and enables comparative effectiveness research across diverse populations with robust analytic tools, including propensity score methods to mitigate baseline imbalances [45]. The objective of this study was to compare long-term outcomes of SPKT versus KTA in patients with diabetes and ESRD using the TriNetX Global Collaborative Network. We evaluated survival, kidney and pancreas graft outcomes, cardiovascular events, diabetes-related acute and chronic complications, malignancies, and mental health, with a particular focus on whether the improved glycaemic control achieved by SPKT translates into clinical benefit in the new era of transplantation.

In this large, real-world analysis, SPKT recipients achieved consistently better glycaemic control than KTA recipients, as reflected by lower HbA1c levels both before and after propensity score matching. Despite this clear metabolic advantage, long-term patient survival, kidney graft survival, and cardiovascular outcomes were indistinguishable between SPKT and KTA once baseline differences were accounted for. The initial signals of improved survival and reduced cardiovascular risk in the unmatched cohorts were largely attributable to selection bias, with SPKT recipients being younger, predominantly affected by type 1 diabetes, and carrying fewer comorbidities at baseline. Importantly, SPKT was associated with higher early risks—including treated acute rejection, hospital readmission, perioperative complications, and infection/sepsis within the first post-transplant year. These excess short-term risks did not translate into inferior long-term outcomes. The only remaining clinical difference was a modest reduction in MAKE during the first post-transplant year, suggesting a possible short-term renoprotective effect of improved glycaemic control, although without sustained long-term impact on major endpoints. Our findings differ from the earliest registry-based and single-centre reports, which consistently suggested a survival and cardiovascular advantage of SPKT over KTA [46–49] particularly among younger recipients with type 1 diabetes [7, 21, 47, 49–51]. However, they align more closely with subsequent analyses that applied more comprehensive multivariable adjustment or propensity-based methods and reported attenuation or disappearance of these differences [25, 52, 53]. This pattern supports the interpretation that much of the apparent survival benefit of SPKT in historical cohorts may have reflected differences in recipient selection, donor quality, and the clinical context of earlier eras.

A notable result from our study is the persistently lower HbA1c observed in SPKT recipients after matching, despite the relatively small absolute difference (6.2% vs. 6.6%). Based on landmark trials such as DCCT/EDIC [54] and UKPDS [54], a 1% reduction in HbA1c corresponds to a 15%–20% reduction in microvascular risk and a 10%–15% reduction in cardiovascular events. Accordingly, the 0.3%–0.4% difference in our study would be expected to confer only a 4%–6% reduction in microvascular risk and a 3%–5% reduction in cardiovascular risk—an effect size insufficient to produce detectable long-term differences in survival or major cardiovascular outcomes in heterogeneous, real-world cohorts. This helps explain why improved glycaemic control after SPKT, while clinically relevant, did not translate into measurable survival advantages at a population level. These short-term risks associated with SPKT—including perioperative morbidity, treated rejection, infections, and early hospital readmissions—are well documented [31, 32, 36, 55, 56] and represent a recognised trade-off against the metabolic benefits. Furthermore, the therapeutic landscape has evolved substantially. Advances in continuous glucose monitoring, automated insulin delivery systems, and the availability of new agents such as SGLT2 inhibitors and GLP-1 receptor agonists have markedly improved glycaemic profiles and cardiovascular risk in patients with diabetes after kidney transplantation. These innovations have likely narrowed the incremental advantage of SPKT over KTA, further contextualising our findings of long-term similarity in hard outcomes.

