Prevalence and risk factors for posttransplant diabetes mellitus: Data from government tertiary care center
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Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician’s perspective. Solid organ transplantation is currently the best choice of treatment for most patients suffering from end-stage organ failure. Successful organ transplantation offers enhanced quality and duration of life with lower morbidity and mortality. Innovations in SOT, advances in surgical techniques, progress in immunosuppressive regimens, and critical care have greatly improved both the patient and graft survival in last several decades. The discovery of calcineurin inhibitors (CNIs) represents a milestone event in the history of immunosuppression and it has revolutionized transplant medicine; further breakthrough in immunosuppressive regimens is the cornerstone for existing successful transplant program. The current 5-year graft survival is about 80% for kidney and heart transplants, and 70% for liver and lung transplants (UNOS-OPTN and SRTR registry data). Cardiovascular disease (CVD), infections, and drug toxicity play an important role in the long-term morbidity and mortality of this patient population. This risk is not only due to presence of underlying pre-existing comorbidities, but also results from adverse effects of the immunosuppressive drugs such as hypertension, dyslipidemia, and PTDM. The risk of PTDM after SOT varies from 10 to 40% during the first 1 year. This risk depends on several factors including the type of transplanted organ [10–20% of kidney transplant recipients (KTRs) and 20–40% of patients with heart, liver, and lung transplants]. Post-transplant diabetes mellitus is widely studied in KTRs, but the risk factors and pathophysiology seem to be similar in all kinds of SOT. Post-transplant diabetes mellitus [previously termed, new-onset diabetes mellitus after transplantation (NODAT)] results in a remarkable proportion of SOT recipients and contributes to increased risk of CVD and infections, leading to significant mortality and morbidity. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells as well as reduced sensitivity to insulin. Consensus guidelines and proceedings from international consensus meeting on PTDM updated its recommendations in 2014, preferred to call it as PTDM rather than NODAT, as few patients could have undiagnosed diabetes prior to transplantation. New-onset diabetes mellitus after transplantation simply indicates exclusion of pretransplant diabetes and it is found that around 10% of KTRs have undetected diabetes prior to transplantation.1 Hence, PTDM represents timing of diagnosis in post-transplant period rather than time of occurrence of disease. The gold standard method to diagnose PTDM is the oral glucose tolerance test (OGTT). Post-transplant diabetes mellitus typically presents with postprandial hyperglycemia [impaired glucose tolerance (IGT)] rather than impaired fasting glucose (IFG). International consensus guidelines for PTDM recommend standard diagnostic criteria by American Diabetes Association (ADA) and World Health Organization (WHO) for the diagnosis of PTDM and these are almost same as to those used for type II diabetes mellitus (T2DM) in the general population with few exceptions (Table 1).2 Following transplantation, there is increased turnover of red blood cells due to perioperative blood loss and regain of renal function in case of kidney transplantation with normal erythropoietin production. The immunosuppressant drugs can have a negative effect on red cell proliferation in the bone marrow. Hence the glycated hemoglobin (HbA1c) can be erratic and accurate interpretation is not possible in the first 2–3 months, and is not a recommended test to identify PTDM in early post-transplant period. After 3 months post-transplant, HbA1c is reliable and ADA cut-off can be followed to diagnose PTDM. As per ADA guidelines, “prediabetes” is diagnosed with OGTT if fasting plasma glucose is 100–125 mg/dL (IFG) or 2-hour plasma glucose is 140–199 mg/dL (IGT). American Diabetes Association and WHO criteria differ with respect to normal ranges of fasting plasma glucose. American Diabetes Association criteria are more sensitive in detecting transplant candidates at risk for PTDM as its threshold value is lower.3 Impaired fasting glucose is diagnosed if fasting plasma glucose is ≥100 mg/dL by the ADA and ≥110 mg/dL by the WHO. Oral glucose tolerance test is more sensitive for detecting prediabetes as IGT is more commonly seen than IFG. The incidence of PTDM is higher in the first year, with a second peak after a few years following transplantation. Early peak is usually the result of metabolic adverse effects of immunosuppressive drugs, whereas late peak is due to post-transplant weight gain, obesity, metabolic syndrome, and insulin resistance. There is a great variability in the prevalence and incidence rates in the published literature. This is due to differences in the proposed diagnostic criteria, definitions used, organs transplanted, timing from transplantation, follow-up duration, population genetics, geographical differences, immunosuppressive drug regimens, and other risk factors. The prevalence of PTDM varied from 15 to 55% in the literature.4–8 It is identified that up to one-third of nondiabetic KTRs develop impaired glucose metabolism by 6 months following transplantation. Currently, the prevalence of PTDM appears to be reducing, mainly due to use of lower doses of immunosuppressive drugs targeting lower trough levels to prevent drug toxicity.9 Transient hyperglycemia is highly prevalent in the early post-transplant period; it can be identified in ~90% of KTRs in the first few weeks. It can result from use of higher doses of immunosuppressive