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Keywords:

  • Cyclosporine;
  • diabetes mellitus;
  • heart;
  • kidney;
  • liver;
  • lung;
  • tacrolimus;
  • transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

New onset diabetes mellitus (NODM) is a serious complication of transplantation. This meta-analysis evaluates the reported incidence of NODM after solid organ transplantation in patients receiving CNI treatment.

Databases from January 1992 to April 2002 were searched. Fifty-six publications providing NODM incidence data were reviewed. Sixteen prospective, randomized comparative studies providing information on incidence of insulin-dependent diabetes mellitus (IDDM) were subjected to meta-analysis.

New onset diabetes mellitus was reported in 13.4% of patients after solid organ transplantation, with a higher incidence in patients receiving tacrolimus than cyclosporine (16.6% vs. 9.8%). This trend was observed across renal, liver, heart and lung transplant groups. Meta-analysis of 16 studies included patients receiving either tacrolimus (n = 1636) or cyclosporine (n = 1407). The incidence of IDDM was significantly higher among tacrolimus-treated patients (10.4% vs. 4.5%, p < 0.00001), an effect observed in renal (9.8% vs. 2.7% p < 0.00001) and nonrenal (11.1% vs. 6.2%; p < 0.003) groups, and among patients receiving equal doses of concomitant medication in both treatment arms (12.0% vs. 3.0%; p < 0.00001).

The reported incidence of NODM during the past decade was significantly higher among patients receiving tacrolimus than cyclosporine. These data provide a quantitative foundation for studies designed to reduce the rates of NODM following solid organ transplantation.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Calcineurin inhibitors (CNIs) exert a potent and selective immunosuppressive effect by inhibiting IL-2 gene transcription, thereby preventing lymphocyte proliferation in response to antigenic stimuli. The introduction of this class of agents in the 1980s dramatically improved patient and graft survival rates, and substantially reduced comorbidity following transplantation. Cyclosporine (CSA) and tacrolimus (TAC) are the two principal CNIs currently available for clinical use, presenting a viable choice for effective immunosuppression following transplantation. Randomized studies have shown that both cyclosporine- and tacrolimus-treated transplant recipients achieve similar patient and graft survival rates in liver (1–3), kidney (4–6) and heart transplantation (7), and acute graft rejection rates tend to be lower in TAC-treated patients following liver and kidney transplantation (1,4,5). Furthermore, TAC has been associated with reduced frequency of hyperlipidemia and hypertension (8). Thus, selection between these immunosuppressive agents is increasingly based on the safety of these agents and freedom from secondary effects (9–14).

New onset diabetes mellitus (NODM) is increasingly recognized as a serious complication of organ transplantation. A recent analysis of the United States Renal Data System showed a markedly increased incidence of diabetes mellitus in CNI-treated renal transplant patients (n = 6943) following transplantation (15). New onset diabetes mellitus results in increased susceptibility to infectious and cardiovascular complications, may lead to diminished long-term graft survival, and has a major impact on the quality and quantity of life (16–19). New onset diabetes mellitus rates as high as 46% were reported before the introduction of CSA, largely related to the use of high-dose steroid immunosuppression required to prevent graft rejection (17,20). The introduction of CSA allowed the use of lower steroid doses, and NODM rates declined to between 3 and 14% (16,17,21–24).

Early reports suggested that TAC may permit a further reduction or elimination in steroid dose (3,25,26), leading to an expected reduction in NODM rates and cardiovascular risk. Subsequent studies have not confirmed this expectation, however, and reported rates of NODM in patients receiving tacrolimus have often been observed to be higher than with CSA (9,27).

This systematic review and meta-analysis was therefore conducted to compare the incidence of NODM between TAC-treated patients and CSA-treated patients following solid-organ transplantation.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The Medline, Embase, and Cochrane databases from January 1992 to April 2002 were searched on the OVID software system using the terms ‘diabetes’, ‘transplantation’, ‘tacrolimus’, ‘FK’, ‘cyclosporine’, ‘Neoral’, ‘Sandimmun’ and various combinations of these terms. In addition, electronic and manual searches of the most recent Congresses of the Transplantation Society, European Society of Organ Transplantation, American Society of Transplantation and International Congress on Immunosuppression conference abstract proceedings were completed. Citations that contained duplicate data were excluded. The methodological quality of all studies included was assessed using the Jadad scoring system (28). It awards a maximum of 5 points to each study based on three main criteria: study randomization (1–2 pts), double-blinding of the study (1–2 pts), and a description of withdrawals or dropouts (1 pt). Any disagreement regarding study quality was resolved by discussion among the authors.

