Prevention of Post-Transplantation Diabetes: Small Steps, Big Opportunities

Post-transplantation diabetes mellitus (PTDM) is common, affecting up to a third of kidney allograft recipients due to generic and transplant-specific risk factors, and is also associated with increased risk for cardiovascular disease, all-cause mortality, and overall graft failure.¹ In addition, patients rank PTDM as a leading cause of concern.² Therefore, exploring strategies that mitigate the risk of developing diabetes after transplantation is strongly advocated by both international consensus statements³ and national guidelines.⁴ However, interventional studies targeting prevention of PTDM as the primary study outcome are limited.

In a previous proof-of-concept study of controlling postoperative hyperglycemia, Hecking et al.⁵ randomly assigned 50 kidney transplant recipients who were nondiabetic to isophane basal insulin therapy (treatment threshold, evening glucose ≥140 mg/dl) versus standard of care, which consisted of short-acting insulin and/or oral glucose-lowering therapy (treatment threshold, glucose ≥180–250 mg/dl). Early insulin intervention reduced the odds of subsequent PTDM development during the first post-transplant year to an astonishing 0.27 (95% CI, 0.10 to 0.72), possibly due to insulin-mediated protection of pancreatic β-cells.⁵ Although the intervention appeared promising, validation in an adequately powered, multicenter study has been eagerly awaited.

In this issue of JASN, Schwaiger and colleagues report findings from the Insulin Therapy for the Prevention of New Onset Diabetes after Transplantation (ITP-NODAT) study, which undertook this corroboration.⁶ In this open-label, multicenter, randomized trial, to control postoperative hyperglycemia, kidney transplant recipients who were nondiabetic were randomly assigned to either intermediate-acting isophane basal insulin therapy (afternoon glucose threshold ≥140 mg/dl) or standard of care, which consisted of short-acting insulin and/or oral glucose-lowering therapy (fasting glucose threshold ≥200 mg/dl). The primary study outcome was incidence of PTDM at 12 months post-transplantation. In the intention-to-treat analysis (n=263), the odds ratios (ORs) for PTDM development at 12 months and 24 months were 0.82 (95% CI, 0.39 to 1.76) and 0.71 (95% CI, 0.34 to 1.49), respectively. In the per-protocol analysis (n=213), the ORs for PTDM development at 12 months and 24 months were 0.40 (95% CI, 0.16 to 1.01) and 0.54 (95% CI, 0.24 to 1.20), respectively. After adjustment for polycystic kidney disease (due to significant baseline between-group differences for this known PTDM risk factor), the per-protocol ORs for PTDM development at 12 months and 24 months were 0.21 (95% CI, 0.07 to 0.62) and 0.35 (95% CI, 0.14 to 0.87), respectively.

The study investigators should be commended for their persistence and perseverance in completion of this clinical trial and their transparency in data reporting. This allows a careful interpretation of the study as we consider translation of these research findings into real-world cohorts. First, observed PTDM rates were lower than anticipated. This corresponds with experience from other centers and likely relates to changes in immunosuppression, reduced burden of rejection, and steroid minimization strategies.⁷ Although this affects study power calculations, similar effect sizes to the original proof-of-concept study are observed in the adjusted per-protocol analyses.⁵ Despite broad study eligibility, predominately younger, slimmer, and/or White kidney transplant recipients were recruited, resulting in a cohort at low risk for PTDM. Benefits of early intervention with basal insulin are likely translatable to higher-risk cohorts, but greater caution in implementation may be warranted. For example, hypoglycemic episodes occurred significantly more frequently in the intervention versus control group (9.8% versus 1.5%, respectively; P=0.007); in the general population, such episodes have been associated with more detrimental long-term consequences for older adults.⁸

The study features transparent reporting of protocol violations; eight of 133 severe violations in the intervention arm possibly obscure any benefit from early basal insulin, with treatment nonadherence strongly associated with development of PTDM. Significant attrition of study participation—from death, graft loss, or participant withdrawal—further amplified the logistical challenges of conducting and completing ITP-NODAT. This raises concerns regarding the ability to translate the research findings of ITP-NODAT, with its study violations and frequency of hypoglycemic episodes, from a carefully monitored and executed academic investigation to a busy clinical practice without additional support, oversight, or both.

What next steps are appropriate? By definition, ITP-NODAT should be considered a negative study, but there are sufficient data to suggest that, if basal insulin intervention is appropriately started and maintained when indicated early postoperatively, prevention of PTDM for kidney transplant recipients can be achieved and maintained up to 2 years after surgery. Data in patients who are critically unwell, where tight glycemic control is associated with frequent hypoglycemic episodes and increased short-term mortality (of predominantly cardiovascular etiology),⁹ and from the ITP-NODAT experience, suggest that translation into clinical practice requires appropriate safety nets. To balance logistical challenges, hypoglycemic risk, and high-risk patient cohorts in the translation of this intervention to a real-world cohort will require careful implementation by transplant programs. However, difficulties in administration and monitoring aside, prevention of PTDM would be a great achievement and a worthwhile undertaking.

The findings from Schwaiger and colleagues are important for other reasons. We can hypothesize that prevention of PTDM leads to reduction of major adverse cardiovascular events and all-cause mortality, but data regarding this outcome will emerge only with time. Fundamentally, prolonging longevity and quality of life for patients with kidney failure is our ultimate goal. Long-term survival after kidney transplantation is likely to be determined more by development of nonimmunologic complications, such as diabetes, than by immunologic hurdles.¹⁰ However, research endeavors have failed to realign resources to acknowledge this shift. In a recent Canadian consultation exercise, with 505 participants taking part in a web-based survey and 46 taking part in an in-person workshop, 53.7% of participants scored “long-term medical complications of transplantation” as one of the leading research priorities (and the highest priority within the post-transplant period).¹¹ Improved post-transplant outcomes will be achieved by a combination of big steps and marginal gains, but research in the former overshadows the latter. For example, a quick search on clinicaltrials.gov at the time of writing reveals more active studies identified by the search terms “tolerance, kidney transplantation” versus active studies associated with the search terms “diabetes, kidney transplantation.” Facilitating more targeted research into prevention and/or management of medical complications such as PTDM is, therefore, long overdue.

In summary, in a field of limited randomized trial evidence, the authors should be applauded for undertaking this important and informative work. The study provides a strategy for prevention of PTDM that is significant and durable in the short term, if logistical constraints can be overcome. In the absence of a major scientific advance, improving long-term outcomes for kidney transplant recipients will be achieved by accruing and combining marginal gains. Therefore, research that achieves incremental improvements in aspects of post-transplant care—such as PTDM prevention, management, or both—must be prioritized.

Disclosures

A. Sharif reports serving as an advisory board member for Astellas, Atara Biotheraputics, Boeringher Ingelheim/Lilly Alliance, Hansa Biopharma, Novartis Pharmaceuticals, and Sandoz; serving on speakers bureaus for meetings/symposia hosted by Astellas, Chiesi Pharmaceuticals, and Novartis; receiving research funding from Chiesi Pharmaceuticals; receiving honoraria from Chiesi Pharmaceuticals, Hansa Biopharma, and Napp Pharmaceuticals; and having consultancy agreements with Hansa Pharmaceuticals.

Funding

None.