Post-transplant new-onset diabetes is a common complication after solid organ transplantation and has a negative impact on both graft survival and patient survival. Although age, weight, race, family history, and hepatitis C infection all play a role in the development of new onset diabetes after transplantation, immunosuppressive drugs, including glucocorticoids, calmodulin inhibitors, and sirolimus, are the primary causes. The current management of post-transplant new-onset diabetes is mainly based on the guidelines for the treatment of type 2 diabetes.
1. Definition
In the 1960s, Dr. Starzl first reported diabetes mellitus as a post-transplant complication. After nearly half a century of research, it has been gradually recognized that in all solid organ transplants, new-onset diabetes after transplantation can promote the development of cardiovascular disease, leading to graft failure and patient death. The term “new-onset diatetes after transplantation (NODAT)” is now used internationally instead of “post-transplant diabetes mellitus (PTDM) ” to distinguish pre-transplant diabetes mellitus.
2. Prevalence
NODAT mostly occurs in the early post-transplantation period, and it is difficult to count the prevalence of NODAT due to the lack of uniform diagnostic criteria. a meta-analysis of 19 studies by Montori et al. showed that the prevalence ranged from 2% to 50% 1 year after transplantation.
The majority of current data on NODAT come from kidney transplant recipients, with 1-year incidence rates ranging from 13% to 24% after kidney transplantation, 2.5% to 38% after liver transplantation, about 13% after heart transplantation, and about 6% after lung transplantation. As more and more elderly and obese patients become transplant recipients, the incidence of NODAT is gradually increasing.
3.Risk factors
NODAT belongs to type 2 diabetes, which is also the result of increased insulin resistance and decreased insulin production. In addition to the traditional risk factors for type 2 diabetes, NODAT is mainly influenced by the type of transplantation as well as immunosuppressive drugs. Possible risk factors include: race, obesity, age, family history of diabetes, reduced glucose tolerance before transplantation, autosomal dominant polycystic kidney, genetic factors, cytomegalovirus and hepatitis C virus infection, immunosuppressive drugs, and weight gain after transplantation.
Similar to the general population, increasing age increases the occurrence of NODAT. The literature reports that the incidence of NODAT is significantly higher in patients older than 45 years of age than in those younger than 45 years of age. Racial differences also affect the prevalence of NODAT, with significantly higher rates of NODAT in African American and Latino patients than in Caucasian and Asian populations. As with type 2 diabetes, obese patients are prone to NODAT. early post-transplant glucocorticoid use and increased appetite both cause weight gain, which exacerbates insulin resistance and promotes the development of diabetes. Several studies have shown that patients with autosomal dominant polycystic kidney disease are prone to NODAT, but the exact pathogenesis is unclear. Genetic factors are also involved in the development of NODAT, and several studies have confirmed the association of susceptibility genes for type 2 diabetes mellitus with the development of NODAT. In renal and liver transplant patients, the incidence of NODAT is significantly higher in cytomegalovirus-infected and hepatitis C patients than in non-infected patients, and the pathogenesis may be due to viral effects on pancreatic islet cell function.
Most immunosuppressive drugs have a significant effect on glucose metabolism and are the main cause of NODAT. Abnormal glucose tolerance is one of the well known side effects of glucocorticoids. Glucocorticoids induce diabetes by increasing gluconeogenesis while inducing insulin resistance. Their pathogenic effect is directly related to the dose administered. The incidence of NODAT has been significantly reduced in recent years with the reduction of glucocorticoid dosage after organ transplantation. Some studies have confirmed that the reduction of glucocorticoid dosage can improve the abnormal glucose tolerance status or even cure diabetes, but these patients may develop recurrence of diabetes later due to the presence of genetic qualities for the development of diabetes. Recent studies have shown no significant difference in the incidence of NODAT between patients with and without glucocorticoids. Therefore, it remains controversial whether discontinuation of long-term glucocorticoid application at low doses can improve glucose metabolism. Future studies should take care to assess the risk of rejection while reducing the dosage of glucocorticoids to reduce the occurrence of diabetes, so as to avoid having to give high-dose glucocorticoid therapy due to the occurrence of rejection.