General analysis of NODM incidence

Prospective and retrospective studies that reported the incidence of NODM in adult recipients treated with either TAC or CSA following solid organ transplantation (excluding pancreatic transplantation) were analyzed to determine the incidence of this disorder. Case studies and review articles were excluded. Data for this analysis were abstracted by one investigator and verified by a second. The following elements were determined from each report: incidence of NODM, time period of NODM assessment, initial year of study enrollment; number of patients treated with either TAC or CSA, use of steroids and/or mycophenolate mofetil (MMF) or azathioprine (AZA) as concomitant immunosuppression, and type of organ transplanted. New onset diabetes mellitus was defined according to the criteria of each study. If the enrollment year of the study was not stated, it was recorded as the year of the article minus the follow-up time of the study. For studies that assessed NODM rates at more than one time point, the rates were averaged before converting the data to graphical form. Finally, although all studies detailed the number of patients with NODM, a number of reports included in the systematic review did not document the number of patients with pretransplant diabetes mellitus. The sample size of the study was therefore employed as the denominator in these reports. Only studies in which both the incidence of pretransplant diabetes and NODM were stated were included in the meta-analysis.

Meta-analysis

The meta-analysis in the current study included 16 prospective, randomized trials that compared the incidence of NODM in adults following solid organ transplantation. All provided a comparable definition of NODM (incidence of insulin dependence) and a clear distinction between NODM and pre-existing disease. The incidence of NODM was recorded for the time period specified by the study. However, where the incidence of NODM was recorded at more than one time point, the 1-year incidence was chosen. Subsidiary analyses were also conducted to examine the incidence of NODM in nonrenal transplantation, in renal transplantation, among patients receiving comparable doses of concomitant immunosuppressants in both study arms, and among studies with similar incidence time periods.

Statistical and heterogeneity analysis

Meta-analysis was conducted using a random effects model (Review Manager Version 4.1, Oxford, UK: The Cochrane Collaboration, 2000). Odds ratios (OR) were calculated for each principal outcome for dichotomous variables. Ninety-five percent confidence intervals were calculated for all parameters. Review Manager (version 4.1) software was used to generate the summary measure and 95% confidence interval for each dichotomous variable. Heterogeneity was assessed utilizing various methods. A visual inspection of the graphical display of the trials' 95% CI of their OR and the summary OR was conducted. A vertical line drawn through the combined OR should intersect most of the horizontal lines (representing 95% confidence intervals) of all individual studies in order for the trials to be considered homogeneous. Formal statistical tests for heterogeneity of the OR were performed using the Cochran Q chi-square test.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

A total of 56 publications were identified between 1992 and 2002 which met the criteria for the study and which reported the incidence of NODM in patients receiving kidney, liver, heart or lung transplantation. Pancreatic transplant recipients were excluded because of the complexity of evaluating treatment effect in the presence of pre-existing diabetes mellitus. Sixteen of these reports were randomized, prospective studies that fulfilled the criteria for meta-analysis. Of the total 56 publications, 25 (44.6%) had a Jadad score of 0, 12 (21.4%) had a score of 1, 18 (32.1%) a score of 2 and one (1.7%) a score of 3.

Kidney transplantation

Thirty-five publications reported the incidence of NODM in patients treated with either TAC or CSA following kidney transplantation (Table 1). Twenty-five of these reported the incidence of NODM in patients receiving TAC, and 21 the incidence in patients receiving CSA. Patients treated with TAC received concomitant therapy with corticosteroids in 23, with AZA in 17, or with MMF in nine of the studies reported. For CSA, patients received concomitant treatment with corticosteroids in 20, with AZA in 13, or with MMF in six of the studies. Two kidney studies did not explicitly describe the use of any concomitant medications (29,30). The NODM rates in these studies are represented graphically in Figure 1. The mean incidence of NODM across all 25 TAC-based studies was 15.4%, compared with 9.8% across all 21 CSA-based studies. The rate of PTDM did not appear to be dependent on the concomitant immunosuppressant employed in either treatment group (Figure 1). Considering only the seven prospective, randomized studies that compared TAC- and CSA-based regimens, the average NODM rate was 11.5% for TAC-treated patients and 4.7% for CSA-treated patients (27,31–37).

