The development of new-onset diabetes after transplantation (NODAT), also called posttransplantation diabetes mellitus, increases the risk of cardiovascular disease, and more than half of deaths after renal transplantation can be attributed to cardiovascular diseases (1–3). In addition, NODAT is a potent contributor to graft loss (4). Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are collectively termed prediabetic states because they potentially precede the development of overt diabetes. In nontransplanted individuals, approximately 25% of patients with prediabetes develop overt diabetes within 3 to 5 years and approximately 50% remain in their abnormal glycemic state (5).
IFG is defined as fasting plasma glucose (FPG) from 100 mg/dL (5.55 mmol/L) to 125 mg/dL (6.9 mmol/L), whereas IGT is defined as 2-hr plasma glucose (2HPG) in a 75 g oral glucose tolerance test (OGTT) from 140 mg/dL (7.78 mmol/L) to 199 mg/dL (11.05 mmol/L) (6). In the general population, the presence of IGT is associated with a 40% increase in mortality (7).
In patients after kidney transplantation, the prevalence of prediabetes ranges between 25% and 35%, and among these patients, isolated IGT is the commonest disturbance (8, 9). A similar degree of prediabetes prevalence has also been observed at our center, where we have detected a prediabetes prevalence of 32% among stable renal transplant patients without a history of type 1 or 2 diabetes mellitus and NODAT (10). Importantly, IGT but not IFG is an independent predictor of all-cause mortality in patients after kidney transplantation; hence, IGT is not only a harbinger of overt diabetes mellitus but also a high-risk condition per se (11).
Despite growing knowledge about the etiology and risks of posttransplantation IGT and NODAT, hardly any evidence about effective therapeutic interventions is available. Pioglitazone, a thiazolidinedione, is a peroxisome proliferator-activated receptor γ agonist that decreases insulin resistance and improves glucose and lipid metabolism in type 2 diabetes mellitus (12). Its use has been demonstrated to be safe and effective in patients after kidney transplantation who suffer from type 2 diabetes mellitus (13) and carotid intima-media thickness was shown to be reduced by pioglitazone in normoglycemic renal transplant recipients (14). In addition, pioglitazone can prevent the development of diabetes in (nontransplanted) patients with IGT (15). Vildagliptin, a dipeptidylpeptidase-4 inhibitor, stabilizes the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, resulting in improved metabolic control and reduction of postprandial hyperglycemia (16). Furthermore, incretin-based therapies are thought to exert a β-cell protective effect (17, 18). The dipeptidylpeptidase-4 inhibitor sitagliptin has been shown to be well tolerated in renal transplant recipients and no influences on tacrolimus or sirolimus levels were observed (19). The use of vildagliptin in mild to severe renal impairment has been shown to be safe (20).
The pathophysiology of impaired glucose metabolism (IGT and NODAT) after transplantation remains controversial, especially with respect to insulin sensitivity and β-cell function (10, 21, 22). It is therefore not clear whether treatment of these metabolic disturbances that are definitely pathophysiologically distinct from type 2 diabetes mellitus should be aimed at improving insulin sensitivity or β-cell function. In a randomized controlled trial, we recently showed that insulin treatment during the early posttransplantation phase decreases NODAT by improving β-cell function (23).
In the present study, we tested the hypothesis that treatment of newly diagnosed IGT in stable renal transplant recipients at least 6 months after transplantation with either the β-cell protective agent vildagliptin or the insulin sensitizer pioglitazone provides superior antihyperglycemic control compared with lifestyle interventions alone.
Baseline Clinical Characteristics
A total of 505 patients underwent an OGTT during the recruitment period and of those 52 patients with IGT were randomized (Figure 1). Demographic and baseline clinical characteristics of all three groups are shown in Table 1. There were no significant differences in age, sex, body mass index, kidney function including levels of proteinuria, time after transplantation, lipid metabolism, liver function, hemoglobin levels, and corticosteroid dose among the three groups at baseline. Tacrolimus trough levels were highest in the vildagliptin group and lowest in the placebo group, almost reaching statistical significance. A significant difference was observed in HbA1c: lowest in the vildagliptin group and highest in the pioglitazone group.