drugs, antirejection therapy, stress, infections, sepsis, and other critical conditions. While detecting transient post-transplantation hyperglycemia is crucial as it is a predisposing factor for consequent PTDM, universally labeling all of them as PTDM in the early post-transplant setting is not acceptable. The diagnosis of PTDM should be delayed until the recipient is clinically stable, with stable allograft function, and is on lower doses of immunosuppression without acute infections. To avoid overdiagnosis, few authors proposed to define PTDM as a long-term (usually more than 3 months) need for antihyperglycemic therapy. The common predisposing factors for the occurrence of PTDM are side effects of immunosuppression and their effect on glucose metabolism, infections especially due to certain viruses, and hypomagnesemia, along with traditionally identified predisposing factors seen with T2DM (Table 2). Risk factors for PTDM should be analyzed during the pretransplant period to prevent or delay the development of PTDM. Some of these include older age, high-risk race or ethnic groups, obesity or metabolic syndrome, prediabetes prior to transplant, gestational diabetes, first degree relative with diabetes, nonalcoholic steatohepatitis, polycystic kidney disease, higher human leukocyte antigen (HLA)—mismatches, acute rejection episodes, cadaver donor, cytomegalovirus (CMV) and hepatitis C virus (HCV) infections, and use of immunosuppression.8 Induction with basiliximab may predispose patients to PTDM as concluded in a study from North India.10 Glucocorticoids induced PTDM seems to be dose-dependent. It is characterized mainly by insulin resistance and higher postprandial blood glucose levels. Although, it could be dose-dependent, there is no evidence that steroid withdrawal prevents or reduces PTDM incidence.11,12 Calcineurin inhibitors have toxic effect on islet cells of pancreas and alter insulin secretion pattern.13 Calcineurin inhibitors by causing hypomagnesemia, precipitate PTDM. Diabetes Incidence after Renal Transplantation: Neoral C Monitoring Versus Tacrolimus (DIRECT) study observed a greater risk of PTDM with tacrolimus than cyclosporine (CsA).14 In the Efficacy Limiting Toxicity Elimination (ELITE) study, low-dose tacrolimus (8.4%) was more diabetogenic at 1 year than standard-dose CsA (6%), low-dose CsA (4.2%), and low-dose sirolimus (6.6%).15 Various meta-analyses also concluded that tacrolimus is more diabetogenic than CsA.16,17 Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus can also induce PTDM. Conversion from one of the CNIs (either tacrolimus or CsA) to sirolimus resulted in worsening of glycemic control and insulin resistance as shown in a study.18 Antimetabolites such as mycophenolate mofetil (MMF) and azathioprine seem to be nondiabetogenic and may not contribute to the pathogenesis of PTDM. The combination immunosuppressive drug regimens were assessed in some s t u d i e s . O n e s t u d y f o u n d t h a t t h e combination of CNI and sirolimus has a greater risk of PTDM than the combination of CNI and MMF.19 Some other drugs such as renin-angiotensin-aldosterone system (RAAS) blockers [angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)], co-trimoxazole and statins may reduce the risk of PTDM.20,21 Hepatitis C virus infection was associated with almost fourfold higher risk of acquiring PTDM than those who were not infected in a meta-analysis among KTRs. 22 The pathogenesis of HCV-induced PTDM seems to be multifactorial including abnormal glucose metabolism, insulin resistance, and beta-cell dysfunction. Anti-HCV treatment and sustained virological remission in pretransplant period may prevent the development of PTDM. A large North Indian retrospective study compared long-term outcomes of HCV-infected and noninfected KTRs and concluded greater risk of PTDM in the HCV-infected group (~40 vs 19%). In the same study, anti-HCV therapy was given to all infected recipients before transplantation.23 Hepatitis C virus-associated PTDM is usually noticed in liver transplant recipients, especially in cases with hepatic steatosis. Association of PTDM with CMV infection is unclear. There was a fourfold greater risk of PTDM in patients with asymptomatic CMV infection in a study.24 Prediabetes before transplantation can predispose to PTDM. A percentage of 35% of KTRs with PTDM had pretransplant IGT in one study.25 Risk adaptive approach and tailoring of immunosuppression seems to be the fundamental concept to delay and prevent the occurrence of PTDM, especially in those with greater risk for PTDM. Transient hyperglycemia is widely prevalent in early post-transplant period; though it can predispose the recipient to PTDM, it should not be considered as an expression of PTDM. The contribution of transient hyperglycemia to the risk of PTDM was assessed in the past. Around 29% of recipients with postoperative transient hyperglycemia progressed to develop PTDM within 1 year, in a study.26 In another similar study, 46.7% of recipients with early transient hyperglycemia developed PTDM. There was a fourfold higher risk of PTDM in patients with transient hyperglycemia.27 Post-transplant diabetes mellitus, due to its predisposition to infections and CVD, adversely affects graft and overall patient survival. Cardiovascular disease is the most common cause of death and poor patient survival in SOT recipients, and PTDM has a correlation with CVD mortality.28 There is also an adverse effect of PTDM on graft survival independent from excessive mortality. Various factors implicate in death-censored graft loss due to PTDM. Some of these include development of de novo diabetic nephropathy in the renal allograft, excessive risk for infections such as pneumonia, urinary tract infection, and viral infections