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Volume: 11 Issue: 6 December 2013

FULL TEXT

ARTICLE
Sitagliptin Might Be a Favorable Antiobesity Drug For New Onset Diabetes After a Renal Transplant

Objectives: The aim of this study was to evaluate the effectiveness of sitagliptin, alone or in combination with metformin, in kidney transplant patients with newly diagnosed new-onset diabetes mellitus after transplant who had inadequate glycemic control, compared with a group of patients receiving insulin glargine with special emphasis on weight gain.

Materials and Methods: Newly diagnosed renal transplant patients with new-onset diabetes mellitus after a transplant was defined by a blood glucose ≥ 11.1 mmol/L after an oral glucose tolerance test were examined. They were treated with standard immunosuppression composed of triple therapy with tacrolimus or cyclosporine, mycophenolate mofetil or azathioprine, and prednisone. They had stable graft function for more than 6 months after the transplant.

Results: Patients with new-onset diabetes mellitus after transplant (n=28) whose glycemia was not controlled adequately with oral hypoglycemic agents (either alone or in combination) received oral sitagliptin 100 mg once daily in addition to existing therapy for 12 weeks. Patients who received insulin glargine as add-on therapy (n=17) served as the control group. Data analyses included glycated hemoglobin, fasting plasma glucose, lipid profile, body weight, and the occurrence of hypoglycemia. We found significant reductions in glycated hemoglobin and fasting plasma glucose values after 12 weeks of additional sitagliptin therapy that were comparable to those with insulin glargine. While the addition of stagliptin resulted in a small weight loss (0.4 kg), the addition of insulin glargine resulted in a weight gain (0.8 kg). The overall incidence of adverse experiences was low and generally mild in both groups.

Conclusions: In a group of renal transplant recipients with new-onset diabetes mellitus after a transplant in whom glycemia was not controlled adequately by oral hypoglycemic agents, the addition of sitagliptin helped to achieve glycemic control similar to insulin glargine but with a marginal weight advantage.


Key words : Kidney, Hyperglycemia, Glargine, DPP-4, Insulin, Weight

Introduction

The major cause of premature death in renal transplant recipients is cardiovascular disease. Development of new-onset diabetes mellitus after transplant (NODAT) increases the risk of cardiovascular disease and poor short-term clinical outcomes.1-3 In transplant recipients, increased mortality and graft failure have been attributed to complications associated with morbid obesity. Little information exists in kidney transplant recipients regarding conventional glucose-lowering therapies, either oral hypoglycemic agents or traditional insulin regimens.3

Sitagliptin is an oral, once-daily, potent, and highly selective dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Dipeptidyl peptidase-4 inhibitors enhance levels of active incretin hormones and gut-derived peptides that are released into the circulation after ingestion of a meal.4-6 Glucagonlike peptide-1 and glucose-dependent insulinotropic peptide account for the majority of incretin action. In the presence of elevated glucose concentrations, glucagonlike peptide-1 and glucose-dependent insulinotropic peptide increase insulin release and glucagonlike peptide-1 lowers glucagon secretion; thereby decreasing the after-meal rise in glucose concentration and reducing fasting glucose concentrations. Both glucagonlike peptide-1 and glucose-dependent insulinotropic peptide are rapidly inactivated by the enzyme DPP-4. By blocking this inactivation, DPP-4 inhibitors increase active incretin levels, enhancing incretin effects, and thereby offer a new therapeutic approach for the management of patients with type 2 diabetes.7-10 Sitagliptin therefore is an interesting additional drug for treating posttransplant diabetes mellitus in transplanted patients. On the other hand, insulin glargine is a once-daily, basal human insulin analog. The 24-hour duration and flat time-action profile of glargine should give flexibility to patients in the injection time, despite targeting fasting blood glucose close to normal.11,12

This study sought to evaluate the effectiveness of sitagliptin alone or in combination with metformin in kidney transplant patients with newly diagnosed NODAT who had inadequate glycemic control, compared with a group of patients who received insulin glargine with special emphasis on weight gain.

Materials and Methods

Patients
Newly diagnosed renal transplant patients with NODAT defined by blood glucose ≥ 11.1 mmol/L after an oral glucose tolerance test were examined. They were treated with standard immuno­suppression, composed of triple therapy with tacrolimus or cyclosporine, mycophenolate mofetil or azathioprine, and prednisone. They had stable graft function for more than 6 months after the transplant. Each patient gave their informed consent. All protocols were approved by the ethics committee of the institution before the study began, and the protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Exclusion criteria were patients with a prior history of type 1 or type 2 diabetes and patients with body mass index > 40, pregnancy, severe renal impairment (glomerular filtration rate < 30 mL/min/1.73 m2), severe liver impairment and severe blood glucose elevation (as evidenced by elevated glycosylated hemoglobin more than 8.5%).