Table 1.  Incidence of new onset diabetes mellitus in patients treated with either tacrolimus- or cyclosporine-based regimens following kidney transplantation
Study authors (yr1) Study description J.S.Period assessedIncidence of NODM: TAC-based regimen2Incidence of NODM: CSA-based regimen2
Baid (2002; 67)Retrospective, single-center, single-arm06 yrTAC + Steroids + (AZA or MMF) = 19% (n = 70) 
Bloom (2002; 68)Retrospective, single-center05 yrTAC + (AZA or MMF) + Steroids = 18% (n = 290)CSA + (AZA or MMF) + Steroids = 9% (n = 137)
Duijnhoven (2002; 32)Prospective, randomized, single-center2upto 3 yrTAC + Steroids = 0% (n = 11)CSA + Steroids = 8% (n = 12)
First (2002; 69)Retrospective, multicenter01 yrTAC + (AZA or sirolimus or MMF) + Steroids = 6% (n = 245)3CSA + (AZA or MMF or sirolimus or everolimus) + Steroids = 3%(n = 121)3
Johny (2002; 70)Retrospective, single-center, single-arm015 yr CSA + Steroids = 26% (n = 23)
 CSA + Steroids + AZA = 19% (n = 404)
 CSA + Steroids + MMF = 18% (n = 17)
Markell (2002; 29)Retrospective, single-center05 yrTAC + n/a = 29% (n = 112)CSA + n/a = 14% (n = 166)
Mysore (2002; 71)Prospective, randomized, single center11 yr CSA + MMF = 0% (n = 17)
 CSA + MMF + Steroids = 0% (n = 10)
Panz (2002; 72)Prospective, single-center, single-arm03 moTAC + Steroids + AZA = 47% (n = 17) 
Boots (2001; 73)Prospective, nonrandomized, single center11 yrTAC + Steriods or TAC + Steroids + (MMF or AZA) = 19% (n = 54)CSA + Steroids or CSA + Steroids + AZA = 11% (n = 74)
Busque (2001; 74)Prospective, single arm, multicenter trial11 yrTAC + Steroids + MMF = 3% (n = 59)4 
Cosio (2001; 75)Retrospective, single-center, single-arm06 mo CSA + Steroids + (AZA or MMF) = 6%
 1 yr = 7%
 3 yr = 10%
 5 yr = 13%
 10 yr = 21%
 15 yr = 30% (n = 2078)
Duijnhoven (2001; 76)Prospective, single-center, single-arm24 yrTAC + Steroids = 18% (n = 17) 
Hjelmesaeth (2001; 77)Prospective, single-arm, observational13 mo CSA + Steroids or CSA + Steroids + AZA = 24% (n = 91)
Jevnikar (2001; 30)Retrospective,01 yrTAC + n/a = 9%50.
 multicenter study (n = 292)
Maes (2001; 78)Prospective, single-center, single-arm01 yrTAC + Steroids + (MMF or AZA) = 32% (n = 139) 
Mourad (2001; 79)Prospective, randomized, multicenter21 yrTAC + Steriods + AZA (induction) = 10% (n = 145) 
 1 yrTAC + Steriod + AZA (non- induction) = 5% (n = 154) 
Nam (2001; 80)Prospective, nonrandomized single-center, single-arm01 yr CSA + Steroids = 24% (n-114)
Revanur (2001; 81)Retrospective, single-center, single-arm012 yr CSA + Steriods + AZA = 5% (n = 939)
Sperschneider (2001; 31)Prospective, randomized, multicenter26 moTAC + Steriods = 5% (n = 286)CSA + Steroids = 2% (n = 271)
Study authors (yr1) Study description J.S.Period assessedIncidence of NODM: TAC-based regimen2Incidence of NODM: CSA-based regimen2
  1. NODM = new-onset diabetes mellitus; TAC = tacrolimus; CSA = cyclosporine; MMF = mycophenolate mofetil; AZA = azathioprine; steriods = corticosteroids.

  2. 1Years of publication.

  3. 2Initial immunosuppressive protocols are described. Immunosuppressants other than TAC, CSA, Steroids, AZA, MMF, Everolimus or Sirolimus are not recorded.

  4. 3During the follow-up period, 60 patients were switched from CSA to TAC, and six different were patients switched from TAC to CSA.

  5. 4This study recorded prevalence rather than incidence of new onset diabetes mellitus (NODM).

  6. 5Of the 292 patients, 58 were started on TAC therapy while 107 were converted from CSA for acute rejection and 127 for adverse events.

  7. 6Of the 85 patients, 61 received tacrolimus as primary immunosuppressive therapy; 24 received tacrolimus as secondary CSA rescue therapy. n/a = not available; NODM = new-onset diabetes mellitus; TAC = tacrolimus; CSA = cyclosporine; steroids = corticosteroids; AZA = azathioprine; MMF = mycophenolate mofetil. Bold highlighting indicates studies included in the meta-analysis.