including CMV.29 Also it could be due to reduced immunosuppression for glycemic control resulting in excessive risk for graft rejection and ultimately graft loss. The treatment of PTDM should be multidisciplinary as it predisposes to various complications including CVD and it is usually associated with other post-transplant complications. The risk for PTDM needs to be assessed during pretransplant assessment by taking thorough history, physical examination, evaluating for metabolic syndrome and prediabetes, and assessing for any other associated cardiovascular risk factors. All SOT recipients should be closely monitored for glycemic control postoperatively while on immunosuppression. Generally, blood sugars are monitored at regular intervals such as every week for initial 4 weeks, then at 3 and 6 months, and annually thereafter. Glycated hemoglobin is not reliable in early post-transplant period, but can be advised 3 months after transplant. Stringent glycemic control is not advisable in majority of SOT recipients as they are at high risk for CVD. Hence, management should target at achieving fair control of blood sugars to near normal glycemic targets without increasing risk for hypoglycemia. Glycated hemoglobin target of <7.5% is acceptable in majority, especially in elderly and those who have CVD. Treatment includes both nonpharmacological and antidiabetic therapies. Diet, exercise, lifestyle modification, control of obesity, and weight reduction constitute main components of nonpharmacologic therapy. Along with PTDM, control of hypertension, dyslipidemia, and other cardiovascular risk factors is also crucial to reduce CVD risk. Kidney Disease: Improving Global Outcomes (KDIGO) and other guidelines suggest statin therapy to all cardiac and renal SOT recipients. For liver and lung transplant recipients, statin therapy should be individualized. The risk of rejection should be analyzed and must be weighted for the potential usefulness of modifying immunosuppression for glycemic control. The doses of glucocorticoids can be cut down, however complete withdrawal can precipitate rejection. Tacrolimus to CsA switching can be considered in patients with PTDM refractory to therapy despite reduction in doses of tacrolimus targeting lower trough levels. In one North-Indian randomized open-label prospective study involving KTRs, there was significant control of PTDM in CsA switching arm vs tacrolimus continuation arm.30 Another randomized controlled trial (RCT) in KTRs also showed easy reversal of PTDM at 12 months after switching from tacrolimus to CsA in comparison with continued treatment with tacrolimus.31 Switching to sirolimus in PTDM is not advisable as it may further aggravate glycemic control. Most patients in initial few months require insulin therapy with or without OHA (single drug or combination OHAs). The preferred therapy for initial few weeks following transplantation is insulin. Intensified therapy with basal insulin-containing regimen for initial few months showed to reduce the risk of development of PTDM at 12 months after transplantation probably due to beta-cell protection mediated by early insulin therapy.32 The concept of “beta-cell rest” was proposed which states that early insulin therapy preserves beta-cell function over the long term. The principle is that early insulin therapy prevents glucotoxicity and stimulation of vulnerable beta-cells whereas OHAs induce overstimulation of beta-cells causing their exhaustion. Oral hypoglycemic agents might be preferred after first 1–2 months of transplantation, and this sequence of therapy (insulin followed by oral agents) is the converse of what is recommended in the management of T2DM. Most of the SOT recipients requiring insulin might not need it after the early post-transplant period. Conversion to oral agents is usually successful when the daily need for insulin dose is less than 20 units. Among OHAs, biguanides (metformin), sulfonylureas, m e glitinides, gliptins [dipeptidyl peptidase-4 (DPP-4) inhibitors], and thiazolidinediones (pioglitazone) have been evaluated for treatment of PTDM in SOT recipients. These are found to be safe and effective with no significant interaction with the immunosuppressive drugs. These classes of OHAs are the preferred agents currently for the treatment of PTDM. Some of the oral drugs need renal dose modification as per glomerular filtration rate (GFR) level. A significant proportion of long-term SOT recipients who are on CNIs develop nephrotoxicity with a drop in GFR level from baseline. Metformin is an age-old drug for management of T2DM. It is considered as first-line drug, especially in patients with obesity and insulin resistance. It can precipitate lactic acidosis in high-risk subgroup of patients, especially in the presence of renal dysfunction. Majority of the reported cases of lactic acidosis have been identified in patients who were already on RAAS blockers (ACEI or ARB) in the presence of renal dysfunction. It can be initiated safely in patients with an estimated glomerular filtration rate (eGFR) up to 45 mL/min/1.73 m2 . It is not recommended to start metformin once eGFR is less than 45 mL/min/1.73 m2 and is currently contraindicated if eGFR of <30 mL/min/1.73 m2 , although data are emerging on its metabolic benefits even in patients with advanced CKD. Due to its safet y concerns, it is necessary to monitor renal function closely while on metformin therapy. It can also aggravate gastrointestinal (GI) side effects of immunosuppressive drugs. Gliclazide, glipizide, and glimepiride are preferred among sulfonylureas in patients with renal dysfunction. Meglitinides, such as repaglinide, due to their short duration of action, may be preferred over sulfonylureas in the presence of low GFR as the latter drugs are associated with