Clinical Trials for Treatment of NODAT

Sarno et al. (1) provide a timely summary of the current state of play with our knowledge of new-onset diabetes after transplantation (NODAT). The authors rightfully advocate further investigation into the pathophysiology of transplant-associated hyperglycemia, to aid our understanding of the development of NODAT. In our opinion, such research into pathophysiology should subsequently be translated into targeted therapeutic intervention to prevent and manage NODAT. There is consensus on the importance of encouraging lifestyle modifications for both prevention and management of NODAT in the first instance, with demonstrable efficacy after transplantation (2). However, the reality is that pharmacological agents are likely to be necessary as a sustainable strategy. Therefore, emphasis for clinical research should be on clinical trials assessing and comparing rival antiglycemic agents on hard outcomes after transplantation. Pathophysiology of NODAT is similar to type 2 diabetes mellitus, but there are important distinctions that make it a separate metabolic entity in its own right. The central pathophysiologic defect is pancreatic β-cell dysfunction in the context of insulin resistance (1). Although this mirrors type 2 diabetes, transplant-specific risk factors will have unique implications on both insulin secretion and sensitivity. Therefore, direct translation of pharmacotherapy evidence from the general to the transplant population may be erroneous. Transplant-specific trials of antiglycemic agents are required and, in light of the distinct pathophysiology of NODAT, should focus on a comparison of safety and efficacy of insulin secretagogues versus insulin-sensitizing agents (see Table 1).TABLE 1: Comparison of currently available antiglycemic agents (advantages and disadvantages extrapolated predominantly from nontransplantation literature)The literature is scattered with observational studies analyzing antiglycemic agents after transplantation, with a paucity of randomized controlled trials. Turk et al. (3) have compared repaglinide, a short-acting secretagogue, to rosiglitazone (insulin-sensitizing thiazolidinedione) in renal transplant recipients with NODAT (diagnosed median of 4 months after transplantation). In this nonrandomized observational trial, comparison of the repaglinide group (n=23) and rosiglitazone group (n=21) demonstrated similar efficacy, tolerable adverse-effect profile, and no deleterious interactions. Lane et al. (4) have reported a 3-month pilot study using sitagliptin, a dipeptidyl peptidase-4 inhibitor that improves insulin secretion through an incretin effect, in 15 renal transplant recipients diagnosed with NODAT and demonstrated its safety and efficacy. Pietruck et al. (5) have reported their experience with rosiglitazone in 22 renal transplant recipients with NODAT, diagnosed 3 months after transplantation. During a mean follow-up of 10 months, 16 patients were deemed to have had successful treatment against 6 without. Although metformin is the most established antiglycemic agent, its experience is limited to a single retrospective report of 24 renal transplant recipients (6). This study compared metformin with thiazolidinediones in renal transplant recipients with NODAT or preexisting diabetes mellitus. Although not demonstrating any superiority of metformin, it did demonstrate safety in the context of close supervision. In theory, metformin has putative advantages that should make it the ideal antiglycemic agent of choice after transplantation (7), but unresolved safety concerns prohibit adoption of metformin as the antiglycemic of choice in contrast to the general population (8). Pharmacological prevention of NODAT has limited evidence base but could be the optimum strategy to attenuate development of NODAT in the first place. Recent evidence suggests attenuation of future risk of NODAT could be improved by protecting pancreatic β-cell function immediately after transplantation. The use of early basal insulin after kidney transplantation has demonstrated improvement in pancreatic β-cell function, with subsequent 73% lower odds of NODAT compared with standard of care management (short-acting insulin or oral antiglycemic agents) (9). Comparing agents targeting insulin secretion and sensitivity, vildagliptin and pioglitazone, respectively, to attenuate abnormal glucose metabolism in renal transplant recipients with impaired glucose tolerance after transplantation is also a work in progress (NCT01346254). NODAT consensus guidelines (10) from 2003 are now outdated and do not reflect the current armamentarium of antiglycemic agents at our disposal. The ideal management option for patients either at risk or with established NODAT is far from certain. In the context of the distinct pathophysiology of NODAT versus type 2 diabetes mellitus, as highlighted by Sarno and colleagues (1), it is of utmost importance that transplant-specific trials are conducted to determine pharmacological interventions to prevent or treat NODAT with adequate safety and efficacy. To achieve this goal, collaboration between centers will be required to facilitate adequately powered randomized controlled trials to answer the question that most challenges our management of NODAT—what is the best treatment? Adnan Sharif 1 Aiko P.J. de Vries2 Esteban Porrini3 Manfred Hecking4 Marcus Saemann4 The European–New-Onset Diabetes After Transplantation (EU-NODAT) Working Group 1 Department of Nephrology and Transplantation Renal Institute of Birmingham Queen Elizabeth Hospital Birmingham, United Kingdom 2 Division of Nephrology and Transplant Medicine Department of Medicine Leiden University Medical Centre Leiden University, Leiden The Netherlands 3 Nephrology Section and Research Unit Hospital Universitario de Canarias University of La Laguna, Tenerife Canary Islands, Spain 4 Division of Nephrology and Dialysis Medical University of Vienna Vienna, Austria