Figure 2 shows the changes in mean metabolic parameters for all three groups. The primary endpoint (difference in change in 2HPG between the groups) did not reach statistical significance, although the changes in HbA1c showed statistical significant differences between the treatment groups and placebo (placebo vs. vildagliptin: −0.11%±0.25% vs. +0.09%±0.26%; P=0.049 and placebo vs. pioglitazone: −0.17%±0.33% vs. +0.09%±0.26%; P=0.013). To control these parameters for differences at baseline and to avoid regression toward the mean, analyses of covariance (ANCOVA) were performed (data not shown). Although all P values were lower using ANCOVA, the primary endpoint still did not reach clinical significance, and the difference in HbA1c became even more significant. Table 2 summarizes the metabolic parameters at baseline and at 3 months. Compared with baseline, 2HPG was significantly reduced after 3 months in the vildagliptin and pioglitazone group. FPG was only significantly reduced in the pioglitazone group and HbA1c in the vildagliptin and the pioglitazone groups. In the placebo group, no changes in FPG and 2HPG were observed and HbA1c was even slightly increased after 3 months. No significant changes in hemoglobin levels were observed (data not shown). Fasting insulin levels showed the highest reduction in the pioglitazone group reaching borderline statistical significance.
To gain insights into the mechanism of action of the two antidiabetic drugs, a subset of patients underwent frequent sampling OGTT both at baseline and at the end of study. Glucose area under the curve was significantly reduced in the vildagliptin group, and oral glucose insulin sensitivity (OGIS) was significantly reduced in the pioglitazone and placebo group (see Table S1, SDC, https://links.lww.com/TP/A736). Total hepatic extraction of insulin was increased in both treatment groups, whereas fasting insulin sensitivity (Quantitative Insulin Sensitivity Check Index) was not significantly influenced (data not shown).
Subject Compliance and Safety Analysis
Adherence to study medications was assessed by at least monthly interviews during and at the end of the study period. Four subjects did not complete the study and were replaced; thus, a total of 52 patients were randomized into the study. Reasons for study discontinuation are shown in Figure 1 and were very similar across the groups. Adverse events occurred in four patients in the vildagliptin group, four patients in the pioglitazone group, and five patients in the placebo group. Adverse events were reversible and generally mild in nature (see Table S2, SDC, https://links.lww.com/TP/A736). Severe adverse events were not observed. Estimated glomerular filtration rate was not significantly influenced by the treatment in either of the study arms. In the liver function tests, glutamic oxaloacetic transaminase did not show any differences between the groups, but glutamic pyruvic transaminase and γ-glutamyltransferase were significantly lower in the pioglitazone group (Table 3). Furthermore, no significant changes in tacrolimus trough levels were observed.
To the best of our knowledge, this is the first randomized controlled study evaluating a pharmacologic intervention in IGT after kidney transplantation. As in the general population, IGT confers a substantially increased mortality risk in patients after kidney transplantation, interestingly to a much higher degree than IFG (7, 11). In addition, patients with IGT already show an increased rate of late diabetic complications such as retinopathy (24). Therefore, interventions at the stage of IGT are highly warranted, especially in renal transplant recipients.
Pioglitazone has already been shown to prevent the development of diabetes in patients with IGT in a study with more than 600 patients (72% risk reduction for conversion of prediabetes to overt diabetes), whereas vildagliptin holds promise in protecting β-cell function during the transition from prediabetes to type 2 diabetes mellitus (15, 25). Incretin-based therapies additionally seem to offer protection against the deleterious proapoptotic effects of glucocorticoids on β-cells (18, 26). In vitro, glucagon-like peptide-1 also renders β-cells resistant to the toxic effects of various immunosuppressive drugs such as calcineurin inhibitors (27).
We show that both compounds significantly improved IGT and HBA1c compared with baseline, whereas pioglitazone also improved IFG. Our OGTT-derived data suggest that pioglitazone acts via improvement of insulin sensitivity. In the pioglitazone group, insulin tended to be reduced possibly due to reduced insulin secretion and an increased hepatic clearance of the hormone (28, 29). Why an increase of extraction of insulin by the hepatocytes was observed under vildagliptin treatment is unclear and it is not believed to depend on incretin action (30). Interestingly, insulin sensitivity was significantly improved in the placebo group as indicated by the increase in OGIS. Lifestyle interventions alone have already been shown to improve glycemic control in patients after kidney transplantation (31).