significant risk of hypoglycemia. However, there are no strong data supporting the use of repaglinide or nateglinide among SOT recipients, as the studies performed were short-term. But they were considered safe and efficacious. Dipeptidyl peptidase-4 inhibitors or gliptins inhibit DPP-4 enzyme which is responsible for degradation of endogenous incretins leading to restoration of insulin secretion and inhibition of glucagon release. They are weight neutral (do not induce weight gain), have glucose-dependent action with lesser risk for hypoglycemia, and are considered to be safe along with immunosuppressive drugs due to least interactions. They may be considered as the potential first-line OHAs to manage PTDM. The studies performed on the available gliptins such as sitagliptin and vildagliptin are of small sample size with short-term follow-up, however, they documented their safety and efficacy in SOT recipients. In T2DM, long-term safety data are available for sitagliptin but not for vildagliptin.33 Vildagliptin was considered as safe and effective in KTRs as concluded in a double-blind RCT.34 There is some drug interaction between sitagliptin and CNIs especially CsA with regard to prolongation of QT interval in the combination group. Linagliptin was found to be safe and effective for PTDM management as concluded in one Indian study. As it is nonrenally eliminated, it does not require dose adjustment in renal failure.35 Thiazolidinediones are considered as the last resort of therapy in SOT recipients with PTDM due to their side effect profile as these patients generally suffer from multiple comorbidities. These drugs can worsen post-transplant mineral bone disease and bone loss, precipitate congestive heart failure, and lead to anemia, fluid overload, and weight gain. Drug interaction with CNIs is observed as they predispose to CNI toxicity. Alpha-glucosidase inhibitors such as acarbose and miglitol are not recommended if eGFR is <30 mL/min/1.73 m2 and they can aggravate GI side effects of MMF. Incretin mimetics [glucagon-like peptide 1 (GLP1) receptor agonists] such as exenatide, liraglutide, lixisenatide, and semaglutide, have not been evaluated for their safety in SOT recipients except for a few small studies. Physicians should be cautious against using GLP1 receptor agonists due to risk of GI tract side effects and precipitation of prerenal acute kidney injury in SOT recipients having GFR <30 mL/min/1.73 m2 . Recent clinical trials with GLP1 receptor agonists in nontransplant population showed their potential benefit on adverse cardiovascular as well as renal outcomes in high-risk CVD patients; the data in SOT recipients are still awaited. The data are emerging for the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in SOT recipients with PTDM. Important drugs include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. They have been evaluated in large clinical trials in nontransplant population and found to significantly reduce the risk of major adverse cardiovascular and renal outcomes. They are now considered as first choice therapies for both cardiovascular and renal protection in patients with heart failure with reduced ejection fraction, diabetic kidney disease, and proteinuric nondiabetic kidney diseases, and this benefit was observed irrespective of presence of diabetes. Their efficacy and safety in patients with kidney and other SOT recipients are not known as these patients were excluded from large clinical trials. The only concern with these drugs is increased predisposition to genital, fungal and lower urinary tract infections, and this could be life-threatening in immunosuppressed SOT recipients. The antihyperglycemic effect of these drugs diminishes once GFR is <60 mL/min/1.73 m2 and is practically nil at GFR <30 mL/min/1.73 m2 . In an RCT that included KTRs with PTDM who were randomized to either SGLT2 inhibitor or placebo found that empagliflozin is safe and efficacious for treatment of PTDM, and moderate weight loss was also observed in the treatment arm.36 A pilot study from India also concluded that canagliflozin use resulted in better glycemic control with lower HbA1c level, body weight, and blood pressure reduction. The requirement of other OHAs was also reduced, with no adverse effects including hypoglycemia in the treatment arm.37 There is an immense need for a large-scale intervention trials in SOT recipients with PTDM with these newer hypoglycemic agents, that is, GLP1 receptor agonists and SGLT2 inhibitors that have been proved to have pleiotropic benefits and lower major adverse cardiovascular and renal events in high-risk patients with T2DM.
Post-transplant diabetes mellitus (PTDM) is a common problem among solid organ transplant recipients contributing to morbidity and affecting patient as well as graft survival adversely. It can occur at any period following transplantation, but maximum incidence is observed in the first few months, with a second peak after a few years after transplantation. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells and insulin resistance. Both nonpharmacologic and antidiabetic therapies are important for adequate glycemic control. This point of view article provides a short review on PTDM in solid organ transplantation (SOT) recipients from a general physician’s perspective. Solid organ transplantation is currently the best choice of treatment for most patients suffering from end-stage organ failure. Successful organ transplantation offers enhanced quality and duration of life with lower morbidity and mortality. Innovations in SOT, advances in surgical techniques, progress in immunosuppressive regimens, and critical care have greatly improved both the patient and graft survival in last several decades. The discovery of calcineurin inhibitors (CNIs) represents a milestone event in the history of immunosuppression and it has revolutionized transplant medicine; further breakthrough in immunosuppressive regimens is the cornerstone for existing successful transplant program. The current 5-year graft survival is about 80% for kidney and heart transplants, and 70% for liver and lung transplants (UNOS-OPTN and SRTR registry data). Cardiovascular disease (CVD), infections, and drug toxicity play an important role in the long-term morbidity and mortality of this patient population. This risk is not only due to presence of underlying pre-existing comorbidities, but also results from adverse effects of the immunosuppressive drugs such as hypertension, dyslipidemia, and PTDM. The risk of PTDM after SOT varies from 10 to 40% during the first 1 year. This risk depends on several factors including the type of transplanted organ [10–20% of kidney transplant recipients (KTRs) and 20–40% of patients with heart, liver, and lung transplants]. Post-transplant diabetes mellitus is widely studied in KTRs, but the risk factors and pathophysiology seem to be similar in all kinds of SOT. Post-transplant diabetes mellitus [previously termed, new-onset diabetes mellitus after transplantation (NODAT)] results in a remarkable proportion of SOT recipients and contributes to increased risk of CVD and infections, leading to significant mortality and morbidity. The pathogenesis is complex and poorly understood, however, it is associated with both dysfunctional beta-cells as well as reduced sensitivity to insulin. Consensus guidelines and proceedings from international consensus meeting on PTDM updated its recommendations in 2014, preferred to call it as PTDM rather than NODAT, as few patients could have undiagnosed diabetes prior to transplantation. New-onset diabetes mellitus after transplantation simply indicates exclusion of pretransplant diabetes and it is found that around 10% of KTRs have undetected diabetes prior to transplantation.1 Hence, PTDM represents timing of diagnosis in post-transplant period rather than time of occurrence of disease. The gold standard method to diagnose PTDM is the oral glucose tolerance test (OGTT). Post-transplant diabetes mellitus typically presents with postprandial hyperglycemia [impaired glucose tolerance (IGT)] rather than impaired fasting glucose (IFG). International consensus guidelines for PTDM recommend standard diagnostic criteria by American Diabetes Association (ADA) and World Health Organization (WHO) for the diagnosis of PTDM and these are almost same as to those used for type II diabetes mellitus (T2DM) in the general population with few exceptions (Table 1).2 Following transplantation, there is increased turnover of red blood cells due to perioperative blood loss and regain of renal function in case of kidney transplantation with normal erythropoietin production. The immunosuppressant drugs can have a negative effect on red cell proliferation in the bone marrow. Hence the glycated hemoglobin (HbA1c) can be erratic and accurate interpretation is not possible in the first 2–3 months, and is not a recommended test to identify PTDM in early post-transplant period. After 3 months post-transplant, HbA1c is reliable and ADA cut-off can be followed to diagnose PTDM. As per ADA guidelines, “prediabetes” is diagnosed with OGTT if fasting plasma glucose is 100–125 mg/dL (IFG) or 2-hour plasma glucose is 140–199 mg/dL (IGT). American Diabetes Association and WHO criteria differ with respect to normal ranges of fasting plasma glucose. American Diabetes Association criteria are more sensitive in detecting transplant candidates at risk for PTDM as its threshold value is lower.3 Impaired fasting glucose is diagnosed if fasting plasma glucose is ≥100 mg/dL by the ADA and ≥110 mg/dL by the WHO. Oral glucose tolerance test is more sensitive for detecting prediabetes as IGT is more commonly seen than IFG. The incidence of PTDM is higher in the first year, with a second peak after a few years following transplantation. Early peak is usually the result of metabolic adverse effects of immunosuppressive drugs, whereas late peak is due to post-transplant weight gain, obesity, metabolic syndrome, and insulin resistance. There is a great variability in the prevalence and incidence rates in the published literature. This is due to differences in the proposed diagnostic criteria, definitions used, organs transplanted, timing from transplantation, follow-up duration, population genetics, geographical differences, immunosuppressive drug regimens, and other risk factors. The prevalence of PTDM varied from 15 to 55% in the literature.4–8 It is identified that up to one-third of nondiabetic KTRs develop impaired glucose metabolism by 6 months following transplantation. Currently, the prevalence of PTDM appears to be reducing, mainly due to use of lower doses of immunosuppressive drugs targeting lower trough levels to prevent drug toxicity.9 Transient hyperglycemia is highly prevalent in the early post-transplant period; it can be identified in ~90% of KTRs in the first few weeks. It can result from use of higher doses of immunosuppressive drugs, antirejection therapy, stress, infections, sepsis, and other critical conditions. While detecting transient post-transplantation hyperglycemia is crucial as it is a predisposing factor for consequent PTDM, universally labeling all of them as PTDM in the early post-transplant setting is not acceptable. The diagnosis of PTDM should be delayed until the recipient is clinically stable, with stable allograft function, and is on lower doses of immunosuppression without acute infections. To avoid overdiagnosis, few authors proposed to define PTDM as a long-term (usually more than 3 months) need for antihyperglycemic therapy. The common predisposing factors