Can Islet Transplantation Possibly Reduce Mortality in Type 1 Diabetes

Abstract

Islet transplantation (IT) is a successful natural cell therapy. But the benefits are known mostly to individuals with severe type 1 diabetes who undergo IT and the health care professionals that work to make the therapy available, reproducible, and safe. Data linking IT to overall survival in T1D might alter this situation and frame the therapy in a more positive light. Recent analysis of mortality in several cohorts suggests that IT has possible survival benefits when used alone or in conjunction with renal transplantation. Multi-center prospective studies with long-term follow-up of individuals that receive stand-alone IT versus individuals who qualify for but do not undergo the procedure would seem reasonable to undertake to confirm an IT survival benefit.

Introduction

Islet transplantation (IT) is an established cell therapy based on isolated human pancreatic islets. Islet transplantation is largely safe ¹ and imparts benefits for individuals with unstable type 1 diabetes including fewer severe hypoglycemic events, improved awareness of dangerous drops in blood glucose ² , and provides relief, albeit not permanent, from exogenous insulin ³ . These bonuses can persist, especially regarding better hypoglycemia awareness. The quality of life of individuals after IT is also improved^4,5. The notion that IT has still other advantages is under consideration. For example, among individual that received IT in combination with kidney transplantation, it was noted that while IT provided metabolic control ⁶ , it unexpectedly appeared to extend life as compared to individuals with poor disease control who had undergone kidney transplantation alone. This study assessed IT against insulin therapy and was noteworthy for being multi-center, prospective, and randomized ⁶ . IT also positively impacted the long-term function and survival of the kidney graft. However, the cohorts were unbalanced and had only a small number of subjects with long-term follow-up. Thus, the results could not confirm that IT alone was the reason for increased survival. Related to this, IT is being evaluated in combination with lung transplantation for individuals with cystic fibrosis-mediated respiratory failure and insulin-dependent diabetes ⁷ , but the impact IT has in such situations remains to be seen.

However, it is unclear if IT alone contributes to increased longevity in individuals with T1D. The reasons why this hypothesis has yet to be confirmed are varied. Perhaps limited application of IT therapy worldwide as compared to solid organ transplantation ⁸ and data that were not uniformly supportive of IT^9–11 contribute to this. Additionally, the continuing improvement in strategies such as closed loop insulin delivery systems ¹² and engineered stem cell-derived islet-like cell therapies^13–15 make comparison of alternative strategies versus IT challenging. All of these issues complicate what might appear to be a straightforward question. A lack of recognition and approval of the therapy as a standard of care by regulatory bodies and bias against IT in pancreas allocation ¹⁶ might also hinder examining the effect of IT on overall survival. Or perhaps the hypothesis is encumbered by confounding factors that would not permit a clean test. Historically, clinical IT focused on short-term outcomes such as HbA1c levels, Clarke and HYPO scores, insulin usage ¹⁷ , and peri-operative issues such as bleeding at the vascular access site or thrombosis of the hepatic vein. Few clinical studies listed long-term survival as a primary outcome^18,19 or properly took into account factors that confounded survival data ²⁰ .

Gathering and enlarging complete data sets is another problem. Even government-funded global research teams called for more complete follow-up data ²¹ . Thus, survival data after IT is sporadic, not long term, and limited to only individuals that underwent IT. The essential controls have yet to be recruited. These data stand isolated from the larger group of individuals whose clinical characteristics identified them as appropriate for IT but that were not treated with cell therapy. Prospective studies comparing both groups at the same time are not available. One is left wondering what might be achieved if the skill and energy displayed in cancer therapy trials were applied to the setting of IT versus standard of care for severe T1D.

T1D Survival

There are only a few large cohort studies of individuals with T1D that explored mortality as a primary metric. Information obtained from the Swedish National Diabetes Register tracked 33,915 individuals with T1D and 169,249 controls from 1998 to 2011. Every individual with T1D enrolled in the study was matched to five without. Among T1D subjects, crude all-cause mortality per 1,000 person-years was 8% with 8 years mean follow-up and 2.9% among controls with a mean follow-up of 8.3 years ²² (Table 1). This is a robust finding from a medical community expert at caring for individuals with T1D. The results emphasize the negative effect of T1D on survival. A multi-country retrospective analysis of medical records and registries over 16 years of 179,514 individuals with T1D reported a crude all-cause mortality per 1,000 person-years of 11.7% ²² . T1D imparted a 2 to 5 times greater risk of death compared to individuals without T1D. Thus, T1D increases overall morality. But what about the effect of IT upon T1D mortality, knowing that subjects receiving IT are usually in a poorer state of health than the average T1D population.

Table 1.