Jawad (2000; 82)Prospective, nonrandomized, single-center0not stated CSA + high Steroids = 21% (n = 62)
 CSA + low Steroids = 6% (n = 62)
Johnson (2000; 33)Prospective, randomized, multicenter21 yrTAC + Steroids + AZA = 14% (n = 57) TAC + Steroids + MMF = 7% (n = 42)CSA + Steroids + MMF = 7% (n = 46)
Khoury (2000; 83)Retrospective, single-center, single-arm0upto 2.5 yrTAC + Steroids + AZA = 24% (n = 85)6 
Miller (2000; 84)Prospective, randomized, multicenter21 yrTAC + Steriods + AZA = 19% (n = 59) 
 TAC + Steroids + MMF (low dose) = 12% (n = 59) 
 TAC + Steroid + MMF (high dose) = 5% (n = 58) 
Park (2000; 85)Prospective, multicenter16 moTAC + Steroids = 28% (n = 64) 
Segoloni (2000; 86)Prospective, randomized, multicenter13 moTAC + Steroids + AZA = 4% (n = 200) 
 TAC + Steroids = 6% (n = 195) 
Silva. (2000; 87)Retrospective, single center010 yr CSA + Steroids or
 CSA + Steroids + AZA = 4% (n = 825)
Mancilla (1999; 88)Prospective, multicenter16 moTAC + Steroids + AZA = 15% (n = 20) 
Shapiro. (1999; 89)Prospective, randomized, single-center22 yrTAC + Steroids = 7% (n = 106) 
 TAC + Steroids + MMF = 3% (n = 102) 
Morris-Stiff (1998; 34)Prospective, randomized, single-center11 yrTAC + Steroids + AZA = 8% (n = 40)CSA + Steroids + AZA = 5% (n = 40)
Tanabe (1998; 90)Retrospective, single center0not statedTAC + Steroids or TAC + Steroids + AZA = 7% (n = 57) 
Mayer (1997; 36)Prospective, randomized, multicenter21 yrTAC + Steroids + AZA = 12% (n = 288)CSA + Steroids + AZA = 2% (n = 139)
Pirsch (1997; 27)Prospective, randomized, multicenter21 yrTAC + Steroids + AZA = 20% (n = 151)CSA + Steroids + AZA = 4% (n = 151)
Saxena (1996; 91)Retrospective, single-center, single-arm05 yr CSA + Steroids + AZA = 15% (n = 53)
Vincenti. (1996; 37)Prospective, randomized, multicenter21 yrTAC + Steroids + AZA = 25% (n = 67)CSA + Steroids + AZA = 5% (n = 20)
Rao (1992; 22)Retrospective, single center03 yr CSA + Steroids = 14% (n = 28)
image

Figure 1. Incidence of new onset diabetes mellitus (NODM) in patients treated with tacrolimus-based (T) and cyclosporine-based (C) regimens in renal transplantation. Corresponding arms within a single prospective study are identified by connecting lines. Trendline is solid for tacrolimus and dashed for cyclosporine. *In studies that did not state the initial year of enrollment, the enrollment year was recorded as the year of publication minus the follow-up time of the study. **This study recorded prevalence rather than incidence of NODM.

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Liver transplantation

Sixteen publications reported the incidence of NODM in patients undergoing liver transplantation (Table 2). Fourteen of these reported the incidence of NODM in patients receiving TAC, and 12 the incidence in patients receiving CSA. All reports indicated that patients were treated with corticosteroids. Those treated with TAC received concomitant therapy with AZA in two studies and with MMF in four studies, while those treated with CSA received concomitant therapy with AZA in eight studies and with MMF in two studies. One study comparing both TAC and CSA did not explicitly describe the use of any concomitant medications (38). The NODM rates in these studies are shown in Figure 2. The mean incidence of NODM across the 14 TAC-based studies was 18.2%, compared with 7.7% across the 12 CSA-based studies. There was no evident impact of concomitant therapy in the incidence of NODM in either treatment group. The average NODM rates in the seven prospective randomized trials were 15.9% for TAC-treated patients and 4.9% for CSA-treated patients.

Table 2.  Incidence of new onset diabetes mellitus in patients treated with either tacrolimus- or cyclosporine-based regimens following liver transplantation
Study authors (yr1) Study description J.S.Period assessedIncidence of NODM: TAC-based regimen2Incidence of NODM: CSA-based regimen2
  1. NODM = new-onset diabetes mellitus; TAC = tacrolimus; CSA = cyclosporine; steroids = corticosteroids; AZA = azathioprine; MMF = mycophenolate mofetil.

  2. 1yr of publication.

  3. 2Initial immunosuppressive protocols are described. Immunosuppressants other than TAC, CSA, Steroids, AZA or MMF are not recorded.

  4. 3This study recorded prevalence rather than incidence of new onset diabetes mellitus (NODM).

  5. 4This study used the development of new, uncontrollable insulin-dependent diabetes mellitus (IDDM) as a criterion for conversion from tacrolimus to cyclosporine.

  6. 5The TAC group includes up to six conversions from CSA, and the CSA group includes up to seven conversions from TAC at least 2 months before PTDM assessment. n/a = not available. Bold highlighting indicates studies included in the meta-analysis.

