Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry

Abstract

Aims/hypothesis: Islet transplantation has been studied in small cohorts of recipients with type 1 diabetes complicated by severe hypoglycaemic events (SHEs). We determined factors associated with favourable outcomes in a large cohort of recipients reported to the Collaborative Islet Transplant Registry (CITR).

Methods: In 398 non-uraemic islet transplant alone (ITA) recipients with type 1 diabetes and SHEs, transplanted between 1999 and 2015 and with at least 1 year follow-up, we analysed specified favourable outcomes against each of all available characteristics of pancreas donors, islet grafts, recipients and immunosuppressive regimens, as well as immunosuppression and procedure-related serious adverse events (SAEs).

Results: Four factors were associated with the highest rates of favourable outcomes: recipient age ≥35 years; total infused islets ≥325,000 islet equivalents; induction immunosuppression with T cell depletion and/or TNF-α inhibition; and maintenance with both mechanistic target of rapamycin (mTOR) and calcineurin inhibitors. At 5 years after the last islet infusion, of the recipients meeting these four common favourable factors (4CFF; N=126), 95% were free of SHEs, 76% had HbA_1c <53 mmol/mol (7.0%), 73% had HbA_1c <53 mmol/mol (7.0%) and absence of SHEs, and 53% were insulin independent, significantly higher rates than in the remaining recipients (<4CFF; N=272). The incidence of procedural and immunosuppression-related SAEs per recipient that resulted in sequelae, disability or death was low in both the 4CFF (0.056 per person) and <4CFF (0.074 per person) groups.

Conclusions/interpretation: In recipients with type 1 diabetes complicated by SHEs, islet transplantation meeting 4CFF protected 95% from SHEs at 5 years after the last islet infusion and exerted a large and significant benefit on glycaemic control, with an acceptable safety profile for this subgroup of type 1 diabetes.

Keywords: Clinical islet transplantation; Favourable factors; Severe hypoglycaemia; Type 1 diabetes.

Fig. 1

Observed prevalence rates of the study outcomes in the 4CFF subgroup (favourable factors, n=126) vs the <4CFF subgroup (others, n=272): HbA1c <53 mmol/mol (7.0%) and absence of SHEs (a); HbA_1c <53 mmol/mol (7.0%) (b); absence of SHEs (c); C-peptide ≥0.1 nmol/l (d); fasting glucose 3.3–7.8 mmol/l (e); and insulin independence (f) in ITA recipients with SHEs and pre-transplant negative C-peptide at baseline and years 1–5 post last infusion

Fig. 2

Prevalence of insulin independence 1–5 years post last infusion, comparing individual induction immunosuppression regimens among recipients aged ≥35 years, with ≥325,000 IEQs infused and maintenance on mTOR inhitor + CNI (‘all other common factors favourable group’, n=238) (a) vs recipients aged <35 years, with <325,000 IEQs infused or maintenance on other than mTOR inhibitor + CNI (‘not all other common factors favourable group’, n=160) (b); p<0.01 for each comparison except TCD+TNFa (p=0.07). The precipitous drop over 5 years in the ‘neither TCD/TNFa’ group was significant at p<0.0001. There was no significant difference between TCD+TNFa, TNFa alone, and TCD alone after controlling for other favourable factors (p=0.5); TCD, TCD antibody; TNFa, TNF-α inhibitor

Fig. 3

Number of SAEs deemed related or possibly related to immunosuppression per recipient (a) and deemed related or possibly related to infusion procedure (b), for the 4CFF subgroup (favourable factors, n=126) vs the <4CFF subgroup (others, n=272). The mean is indicated by a blue diamond and the median by a blue line. A black box shows the IQR with whiskers for 1.5 times the IQR. Outliers are plotted as black circles