Objectives: The appearance of new onset diabetes is common after kidney transplant. Treatment options are limited because of renal function-related contraindications, interactions with immunosuppressive drugs, and side effects. We investigated the long-term safety and efficacy of dipeptidyl peptidase IV inhibitors in renal transplant recipients with new onset diabetes.
Materials and Methods: We treated 12 patients with dipeptidyl peptidase IV inhibitors, and 5 patients received insulin monotherapy as initial treatment of new onset diabetes after kidney transplant. All patients were followed for 12 months after diagnosis. Glycosylated hemoglobin A1c, estimated glomerular filtration rate (Chronic Kidney Disease Epidemiology Collaboration equation), plasma immunosuppressive trough levels, serum lipids, blood pressure, and body weight were measured during outpatient visits. Effects of dipeptidyl peptidase IV inhibitors and insulin on the aforementioned parameters were measured to compare values at time of diagnosis versus mean values of the last 6 months of follow-up.
Results: Patients were treated with linagliptin (4 patients), sitagliptin (4 patients), vildagliptin (2 patients), and alogliptin (2 patients). Patients had a mean age of 59.4 ± 12 years and a mean glycosylated hemoglobin A1c of 6.6% at diagnosis, which was decreased to 6.1% (P = .03) at 1 year of follow-up. Renal function remained stable, and plasma tacrolimus levels did not appear to be affected. No significant differences were shown in serum total, low-density lipoprotein, and high-density lipoprotein cholesterol levels after treatment. Nevertheless, triglyceride levels were significantly reduced (from 214.4 to 174.9 mg/dL; P = .0039). A decrease in body weight was also observed. Finally, patients treated with dipeptidyl peptidase V inhibitors achieved better glycosylated hemoglobin A1c levels than those treated with insulin.
Conclusions: Dipeptidyl peptidase IV inhibitors appear to be a safe, effective, and hypoglycemia-free option for treatment of new onset diabetes in renal transplant recipients and possibly provide better diabetes control than insulin therapy.
Key words : Linagliptin, Sitagliptin, Tacrolimus
Kidney transplant has become the treatment of choice for end-stage renal disease.1 With modern advances in surgical techniques and immunosuppression, life expectancy after kidney transplant has increased, whereas control of consequent chronic metabolic complications, such as dyslipidemia or diabetes mellitus, has emerged as an important medical issue.1,2 Especially, new onset diabetes after transplant (NODAT) is a serious and common complication in solid-organ transplantation. Prevalence of NODAT in kidney transplant recipients ranges from 4% to 25%, with NODAT associated with inferior outcomes, including lower rates of graft survival (graft rejection and loss), higher incidence of infections, and higher risk of cardiovascular disease.3,4
Multiple risk factors are associated with the development of NODAT and are classified into 3 categories: (1) nonmodifiable risk factors such as age >40 years,5 family history of diabetes,6 male recipient, male donor, deceased donor, polycystic kidney disease,7 HLA antigen mismatches; HLA antigen A30, B27, and B42; and ethnicity (African American, Hispanic)8; (2) modifiable risk factors such as immunosuppressive therapy (mainly corticosteroids and tacrolimus but also everolimus, sirolimus, and cyclosporine),9,10 obesity, or other components of the metabolic syndrome11; and (3) potentially modifiable risk factors such as infection (cytomegalovirus and hepatitis C),12,13 pretransplant impaired fasting glucose or impaired glucose tolerance, and hypomagnesemia.
