NATURE REVIEWS | NEPHROLOGY ADVANCE ONLINE PUBLICATION | 1 Research Group of Nephrology and Metabolism, Department of Clinical Medicine, UIT Arctic University of Norway, Hansine Hansens Veg 18, PO Box 6050 Langnes, 9037 Tromsø, Norway (T.J.). Department of Transplant Medicine, Section of Nephrology, Oslo University Hospital Rikshospitalet, Sognsvannvegen 20, PO Box 4950, Nydalen, Oslo 0424, Norway (A.H.). Correspondence to: T.J. trond.jenssen@ ous-hf.no Emerging treatments for post-transplantation diabetes mellitus Trond Jenssen and Anders Hartmann Abstract | Post-transplantation diabetes mellitus (PTDM), also known as new-onset diabetes mellitus (NODM), occurs in 10–15% of renal transplant recipients and is associated with cardiovascular disease and reduced lifespan. In the majority of cases, PTDM is characterized by β-cell dysfunction, as well as reduced insulin sensitivity in liver, muscle and adipose tissue. Glucose-lowering therapy must be compatible with immunosuppressant agents, reduced glomerular filtration rate (GFR) and severe arteriosclerosis. Such therapy should not place the patient at risk by inducing hypoglycaemic episodes or exacerbating renal function owing to adverse gastrointestinal effects with hypovolaemia. First-generation and second- generation sulphonylureas are generally avoided, and caution is currently advocated for the use of metformin in patients with GFR <60 ml/min/1.73 m 2 . DPP-4 inhibitors do not interact with immunosuppressant drugs and have demonstrated safety in small clinical trials. Other therapeutic options include glinides and glitazones. Evidence-based treatment regimens used in patients with type 2 diabetes mellitus cannot be directly implemented in patients with PTDM. Studies investigating the latest drugs are required to direct the development of improved treatment strategies for patients with PTDM. This Review outlines the modern principles of glucose-lowering treatment in PTDM with specific reference to renal transplant recipients. Jenssen, T. & Hartmann, A. Nat. Rev. Nephrol. advance online publication 28 April 2015; doi:10.1038/nrneph.2015.59 Introduction New-onset diabetes mellitus (NODM) is a term that is commonly used to describe diabetes mellitus that devel- ops after organ transplantation. 1,2 An international group of experts, however, has proposed that NODM is replaced by the term post-transplantation diabetes mel- litus (PTDM), since some of these cases might represent unknown diabetes mellitus that was present before trans- plantation. 3 PTDM describes the time of diagnosis rather than the time of onset, and accordingly we use this term throughout this Review. The majority of our knowledge on PTDM treatment strategies derives from studies that have included kidney transplant recipients. Recipients of renal transplants usually exhibit excessive arteriosclerosis owing to long- standing uraemia before transplantation, a marked reduc- tion in glomerular filtration rate (GFR), and autonomic neuropathy with delayed gastric emptying. PTDM is a risk factor for cardiovascular disease and mortality among recipients of renal transplants; 1,2,4,5 these risks are also evident among patients with intermediate hyperglycaemia or impaired glucose tolerance (IGT). 6 Hyperglycaemia in PTDM is associated with a distinct dysfunction of β cells, 7–9 but as observed in type 2 diabetes mellitus (T2DM), hyperglycaemia also occurs together with a substantial decrease in insulin sensitivity. 8,10–12 The pathogenesis of PTDM implies that stimulating or substituting insulin release would be the most effective therapeutic regimen, but insulin-sensitizing treatment has also proven efficient in this context. 13,14 PTDM occurs in conjunction with the use of immunosuppressive agents, the majority of which are diabetogenic by either reducing β-cell function 9,15 or by inducing central 16 or peripheral 12,16,17 insulin resist- ance. Therapies that are recommended for T2DM might not necessarily be recommended in PTDM owing to dif- ferences in some characteristics, such as risk of lactacid- osis with metformin in patients with severe renal failure, or risk of hypoglycaemia with sulphonylureas in patients with advanced atherosclerosis. Optimal glucose-lowering therapies for use among patients with PTDM should lower plasma glucose levels by targeting the cause of hypergly- caemia. In addition, such therapies should not interact with concurrent medications, such as immunosuppressive drugs, induce adverse effects that might hamper compli- ance with the therapeutic regimen or place the allograft at risk of rejection. This Review outlines the current therapeutic strat- egies for patients with PTDM and the issues that must be considered that are specific to transplant recipients. We discuss treatments that are in development for PTDM and T2DM, and propose an algorithm for PTDM therapy. Post-transplantation diabetes mellitus Definition PTDM presents as chronic hyperglycaemia after organ transplantation. The cumulative incidence of PTDM Competing interests T.J. has received lecture honoraria from AstraZeneca, Novartis, Sanofi and Merck Sharp & Dohme. A.H. declares no competing interests. REVIEWS © 2015 Macmillan Publishers Limited. All rights reserved