Adverse effects associated with calcineurin inhibitors may impact their clinical utility in some patients. This study characterizes the clinical outcomes of liver transplanted (LT) patients who experienced diabetes mellitus (DM) on tacrolimus-based regimen and were converted to cyclosporine-based therapy. Since January 2002, all patients with DM on a tacrolimus-based regimen were recruited and converted to cyclosporine-based therapy, after a 6-month minimal follow-up after LT. Clinical and laboratory data related to the clinical course of the patients were recorded. Twenty-five patients were included after a median delay of 54 months after LT [seven women and 18 men, 51 years (range 30-69)]. There were 11 patients with insulin-treated DM (ITDM), 14 patients with noninsulin-treated DM (NITDM), and the glycemic control was poor (HbA1c > 6.5%) in 13/25 patients (52%). After a median follow-up of 20 months after conversion, there were four patients with ITDM, 17 patients with NITDM, and four patients without DM, and the glycemic control was poor in 3/25 patients (12%). Four patients returned to tacrolimus because of arterial hypertension or digestive side-effects. In conclusion, our results suggest that conversion from tacrolimus to cyclosporine in stable LT patients with DM is well tolerated and beneficial on glycemic control. Liver Transpl 12:659–664, 2006. © 2006 AASLD.
During the past 20 years, the introduction of cyclosporine (CyA) and tacrolimus significantly improved the results of organ transplantation, especially liver transplantation (LT). Long-term outcomes, however, are still compromised by rejection, infection, cancer, and CyA- or tacrolimus-induced adverse effects. When compared to CyA, tacrolimus has been associated with a reduced incidence of hypertension and hyperlipidemia.1 However, tacrolimus is known to cause a variety of adverse effects, including nephrotoxicity, neuro-psychiatric toxicity, diabetogenicity, gastrointestinal toxicity, and other less common toxicities.1–5 Usually, these adverse effects are dose-related and reversible with dose adjustment.6 When side effects persist despite dose reduction, conversion to CyA might be an alternative.7, 8
Diabetes mellitus (DM) occurring after organ transplantation has been recognized for many years, ranging between 2% and 53% of the patients.9 Initial high rate of DM in transplanted patients was related to the use of high dose of steroids.10 The introduction of calcineurin inhibitors allowed to drastically reducing the dose of steroids and the rate of DM declined. New onset insulin dependant DM (IDDM) has been estimated to occur in 13.4% of the patients after organ transplantation, with a higher incidence in tacrolimus- than in CyA-treated patients (16.6 vs. 9.8%).11
Recently, it has been demonstrated that development of DM after LT is associated with reduced patient survival.12, 13 This led us to prospectively investigate the safety and accuracy of a conversion from tacrolimus to CyA in LT patients with DM.
PATIENTS AND METHODS
Between October 1990 and January 2005, 738 liver transplantations were performed at our center. In the case of 408 adult patients, tacrolimus was the primary immunosuppressive agent. These patients received an initial tacrolimus dose of 0.1 mg/kg per day, which was adjusted to maintain a blood trough level of 15 ± 20 ng/mL during the first month after transplantation, 10 ± 15 ng/mL during the second and third months, and 5 ± 10 ng/mL thereafter. In addition, patients received 500 mg IV methylprednisolone after reperfusion. Starting on postoperative day 1, methylprednisolone was tapered from 200 mg to 20 mg within 5 days; thereafter, methylprednisolone was maintained at 20 mg/day and then tapered by 2.5 mg/d/month to a maintenance dose of 0 to 5 mg/day after 6 months post-transplantation. For all the patients included in this study, age, liver disease, interval to conversion, tacrolimus dose (mg/kg), and trough blood level (ng/mL) at conversion were recorded.
Post-transplant [insulin-treated (ITDM) or non insulin-treated (NITDM)] DM was defined as a fasting blood glucose (FBG) levels higher than 126 mg/dL on at least two occasions, as recommended by the American Diabetes Association,14 or treated by hypoglycaemic agent (oral hypoglycaemic agent or insulin). All the patients received dietary restriction only as initial therapy; those patients refractory to diet control alone or those with FBG of 180 to 250 mg/dL or glycosylated hemoglobin (HbA1C) over 8% were started on oral hypoglycemic agents; patients with FBG over 250 mg/dL or those unresponsive to oral hypoglycaemic agents (HbA1C over 8%) were started on insulin subcutaneously. Patients with a diagnosis of ITDM were given a glucometer and instructed on monitoring blood sugars at home on a 2 to 3 times daily basis.