Islet Transplantation and T1D Mortality.

Study	Individuals with T1D	Study duration	Mortality rate (%)	Cause of death (%)
N Engl J Med. 2014 Nov 20;371(21):1972	33,915	January 1998–December 2011 mean follow-up 8 y	8 (controls 2.9) a	cardiovascular T1D, 2.9 vs controls, 0.9
Diabetologia. 2022 Jun;65(6):964	179,514	2000–2016	11.7	NA
CITR 11th Allograft Report (Feb 2022)	1,371	January 1999–February 2022 mean follow-up 5.8y	5.5	cardiovascular, cancer, infection (each <0.011)
Lancet Diabetes Endocrinol. 2024 Oct;12(10):716	327 (40 IT c /kidney; 80 kidney)	January 2000–December 2017	IT + kidney, 20 kidney alone, 31.3 b	infection, 3.3, cardiovascular, 2.4

^aCrude all-cause mortality per 1,000 person-years.

^bDeath, return to dialysis, re-transplantation, or end of follow-up.

^cIT, islet transplantation.

T1D Survival Following IT

The last two decades of clinical IT validate the safety of the procedure and consistent lengthening of the interval of glucose homeostasis free from exogenous insulin^20,21. Converging advances in administration of the cell product ²³ and specifically interventional radiology^3,24, pancreas harvesting and processing, cGMP islet isolation ²⁵ and quality assurance analysis^26,27, and pre- and post-procedure immune modulation ²¹ contributed to the rarity of procedural or early deaths after IT. Analysis of registry data found that at 5 years, survival among IT recipients was close to 90%, although causes of death were not detailed ²¹ . More recent information from the same group reported that, among 1,373 individuals who had IT, there were 77 deaths (5.5%) during a mean follow-up of 5.8 ± 3.8 years and comprising 7,963 person-years of follow-up. Of these, 10 deaths were judged related to IT or IT-associated immune modulation ²⁸ . Simultaneous islet kidney transplant recipients comprised 15.6% of deaths and were more likely to had experienced severe adverse events after IT compared to IT alone and IT after kidney transplantation, hinting that in this group, IT imparted some advantage when preceded by kidney transplantation. Furthermore, the mortality rate among all individuals that underwent IT was still far less that that reported for individuals with T1D receiving standard of care^22,29, pointing to a possible survival advantage from IT regardless of the situation. Another large cohort of 2,391 individuals that had kidney transplantation included 47 that also had IT ³⁰ . A sub-analysis of 80 subjects that had kidney transplant alone and 40, of the 47, that had kidney and islet transplantation discovered an advantage in the combined procedure. Specifically, only 33% of the individuals that had kidney and islet transplants died or were back on dialysis versus 45% of those that had kidney transplant alone ³⁰ . The data indicated that islet and kidney recipients had a >93% and >90% chance of survival at 5 and 10 years, respectively. This compared to a ~90 and 73% chance of survival for individuals that underwent kidney transplant only ³⁰ .

And while a small cohort, 49 subjects that underwent IT had 100% survival at 10 years and 80% survival at 20 years for a mortality rate of 3.28 per 1,000 person-years ³¹ . More to the point, in each of these studies, the mortality rate of individuals after IT, who began with advanced disease, was overall less when considered in relation to that noted for individuals with T1D and standard of care, although many of the latter no doubt had early to mid-stage disease and fewer diabetes-related complications. Additionally, IT was found value-added as several parameters of cardiac function improved among 17 individuals that received islet and kidney transplants versus 25 that underwent kidney only transplantation ³² . Of course, post hoc comparisons cannot provide strong proof that IT extends life in T1D. But the data might be a stimulant to look into such an idea.

The Glass Should Be Half or Three-Quarters Full

Research into the effects of IT assumes that metabolic outcomes are the most important. In point of fact, when available, survival data from individuals after IT is found at the end of study reports along with consideration of other adverse events. This may not be unreasonable given the short-term safety of the procedure. However, this point of view contrasts with cancer trials where the primary end point is survival. It is important to remember that individuals who qualify for IT alone or with kidney transplant are less healthy than the general T1D population, and are likely to have higher baseline mortality. Thus, the fact that mortality in IT subjects was reported to be roughly one-half that of the general T1D population implies a substantial life-saving effect. We propose that survival is a legitimate endpoint that should be included in the analysis of IT outcomes. A start could be made by exploring archival data from international collectives, particularly in countries where diabetes registries exist, and assessing survival among T1D individuals with comparable disease that had IT versus other forms of diabetes care. Such studies are low-hanging fruit. If the results implicate IT in the overall survival of individuals with T1D, this could be followed by prospective long-term clinical trials of IT alone and islet with kidney transplantation.