Diagnostic criteria of NODAT are identical to the criteria for diabetes mellitus, as follows: (1) symptoms of diabetes and random plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L), or (2) fasting plasma glucose greater than or equal to 126 mg/dL (7.0 mmol/L) on 2 separate days, or (3) 2-hour plasma glucose greater than or equal to 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test,14 which is the gold standard for NODAT diagnosis, especially in the early stages of transplant. The diagnosis of NODAT based on hemoglobin A1c (HbA1c) levels is not accurate in the first 3 months after transplant because red blood cell survival is reduced.15 Beyond 3 months, the American Diabetes Association and the European Association for the Study of Diabetes recommend a HbA1c target of less than 7% in most patients to reduce the incidence of microvascular disease.16
Current therapeutic strategies against NODAT are based on treatment guidelines for type 2 diabetes. Although type 2 diabetes is considered a problem of increased insulin resistance, recent data have demonstrated that impaired insulin secretion rather than impaired insulin sensitivity may be the principal pathophysiological defect in kidney transplant recipients.17,18 Thus, antidiabetic drugs that protect or improve pancreatic beta cell function may be optimal in NODAT treatment.19 Although metformin remains the initial choice in the treatment of type 2 diabetes because of its potential pleiotropic effects and safety profile, its use in patients with impaired renal function is prohibited because of the increased risk of lactic acidosis.20 Thiazolidinediones could be an interesting alternative, but these have side effects such as weight gain, increased risk for congestive heart failure, and osteoporosis.21 Sulfonylureas, despite the ability to enhance insulin secretion, do not prevent or delay the loss of islet cells and increase the rate of hypoglycemia.22
Dipeptidyl peptidase 4 inhibitors (DPP4i) are selective inhibitors of DPP4, which is an enzyme that regulates degradation of the 2 major incretins, glucagon-like peptide 1 and glucose inhibitory peptide. Dipeptidyl peptidase 4 inhibitors are effective antidiabetic drugs, without the risk of weight gain or hypoglycemia.23 Increasing evidence has demonstrated that DPP4i exert potential pleiotropic effects including anti-inflammatory, antihypertensive, antiapoptotic, and immunomodulatory effects on the heart, vessels, and kidney, independent of the hypoglycemic effects.24 Five DPP4i have been approved for clinical use, ie, sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin.
The primary aim of this study was to investigate the safety and efficacy of DDP4i monotherapy in patients with NODAT after kidney transplant, and the secondary aim was to compare their effectiveness versus standard insulin treatment.
Materials and Methods
In this retrospective study, we included 12 patients treated with DPP4i and 5 patients who received insulin therapy as initial treatment after diagnosis with NODAT from a pool of 187 patients with kidney transplant who were being followed in our outpatient clinic. Inclusion criteria were age >18 years, a history of kidney transplant, diagnosis of NODAT according to the standard criteria as mentioned previously, and no history of previous antidiabetic treatment. Exclusion criteria were diagnosis of diabetes before transplant and loss of follow-up within 12 months after initiation of treatment. The criteria for initiation of either an insulin-based regimen or DPP4i were completely based on the available treatment options and the physician’s preference at the time of initiation, ie, patients who received a kidney transplant during the recent decade and developed NODAT were treated with DPP4i, whereas recipients of earlier transplanted kidneys were treated with insulin. None of the patients between groups was a duplicate, ie, received an insulin-based regimen at first and then changed treatment to DPP4i or an alternate treatment.
All patients included in the study provided written informed consent for use of their historical clinical data, and this protocol was approved by the local ethics committee on human research and is in accordance with the Helsinki Declaration as revised in 2000. All patients were followed for at least 1 year after diagnosis by measurement of fasting blood glucose (FBG) levels, HbA1c, renal function (estimated glomerular filtration rate [eGFR] was calculated using the Chronic Kidney Disease Epidemiology Collaboration formula), plasma trough levels of immunosuppressive drugs, lipids, and body weight. Details of clinical and demographic information such as age, sex, body mass index (BMI, calculated as weight in kilograms divided by height in meters squared), family history of diabetes, cause of end-stage renal disease, and concomitant medication were also collected and are presented in Table 1.
Continuous variables are presented as mean values with SD and range of values as appropriate. The Kolmogorov-Smirnov test was used for normality analysis of the quantitative variables. Comparisons of changes were made between the values at NODAT diagnosis before DPP4i treatment initiation and the mean value of each examined parameter of the last 6 months of the 12-month posttreatment period. These comparisons were performed with the paired t test or the Wilcoxon matched-pairs signed rank test in case of violation of normality between patients in the same treatment group and with the simple t test or the Mann-Whitney test between patients in different treatment groups. Statistical analyses were performed with GraphPad software (version 5.03).