for the occurrence of PTDM are side effects of immunosuppression and their effect on glucose metabolism, infections especially due to certain viruses, and hypomagnesemia, along with traditionally identified predisposing factors seen with T2DM (Table 2). Risk factors for PTDM should be analyzed during the pretransplant period to prevent or delay the development of PTDM. Some of these include older age, high-risk race or ethnic groups, obesity or metabolic syndrome, prediabetes prior to transplant, gestational diabetes, first degree relative with diabetes, nonalcoholic steatohepatitis, polycystic kidney disease, higher human leukocyte antigen (HLA)—mismatches, acute rejection episodes, cadaver donor, cytomegalovirus (CMV) and hepatitis C virus (HCV) infections, and use of immunosuppression.8 Induction with basiliximab may predispose patients to PTDM as concluded in a study from North India.10 Glucocorticoids induced PTDM seems to be dose-dependent. It is characterized mainly by insulin resistance and higher postprandial blood glucose levels. Although, it could be dose-dependent, there is no evidence that steroid withdrawal prevents or reduces PTDM incidence.11,12 Calcineurin inhibitors have toxic effect on islet cells of pancreas and alter insulin secretion pattern.13 Calcineurin inhibitors by causing hypomagnesemia, precipitate PTDM. Diabetes Incidence after Renal Transplantation: Neoral C Monitoring Versus Tacrolimus (DIRECT) study observed a greater risk of PTDM with tacrolimus than cyclosporine (CsA).14 In the Efficacy Limiting Toxicity Elimination (ELITE) study, low-dose tacrolimus (8.4%) was more diabetogenic at 1 year than standard-dose CsA (6%), low-dose CsA (4.2%), and low-dose sirolimus (6.6%).15 Various meta-analyses also concluded that tacrolimus is more diabetogenic than CsA.16,17 Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus can also induce PTDM. Conversion from one of the CNIs (either tacrolimus or CsA) to sirolimus resulted in worsening of glycemic control and insulin resistance as shown in a study.18 Antimetabolites such as mycophenolate mofetil (MMF) and azathioprine seem to be nondiabetogenic and may not contribute to the pathogenesis of PTDM. The combination immunosuppressive drug regimens were assessed in some s t u d i e s . O n e s t u d y f o u n d t h a t t h e combination of CNI and sirolimus has a greater risk of PTDM than the combination of CNI and MMF.19 Some other drugs such as renin-angiotensin-aldosterone system (RAAS) blockers [angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)], co-trimoxazole and statins may reduce the risk of PTDM.20,21 Hepatitis C virus infection was associated with almost fourfold higher risk of acquiring PTDM than those who were not infected in a meta-analysis among KTRs. 22 The pathogenesis of HCV-induced PTDM seems to be multifactorial including abnormal glucose metabolism, insulin resistance, and beta-cell dysfunction. Anti-HCV treatment and sustained virological remission in pretransplant period may prevent the development of PTDM. A large North Indian retrospective study compared long-term outcomes of HCV-infected and noninfected KTRs and concluded greater risk of PTDM in the HCV-infected group (~40 vs 19%). In the same study, anti-HCV therapy was given to all infected recipients before transplantation.23 Hepatitis C virus-associated PTDM is usually noticed in liver transplant recipients, especially in cases with hepatic steatosis. Association of PTDM with CMV infection is unclear. There was a fourfold greater risk of PTDM in patients with asymptomatic CMV infection in a study.24 Prediabetes before transplantation can predispose to PTDM. A percentage of 35% of KTRs with PTDM had pretransplant IGT in one study.25 Risk adaptive approach and tailoring of immunosuppression seems to be the fundamental concept to delay and prevent the occurrence of PTDM, especially in those with greater risk for PTDM. Transient hyperglycemia is widely prevalent in early post-transplant period; though it can predispose the recipient to PTDM, it should not be considered as an expression of PTDM. The contribution of transient hyperglycemia to the risk of PTDM was assessed in the past. Around 29% of recipients with postoperative transient hyperglycemia progressed to develop PTDM within 1 year, in a study.26 In another similar study, 46.7% of recipients with early transient hyperglycemia developed PTDM. There was a fourfold higher risk of PTDM in patients with transient hyperglycemia.27 Post-transplant diabetes mellitus, due to its predisposition to infections and CVD, adversely affects graft and overall patient survival. Cardiovascular disease is the most common cause of death and poor patient survival in SOT recipients, and PTDM has a correlation with CVD mortality.28 There is also an adverse effect of PTDM on graft survival independent from excessive mortality. Various factors implicate in death-censored graft loss due to PTDM. Some of these include development of de novo diabetic nephropathy in the renal allograft, excessive risk for infections such as pneumonia, urinary tract infection, and viral infections including CMV.29 Also it could be due to reduced immunosuppression for glycemic control resulting in excessive risk for graft rejection and ultimately graft loss. The treatment of PTDM should be multidisciplinary as it predisposes to various complications including CVD and it is usually associated with other post-transplant complications. The risk for PTDM needs to be assessed during pretransplant assessment by taking thorough history, physical examination, evaluating for metabolic syndrome and prediabetes, and assessing for any other associated cardiovascular risk factors. All SOT recipients should be closely monitored for glycemic control postoperatively while