AlDosary (2002; 92)Retrospective, single center011 yrTAC + Steroids = 25% (n = 53)CSA + Steroids = 15% (n = 111)
Lerut (2001; 93)Prospective, single-arm, single-center06 mo CSA + Steroids + AZA = 28% (n = 70)3
 1 yr CSA + Steroids + AZA = 10% (n = 70)
 2 yr CSA + Steroids + AZA = 6% (n = 70)
Washburn (2001; 94)Prospective, single-center, single-arm118 moTAC + Steroids + MMF = 0% (n = 30) 
Emre (2000; 64)Retrospective, single center0< 30 dTAC + Steriods = 17% (conversion to CSA < 30d, n = 29)4 
 > 30 dTAC + Steriods = 29% (conversion to CSA > 30d, n = 41)4 
Lohmann (2000; 44)Prospective, randomized, single-center23 yrTAC + Steroids + (MMF or AZA)= 32% (n = 28)CSA + Steroids + (MMF or AZA) = 0% (n = 25)
Belli (1998; 95)Prospective, randomized, single-center21 yr CSA + Steroids(3 mo) + AZA = 7% (n = 46)
 CSA+ Steroids (continuous) + AZA = 28% (n = 43)
Cai (1998; 96)Retrospective, nonrandomized, single center01 yrLow TAC + Steriods + MMF = 23% (n = 13)CSA + Steroids = 11% (n = 9)
 1 yrHigh TAC + Steroids = 40%(n = 15) 
Jain (1998; 97)Retrospective, single center03 moTAC + Steroids = 24%3 
 6 moTAC + Steroids = 13% 
 1 yrTAC + Steroids = 16% 
 2 yrTAC + Steroids = 15% 
 3 yrTAC + Steroids = 16% 
 4 yrTAC + Steroids = 17% 
 5 yrTAC + Steroids = 18% (n = 1000) 
Margarit (1998; 98)Prospective, multicenter11 yrTAC + Steroids = 26% (n = 76) 
Stegall (1997; 45)Prospective, randomized, single center26 moTAC + Steriods + MMF = 4%(n = 24)5CSA + Steroids + MMF = 0% (n = 25)5
Bismuth (1995; 43)Prospective, randomized, single center31 yrTAC + Steroids = 18% (n = 264)CSA + Steroids + AZA = 11% (n = 265)
Senninger (1995; 38)Prospective, nonrandomized, single-center02 yrTAC + Steroids + n/a = 21% (n = 14)CSA + Steroids + n/a = 0% (n = 13)
Jindal (1994; 99)Prospective, randomized, single center11 yrTAC + Steroids = 23% (n = 30)CSA + Steroids + AZA = 21% (n = 33)
Steinmuller (1994; 46)Prospective, randomized, multicenter22 yrTAC + Steroids = 0% (n = 46)CSA + Steroids + AZA = 0% (n = 51)
The US Multicenter FK506 Liver Study Group (1994; 1)Prospective, randomized, multicenter21 yrTAC + Steroids = 4% (n = 263)CSA + Steroids or CSA + Steroids + AZA = 2% (n = 266)
Krentz (1993; 60)Prospective, randomized, single center28 moTAC + Steroids = 30% (n = 10)CSA + Steroids or CSA + Steroids + AZA = 0% (n = 10)
image

Figure 2. Incidence of new onset diabetes mellitus (NODM) in patients treated with tacrolimus-based (T) and cyclosporine-based (C) regimens in liver transplantation. Corresponding arms within a single prospective study are identified by connecting lines. Trendline is solid for tacrolimus and dashed for cyclosporinee. *In studies that did not state the initial year of enrollment, the enrollment year was recorded as the year of publication minus the follow-up time of the study. **This study recorded prevalence rather than incidence of NODM.

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Heart and lung transplantation

Four articles reported the incidence of NODM following heart transplantation (Table 3).Three of these reported the incidence in patients receiving TAC, and four in patients receiving CSA. All reports indicated that patients were treated with corticosteroids. Those treated with TAC received concomitant therapy with AZA in all three studies, while those treated with CSA received concomitant therapy with AZA in all four studies. The NODM rates in these studies are shown in Figure 3. The average rate of NODM in the three TAC-based studies was 18.7%, compared with 14.8% in the four CSA-based studies. New onset diabetes mellitus rates in the two randomized heart transplant studies were 15% (TAC) and 10.5% (CSA) (11,12,39,40). One nonrandomized study reported the incidence of NODM in lung transplant recipients (Table 4). Patients receiving TAC were treated with corticosteroids and either AZA or MMF, while those receiving CSA were treated with corticosteroids and AZA. The average NODM rates were 17.5% (TAC) and 15.0% (CSA) (41,42) (Figure 4).

Table 3.  Incidence of new onset diabetes mellitus in patients treated with either tacrolimus- or cyclosporine-based regimens following heart transplantation
Study authors (yr1) Study description J.S.Period assessedIncidence of NODM: TAC-based regimen2Incidence of NODM: CSA-based regimen2
  1. 1Years of publication.

  2. 2Initial immunosuppressive protocols are described. Immunosuppressants other than TAC, CSA, Steroids, AZA or MMF are not recorded.

  3. 3This paper does not explicitly define the incidence of diabetes as being new-onset or new onset diabetes mellitus (NODM). Bold highlighting indicates studies included in the meta-analysis. NODM = new-onset diabetes mellitus; TAC = tacrolimus; CSA = cyclosporine; steroids = corticosteroids; AZA = azathioprine.