Overall, 12 patients (11 men) with a mean age of 59.4 ± 12 years at NODAT diagnosis who received DPP4i and 5 patients (4 men) with a mean age of 53.6 ± 10.1 years who received insulin as first treatments for NODAT were included in the study. All included patients received a deceased donor kidney transplant performed by the same surgical team at the same transplant center. The DPP4i were prescribed as follows: linagliptin in 4 patients, sitagliptin in 4 patients, vildagliptin in 2 patients, and alogliptin in 2 patients. Insulin-based treatment regimens for each patient are presented in Table 2. Nine of 12 patients who received DPP4i and 3 of 5 who received insulin were treated with tacrolimus-based immunosuppression.
Safety of treatment
Renal function remained stable after the initiation of treatment with DPP4i (mean serum creatinine from 1.39 ± 0.36 to 1.34 ± 0.45 mg/dL [P = .48, not significant] and eGFR from 58.83 ± 16.9 to 61.73 ± 19.9 mL/min/1.73 m2 [P = .14, not significant]) (Figure 1). Plasma tacrolimus trough levels were not affected after DPP4i initiation (from 6.2 ± 1.37 to 5.5 ± 1.13 ng/mL; P = .07, not significant). The mean dose of tacrolimus at 1 year after initiation of DPP4i treatment was slightly lower than baseline (from 2.9 ± 1.4 to 2.6 ± 0.97 mg/24 h; P = .54, not significant). The insignificant decrease in tacrolimus trough levels could be attributed to the reduction of tacrolimus dose, consistent with per protocol immunosuppression reduction during follow-up (Figure 2).
Efficacy of treatment
The mean FBG level at the time of diabetes onset was 114.5 ± 25.4 mg/dL, whereas 1 year after the initiation of DPP4i treatment the mean FBG level was 111.1 ± 14.7 mg/dL (P = .77, not significant). The mean HbA1c value at the time of diagnosis was 6.6 ± 0.7%, whereas 1 year after treatment with DPP4i the mean value had decreased to 6.1 ± 0.7% (P = .03) (Figure 3).
Effect of treatment on lipids profile, weight, and blood pressure
No significant differences in total, low-density lipoprotein, and high-density lipoprotein cholesterol levels were observed after initiation of treatment. Nevertheless, triglyceride levels decreased significantly (from 214.4 ± 83 to 174.9 ± 75 mg/dL; P = .0039) (Figure 4). Statistically nonsignificant weight loss was observed in 8 of the 12 patients who received DPP4i (from 79.9 ± 12.3 to 77.9 ± 12.7 kg; P = .37, not significant) (Figure 5). Blood pressure, both systolic and diastolic, was not significantly altered during the posttreatment period compared with pretreatment values in patients who received DPP4i (systolic blood pressure, from 132.5 ± 18.8 to 132.9 ± 14.8 mm Hg [P = .76, not significant]; diastolic blood pressure, from 78.8 ± 9.9 to 79.6 ± 6.6 mm Hg [P = .25, not significant]) (Figure 6).
Comparison of dipeptidyl peptidase 4 inhibitors versus standard insulin-based treatment
There were no differences in basic clinical characteristics, comorbidities, risk factors, and immunosuppression regimen between patients who received insulin and those who received DPP4i (Table 1). Patients treated with DPP4i achieved lower HbA1c levels than patients treated with insulin (6.1 ± 0.65% vs 7.1 ± 0.2%, respectively; P = .01). The reduction in HbA1c was greater in patients treated with DPP4i (?HbA1c, -0.5 ± 0.6% vs -0.03 ± 0.85%, respectively; P = .22, not significant) (Figure 7).
No side effects, including hypoglycemia or acute rejection episodes, were reported during the follow-up period of more than 12 months, and no patient discontinued the prescribed DPP4i treatment. None of the study participants reported symptoms that could be attributed to DPP4i, including nausea.
For those patients who were treated with an insulin-based regimen, although we could not retrieve any historical data on daily blood glucose home measurements, we were able to assess all medical records (from physician notes to serum biochemistry) at every scheduled and unscheduled follow-up visit. These records indicated that only 1 patient (patient 5 as shown in Table 2) experienced hypoglycemic episodes during the night, and her regimen was changed appropriately.
The main findings of our study highlight the safety and effectiveness of DPP4i in the treatment of NODAT in kidney transplant recipients. Kidney function (as expressed with eGFR) and immunosuppression trough levels were not affected by DPP4i, and adequate control of diabetes was achieved. Moreover, DPP4i were able to provide better control of diabetes than insulin therapy, possibly because of better compliance.