It is still an unanswered question whether NODAT is rather caused by decreased insulin sensitivity or impaired insulin secretion, although evidence supports the idea that a defect in β-cell function is the central problem in these patients (10, 22). In the present study, therapy with the insulin sensitizer pioglitazone proved successful in patients with IGT. The clear tendency to improved insulin sensitivity conferred by the pharmacologic intervention therefore seems to compensate for the defect in insulin secretion in our patient population. There were no significant differences in safety endpoints. Pioglitazone even led to a significant reduction in liver enzymes, as it has already been observed by others (32).
Long-term efficacy and safety cannot be judged from this study and it is still under debate whether incretin-based therapies confer a risk for pancreatitis, pancreatic cancer, and thyroid cancer (33). The thiazolidinedione rosiglitazone was associated with an increased cardiovascular risk and therefore withdrawn from the market (34). Although pioglitazone does not seem to increase the cardiovascular risk, its use is not recommended in patients with heart failure. In addition, long-term pioglitazone use has been associated with an increased rate of bone fractures and occurrence of bladder cancer (35, 36), and pioglitazone was therefore withdrawn from the market in some countries. Physicians should be aware of these risks when prescribing these drugs.
This trial has a number of limitations such as the small sample size and the relatively short treatment duration. Although the primary outcome did not reach statistical significance, a number of important secondary endpoints were improved. We analyzed a prediabetic patient population, in which potential improvements in glucose metabolism will a priori be small. Inclusion criteria and the primary endpoint are based on OGTT results— a method that is now seen as an important tool for the detection of NODAT (37), but it shows high internal variability (38) and only one OGTT was performed at baseline and at the end of the treatment period. Whether the studied pharmacologic interventions may prevent future diabetes or cardiovascular disease cannot be judged from this study, because larger patient numbers and longer observation periods would be necessary.
In conclusion, our study demonstrates a benefit of a pharmacologic intervention with vildagliptin or pioglitazone in IGT. Because IGT is associated with conversion to NODAT and increased rates of mortality further studies should evaluate whether interventions with vildagliptin or pioglitazone in prediabetic renal transplant patients may help to prevent or delay such events.
MATERIALS AND METHODS
We recruited study participants between December 2009 and June 2011 from the Vienna General Hospital/Medical University of Vienna (Vienna, Austria). At our center, all patients at least 6 months after kidney transplantation are routinely screened for glucose metabolism alterations using a standard 75 g glucose OGTT. Patients with IGT were invited to take part in the study. Further inclusion criteria were stable graft function and informed consent of the patient. Exclusion criteria consisted of prior history of diabetes mellitus type 1 or 2, pregnancy, severe renal impairment with estimated glomerular filtration rate below 15 mL/min/1.73 m2 (Modification of Diet in Renal Disease formula), and need for dialysis and severe liver impairment with glutamic oxaloacetic transaminase and glutamic pyruvic transaminase levels increased at least three times above the upper reference values. Written consent was obtained from all subjects before participation in the study, which was approved by the local ethics committee (EK#681/2009). Participants were followed until they withdrew from the study or until study completion.
Study Design and Treatments
This was a 3-month, double-blind, placebo-controlled, randomized clinical study. Patients were informed about the result of their OGTT and eligible patients were simultaneously offered to take part in the study. Advice by study investigators was given to all patients concerning diet and level of physical activity according to American Diabetes Association guidelines (39). Study participants were randomized in a 1:1:1 ratio to receive 50 mg vildagliptin (Galvus; Novartis Europharm, West Sussex, UK), 30 mg pioglitazone (Actos; Takeda Pharma, Osaka, Japan), or placebo tablets once daily. Randomization and blinding was performed by the pharmacy department. Sealed numbered envelopes with medication in opaque flasks were dispensed by the hospital pharmacy in the order of randomization. Changes in steroid dosing during the study period were not allowed. The intended size of the per-protocol population was 48 patients (16 subjects in each of the three groups). Participants were instructed to take their medication once daily 15 to 30 min before breakfast for 3 months. At the end of month 3, an OGTT was performed. Depending on the result of this OGTT, patients were instructed to continue their lifestyle modifications or were prescribed oral antidiabetic therapy at the discretion of the study investigator.
Assessments and Calculations
Primary outcome of the study was the difference in change in 2HPG between the treatment arms. Secondary outcomes included difference in 2HPG, FPG, HbA1c, and fasting insulin within the groups before and after treatment, change in kidney function, change in liver parameters, and rate of side effects.