Direct evidence for the diabetogenic effect of calmodulin inhibitors comes from animal studies. Cyclosporine application can cause a decrease in pancreatic insulin content and b-cell count, and also cause islet cytotoxicity in dogs, affecting the release of insulin from human islet cells cultured in vitro. In addition, cyclosporine can induce the development of insulin resistance. In animal models, tacrolimus reduces insulin secretion from pancreatic b-cells; in humans, tacrolimus can also induce insulin resistance. Compared to cyclosporine, tacrolimus has a more potent diabetogenic effect after renal, liver and heart transplantation. Hypomagnesemia is a common problem after transplantation, and the development of hypomagnesemia is closely associated with the use of calmodulin inhibitors. It has been found that hypomagnesemia decreases islet sensitivity and that increased magnesium intake reduces the risk of reduced glucose tolerance. Thus the diabetogenic effect of calmodulin inhibitors is at least in part related to hypomagnesemia, and increased magnesium intake is expected to be a preventive tool for NODAT.
Although there are fewer studies on sirolimus, it has been documented that its application increases the incidence of NODAT. Sirolimus can impair insulin regulation of hepatic glycogen synthesis and induce NODAT through ectopic accumulation of triglycerides or direct toxic effects on b cells causing insulin resistance.
Bariximab is an antibody to the IL-2 receptor and is mainly used for induction therapy in organ transplantation. One study found that the incidence of NODAT was significantly higher in renal transplant recipients treated with bariximab induction therapy, but the pathogenesis is unclear.
4. Diagnosis
The vast majority of experts currently recommend diagnosing NODAT with reference to the American Diabetes Association’s diagnostic criteria for diabetes mellitus. the specific diagnostic criteria are as follows.
For patients who do not have diabetes before surgery and develop diabetic symptoms after organ transplantation, random blood glucose ≥ 11.1 mmol/L or fasting blood glucose ≥ 7.0 mmol/L or glucose tolerance test 2 hours blood glucose ≥ 11.1 mmol/L can diagnose NODAT; for those who do not have diabetic symptoms, repeat examination on another day is required.
Impaired fasting glucose between 6.1 and 6.9 mmol/L was defined as impaired fasting glucose, and abnormal glucose tolerance between 7.8 and 11.1 mmol/L after meal or oral glucose tolerance test 2 hours was defined as abnormal glucose tolerance. Both impaired fasting glucose and abnormal glucose tolerance are prognostic factors for the progression to clinical diabetes and risk factors for the development of macrovascular and microvascular disease.
In recent years there has been an increasing tendency to use glycosylated hemoglobin as a method to screen for people at risk for diabetes and to diagnose diabetes. The 2010 ADA guidelines have included HbA1c ≥6.5% as one of the diagnostic criteria for diabetes mellitus. For organ transplant recipients, HbA1c can also be used to screen and monitor NODAT. however, given that HbA1c testing is not yet common in China, whether the cut point for HbA1c diagnosis of diabetes in the Chinese population is consistent with that in international studies has yet to be confirmed, and its application is not recommended for the time being.
Close follow-up is important for the early diagnosis of NODAT, which should be done weekly within 1 month after surgery, every 3 months for 1 year after surgery, and subsequently can be done annually. The content of the follow-up visit is based on medical history, physical examination and fasting glucose test, and glucose tolerance test and HbA1c measurement if necessary.
5.Treatment
Treatment for NODAT includes identification of high-risk patients before transplantation, regular screening after transplantation, rational selection of immunotherapy regimens, and treatment of diabetes mellitus. The goal of treatment is to prevent the symptoms caused by hyperglycemia and the vascular complications of diabetes. Self-monitoring of blood glucose, dietary control, and rational use of hypoglycemic agents and insulin are essential measures in the treatment of NODAT.
Given that obesity and the use of immunosuppressive drugs are the main causative factors of NODAT, once NODAT, abnormal glucose tolerance or impaired fasting glucose is diagnosed, reasonable dietary control, weight loss and increased exercise should be implemented in order to control blood glucose. At the same time, immunosuppressive regimens should be re-evaluated. The following immunosuppressive treatment options are available.
Reduce the dose of tacrolimus, cyclosporine A or glucocorticoids
Discontinue tacrolimus, cyclosporine A, or glucocorticoids
Replace tacrolimus with cyclosporine A, mycophenolate or azathioprine
Apply mycophenolate or azathioprine instead of cyclosporine A
(1) Oral hypoglycemic drugs
Oral hypoglycemic agents are recommended as first-line agents for NODAT, but the effects of hypoglycemic agents on immunosuppressive drugs, glomerular filtration rate, and transplant-related osteoporosis need to be considered when selecting drugs. Metformin should be used with caution in transplant patients with impaired renal function. Although there is a risk of lactic acidosis with metformin in patients with abnormal renal function, treatment with metformin is beneficial in preventing macrovascular complications of diabetes mellitus; therefore, metformin can still be used in patients with creatinine clearance greater than 45 mL/min who can be followed up regularly.