Hyperglycemia is associated with adverse long-term outcomes in renal allograft recipients with diabetes, and glycemic control is an important factor to prevent graft loss.25,26 Recent data have demonstrated that impaired insulin secretion, rather than increased insulin resistance, is a key factor in the development of NODAT.17 As a result, an antidiabetic agent that protects beta cells could be the optimal therapy for transplant recipients with diabetes.27 Dipeptidyl peptidase 4 inhibitors constitute a class of antidiabetic drugs that stabilize the incretin hormones glucagon-like peptide 1 and glucose inhibitory peptide, which result in improved metabolic control and reduction of postprandial hyperglycemia and less risk of hypoglycemic episodes.23
In our study, the mean FBG level at the time of diabetes onset was 114.5 mg/dL, whereas 1 year after the initiation of DPP4i treatment the mean FBG level was down to 111.1 mg/dL. According to Halden and colleagues, the median FBG was significantly lower after 4 weeks of sitagliptin treatment. Moreover, sitagliptin treatment also resulted in significant and consistent reductions in at-home measurements of plasma glucose throughout the day.28 Nevertheless, in the study of Haidinger and colleagues, vildagliptin did not result in significantly lower FGB compared with placebo.29 As for HbA1c, in our present study, the mean value at the time of diagnosis was 6.6%, whereas after 1 year of treatment with DPP4i it had significantly decreased to 6.1%. This result is consistent with the results of a study by Boerner and colleagues, in which HbA1c was significantly improved at the end of 6 months, with effect persisting at 12 months of follow-up.30 Similarly, Haidinger and colleagues demonstrated a significant reduction in HbA1c in patients treated with vildagliptin compared with placebo.29
Our results showed that DPP4i treatment has no detrimental renal effects, because kidney function had remained stable 1 year after the initiation of treatment. Similarly, no difference in kidney function was observed in the studies of Haidinger, Boerner, Halden, and colleagues.28-30 More specifically, in the study by Halden and colleagues, in which patients followed a crossover treatment schedule and were randomized to first receive either sitagliptin at 50 to 100 mg/day or a sitagliptin-free period of 4 weeks, the mean baseline creatinine did not change significantly between the on-treatment or off-treatment periods.28 More importantly, no acute rejection episodes were reported in any of the aforementioned studies.
Furthermore, in the study by Boerner and colleagues, there was a modest but significant decrease in BMI after 12 months of follow-up, although this decrease may have been the result of multiple factors, including lifestyle modifications.30 In our study, we also observed a considerable mean weight loss of 2 kg during a 12-month period, but this was not statistically significant. In another study by Halden and colleagues, there was no effect on patient weight with the addition of DPP4i in the treatment of NODAT.28,30 With regard to effects of DPP4i on the patient lipids profiles, no differences in high-density and low-density lipoprotein cholesterol levels were observed in either our study or the study by Boerner and colleagues, whereas triglyceride levels in our study decreased significantly.30
Hypertension is an important cause of chronic kidney disease and a common clinical feature of kidney transplant recipients. In addition to the hypoglycemic effect, DPP4i have also shown potent actions on the cardiovascular system, particularly in the regulation of blood pressure. The molecular mechanism that underlies the antihypertensive effect of DPP4i is multifactorial and may involve neuropeptide Y and peptide YY. According to Ogawa and colleagues, an alternate day treatment with sitagliptin significantly reduced systolic blood pressure in Japanese patients with hypertension and type 2 diabetes.31 Nevertheless, according to Haidinger and colleagues, vildagliptin compared with placebo failed to reduce blood pressure in patients with NODAT.29 Moreover, in the study by Halden and colleagues, sitagliptin had no significant effects on median systolic and diastolic blood pressure.28 Likewise, in our study, we did not observe any significant differences in systolic or diastolic pressure of our DPP4i-treated patients.