The primary end-point of this study was response to conversion, which was graded as resolved, improved, or unchanged, based on the evolution of initial characteristics of DM.
Aim of the Study
Since January 2002, all patients with DM on a tacrolimus-based regimen were recruited and converted to cyclosporine-based therapy, after a 6-month minimal follow-up after LT. Informed consent was obtained from all the patients. The indication/justification to convert patients was the occurrence of de novo post-transplantation DM and/or the diagnosis of unstable DM. Clinical and laboratory data related to the clinical course of the patients were prospectively recorded to investigate the safety and accuracy of conversion.
The administration of CyA (microemulsion formulation) was delayed for approximately 24 hours after the discontinuation of tacrolimus (day 0). The timing and amount of the first CyA dose depended on hepatic and renal functions of the patient and tacrolimus dose. The initial dose of CyA was divided two doses. Doses of CyA were titrated to maintain CyA trough level between 50 and 150 ng/mL, according to renal and hepatic functions.
Following conversion, patients were evaluated weekly for the first 4 week and then at months 2, 3, 6, and every 3 months thereafter. The clinical data of body weight, daily requirement of insulin or oral blood glucose-lowering agents, CyA blood levels, CyA side-effects (especially arterial hypertension and hyperlipidemia), and occurrence of acute rejection episodes were monitored. The laboratory data of serum creatinine, FBG, whole blood CyA level, uric acid, and serum cholesterol/triglycerides were tested at each visit. The dose reduction of insulin or oral blood glucose-lowering agents, the adequacy of glucose control reflected in FBG and level of HbA1C were the criteria for evaluating outcome of DM. Patients showing severe side effects or rejection episodes returned to tacrolimus. The minimum follow-up after entry into the study was 6 months. In addition, were analyzed the graft and patient survival after conversion.
Variables in the two groups of patients were compared using the Student's t-test, χ2 test, and Mann-Withney non-parametric test and considered as significant if P < 0.05.
Characteristics of the Patient Population
Since January 2002, 25 patients were included in the study, after a median delay of 54 months after LT [seven women and 18 men, median age 51 years (range 30-69)]. At the time of inclusion, DM was known for 47 months as a median. There were 11 patients treated with insulin and 14 patients treated with oral blood glucose-lowering agents. The main baseline characteristics of the patients are summarized in Table 1. Among this cohort of patients, seven had prior history of DM, before LT. All the patients received tacrolimus with or without mycophenolate mofetil and without steroids, at the time of conversion. Median follow-up after conversion was 20 months (range 6-36). Before conversion, median trough level of tacrolimus was 6.4 ng/mL (range 2.3-8.1) and median daily dosage was 4.5 mg/day.1–14 After conversion, median trough level of CyA was 68 ng/mL (range 37-128) and median daily dosage was 200 mg/day (100-300). Dosage of mycophenolate mofetil was not significantly modified during follow-up: 1.5 g/day in mean for the 18/25 treated patients.
Table 1. Characteristics of the Patients at Conversion
|Median age||51 (range 30–69)|
|Sex ratio (male/female)||18/7|
|Indication for LT|| |
| Alcoholic cirrhosis||16|
| Viral cirrhosis||8|
|History DM before LT|| |
|Median delay between LT and conversion (months)||54 (range 6–92)|
|Immunosuppressive regimen at conversion|| |
Evolution of Diabetes Mellitus
Outcome of DM is summarized in Table 2. Body weight (and BMI) was stable during the study period, with a mean weight of 81.7 kg before conversion and 82 kg after conversion.