In addition to an OGTT at baseline and at end of the study, additional metabolic variables were determined: HbA1c, lipids, liver enzymes, and serum creatinine. All patients underwent a frequent sampling OGTT (blood collection of glucose, insulin, and C-peptide at 0, 10, 20, 30, 60, 90, and 120 min) at the end of the study. At baseline, not all patients underwent a complete test but at least an OGTT with sampling at 0 min for glucose, insulin, and C-peptide and at 120 min for glucose only.
The methods for the calculation of insulin sensitivity at fasting (Quantitative Insulin Sensitivity Check Index) and in dynamic conditions (postprandial), OGIS, and of β-cell function (Insulinogenic Index) are described elsewhere (40). Areas under the curve for glucose, insulin, and C-peptide were calculated from plasma levels using the trapezoidal rule. Hepatic extraction was calculated according to Stadler et al. (41).
Data are presented as means±standard deviations or frequencies and percentages. For comparisons among the three groups including the primary endpoint (difference in change in 2HPG at 3 months), analyses of variance were used followed by the least significant difference post hoc tests. In addition, ANCOVA was performed to control for differences at baseline. For nominal parameters, chi-square tests were used. Comparisons between baseline and 3-month values were performed using paired t tests (one or two-sided, where appropriate). P<0.05 was considered significant. Efficacy analysis was performed based on the per-protocol population and safety outcomes were analyzed based on the intention-to-treat population. Outliers were excluded from the efficacy analysis but not the safety analysis (n=1).
Sample Size Calculation
Based on an expected σ of 20% within the three groups, α=0.05 (two-sided) and β=0.2, a sample size of 16 patients per group was determined to detect a minimum difference of 12% in change in 2HPG among the three groups. These assumptions were based on data from patients from our outpatient department and on data from the literature (15, 42).
The authors thank the study volunteers for participating in this investigation and the nursing staff of the Vienna General Hospital for their skilled work.
1. Cosio FG, Kudva Y, van der Velde M, et al.. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 2005; 67: 2415.
2. Hjelmesaeth J, Hartmann A, Leivestad T, et al.. The impact of early-diagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events. Kidney Int 2006; 69: 588.
3. Saleem TF, Cunningham KE, Hollenbeak CS, et al.. Development of diabetes mellitus post-renal transplantation is associated with poor short-term clinical outcomes. Transplant Proc 2003; 35: 2916.
4. Kasiske BL, Snyder JJ, Gilbertson D, et al.. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3: 178.
5. Nathan DM, Davidson MB, DeFronzo RA, et al.. Impaired fasting glucose and impaired glucose tolerance: implications for care. Diabetes Care 2007; 30: 753.
6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33: S62.
7. Saydah SH, Loria CM, Eberhardt MS, et al.. Subclinical states of glucose intolerance and risk of death in the U.S. Diabetes Care 2001; 24: 447.
8. Delgado P, Diaz JM, Silva I, et al.. Unmasking glucose metabolism alterations in stable renal transplant recipients: a multicenter study. Clin J Am Soc Nephrol 2008; 3: 808.
9. Porrini E, Moreno JM, Osuna A, et al.. Prediabetes in patients receiving tacrolimus in the first year after kidney transplantation: a prospective and multicenter study. Transplantation 2008; 85: 1133.
10. Hecking M, Kainz A, Werzowa J, et al.. Impaired glucose metabolism despite decreased insulin resistance after renal transplantation. XVI International Congress on Nutrition and Metabolism in Renal Disease, Hawaii. Kidney Res Clin Pract 2012: 31: A35.
11. Valderhaug TG, Hjelmesaeth J, Hartmann A, et al.. The association of early post-transplant glucose levels with long-term mortality. Diabetologia 2011; 54: 1341.
12. Miyazaki Y, DeFronzo RA. Rosiglitazone and pioglitazone similarly improve insulin sensitivity and secretion, glucose tolerance and adipocytokines in type 2 diabetic patients. Diabetes Obes Metab 2008; 10: 1204.
13. Luther P, Baldwin D Jr. Pioglitazone in the management of diabetes mellitus after transplantation. Am J Transplant 2004; 4: 2135.
14. Han SJ, Hur KY, Kim YS, et al.. Effects of pioglitazone on subclinical atherosclerosis and insulin resistance in nondiabetic renal allograft recipients. Nephrol Dial Transplant 2010; 25: 976.
15. DeFronzo RA, Tripathy D, Schwenke DC, et al.. Pioglitazone for diabetes prevention in impaired glucose tolerance. N Engl J Med 2011; 364: 1104.