on immunosuppression. Generally, blood sugars are monitored at regular intervals such as every week for initial 4 weeks, then at 3 and 6 months, and annually thereafter. Glycated hemoglobin is not reliable in early post-transplant period, but can be advised 3 months after transplant. Stringent glycemic control is not advisable in majority of SOT recipients as they are at high risk for CVD. Hence, management should target at achieving fair control of blood sugars to near normal glycemic targets without increasing risk for hypoglycemia. Glycated hemoglobin target of <7.5% is acceptable in majority, especially in elderly and those who have CVD. Treatment includes both nonpharmacological and antidiabetic therapies. Diet, exercise, lifestyle modification, control of obesity, and weight reduction constitute main components of nonpharmacologic therapy. Along with PTDM, control of hypertension, dyslipidemia, and other cardiovascular risk factors is also crucial to reduce CVD risk. Kidney Disease: Improving Global Outcomes (KDIGO) and other guidelines suggest statin therapy to all cardiac and renal SOT recipients. For liver and lung transplant recipients, statin therapy should be individualized. The risk of rejection should be analyzed and must be weighted for the potential usefulness of modifying immunosuppression for glycemic control. The doses of glucocorticoids can be cut down, however complete withdrawal can precipitate rejection. Tacrolimus to CsA switching can be considered in patients with PTDM refractory to therapy despite reduction in doses of tacrolimus targeting lower trough levels. In one North-Indian randomized open-label prospective study involving KTRs, there was significant control of PTDM in CsA switching arm vs tacrolimus continuation arm.30 Another randomized controlled trial (RCT) in KTRs also showed easy reversal of PTDM at 12 months after switching from tacrolimus to CsA in comparison with continued treatment with tacrolimus.31 Switching to sirolimus in PTDM is not advisable as it may further aggravate glycemic control. Most patients in initial few months require insulin therapy with or without OHA (single drug or combination OHAs). The preferred therapy for initial few weeks following transplantation is insulin. Intensified therapy with basal insulin-containing regimen for initial few months showed to reduce the risk of development of PTDM at 12 months after transplantation probably due to beta-cell protection mediated by early insulin therapy.32 The concept of “beta-cell rest” was proposed which states that early insulin therapy preserves beta-cell function over the long term. The principle is that early insulin therapy prevents glucotoxicity and stimulation of vulnerable beta-cells whereas OHAs induce overstimulation of beta-cells causing their exhaustion. Oral hypoglycemic agents might be preferred after first 1–2 months of transplantation, and this sequence of therapy (insulin followed by oral agents) is the converse of what is recommended in the management of T2DM. Most of the SOT recipients requiring insulin might not need it after the early post-transplant period. Conversion to oral agents is usually successful when the daily need for insulin dose is less than 20 units. Among OHAs, biguanides (metformin), sulfonylureas, m e glitinides, gliptins [dipeptidyl peptidase-4 (DPP-4) inhibitors], and thiazolidinediones (pioglitazone) have been evaluated for treatment of PTDM in SOT recipients. These are found to be safe and effective with no significant interaction with the immunosuppressive drugs. These classes of OHAs are the preferred agents currently for the treatment of PTDM. Some of the oral drugs need renal dose modification as per glomerular filtration rate (GFR) level. A significant proportion of long-term SOT recipients who are on CNIs develop nephrotoxicity with a drop in GFR level from baseline. Metformin is an age-old drug for management of T2DM. It is considered as first-line drug, especially in patients with obesity and insulin resistance. It can precipitate lactic acidosis in high-risk subgroup of patients, especially in the presence of renal dysfunction. Majority of the reported cases of lactic acidosis have been identified in patients who were already on RAAS blockers (ACEI or ARB) in the presence of renal dysfunction. It can be initiated safely in patients with an estimated glomerular filtration rate (eGFR) up to 45 mL/min/1.73 m2 . It is not recommended to start metformin once eGFR is less than 45 mL/min/1.73 m2 and is currently contraindicated if eGFR of <30 mL/min/1.73 m2 , although data are emerging on its metabolic benefits even in patients with advanced CKD. Due to its safet y concerns, it is necessary to monitor renal function closely while on metformin therapy. It can also aggravate gastrointestinal (GI) side effects of immunosuppressive drugs. Gliclazide, glipizide, and glimepiride are preferred among sulfonylureas in patients with renal dysfunction. Meglitinides, such as repaglinide, due to their short duration of action, may be preferred over sulfonylureas in the presence of low GFR as the latter drugs are associated with significant risk of hypoglycemia. However, there are no strong data supporting the use of repaglinide or nateglinide among SOT recipients, as the studies performed were short-term. But they were considered safe and efficacious. Dipeptidyl peptidase-4 inhibitors or gliptins inhibit DPP-4 enzyme which is responsible for degradation of endogenous incretins leading to restoration of insulin secretion and inhibition of glucagon release. They are weight neutral (do not induce weight gain), have glucose-dependent action with lesser risk for hypoglycemia, and are considered to be safe along with immunosuppressive drugs due to least interactions. They may be considered