Table 2. Characteristics of the Patients (n=25) Before and After (End of Follow-Up) Conversion
|Diabetes Mellitus|| || || |
|ITDM/NITDM/no DM (n)||11/14/0||4/17/4||<0.05|
|HbA1c (%), mean (range)||8.3 (6–12)||6.8 (5–8.5)||<0.05|
|HbA1c<6.5%/ HbA1c>6.5% (n)||12/13||22/3||<0.05|
|FBG (mg/dL), mean (range)||185 (142–389)||133 (86–289)||<0.05|
|Tolerance|| || || |
|ALT level (IU), mean (range)||19 (7–112)||22 (9–77)||NS|
|Serum creatinine (μmol/L), mean (range)||115 (73–150)||122 (71–176)||NS|
|Total cholesterol (mmol/L), mean (range)||4.7 (3.4–5.7)||5.1 (3.6–6.7)||NS|
|LDL cholesterol (mmol/L), mean (range)||3.7 (2.5–5.1)||3.9 (2.5–5.2)||NS|
|Triglycerides (mmol/L), mean (range)||1.6 (0.80–3.40)||1.8 (0.75–5.40)||NS|
|Uric acid (μmol/L), mean (range)||370 (210–520)||380 (220–550)||NS|
|PAS/PAD||130/75 (110/55–160/95)||135/75 (110/60–160/95)||NS|
|Body mass index||27 (20–38)||27 (20–36)||NS|
|Body weight (kg), mean (range)||81.7 (52–127)||82 (50–126)||NS|
After conversion, mean FBG levels decreased from 185 mg/dL (on day 0) to 133 mg/dL (at the time of evaluation; P < 0.05). From the 11 patients with ITDM, after conversion, decreasing glucose levels necessitated decreasing insulin doses in two patients, discontinuing insulin in seven patients (six patients received oral hypoglycemic agent). Similarly, after conversion, from the 14 patients with NITDM, decreasing glucose levels necessitated decreasing oral hypoglycemic agent doses in 4 patients, and discontinuing oral hypoglycemic agent therapy in three patients. Mean HbA1C decreased from 8.3% (on day 0) to 6.8% (at the time of evaluation; P < 0.05). Moreover, initial HbA1C was under 6.5% (good glycemic control) in 12/25 patients (48%), whereas glycemic control was good in 22/25 patients (88%) after conversion.
In summary, response to conversion, based on the evolution of DM, was graded as resolved in four patients (HbA1c and FBG within the normal range and no hypoglycaemic treatment), improved in 15 patients (normalized HbA1C, i.e., <6.5% or decreasing oral hypoglycemic agent or insulin doses for patients with initial HbA1C<6.5%), or unchanged in six patients. So, resolution or improvement of DM occurred in 19/25 patients (76%). An analysis-based several clinical variables failed to identify parameters that may predict which patients may benefit from conversion (Table 3).
Table 3. Characteristics of the Patients (n=25) According to the Outcome After Conversion
|Median age||50 (range 30–62)||52 (range 33–69)||NS|
|Sex ratio (male/female)||14/5||4/2||NS|
|History of DM before LT (n, %)||5 (26%)||2 (33%)||NS|
|Initial HbA1c (%), mean (range)||8.2 (6–9.5)||8.5 (6–12)||NS|
|HCV related cirrhosis (n, %)||3 (16%)||1 (17%)||NS|
|Alcoholic cirrhosis (n, %)||12 (63%)||4 (67%)||NS|
|Median delay between LT and conversion (months)||52 (6–92)||55 (8–80)||NS|
|Initial FBG (mg/dL), mean (range)||180 (142–389)||190 (150–350)||NS|
|Body mass index||27 (20–38)||27 (20–37)||NS|
Safety and Tolerance of Conversion
Target CyA trough concentrations were achieved by 2 weeks following conversion in 22/25 patients (80%), with 100% of patients achieving their target levels after 6 weeks. Outcome after conversion is summarized in Table 2. No graft lost or patient death occurred.
Mean serum creatinine was stable during the study period: 115 μmol/L before conversion and 122 μmol/L after conversion. Similarly, mean serum ALT was stable during the study period: 19 IU/L (normal <45 IU/L) before conversion and 22 IU/L after conversion. One mild acute rejection episodes occurred during the study period, but a liver biopsy was available in only 8/25 patients. There were six patients with treated hyperlipidemia before conversion, with stable biological parameters during the study. No de novo case of hyperlipidemia occurred during the study. Mean cholesterol and triglycerides levels were stable during the study: 4.7 mmol/L and 1.6 mmol/L before conversion and 5.1 mmol/L and 1.8 mmol/L after conversion, respectively. There were 10 patients with previously treated arterial hypertension before conversion, that was stable in seven patients and uncontrolled in three (see above) during the study. One case of de novo arterial hypertension occurred during the study.