16. Richter B, Bandeira-Echtler E, Bergerhoff K, et al.. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2008: CD006739.
17. Wajchenberg BL. Beta-cell failure in diabetes and preservation by clinical treatment. Endocr Rev 2007; 28: 187.
18. van Raalte DH, van Genugten RE, Linssen MM, et al.. Glucagon-like peptide-1 receptor agonist treatment prevents glucocorticoid-induced glucose intolerance and islet-cell dysfunction in humans. Diabetes Care 2011; 34: 412.
19. Lane JT, Odegaard DE, Haire CE, et al.. Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation. Transplantation 2011; 92: e56.
20. Lukashevich V, Schweizer A, Shao Q, et al.. Safety and efficacy of vildagliptin
versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24-week randomized placebo-controlled trial. Diabetes Obes Metab 2011; 13: 947.
21. Midtvedt K, Hartmann A, Hjelmesaeth J, et al.. Insulin resistance is a common denominator of post-transplant diabetes mellitus and impaired glucose tolerance in renal transplant recipients. Nephrol Dial Transplant 1998; 13: 427.
22. Hagen M, Hjelmesaeth J, Jenssen T, et al.. A 6-year prospective study on new onset diabetes mellitus, insulin release and insulin sensitivity in renal transplant recipients. Nephrol Dial Transplant 2003; 18: 2154.
23. Hecking M, Haidinger M, Doller D, et al.. Early basal insulin therapy decreases new-onset diabetes after renal transplantation. J Am Soc Nephrol 2012; 23: 739.
24. Nathan DM, Chew EY, Christophi CA, et al.. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabetes Med 2007; 24: 137.
25. Ahren B, Pacini G, Foley JE, et al.. Improved meal-related beta-cell function and insulin sensitivity by the dipeptidyl peptidase-IV inhibitor vildagliptin
in metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care 2005; 28: 1936.
26. Ranta F, Avram D, Berchtold S, et al.. Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 2006; 55: 1380.
27. D’Amico E, Hui H, Khoury N, et al.. Pancreatic beta-cells expressing GLP-1 are resistant to the toxic effects of immunosuppressive drugs. J Mol Endocrinol 2005; 34: 377.
28. Kim SH, Abbasi F, Chu JW, et al.. Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals. Diabetes 2005; 54: 2447.
29. Osei K, Gaillard T, Schuster D. Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone. Metabolism 2007; 56: 24.
30. Meier JJ, Holst JJ, Schmidt WE, et al.. Reduction of hepatic insulin clearance after oral glucose ingestion is not mediated by glucagon-like peptide 1 or gastric inhibitory polypeptide in humans. Am J Physiol Endocrinol Metab 2007; 293: E849.
31. Sharif A, Moore R, Baboolal K. Influence of lifestyle modification in renal transplant recipients with postprandial hyperglycemia. Transplantation 2008; 85: 353.
32. Sanyal AJ, Chalasani N, Kowdley KV, et al.. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362: 1675.
33. Elashoff M, Matveyenko AV, Gier B, et al.. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011; 141: 150.
34. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457.
35. Aubert RE, Herrera V, Chen W, et al.. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab 2010; 12: 716.
36. Hillaire-Buys D, Faillie JL, Montastruc JL. Pioglitazone and bladder cancer. Lancet 2011; 378: 1543.
37. Sharif A, Moore RH, Baboolal K. The use of oral glucose tolerance tests to risk stratify for new-onset diabetes after transplantation: an underdiagnosed phenomenon. Transplantation 2006; 82: 1667.
38. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care 2012; 35: S11.
39. Bantle JP, Wylie-Rosett J, Albright AL, et al.. Nutrition recommendations and interventions for diabetes: a position statement of the American Diabetes Association. Diabetes Care 2008; 31: S61.
40. Pacini G, Mari A. Methods for clinical assessment of insulin sensitivity and beta-cell function. Best Pract Res Clin Endocrinol Metab 2003; 17: 305.
41. Stadler M, Anderwald C, Karer T, et al.. Increased plasma amylin in type 1 diabetic patients after kidney and pancreas transplantation: a sign of impaired beta-cell function? Diabetes Care 2006; 29: 1031.
42. Utzschneider KM, Tong J, Montgomery B, et al.. The dipeptidyl peptidase-4 inhibitor vildagliptin
improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose. Diabetes Care 2008; 31: 108.