Of 135 renal transplant patients screened, 62 with NODAT taking metformin at a dosage of at least 1500 mg/d with A1C levels ≥ 7 and ≤ 8.5% were randomly assigned to receive an addition of either sitagliptin 100 mg daily or insulin glargine. The 2 treatment groups were composed of 31 patients each. One week after randomization, those needing multiple short-acting dosages of insulin were excluded. They were 3 in sitagliptin group, and 6 in glargine patients. During follow-up, 3 patients in glargine were lost to follow-up, while another 5 denied continuation of insulin injections for fear of long-term need for insulin. We finally ended with 45 patients, 28 in sitagliptin, and 17 in glargine treatment. Patients exceeding specific glycemic limits during the 12-week treatment period were provided rescue therapy (pioglitazone, up to 45 mg/d orally) until the end of the study.

Patients with NODAT in the sitagliptin group (28 patients) received oral sitagliptin 100  mg daily in addition to existing therapy for 12 weeks. If the glomerular filtration rate < 50 mL/min/1.73 m2, the dosage was 100 mg/d. If the glomerular filtration rate was from 25 to 49 mL/min/1.73 m2, the dosage was modified to 50 mg/day. Patients who received insulin glargine given subcutaneously in a sliding scale pattern titrated to target fasting blood glucose ≤ or equal to 5.5 mmol/L served as a control group (n=17).

Data analysis included glycated hemoglobin, fasting plasma glucose, lipid profile, body weight, and the occurrence of hypoglycemia. The study was interventional randomized open label.

Study endpoints
The primary efficacy endpoint was change in A1C from baseline to week 12. Secondary efficacy endpoints included change from baseline to week 12 in body weight, fasting plasma glucose, and a lipid panel (ie, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, and triglyceride–to–high-density lipid lipoprotein cholesterol ratio). All assays were performed by technicians blinded to the treatment sequence at the hospital central laboratory.

Safety and tolerability were assessed throughout the study. Monitoring for adverse experiences, physical examinations, vital signs, body weight, 12-lead electrocardiograms, and safety laboratory measurements comprising serum chemistry were performed. Investigators evaluated each clinical adverse experience for intensity (mild, moderate, or severe), duration, outcome, and relation to the study drug. Adverse experiences of special interest included hypoglycemia and gastrointestinal adverse experiences.

Statistical analyses
All data were presented as a means ± standard deviation. An analysis of variance model was used to analyze the treatment groups for the continuous continuing efficacy parameters, comparing changes from baseline at week 12. Safety analyses were performed using the all-patients-as-treated population, which included all randomly assigned patients who received at least 1 dose of the drug studied. For hypoglycemia—as well as for prespecified selected gastrointestinal adverse experiences (ie, abdominal pain, diarrhea, nausea, and vomiting) and change in body weight—inferential testing was done to determine statistical significance levels for between-group comparisons.

Results

Demographics and baseline characteristics
Data are shown in Table 1. The characteristics of the randomly assigned patients were similar between the treatment groups. For the entire study population, the average duration of new-onset diabetes after a transplant was 11.5 months (range, 0.1-19.7 months), average baseline A1C was 7.7% (range, 6.9%-8.6%), and the average baseline fasting plasma glucose was 9.38 mmol/L. There were no clinically meaningful changes in electrocardiograms or vital signs in both sitagliptin and glargine treatment groups.

Side effects and safety
The overall incidence of adverse experiences was low and generally mild in both groups (Table 2). The frequency of hypoglycemia was equivalent between the groups, with sitagliptin comparable to glargine (5 of 28 patients [17.8%] vs 3 of 17 patients [17.6%]).

Efficacy
Data are shown in Table 3. We found significant reductions in glycated hemoglobin and fasting plasma glucose values after 12 weeks of additional sitagliptin therapy that were comparable to those with insulin glargine. At the endpoint, clinically meaningful reductions in glycosylated hemoglobin were observed in both groups: -0.6% ± 0.5%, from 7.7% ± 0.9% to 7.1% ± 0.8% (sitagliptin) and -0.6% ± 0.6%, from 7.5% ± 0.7% to 6.9% ± 0.9% (glargine). While additional sitagliptin resulted in a minimal weight loss (0.4 kg), insulin glargine addition resulted in a weight gain (0.8 kg). The difference was statistically significant (P < .05). Treatment with sitagliptin 100 mg led to statistically significant, albeit generally small, decreases in total cholesterol, triglycerides, non–high-density lipoprotein cholesterol, and triglyceride–to–high-density lipoprotein cholesterol ratio, as well as a small statistically significant increase in high-density lipoprotein cholesterol relative to glargine at week 12.