In patients with impaired renal function, glipizide, glimepiride and gliclazide should be used first, followed by gliphenylurea and a generation of sulfonylureas. Chlorantraniliprole drugs such as nateglinide and repaglinide can be used in patients with renal and hepatic failure and do not cause adverse drug interactions. However, cyclosporine elevates the drug concentration of repaglinide, enhancing the hypoglycemic effect and increasing the risk of hypoglycemia. Acarbose and other a-glucosidase inhibitors can both inhibit carbohydrate absorption and lower postprandial glucose, but their hypoglycemic effects are weaker and the risk of hypoglycemia and drug interactions are less severe. Thiazolidinediones are peroxisome proliferator-activated receptor agonists that promote glucose uptake by peripheral tissues and inhibit hepatic glucose synthesis. No interaction has been found between calmodulin inhibitors and rosiglitazone or pioglitazone. However, these drugs tend to trigger edema and are therefore not suitable for people with reduced left ventricular ejection function. Moreover, thiazolidinediones can cause a decrease in bone mineral density and increase the risk of fracture. Therefore, these drugs should be used with caution in transplant patients.
Exenatide, a glucagon-like peptide 1 analogue administered subcutaneously, is approved by the U.S. Food and Drug Administration for use in patients with type 2 diabetes uncontrolled by oral medications, but has not been studied in transplant recipients. Dipeptidyl peptidase-4 inhibitors may also be used to treat diabetes, but again there is no experience with their use in transplant recipients.
In post-transplant patients, high risk factors for cardiovascular disease such as hypertension and dyslipidemia should be actively controlled. However, only a few randomized controlled studies have looked at the safety and efficacy of cardiovascular disease-reducing treatment strategies in transplant recipients, and it is unclear whether internists will apply treatment guidelines for the general population to transplant recipients. Although the evidence that the benefits of aspirin outweigh the risks in transplant recipients is insufficient, aspirin should be given for primary and secondary prevention of cardiovascular disease because of the increased risk of cardiovascular disease in patients with new-onset diabetes after transplantation.
(2) Insulin
Many patients will eventually require insulin therapy. Even when small doses of glucocorticoids are given daily in the morning, there is an increase in blood glucose around the evening. Early morning administration of intermediate-acting insulin is particularly suitable for patients with elevated blood glucose around evening. If postprandial blood glucose cannot be controlled by medium-acting insulin alone, short-acting insulin should be added. If fasting blood sugar is elevated, medium-acting insulin should be given in the evening.
6. Prognosis
In the general population, diabetes mellitus is closely related to the development of cardiovascular disease as a result of damage to blood vessels by various factors such as hyperglycemia, dyslipidemia, hypertension and insulin resistance. In transplant patients, new onset diabetes after transplantation is not yet universally accepted as a serious complication, and the results of clinical studies assessing graft and patient survival are still divergent.
NODAT severely affects the survival time of renal transplant patients. Studies have shown a 10-year survival rate of 75% for patients without NODAT after renal transplantation, 49% for those with NODAT, and 39% for patients with insulin-dependent NODAT. The leading cause of patient death was cardiovascular disease, followed by infection and malignancy. However, due to the time lapse between the onset of NODAT and the development of cardiovascular complications, NODAT does not increase patient mortality up to 8 years postoperatively.NODAT also has adverse effects on renal grafts, significantly increasing the incidence of graft failure.
In liver transplant patients, there are fewer studies related to NODAT and patient survival, and the findings are still controversial. a study by Baid et al. showed an increased overall risk of death in NODAT patients, and a study by John et al. showed an increased incidence of cardiovascular or neurological disease, infectious disease, and acute rejection in NODAT patients, but no difference in 5-year mortality. NODAT can increase the risk of post-transplant fibrosis in patients with hepatitis C. The incidence of fibrosis is further increased if the donor is older than 55 years of age.
Information on NODAT in lung and heart transplant patients is even rarer, with a 27% increase in 5-year mortality in those who develop NODAT after lung transplantation and an increased incidence of acute rejection in heart transplant recipients after NODAT, but no significant impact on long-term survival has been reported.