This finding warrants further clinical interpretation. In SPKT recipients, an HbA1c in the low-to-mid 6% range reflects physiological insulin secretion, typically associated with minimal risk of severe hypoglycaemia and lower glycaemic variability. In contrast, similar HbA1c values in insulin-treated KTA recipients may mask substantial hypoglycaemia burden, glycaemic fluctuations, and the cognitive and emotional load of intensive insulin management. Because our dataset did not include continuous glucose monitoring metrics—such as time-in-range, glucose excursion indices, or asymptomatic hypoglycaemia—the true metabolic benefit of SPKT is likely underestimated. These considerations reinforce that the metabolic advantage of SPKT remains clinically meaningful even in the absence of detectable long-term survival differences. Our findings should also be interpreted in the context of prior evidence, which for decades has consistently shown a survival advantage of SPKT over KTA. Several factors likely explain why our real-world findings differ from these earlier observations. First, historical cohorts reflect an era of higher dialysis mortality and less effective diabetes and cardiovascular management. Second, donor and recipient selection practices have evolved: SPKT recipients typically receive younger, lower-risk organs and enter transplantation earlier in the course of diabetic complications, whereas KTA recipients accumulate greater comorbidity and longer pre-transplant dialysis exposure. These factors likely amplified earlier survival signals. Third, improvements in perioperative care, modern immunosuppression, and cardiovascular therapy have narrowed the survival gap. Finally, because our dataset lacked key transplant-specific variables—such as donor quality indices, HLA matching, cold ischaemia time, and immunosuppression—an intrinsic survival benefit of SPKT cannot be excluded and may be masked by unmeasured confounding. Together, these considerations reconcile our findings with the broader literature and suggest that, in current practice, the dominant advantage of SPKT lies in its metabolic and quality-of-life benefits rather than in large differences in long-term survival.

This study has several important limitations First, despite rigorous propensity score matching, residual confounding is unavoidable because the TriNetX platform lacks key transplant-specific variables. Donor quality metrics such as Kidney Donor Profile Index (KDPI) and Pancreas Donor Risk Index (PDRI), which strongly influence kidney outcomes and differ systematically between SPKT and KTA, were not available. Similarly, no information was provided on HLA matching, panel reactive antibodies, donor-specific antibodies, cold ischaemia time, centre experience or detailed immunosuppression protocols. These unmeasured factors may attenuate or obscure a true intrinsic survival benefit of SPKT or, conversely, magnify early procedural risk. Second, exposures, comorbidities and outcomes were identified using ICD-10 and procedure codes. The complete lists of codes used in this study are provided in the Supplementary Methods. Although these coding-based definitions follow established conventions, they remain prone to misclassification, under-reporting and variability across institutions—particularly for complex outcomes such as cardiovascular events, rejection, infection or neuropathy, for which clinical adjudication would be preferable. Third, the database does not capture patient-reported outcomes, continuous glucose monitoring metrics or hypoglycaemia burden—elements that represent the most meaningful clinical benefits of SPKT for many patients [57, 58]. As a result, the metabolic advantage observed in this study likely underestimates the full quality-of-life impact of successful pancreas transplantation [59, 60]. Fourth, diabetes type was defined using diagnosis codes, which may misclassify insulin-treated type 2 diabetes as type 1. Although sensitivity analyses restricted to patients coded as type 1 diabetes and to non-obese recipients were performed, some residual misclassification may persist. Finally, because SPKT by definition requires a deceased donor, our comparison group included only deceased-donor KTA recipients. These findings cannot be extrapolated to living-donor kidney transplantation, which often provides superior survival and represents a distinct clinical pathway.

Taken together, these limitations suggest that while our findings demonstrate no detectable long-term survival advantage of SPKT after adjustment for measured variables, a modest true benefit cannot be excluded. Rather, our results underscore the extent to which survival outcomes are shaped by patient selection, donor quality, and centre-level variation. In this context, the principal justification for SPKT in contemporary practice lies in its profound metabolic and quality-of-life benefits, balanced against higher early procedural risks.

In summary, this large, contemporary real-world analysis shows that the apparent survival advantage of SPKT over KTA disappears after balancing for measurable clinical covariates. Because donor quality and other key transplant-specific factors were not captured, a residual survival benefit cannot be excluded. Nevertheless, SPKT provides durable metabolic benefits, including excellent glycaemic control and freedom from insulin. In the setting of comparable observed survival, decisions about SPKT should be individualised, considering each patient’s preference for insulin independence, glycaemic stability, and quality-of-life improvement, as well as willingness to accept higher short-term risks. These findings also highlight a broader issue: despite clear metabolic and quality-of-life benefits, SPKT remains underutilised, and many eligible patients are not systematically referred to transplant centres. Variability in referral pathways, limited awareness among non-transplant clinicians, and the absence of structured evaluation frameworks likely prevent equitable access. In light of our results—showing that the decision for SPKT increasingly centres on metabolic benefit and patient preference—timely and systematic referral becomes critical. Strengthening referral pathways and enhancing collaboration between diabetologists, nephrologists, and transplant teams will be essential to ensure that all suitable candidates are appropriately evaluated.