Discussion

Our study is the first randomized controlled study that showed a group of renal transplant with NODAT, in whom glycemia was not controlled adequately by oral hypoglycemic agents, the addition of sitagliptin helped achieve glycemic control to a similar extent as insulin glargine, but with a marginal weight advantage. Our review of the literature, especially of PubMed and the National Library of Medicine, revealed only 1 case report in a cardiac transplant patient13 and a letter to the editor after renal transplant.14

New-onset diabetes after transplant or posttransplant diabetes mellitus is a frequent metabolic complication of organ transplant. Diabetes incidence rates among transplant recipients are higher than in the general population. The estimated rates are 9%-18% after kidney transplants, 20%-33% after liver transplants, 26%-40% after lung transplants, and 29% after heart transplants. In retrospective studies, NODAT was associated with higher costs of posttransplant care and increased risks of graft failure, infection, cardiovascular disease, and death. The incidence of NODAT is influenced by both traditional risk factors for type 2 diabetes (age, family history, obesity, hepatitis C infection, and ethnicity) and transplant-specific risk factors. Managing NODAT is challenging because posttransplant care is complex and characterized by multiple variables including immunosuppressive regimens, choice of antidiabetes agents, and optimal use of insulin therapy. Therefore, predicting and preventing NODAT would be a compelling objective for improving care of posttransplant patients. Before transplant, lifestyle modifications in patients at risk for NODAT should be considered, recognizing that no randomized controlled trials exist to inform specific modalities or cost-effectiveness of such an approach. After hospital discharge, close monitoring of blood glucose during the first month, and every 3 months thereafter for the first year, is recommended for those without a history of diabetes mellitus. Future areas of investigation include clinical validation of NODAT risk score engines, validating interventions for primary prevention of NODAT, developing immunosuppressive regimens with minimal diabetogenic effects, and prospectively determining glycemic control on graft survival and cardiovascular outcomes.15-20

Our study showed significant reductions in glycated hemoglobin and fasting plasma glucose values after 12 weeks of additional sitagliptin therapy that were comparable to those with insulin glargine. While sitagliptin addition resulted in a small weight loss (0.4 kg), insulin glargine addition resulted in a weight gain (0.8 kg). The difference was statistically significant (P < .01). These findings indicate a robust benefit of sitagliptin therapy, agree with hypothesis of β-cell protection and warrant thorough interpretation.

The use of glycosylated hemoglobin at 3 months as the primary endpoint of this study is debatable because glycosylated hemoglobin may be considered a trivial outcome in patients receiving a more-intensive versus a less-intensive antidiabetic treatment, at least after transplant. Moreover, glycosylated hemoglobin in renal transplant recipients may not adequately reflect glycemia.16 Therefore, it might be argued that NODAT prevalence would have been a better primary outcome measure. Choosing glycosylated hemoglobin as the primary endpoint was therefore our only option, given the current state of research. Regarding glycosylated hemoglobin’s potentially inadequate reflection of glycemia because of posttransplant caveats18 (eg, anemia and various degrees of impaired renal function after transplant), we therefore examined patients with stable graft function for more than 6 months posttransplant.

Our study may ignite a change in clinical practice toward early sitagliptin therapy after transplant, if our results can be reproduced by other centers, and with non–tacrolimus-based immunosuppression protocols. Of note, a prospective NODAT trial should be extended to more than 12 months to ensure that the proposed regimen may prove beneficial, despite the possibility that some patients with postoperative hyperglycemia may revert to normoglycemia without intervention.

We can conclude that in a group of renal transplant with NODAT in whom glycemia was not controlled adequately by oral hypoglycemic agents, addition of sitagliptin helped to achieve glycemic control to a similar extent as insulin glargine but with a marginal weight advantage. The results of this study suggest the preferential use of sitagliptin to avoid weight gain during treatment of NODAT that might improve quality of life and overall health of transplant candidates.