Depczynski (2000; 40)Retrospective, nonrandomized, single center04 yr CSA + Steroids + AZA = 16% (n = 83)
Meiser (1998; 39)Prospective, randomized, single-center26 moTAC + Steroids + AZA = 23% (n = 43)CSA + Steroids + AZA = 17% (n = 30)
Reichart (1998; 12)Prospective, randomized, multicenter21 yrTAC + Steroids + AZA = 7%3 (n = 43)CSA + Steriods + AZA = 4%3(n = 23)
Pham (1996; 11)Retrospective, single center05 yrTAC + Steroids or TAC + Steroids + AZA = 26% (n = 80)CSA + Steroids + AZA = 22% (n = 111)
image

Figure 3. Incidence of new onset diabetes mellitus (NODM) in patients treated with tacrolimus-based (T) and cyclosporine-based (C) regimens in heart transplantation. Corresponding arms within a single prospective study are identified by connecting lines. Trendline line is solid for tacrolimus and dashed for cyclosporinee. *In studies that did not state the initial year of enrollment, the enrollment year was recorded as the year of publication minus the follow-up time of the study.

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Table 4.  Incidence of new onset diabetes mellitus in patients treated with either tacrolimus- or cyclosporine-based regimens following lung transplantation
Study authors (yr1) Study description J.S.Period assessedIncidence of NODM: TAC-based regimen2Incidence of NODM: CSA-based regimen2
  1. 1Years of publication. Initial immunosuppressive protocols are described. Immunosuppressants other than TAC, CSA, Steroids, AZA or MMF are not recorded. NODM = new-onset diabetes mellitus; TAC = tacrolimus; CSA = cyclosporine; steroids = corticosteroids; AZA = azathioprine; MMF = mycophenolate mofetil.

Reichenspurner (1999; 41)Retrospective, single center study11 yrTAC + Steriods + AZA = 27% (n = 30)CSA + Steriods + AZA = 15% (n = 34)
 TAC + Steroids + MMF = 8% (n = 12) 
image

Figure 4. Incidence of new onset diabetes mellitus (NODM) in patients treated with tacrolimus-based (T) and cyclosporine-based regimens (C) in lung transplantation.*In studies that did not state the initial year of enrollment, the enrollment year was recorded as the year of publication minus the follow-up time of the study.

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Meta-analysis

A total of 16 prospective, randomized studies fulfilled the criteria established for meta-analysis. These included a total of 3043 patients, comprising 1636 TAC-treated patients and 1407 CSA-treated patients who received either a kidney, liver, or heart transplant (2,12,13,27,32–37,39,43–47). Of the 10 studies that described donor source, nine included only cadaveric transplants while one documented 95.5% cadaveric transplants in the TAC arm and 97% in the CSA arm. None of the studies explicitly included multiorgan transplants, while 8/16 listed multiorgan transplantation under exclusion criteria. All studies with available data either excluded retransplant patients (8/16) or reported a similar proportion of retransplant patients in each treatment arm (5/16). Of the total 16 publications, none (0.0%) had a Jadad score of 0, two (12.5%) had a score of 1, 13 (81.3%) a score of 2 and one (6.3%) a score of 3. New onset diabetes mellitus was assessed as the development of new-onset IDDM. Meta-analysis showed that TAC-treated patients had a significantly higher rate of NODM (170/1636; 10.4%) than did CSA-treated patients (63/1407; 4.5%) (p < 0.00001, Figure 5A). The odds ratio (OR) for development of NODM was 2.38 (1.68–3.37) among patients treated with TAC by comparison with CSA, with an interstudy range in OR of 1.10–14.73 in favor of CSA. The analysis did not show significant heterogeneity.

image

Figure 5. (A,B) Random effects model meta-analysis comparing new onset diabetes mellitus (NODM) rates in tacrolimus- and cyclosporine-treated patients. The general analysis included 16 prospective randomized trials comparing tacrolimus to cyclosporine. (A). A more stringent subanalysis included seven of the studies with identical concomitant immunosuppressive therapies including steroid dosage (B). For both analyses, NODM was defined as new-onset insulin-dependent diabetes mellitus (IDDM). If NODM incidence was recorded at more than one time point, the 1-year incidence was chosen. The notation ‘not estimable’ indicates that zero patients experienced NODM; however, the n-values still contributed to the overall analysis of all patients.

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Subsidiary analyses were performed to explore the incidence of NODM according to transplanted organ, concomitant treatment and period of follow up. Among the 16 studies selected, seven reported data on a total of 1564 patients receiving a kidney transplant. As in the overall analysis, patients receiving TAC experienced a significantly higher rate of NODM (87 out of 885, 9.8%) compared with those receiving CSA (18 out of 679, 2.7%) with an OR of 3.70 (2,6,15,36) in favor of CSA (p < 0.00001; interstudy range: 1.10–6.46, test for heterogeneity not significant). The nine remaining studies reported data on a total of 1479 patients receiving a liver or heart transplant. These also displayed a higher incidence of NODM in patients receiving TAC (83 out of 751, 11.1%) compared with those receiving CSA (45 out of 728, 6.2%) with an OR of 1.82 (1.23–2.69) in favor of CSA (p < 0.003; interstudy range: 1.13–14.73; test for heterogeneity not significant). A total of seven of the 16 studies, comprising 1056 patients, reported data on patients in whom the doses of concomitant immunosuppressants and steroids were comparable in each study arm (Figure 5B). Meta-analysis confirmed the higher incidence of NODM in patients receiving TAC (75 out of 623, 12.0%) compared with patients treated with CSA (13 out of 433, 3.0%) with an OR of 4.21 (2.26–7.85) in favor of CSA (p < 0.00001; interstudy range: 1.10–6.46, test for heterogeneity not significant). Finally, data were analyzed according to the length of follow up: 12 of the 16 studies provided data at least 1 year post-transplantation, while four of 16 analyzed NODM at 6–8 months' post-transplantation. At both 1 year (OR = 2.53, p < 0.0001) and 6–8 months (OR = 2.27, p = 0.05), there was a significantly higher incidence of NODM in patients receiving TAC compared with CSA.