In solid-organ transplant recipients, drug-drug interactions and adverse effects of medications on graft function are of great importance when considering medications to treat comorbid conditions. In our study, plasma tacrolimus trough levels were not affected after DPP4i initiation, whereas the mean dose of tacrolimus for 1 year after initiation of DPP4i treatment was slightly lower than baseline. The insignificant decrease in tacrolimus trough levels could be attributed to the reduction of tacrolimus dose consistent with per protocol immunosuppression reduction during follow-up. Similarly, in the studies by Boerner and colleagues and Halden and colleagues, there was no difference in tacrolimus trough levels in patients treated with sitagliptin.28,30 Although the safety profile of each member of the DPP4i family could not be assessed in this study because of the inadequate number of recipients for each drug, we could not detect any important interaction of either the immunosuppression regimen or the standard-of-care treatment with statins and antihypertensive drugs. Nevertheless, in 1 study in which DPP4i were administered in kidney transplant recipients on cyclosporine, cyclosporine trough levels were significantly increased in those treated with sitagliptin, but these were minimally changed in those who received linagliptin.32 Finally, it is worth noting that sitagliptin is primarily eliminated in an unchanged form in the urine, and a relatively small portion is metabolized by the hepatic cytochrome P450 3A4 and 2C8 systems; in contrast, linagliptin is mainly eliminated unchanged via the feces, and renal excretion only accounts for 5.4% of elimination.32
For the efficacy of different treatment protocols for NODAT, we are not aware of any other comparative studies on DPP4i versus insulin. In this retrospective study, we were able to compare 2 groups of patients who received the aforementioned regimens; however, we acknowledge that the number of patients who received insulin was limited, and this severely limits the power of any significant clinical findings. Nevertheless, the inclusion of such an arm in this study highlights the importance and effectiveness of new treatments for diabetes in patients with NODAT outside of standard insulin therapy, especially in patients with established chronic kidney disease (such as kidney transplant recipients).
Unfortunately, we were not able to show differences in the safety profile or effectiveness among the different DPP4i prescriptions because of the low number of patients included in the study. Thus, we must emphasize that these results regarding DPP4i should be evaluated as a group effect. Moreover, the lack of randomization of treatment modalities either between DPP4i and other oral antidiabetic agents or between DPP4i and insulin treatment does not allow definitive conclusions on efficacy. Nevertheless, despite the retrospective nature of this study, we were able to monitor medication prescription changes, laboratory values, and reports of potential side effects and transplant-related comorbid events. Finally, the inclusion of a small group of patients who received an insulin-based regimen, albeit an acknowledged limitation of this study, can demonstrate the efficacy of treatment with DPP4i in NODAT.
In conclusion, we have shown that DPP4i were effective as monotherapy in kidney transplant recipients who developed NODAT. Also, these were well tolerated, and both kidney function and immunosuppression levels remained stable during the 12 months of treatment, with the advantageous avoidance of hypoglycemic episodes.
Volume : 19
Issue : 5
Pages : 411 - 419
DOI : 10.6002/ect.2020.0519
From the Department of Nephrology and Renal Transplantation, University Hospital of Patras, Patras, Greece
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Dimitrios S. Goumenos, Department of Nephrology and Renal Transplantation, University Hospital of Patras, Patras 265 00, Greece
Phone: +30 2613 603 361
Table 1. Baseline Clinical Characteristics and Immunosuppression Regimen
Table 2. Summary of Insulin Regimens for Transplant Recipients After New Onset Diabetes
Figure 1. Safety of Treatment With Dipeptidyl Peptidase 4 Inhibitors as Expressed in Kidney Function With Serum Creatinine and Estimated Glomerular Filtration Rate
Figure 2. Effects of Treatment With Dipeptidyl Peptidase 4 Inhibitors on Tacrolimus Trough Levels and Concomitant Dosage
Figure 3. Efficacy of Treatment With Dipeptidyl Peptidase 4 Inhibitors on Fasting Blood Glucose and Hemoglobin A1c
Figure 4. Effect of Treatment With Dipeptidyl Peptidase 4 Inhibitors on Lipid Profile
Figure 5. Effect of Treatment With Dipeptidyl Peptidase 4 Inhibitors on Weight Reduction
Figure 6. Effect of Treatment With Dipeptidyl Peptidase 4 Inhibitors on Systolic and Diastolic Blood Pressures
Figure 7. Comparison of Treatment With Dipeptidyl Peptidase 4 Inhibitors Versus Treatment with Standard Insulin