References:

  1. Oterdoom LH, de Vries AP, van Son WJ, et al. Validation of insulin resistance indexes in a stable renal transplant population. Diabetes Care. 2005;28(10):2424-2429.
    CrossRef - PubMed
  2. Sharif A, Ravindran V, Moore RH, et al. Insulin resistance indexes in renal transplant recipients maintained on tacrolimus immunosuppression. Transplantation. 2010;89(3):327-333. doi: 10.1097/TP.0b013e3181bbf2c4.
    CrossRef - PubMed
  3. Luan FL, Stuckey LJ, Ojo AO. Abnormal glucose metabolism and metabolic syndrome in non-diabetic kidney transplant recipients early after transplantation. Transplantation. 2010;89(8):1034-1039. doi: 10.1097/TP.0b013e3181d05a90.
    CrossRef - PubMed
  4. Kim D, Wang L, Beconi M, et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005;48(1):141-151.
    CrossRef - PubMed
  5. Herman GA, Stevens C, Van Dyck K, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005;78(6):675-688.
    CrossRef - PubMed
  6. Herman GA, Bergman A, Stevens C, et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J Clin Endocrinol Metab. 2006;91(11):4612-4619.
    CrossRef - PubMed
  7. Holst JJ, Deacon CF. Inhibition of the activity of dipeptidyl-peptidase IV as a treatment for type 2 diabetes. Diabetes. 1998;47(11):1663-1670.
    CrossRef - PubMed
  8. Deacon CF, Ahrén B, Holst JJ. Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes? Expert Opin Investig Drugs. 2004;13(9):1091-1102.
    CrossRef - PubMed
  9. Holst JJ, Deacon CF. Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus. Curr Opin Pharmacol. 2004;4(6):589-596.
    CrossRef - PubMed
  10. Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab. 2004;287(2):E199-E206.
    CrossRef - PubMed
  11. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care. 2000;23(5):644-649.
    CrossRef - PubMed
  12. Fritsche A, Schweitzer MA, Häring HU; 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med. 2003;138(12):952-959.
    CrossRef - PubMed
  13. Pinelli NR, Nemerovski CW, Koelling TM. Successful long-term use of sitagliptin for the treatment of new-onset diabetes mellitus after solid organ transplantation: a case report. Transplant Proc. 2011;43(5):2113-5. doi: 10.1016/j.transproceed.2011.02.059.
    CrossRef - PubMed
  14. Lane JT, Odegaard DE, Haire CE, Collier DS, Wrenshall LE, Stevens RB. Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation. Transplantation. 2011;92(10):e56-e57. doi: 10.1097/TP.0b013e3182347ea4.
    CrossRef - PubMed
  15. Shah A, Kendall G, Demme RA, et al. Home glucometer monitoring markedly improves diagnosis of post renal transplant diabetes mellitus in renal transplant recipients. Transplantation. 2005;80(6):775-781.
    CrossRef - PubMed
  16. Sharif A, Baboolal K. Diagnostic application of the A(1c) assay in renal disease. J Am Soc Nephrol. 2010;21(3):383-385. doi: 10.1681/ASN.2010010031.
    CrossRef - PubMed
  17. Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant. 2007;7(6):1506-1514. Epub 2007 Mar 12. Erratum in: Am J Transplant. 2008;8(1):1. Am J Transplant. 2008;8(4):908. Dosage error in article text.
    CrossRef - PubMed
  18. Sumrani NB, Delaney V, Ding ZK, et al. Diabetes mellitus after renal transplantation in the cyclosporine era--an analysis of risk factors. Transplantation. 1991;51(2):343-347.
    CrossRef - PubMed
  19. Chakkera HA, Weil EJ, Castro J, et al. Hyperglycemia during the immediate period after kidney transplantation. Clin J Am Soc Nephrol. 2009;4(4):853-859. doi: 10.2215/CJN.05471008.
    CrossRef - PubMed
  20. Hecking M, Haidinger M, Döller D, et al. Early basal insulin therapy decreases new-onset diabetes after renal transplantation. J Am Soc Nephrol. 2012;23(4):739-749. doi: 10.1681/ASN.2011080835.
    CrossRef - PubMed


Volume : 11
Issue : 6
Pages : 494 - 498
DOI : 10.6002/ect.2013.0018


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From the Departments of 1Nephrology and 2Clinical Pathology, Cairo University, Cairo, Egypt
Acknowledgements: The authors have no conflicts of interest to declare. No grants were received for this study.
Corresponding author: Amin R. Soliman, Professor and Chairman, 41 Manial Street, Cairo11451, Egypt
Phone: +20 2 229 125 55
Fax: +20 2 229 125 55
E-mail: aroshdy@hotmail.com