Eight out of 16 studies selected for NODM meta-analysis provided data on 1-year graft rejection rates. Meta-analysis of patients treated with TAC (n = 1271, 38.6%) displayed significantly lower acute rejection rates compared with those treated with CSA (n = 1048, 50.0%) with an OR of 0.64 in favor of TAC (p = 0.0001, interstudy range: 0.51–0.81, test for heterogeneity not significant). An additional two studies displayed data on 6-month graft rejection with similar results (OR = 0.49, p = 0.02). Data on patient and graft survival, however, did not display statistically significant differences between the two treatments: seven out of 16 studies containing data on 1-year graft survival rates showed an OR of 1.15 for TAC (n = 1231) vs. CSA (n = 1008, p = n.s.), and the two studies containing 6-month graft survival rates showed no statistically significant differences (OR = 1.13, p = n.s.). Patient survival rates were also not significantly different between the two treatment groups at either 1 year (OR = 1.02, seven studies, p = n.s.) or 6 months (OR = 0.93, 2 studies, p = n.s.).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Cyclosporine and TAC have produced a remarkable improvement in patient and graft survival and represent the current foundation therapy for solid organ transplantation. However, both of these agents have been implicated in the development of NODM, now recognized as a serious adverse consequence of immunosuppressive therapy following transplantation. This systematic review of NODM incidence data reported over the past decade shows that TAC has been associated with a higher rate of NODM throughout this time, and that this trend has been observed across all transplanted organs. These world-wide data are concordant with a recent meta-analysis by Kasiske et al. comparing TAC vs. CSA using renal data derived from US centres only (RR = 1.53 in favor of CSA) (48). Furthermore, early results of a recent randomized trial in liver transplant patients (n = 499) also showed a higher NODM rate for TAC than for CSA (14% and 7%, respectively; p < 0.05; 49).

The doses of both calcineurin inhibitors have been cautiously reduced during the past decade in an attempt to optimize the risk/benefit of these drugs. Linear regression of the kidney, liver and heart transplantation data reported here show an apparent trend towards a reduction in average NODM rates over this time for both TAC and CSA, particularly when these agents are used with MMF (33,45). It is difficult to establish the statistical precision of this trend owing to the varying sample weights and study conditions. However, significant differences in the NODM rates associated with TAC vs. CSA have persisted in recent studies (31,32,44,49). This observation may not pertain following pancreas transplantation, where TAC is now the principal therapy, although few direct comparisons of CNIs were published during the period of study (50–52).

The meta-analysis in the current study included 16 prospective, randomized studies with a comparable definition of NODM (incidence of insulin dependence) and a clear distinction between NODM and pre-existing disease. The analysis showed an incidence of NODM of 10.4% in patients receiving TAC compared with 4.5% in patients receiving CSA [OR (2.38, 1.68–3.37) in favor of CSA; p < 0.00001]. This correlation was consistent in patients undergoing renal transplantation [TAC 9.8% vs. CSA 2.7%; OR 3.70 (2.15–6.36) in favor of CSA; p < 0.00001], and nonrenal transplantation [TAC 11.1% vs. CSA 6.2%; OR 1.82 (1.23–2.69) in favor of CSA; p = 0.003].

It is possible that the results of the above meta-analyses may have been influenced by the steroid doses employed rather than simply reflecting an increased diabetogenicity of TAC. The data reported were generally not sufficiently precise to enable direct analysis of this effect. A meta-analysis was therefore performed on the seven studies in which both study arms were comparable for steroid dosages and concomitant therapies. Once again a similar correlation between NODM rates with TAC and CSA was observed [TAC 12.0% vs. CSA 3.0%; OR 4.21 (2.26–7.85) in favor of CSA; p < 0.00001].

The data reported here represent the cumulative best evidence of NODM incidence for patients receiving CNIs, but must be interpreted cautiously because critical evaluation of the scientific literature employing an evidence-based approach indicates an important lack of highly rated studies. The Jadad system used in this review awards a total of five points based on three main criteria: study randomization (1–2 pts), double-blinding of the study (1–2 pts), and a description of withdrawals or dropouts (1 pt) (28). The studies used in this meta-analysis all received at least one point for randomization, but forfeited points for a lack of description of the randomization process, of withdrawals/dropouts, or of double blinding. Cyclosporine and TAC concentrations are normally closely monitored and the dose adjusted to ensure optimal therapeutic effect. Double-blinding is therefore difficult, and has often been forgone in immunosuppression research throughout the past decade.

