Antidiabetic therapy in post kidney transplantation diabetes mellitus

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Abstract

Post-transplantation diabetes mellitus (PTDM) is a common complication after kidney transplantation that affects up to 40% of kidney transplant recipients. By pathogenesis, PTDM is a diabetes form of its own, and may be characterised by a sudden, drug-induced deficiency in insulin secretion rather than worsening of insulin resistance over time. In the context of deteriorating allograft function leading to a re-occurrence of chronic kidney disease after transplantation, pharmacological interventions in PTDM patients deserve special attention. In the present review, we aim at presenting the current evidence regarding efficacy and safety of the modern antidiabetic armamentarium. Specifically, we focus on incretin-based therapies and insulin treatment, besides metformin and glitazones, and discuss their respective advantages and pitfalls. Although recent pilot trials are available in both prediabetes and PTDM, further studies are warranted to elucidate the ideal timing of various antidiabetics as well as its long-term impact on safety, glucose metabolism and cardiovascular outcomes in kidney transplant recipients.

Introduction

In the last decade increased emphasis on the integrated management of care for patients with type 2 diabetes was followed by steady improvements in self-management behaviours and risk-factor control. In combination with the adoption of new, effective pharmacological approaches, these strategies were associated with large reductions in the rates of acute myocardial infarction, stroke, amputation, and end-stage renal disease among adults with diabetes between 1990 and 2010 [1]. Moreover, patients with diabetes have experienced a disproportionate reduction in in-hospital mortality and a complete reversal in risk of mortality relative to patients without diabetes [2]. Severe hypoglycaemia, however, is still the most common adverse effect of glucose-lowering therapies and associates with poor outcomes especially in vulnerable patients with multiple comorbidities [3]. Hospital admission rates for hypoglycaemia among older patients have now even surpassed hospitalisations for hyperglycaemia [4]. Thus, the efforts to improve metabolic control in patients with diabetes – although generally successful – have still been linked with unacceptably high rates of hypoglycaemia. New pharmacologic strategies including incretin-based therapies as a component of multimodal individualised diabetes management might help to increase the safety of lowering glucose.

PTDM has previously been suggested to be just a form of type 2 diabetes [5], [6]. However, although PTDM is not mentioned in the American Diabetes Association (ADA) position statement [7], it most reasonably classifies in the category of “other specific types” of diabetes mellitus rather than in the type 2 diabetes category. According to the ADA experts, it is less important to label the particular type of diabetes than to understand the pathogenesis of hyperglycaemia in order to treat it effectively. We have previously pointed out that hyperglycaemia after kidney transplantation appears rapidly, and that the appearance of overt PTDM is steeper in kidney transplant patients than the development of type 2 diabetes in the general population [8], [9], due to a variety of transplant-specific mechanisms [10]. Adding to this pathomechanistic difference, evidence generated by us and others suggests that β cell dysfunction rather than insulin resistance is the principal factor contributing to PTDM development [11], [12], [13], [14], [15], mainly as a consequence of calcineurin inhibitor action on β cells [16], [17], [18], [19], [20]. Previous consensus guidelines have emphasised the individualisation of immunosuppressive therapy as a hallmark of PTDM management [6]. However, a large international group of clinicians and scientists most recently recommended using strategies for prevention and treatment of PTDM beyond modification of immunosuppression [21]. Therefore, we here aim at reviewing and discussing pharmacological antihyperglycaemic therapy after kidney transplantation.

Our review focusses on antidiabetic substances for which at least some evidence regarding their use in PTDM is available or for which – at least theoretically – a positive impact on PTDM can be expected. This holds true for insulin, incretin-based therapies (in particular DPP-4 inhibitors), glitazones and metformin, as will be discussed below. From our point of view there is little rationale for the use of sulfonylureas and glinides in PTDM patients because of the negative cardiovascular profile of at least some of these compounds in the non-transplanted population [22]. In addition sulfonylureas failed to produce a sustained antihyperglycaemic effect in type 2 diabetes and appear to have a negative impact on β cell function, being particularly undesirable in the context of PTDM [23]. α-Glucosidase inhibitors show limited glucose-lowering efficacy in general combined with high rates of gastrointestinal side-effects making their use in transplant recipients less attractive [24]. Furthermore, their use in CKD stages 3 and higher is not recommended [25]. SGLT2 inhibitors will also not be discussed here, due to the lack of available data in kidney transplant recipients.

Section snippets

Insulin

Insulin treatment in patients with type 2 diabetes is typically introduced late during disease development [26], and this strategy has previously also been advocated for patients after renal transplantation in the previous PTDM consensus guidelines dating back to 2003 [6]. However, there are several potential advantages for earlier insulin administration in type 2 diabetes [27], most importantly protection of β cells by aggressive lowering of hyperglycaemia. An intermittent insulin therapy of

Incretin-based therapies

The first incretin was identified in the 1970s and was given the name glucose-dependent insulinotropic peptide (GIP) followed by the discovery of the even more potent incretin Glucagon-like peptide-1 (GLP-1) 1in the 1980s [37]. Among the plethora of physiologic reactions to GLP-1 are increased insulin biosynthesis and β cell proliferation with decreased glucagon secretion, delayed gastric emptying, and an increase in insulin sensitivity in muscle cells along with appetite down-regulation (Fig. 3

Metformin

Chemically, metformin belongs to the group of biguanides that are derived from the plant Galega officinalis (French lilac). Metformin has been in clinical use since the late 1950s although approval by the Food and Drug Administration (FDA) was granted as late as 1994. It is now the most widely prescribed antidiabetic drug in the world serving as first-line agent in patients with type 2 diabetes mellitus who did not reach their HbA1c target with life-style modifications alone [98], [99].

Glitazones

Glitazones or thiazolidinediones including rosiglitazone and pioglitazone can be used in patients with glomerular filtration rates below 30 ml/min. They act via modulation of the peroxisome proliferator-activated receptor γ (PPAR- γ) thereby improving glucose metabolism by acting as insulin sensitisers [118]. PPAR-γ activation increases insulin sensitivity in several tissues including muscle, fat and liver and leads to reduced levels of free fatty acids. In type 2 diabetes mellitus glitazones

Conclusion

Improving long-term outcomes of kidney transplantation is the major challenge of transplantation medicine today and reducing the rate of cardiovascular events in this particularly vulnerable population represents a major goal. PTDM is an important contributor to mortality in kidney transplanted patients, and effective management of this comorbidity could therefore lead to a profound improvement in long-term outcomes after kidney transplantation. Although evidence from prospective trials for the

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