By the end of follow-up, four patients (16%) returned to tacrolimus because of the development of gingival hyperplasia, digestive side-effects and oedema (n=1) or uncontrolled arterial hypertension in previously treated patients (n=3). Two of those four patients have initial improvement of DM but returned to initial status after re-conversion to tacrolimus. All side-effects resolved after return to tacrolimus.
The introduction of calcineurin inhibitors, 20 years ago, has resulted in significant advances in management and outcome in solid organ transplantation. Tacrolimus afforded the possibility of an alternative to CyA, albeit with several toxic side-effects, which in some ways differ from those of CyA. These potentially severe side-effects can limit effective immunosuppression and patient survival following transplantation. DM after organ transplantation has been recognized for occurring with a higher incidence in tacrolimus-treated patients11 and is associated with poorer patient survival.12, 13 The results of the present report strongly suggest that conversion from tacrolimus to CyA in stable LT patients with DM is well tolerated regarding renal function, cardiovascular risk profile, and side-effects, and is beneficial. Since conversion was made after a median delay of 54 months after LT, spontaneous improvement (or resolution) of DM can probably be excluded. Nevertheless, in the absence of controls, it can be postulated that closer follow-up and better dietary intervention after inclusion could perhaps partially explain the better control of DM in our patients. Moreover, results of glucose tolerance tests before LT were unavailable and would have been of great relevance for the interpretation of our results.
In all of our patients, reduction in tacrolimus dosage was the first step in clinical management, as demonstrated by the fact that all of our patients had tacrolimus levels at subtherapeutic to therapeutic range with low trough levels (<8 ng/mL) before conversion. As a result, we did not consider reduction in tacrolimus concentrations to even lower levels as a reasonable therapeutic option. Moreover, other immunosuppressive agents were not modified during follow-up, and the influence of steroids can be ruled out because none of these patients was under steroids as a maintenance immunosuppressive therapy.
The mechanism of tacrolimus-induced DM is still discussed. Filler et al. investigated intravenous glucose tolerance (glucose, insulin, C-peptide concentrations, and HbA1c) in paediatric renal transplant recipients on CyA or tacrolimus.15 The mean concentration of tacrolimus was 7.5 ± 2.2 ng/mL. Baseline glucose concentration was significantly higher in patients under tacrolimus. Interestingly, baseline insulin concentrations and C-peptide concentrations were identical in both groups, but there was a significant reduction (by two-fold) of the insulin first-phase concentrations, both after 1 and 3 minutes in the tacrolimus group, suggesting that post-transplant glucose intolerance could be due to a dose-dependent, direct effect of tacrolimus on the pancreatic beta cell function. These results were confirmed by Uchizono et al. who studied the mechanism of tacrolimus-induced impairment of insulin secretion using isolated rat pancreatic islets.16 These authors observed that tacrolimus time-dependently suppressed glucose-stimulated insulin secretion, and at a therapeutic concentration, it suppressed glucose-stimulated insulin secretion to 32 ± 5% of the control value. Moreover, their results suggest that tacrolimus impairs insulin secretion at multiple steps in stimulus-secretion coupling. Interestingly, tacrolimus- induced impaired insulin secretion was reversed 3 days after removal of the drug.