as the potential first-line OHAs to manage PTDM. The studies performed on the available gliptins such as sitagliptin and vildagliptin are of small sample size with short-term follow-up, however, they documented their safety and efficacy in SOT recipients. In T2DM, long-term safety data are available for sitagliptin but not for vildagliptin.33 Vildagliptin was considered as safe and effective in KTRs as concluded in a double-blind RCT.34 There is some drug interaction between sitagliptin and CNIs especially CsA with regard to prolongation of QT interval in the combination group. Linagliptin was found to be safe and effective for PTDM management as concluded in one Indian study. As it is nonrenally eliminated, it does not require dose adjustment in renal failure.35 Thiazolidinediones are considered as the last resort of therapy in SOT recipients with PTDM due to their side effect profile as these patients generally suffer from multiple comorbidities. These drugs can worsen post-transplant mineral bone disease and bone loss, precipitate congestive heart failure, and lead to anemia, fluid overload, and weight gain. Drug interaction with CNIs is observed as they predispose to CNI toxicity. Alpha-glucosidase inhibitors such as acarbose and miglitol are not recommended if eGFR is <30 mL/min/1.73 m2 and they can aggravate GI side effects of MMF. Incretin mimetics [glucagon-like peptide 1 (GLP1) receptor agonists] such as exenatide, liraglutide, lixisenatide, and semaglutide, have not been evaluated for their safety in SOT recipients except for a few small studies. Physicians should be cautious against using GLP1 receptor agonists due to risk of GI tract side effects and precipitation of prerenal acute kidney injury in SOT recipients having GFR <30 mL/min/1.73 m2 . Recent clinical trials with GLP1 receptor agonists in nontransplant population showed their potential benefit on adverse cardiovascular as well as renal outcomes in high-risk CVD patients; the data in SOT recipients are still awaited. The data are emerging for the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in SOT recipients with PTDM. Important drugs include canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. They have been evaluated in large clinical trials in nontransplant population and found to significantly reduce the risk of major adverse cardiovascular and renal outcomes. They are now considered as first choice therapies for both cardiovascular and renal protection in patients with heart failure with reduced ejection fraction, diabetic kidney disease, and proteinuric nondiabetic kidney diseases, and this benefit was observed irrespective of presence of diabetes. Their efficacy and safety in patients with kidney and other SOT recipients are not known as these patients were excluded from large clinical trials. The only concern with these drugs is increased predisposition to genital, fungal and lower urinary tract infections, and this could be life-threatening in immunosuppressed SOT recipients. The antihyperglycemic effect of these drugs diminishes once GFR is <60 mL/min/1.73 m2 and is practically nil at GFR <30 mL/min/1.73 m2 . In an RCT that included KTRs with PTDM who were randomized to either SGLT2 inhibitor or placebo found that empagliflozin is safe and efficacious for treatment of PTDM, and moderate weight loss was also observed in the treatment arm.36 A pilot study from India also concluded that canagliflozin use resulted in better glycemic control with lower HbA1c level, body weight, and blood pressure reduction. The requirement of other OHAs was also reduced, with no adverse effects including hypoglycemia in the treatment arm.37 There is an immense need for a large-scale intervention trials in SOT recipients with PTDM with these newer hypoglycemic agents, that is, GLP1 receptor agonists and SGLT2 inhibitors that have been proved to have pleiotropic benefits and lower major adverse cardiovascular and renal events in high-risk patients with T2DM.
Risk Factors for Development of Early Onset Post-Transplant Diabetes Mellitus (PTDM) – A Prospective Study from a Tertiary Care Centre in India
Introduction: Kidney transplantation is the best form of kidney replacement therapy. Posttransplant diabetes mellitus (PTDM) is an important complication seen in transplant recipients. The present study was done to identify the incidence and risk factors for the development of early-onset PTDM at a tertiary care center in India. Materials and Methods: This was a prospective study carried out from May 1, 2016, to April 30, 2017, at a tertiary care center and included all the adult first transplant recipients. The patients were followed up for six months after transplantation and the incidence of early PTDM was noted. The patients were divided into two groups, namely, PTDM and non-PTDM groups to identify risk factors for PTDM and to compare the outcome between the two groups. Results: This study included 66 patients. Patients developing PTDM had higher age (44.07 ± 9.69 years vs. 35.98 ± 11.17 years; P = 0.013), significantly higher prevalence of family history of diabetes (57.14% vs. 15.38%; P = 0.001), higher pretransplant fasting plasma blood glucose (93.86 ± 8.59 mg/dL vs. 86.21 ± 7.53 mg/dL; P = 0.007), and higher pretransplant glycated hemoglobin (HbA1c) level (5.2% ± 0.39% vs. 4.9% ± 0.52%; P = 0.006). We did not find any association of PTDM with obesity, gender, type of induction therapy, hepatitis C infection, cytomegalovirus infection, and mean trough tacrolimus levels. Conclusions: In our study, patients who developed PTDM were of higher age, with increased levels of fasting blood sugar and HbA1c pretransplant, had a family history of diabetes, and were likely to have received antirejection therapy.
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