Can early, tight glycaemic control prevent post-transplant diabetes mellitus?

Early post-transplant hyperglycaemia (EPTH) occurs in more than 75% of patients after kidney transplantation (KT), often evolving towards post-transplant diabetes mellitus (PTDM), defined as newly diagnosed diabetes >45 days after transplantation [1]. Even with low-dose calcineurin inhibitors and steroids, PTDM incidence ranges between 10% and 40%, and mostly develops within 3–6 months post-transplant [2, 3].

Several pre- and post-transplant factors contribute to EPTH and PTDM. In kidney failure, uraemic toxins and a sedentary lifestyle can induce insulin resistance, although patients may remain normoglycaemic because of a decreased appetite, reduced gluconeogenesis and impaired degradation of insulin [1]. After KT, improved insulin clearance and gluconeogenesis may unmask the pre-existing glucose intolerance [1]. In addition, surgical stress, inflammation, pain and administration of immunosuppressive therapy contribute to EPTH. Hyperglycaemia causes glucotoxicity and can subsequently lead to β-cell dysfunction [4]. Ultimately, PTDM will be the result of both increased insulin resistance and β-cell dysfunction [1, 2, 5].

Can early, tight glycaemic control post-transplant prevent PTDM?

In a pilot study, Hecking et al. randomized 50 non-diabetic kidney transplant recipients (KTR) to either tight glycaemic control using immediate-postoperative, intermediate-acting isophane insulin for evening glycaemia ≥140 mg/dL or a standard-of-care management with short-acting insulin and/or oral antidiabetic agents for glycaemia ≥180–250 mg/dL [6]. At 12 months post-transplant, PTDM risk was reduced by 73% in the patients managed with tight glycaemic control [odds ratio (OR) 0.27; 95% confidence interval (95% CI) 0.08–0.95; PTDM incidence of 20% versus 48%, P = 0.04]. The treatment group showed a better β-cell function. This result encouraged the researchers to repeat this intervention in a larger, multicentre randomized trial involving 263 KTR [7]. This trial, disappointingly, found no significant difference in PTDM rates between groups in the intention-to-treat analysis: at 12 months, PTDM rates were 12% versus 15% (OR 0.82; 95% CI 0.39–1.76) and at 24 months 13% versus 17% (OR 0.71; 95% CI 0.34–1.49). However, several protocol violations might have blurred the benefit of early basal insulin intervention: three patients did not receive insulin (although needed), insulin was not stopped in four patients despite normal glycaemia and one patient declined treatment. In the per-protocol population, treatment with basal insulin showed a strong trend towards reduced odds for PTDM at 12 months (OR 0.40; 95% CI 0.16–1.01) and 24 months (OR 0.54; 95% CI 0.24–1.20). After adjustment for the imbalance in polycystic kidney disease (PKD) between groups, the per-protocol analysis showed a significant reduction of PTDM in the treatment arm, with an OR of 0.24 (95% CI 0.07–0.62) and 0.35 (95% CI 0.14–0.87) at month 12 and 24, respectively. A post hoc analysis of high-risk patients, defined as those with a family history of diabetes, PKD, age ≥60 years, or age 45–59 years plus (i) triglycerides 200 mg/dL, (ii) triglycerides 150–200 mg/dL and body mass index >27 kg/m², (iii) triglycerides 150–200 mg/dL and high-density lipoprotein <40 mg/dL (men) or <50 mg/dL (women), also showed a significant reduction of PTDM with tight glycaemic control, with an OR at 12 months of 0.20 (0.07–0.59) and a number needed to treat five. Nonadherence to the insulin protocol was associated with higher odds (2.26; 95% CI 1.25–3.93) for PTDM at 12 months. Of note, the incidence of PTDM was lower than anticipated, probably related to the lower doses of tacrolimus and steroids than used in the previous trial 10 years ago. Therefore, the trial might have been underpowered. Significantly more hypoglycaemic events occurred in the treatment (9.8%) versus the control group (1.5%), although they were mostly asymptomatic or mildly symptomatic. Despite its limitations, this study suggests that early, tight glycaemic control with the use of basal insulin may prevent β-cell exhaustion and reduce PTDM, especially in patients at higher baseline risk.

Could the newer antidiabetic drugs be used as a safer and easier alternative to basal insulin for EPTH and PTDM prevention?

Several safer therapeutic drugs for diabetes have become available; however, data on their use to prevent PTDM are lacking.

It is unlikely that sodium-glucose transporter 2 inhibitors (SLGT2-i) could play an important role in EPTH because their glucose-lowering effects largely depend on glomerular filtration rate (GFR). In patients with a GFR <30 mL/min, which is common in the early phase after KT, SGLT2-i have very little to no effect on glycaemia and are therefore unlikely to have a pancreas ‘sparing’ effect [2, 5, 8].

Glucagon-Like Peptide-1 Receptor agonists (GLP-1 RA) have a powerful glucose-lowering effect regardless of GFR and can be administered in patients with a GFR >15 mL/min [2]. Therefore, GLP-1 RA theoretically might be effective to spare the pancreas and prevent PTDM. However, the major concern is the risk of nausea and vomiting, especially in the first days after the start of the treatment. In the early posttransplant setting, where patients already experience abdominal discomfort due to surgery and immunosuppressive therapy, the use of GLP-1 RA may lead to an unacceptable risk of nausea and vomiting and possibly impaired intake/absorption of immunosuppressive agents [2, 5]. Yet, the potential of this drug in PTDM prevention prompted researchers to a first, currently ongoing randomized controlled trial (RCT) (NCT03961256). To stay on the safer side, however, patients will only start the treatment at 4 months post-KT.

Dipeptidyl Peptidase-4 inhibitors (DPP-4i) are less potent than GLP-1 RA but better tolerated. Beyond their glucose-lowering effects, DPP-4i are suggested to promote β-cell proliferation, neogenesis and inhibit β-cell apoptosis in animal models [9]. Two studies report improved insulin sensitivity with DPP-4i after KT [5]. The hypothesis that short-term treatment of vildagliptin in the early post-transplant period could be used to prevent PTDM is currently being tested in an RCT [Prevention of new onset diabetes after transplantation by a short term treatment of Vildagliptin in the early renal post-transplant period (PRODIG) study, NCT02849899].

In summary, recent data support the hypothesis that early tight glycaemic control post-transplant could reduce the risk of PTDM, presumably by preventing β-cell exhaustion. Recent RCTs suggest that immediate post-operative basal insulin therapy for blood glucose ≥140 mg/dL may reduce PTDM risk by as much as 60–75% in the first year, or even more in high-risk patients. Nevertheless, nephrologists might still hesitate to implement this strategy because of its complexity, additional workload and fear of hypoglycaemia. Newer antidiabetic drugs might be easier and safer alternatives. DPP4-i and possibly also GLP-1 RA currently appear to be the most appropriate candidates. The results from the first clinical trials with these drugs are eagerly awaited.

CONFLICT OF INTEREST STATEMENT

None declared.

References