The clinical negative impact of DM on LT patients survival was demonstrated from large cohort studies12, 13 and led us to start the pilot study we report here. In the study of Baid et al. on 176 LT patients treated with tacrolimus, the development of post-transplant diabetes was significantly higher in patients who presented with HCV infection and methylprednisolone boluses and negatively influenced patients survival (hazard ratio 3.67).12 These results were confirmed from the retrospective analysis of the UNOS data from 1994 to 2001, on 1,629 patients with type 1 DM and 1,618 patients with type 2 DM, compared to 17,974 nondiabetic patients.13 Five-year patient survival was significantly lower for type 1, and in a lesser extent for type 2, diabetics compared with nondiabetics. Preexisting coronary artery disease (CAD), but not hypertension, was also an independent predictor of poor 5-year survival, and LT recipients with type 1 or CAD had approximately 40% lower 5-year survival compared with patients without DM or CAD. The potential effect of improvement of DM after conversion from tacrolimus to CyA on cardiovascular complications and survival needs further investigation on large cohorts. This must be evaluated with caution because the cardiovascular effects of CyA have been well recognized (by the way of CyA-induced hpertension and hyperlipidemia), and could counterbalance the beneficial effect on DM. In this field, the recent and comprehensive report of Baid- Agrawal et al. is of great relevance. These authors reported their results on conversion from CyA to tacrolimus in 22 adult renal transplant recipients with serum total cholesterol greater than 200 mg/dL,17 showing a significant improvement in fibrinogen, total cholesterol and LDL cholesterol after conversion, with no new onset or worsening of DM or significant differences in HDL cholesterol, triglycerides, homocysteine, C-reactive protein, HbA1c levels, serum creatinine, mean blood pressure, and mean number of antihypertensive medications required. Similarly, Artz et al. reported the results of a randomized controlled study on a conversion from CyA to tacrolimus in 124 renal transplant recipients, with a 2 years follow-up.18. In this study, conversion from cyclosporine to tacrolimus resulted in stable renal function, whereas continuation of cyclosporine was accompanied by a significant rise in serum creatinine. Moreover, conversion to tacrolimus resulted in a sustained reduction in systolic and diastolic blood pressure, and a sustained improvement in the serum lipid profile, leading to a reduction in the Framingham risk score. It can therefore be postulated that conversion from tacrolimus to CyA must not be proposed in patients with poor cardiovascular risk profile (hypertension and hyperlipidemia).
Conversion from a tacrolimus-based immunosuppressive regimen to a CyA-based immunosuppressive regimen is an attractive option for transplanted patients intolerant of tacrolimus. The results of such strategy have been reported only in few articles in the literature.7, 8 Moreover, our study is, to our knowledge, the largest one focusing on patients presenting with DM. Emre et al. initially reported 70 patients requiring conversion from tacrolimus to CyA [early conversion in 29 patients (41.4%) and late in 41 (58.6%)]. Indication for conversion was neurotoxicity in a third of the patients (23/70), and IDDM, only in 5 patients (early conversion for all).7 All early-conversion patients showed improvement/resolution of symptoms. A limitation of this study was that resolution of symptoms, especially DM, might have been spontaneous resulted from changes in other immunosuppressive agents (especially steroids for patients with DM). More recently, Abouljoud et al. reported the results of a multicenter study and characterized the clinical outcomes of transplanted patients rescued with CyA because of intolerance to tacrolimus.8 The indication for conversion to CyA in the 157 enrolled patients was neurotoxicity, gastrointestinal intolerance, nephrotoxicity, or DM. After conversion to CyA, more than two thirds of the patients had improvement or resolution of their neurotoxic, gastrointestinal, or diabetic symptoms, recalling our present report (76% of improvement or resolution of DM). Similarly to the study of Emre et al., as assessed by the authors, a limitation of this study was its observational design, which cannot exclude whether resolution of symptoms resulted from changes in other immunosuppressive agents or from the addition of other medications.
Importantly, as previously reported, the conversion of tacrolimus for CyA was not associated with a significantly increased risk of adverse effects in our study. Hypertrichosis and gingival hyperplasia have been reported to develop infrequently after conversion to CyA, and increases in systolic and diastolic blood pressures were usually clinically insignificant, excepting our three patients who required return to tacrolimus. Lipid profile was not modified in our study, but this is a major point that needs further investigation, in a larger cohort, with a long follow-up, as discussed above. In the report of Abouljoud et al., 27% of patients developed an episode of acute rejection, half of which occurred within the first 6 months after transplantation, and on average occurred within the first 3 months post-conversion.8 The low rate of rejection in our cohort (1/25, i.e., 4%) might be due to underdiagnosis, since a liver biopsy was not available for all the patients, but more probably to the long delay of conversion after LT (more than 4 years in mean).
In conclusion, conversion from tacrolimus to CyA is an effective treatment strategy for in stable LT patients with DM under of tacrolimus-based immunosuppression, with resolution or improvement of DM, without an increased risk of adverse events. These results have to be confirmed from larger studies. Therefore, in LT patients with DM, CyA might be the drug of choice when long-term treatment with a calcineurin inhibitor is indicated.