Several cautionary factors must be considered when extrapolating these results to current clinical practice. First, it appears that the incidence of NODM may have been reduced perceptibly over time owing to increased therapeutic proficiency or change in comedication, specifically through the introduction of MMF. Careful scrutiny of studies now in progress will be essential to determine this. Second, while there was no conclusive evidence that complementary immunosuppressive therapy had an important influence on the incidence of NODM, dosing was not always reported in the necessary detail and treatment was often modified during the course of the studies. Evidence was therefore inadequate in many of the publications to accurately determine the influence of this variable. Third, this study did not investigate the influence of cadaveric vs. living donors, single vs. multiple organ transplants, primary transplant vs. retransplant, or extended donor criteria owing to a lack of explicit information in the articles analyzed. However, of the meta analysis studies that did provide specific details, all overwhelmingly employed cadaveric over living transplants, excluded multiorgan transplant patients, and either excluded retransplant patients or had a similar proportion of retransplants in each treatment arm. Finally, the diagnostic threshold for detection and reporting of NODM varied between articles in this systematic review. For this reason, the meta-analyses reported the incidence of de-novo requirement for insulin treatment, thus selecting the most clearly defined measure of diabetes. New criteria for diagnosis of diabetes have recently been established, and the relative incidence of abnormal fasting glucose or impaired glucose tolerance has not yet been well established for either of these agents.

Cyclosporine and TAC share a similar therapeutic action, and common mechanisms have been proposed to explain their diabetogenic potential, which include decreased insulin secretion, increased insulin resistance and inhibition of steroid metabolism (17). There is a significant body of evidence linking CSA and TAC to decreased insulin secretion. A dose-dependent CSA-induced decrease in insulin secretion has been observed in rat and human islet cells, while dogs treated with CSA show decreased insulin secretion following glucagon stimulation (53–55). A similar dose-dependent TAC-induced decrease in insulin secretion has also been observed in a variety of models, including mice with human pancreatic islet transplants, and in rats and dogs (56–58). Decreased insulin secretion may result from compromised insulin production either via direct B-cell toxicity or via inhibition of DNA synthesis. Morphological changes indicating B-cell toxicity after exposure to CSA or TAC include vacuolization and degranulation (58,59). Inhibition of DNA synthesis by either immunosuppressant may result from the blockade of calcineurin signaling required to activate the NFAT transcription factor that mediates insulin gene transcription. Links between CSA, TAC and insulin resistance have been established by various clinical observations. Studies of CSA-treated kidney transplant recipients have shown that even patients with normal glucose tolerance have increased insulin secretion, while studies of liver transplant recipients have shown hyperinsulinemia in both CSA- and TAC-treated patients (60,61).

Despite the similarity in proposed diabetogenic mechanisms, the explanation for the higher observed risk of NODM among TAC-treated patients is not yet clear. One answer may lie in the localization of the specific binding proteins for TAC (FKBP-12) and CSA (cyclophilin). FKBP-12 has been shown to be highly concentrated in the insulin-producing beta-cells of the pancreas, while cyclophilin appears to be preferentially localized to heart, liver and kidney (62,63). This binding protein distribution may result in a more potent effect of TAC than of CSA on pancreatic cells, with a greater reduction in insulin production and a greater diabetogenic effect.

Important risk factors for the development of NODM include African ethnicity, increased age, obesity, increased number of transplants, a family history of diabetes, and the use of prednisone (48). No standardized recommendations have yet been developed to guide the selection of CNI in such patients, or their use once this condition has developed. Studies of glucose metabolism in nondiabetic kidney transplant recipients demonstrate lower C-peptide and insulin levels following glucose administration and higher HbAlc in TAC-treated patients compared with CSA-treated patients (32,38). This suggests that patients at high risk may benefit from treatment with CSA, although prospective studies are required to elucidate this. Furthermore, there are reports that indicate patients who develop NODM while receiving TAC may benefit from conversion to CSA (32,64,65). At least one study also indicates that TAC patients who develop NODM may become normoglycemic without conversion (66).

In summary, CSA and TAC represent important advances in clinical immunosuppression. The data analyzed here indicate that they produce comparable results for patient and graft survival throughout the first post-transplant year, while the incidence of acute graft rejection was lower in patients treated with TAC. Both of these drugs are associated with an increase in the development of NODM. However, the results of this literature review and meta-analyses indicate that the risk of NODM has been significantly higher during the past decade in patients receiving TAC, and suggest that selection of immunosuppression may help to reduce the risk of NODM in transplant patients with risk factors for the disease.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

This study was funded by a research contract from Novartis Pharma Basel to Syreon Corporation.

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  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
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