Diabetes mellitus tacrolimus

Insulin-dependent posttransplant diabetes mellitus (PTDMj. lnsulin-dependent PTDM was reported in 20% of tacrolimus-treated kidney patients without pretransplant history of diabetes mellitus in the Phase 3 study. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at 1 year and in 50% at 2 years posttransplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. 

The side effects associated with tacrolimus administration include nephro- and hepa-totoxicity, hypertension, tremors, seizures, diabetes mellitus, neuropathy, blurred vision, depression, loss of appetite andconfusion. Tacrolimus may cause opportunistic... 

Tacrolimus + sirolimus, tacrolimus + mycophenolate mofetil, and ciclosporin + sirolimus have been compared in recipients of their first kidney transplant (52). One-year patient and graft survival did not differ. Ciclosporin + sirolimus was associated with increased serum creatinine concentrations, reduced creatinine clearance, more frequent protocol discontinuation, more antihyperlipidemic drug therapy, and a higher incidence of post-transplant diabetes mellitus. 

The risk of post-transplant diabetes mellitus is greater with tacrolimus than with ciclosporin, but this was mostly true in black patients and during the initial months after transplantation (1084). In one study, insulin sensitivity, alpha and beta cell function, and beta cell reserve were studied in 14 hepatitis C-positive patients with liver transplants, who took tacrolimus or ciclosporin maintenance for 1 year (1085). The patients were matched for low prednisolone dosage (1.1 mg/day versus 1.3 mg/day), body mass index, lean body mass, and sex, and compared with eight controls. Insulin sensitivity and insulin secretory reserve were significantly different from controls, but there was no significant difference between ciclosporin and tacrolimus. 

The incidence, mechanism, and risk factors of tacroli-mus-associated diabetes mellitus are still debated. In 58 patients investigated 1-3 years after liver transplantation there was a significantly higher incidence of diabetes mellitus with tacrolimus (n = 32) compared with ciclosporin (n = 26) (1086). Newly-diagnosed diabetes... 

In a pooled analysis of four randomized trials of tacrolimus versus ciclosporin after renal transplantation, the prevalence of post-transplant diabetes mellitus at 1 year (two studies, 532 patients) was five times higher with tacrolimus than with ciclosporin (OR = 5.0 95% Cl = 2.0, 12.4) (1094). In the opinion of the US FDA, diabetes mellitus after transplantation was a significant hazard in tacrolimus-treated patients, even though about half of the patients were no longer taking insulin at 2 years after transplantation (1095). 

The exact mechanisms of tacrolimus-induced diabetes are unknown. In one renal transplant patient with genetic susceptibility, tacrolimus was associated with insulin-dependent diabetes mellitus and the simultaneous occurrence of anti-glutamic acid decarboxylase antibody (1096). Within 2 months after conversion from tacrolimus to ciclosporin, the antibody was no longer detected and the patient s insulin requirements fell dramatically. Tacrolimus-induced direct beta cell toxicity, with... 

Diabetes mellitus after transplantation occurred more often in hepatitis C virus-positive patients taking tacrolimus than in those taking ciclosporin (58 versus 7.7%). In hepatitis C virus-negative patients, the rates of diabetes mellitus were similar. The authors concluded that hepatitis C is strongly associated with diabetes mellitus after renal transplantation because of the greater dia-betogenicity of tacrolimus. 

In a meta-analysis of 16 studies of patients who were taking tacrolimus (n — 1636) or ciclosporin (n = 1407) the incidence of type 1 diabetes mellitus was significantly higher among those taking tacrolimus (10% versus 4.5%)... 

The effect was observed in those with renal transplants (9.8% versus 2.7%) and those with other organ transplants (11.1% versus 6.2%), and among patients who were taking equal doses of concomitant medications in both treatment arms (12% versus 3%). Further factors associated with diabetes mellitus after kidney transplantation were older recipient age, a cadaveric organ, hepatitis C antibody status, an episode of rejection, and the use of tacrolimus (versus ciclosporin) cumulative glucocorticoid dose and calcineurin inhibitor trough concentration were not associated factors (1100). 

Paolillo JA, Boyle GJ, Law YM, Miller SA, Lawrence K, Wagner K, Pigula FA, Griffith BP, Webber SA. Posttransplant diabetes mellitus in pediatric thoracic organ recipients receiving tacrolimus-based immunosuppression. Transplantation 2001 71(2) 252-6. 

Lohmann T, List C, Lamesch P, Kohlhaw K, Wenzke M, Schwarz C, Richter O, Hauss J, Seissler J. Diabetes mellitus and islet cell specific autoimmunity as adverse effects of immunsuppressive therapy by FK506/tacrolimus. Exp Clin Endocrinol Diabetes 2000 108(5) 347-52. 

Moxey-Mims MM, Kay C, Light JA, Kher KK. Increased incidence of insulin-dependent diabetes mellitus in pediatric renal transplant patients receiving tacrolimus (FK506). Transplantation 1998 65(5) 617-9. 

Tanabe K, Koga S, Takahashi K, Sonda K, Tokumoto T, Babazono T, Yagisawa T, Toma H, Kawai T, Fuchinoue S, Teraoka S, Ota K. Diabetes mellitus after renal transplantation under FK 506 (tacrolimus) as primary immunosuppression. Transplant Proc 1996 28(3) 1304-5. 

Adverse Effects. Common side effects of tacrolimus include gastrointestinal disturbances (cramps, nausea, diarrhea, constipation), weakness, fever, and skin rashes and itching. More serious problems include renal and central nervous system (CNS) toxicity (headache, anxiety, nervousness, seizures).41 Tacrolimus is also associated with problems with glucose metabolism (hyperglycemia, glucose intolerance), and can cause diabetes mellitus in certain individuals.73... 

Clinical experience following kidney transplantation suggests that primary prophylaxis with tacrolimus results in 1-year graft and patient survival rates that are equivalent to those achieved with Cy A therapy, although with lower rates of acute rejection episodes.Five-year follow-up data suggest improved graft survival with tacrolimus compared with Cy A. Nephrotoxicity, hypertension, and posttransplant diabetes mellitus may occur and v/ere reported commonly in the early studies. ... 

Ciclosporin versus tacrolimus In a retrospective comparison of ciclosporin and tacrolimus in 100 liver transplant recipients who were followed for 12 months, the incidences of new-onset arterial hypertension and diabetes mellitus were not different [6 ]. However, there was a significantly higher incidence of hyperlipidemia in those who took ciclosporin, with a greater difference at 6 months than at 12 months. 

Systematic reviews In a systematic review of 10 randomized trials in 952 heart transplant recipients, a ciclosporin-based immunosuppressive regimen caused more hypertension, hyperlipidemia, gingival hyperplasia, and hirsutism than tacrolimus [7 ]. There were no significant differences with regard to acute rejection, diabetes mellitus, renal dysfunction, infection, malignancy, or neurotoxicity. 

Kurzawski M, Dziewanowski K, Kedzierska K, Gomik W, Banas A, Drozdzik M. Association of calpain-10 gene potymorphism and posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus. Phar-macogenomics J 2010 10(2) 120-5. 

Metabolism The rate of new-onset diabetes mellitus has been studied in 20 124 patients taking sirolimus after kidney transplantation, using data from the US Renal Data System, compared with patients taking ciclosporin, mycophenolate mofetil, or aza-thioprine [60 ]. Those who took sirolimus were at increased risk of diabetes, whether it was used in combination with ciclosporin (adjusted HR = 1.61 95% Cl = 1.36,1.90), tacrolimus (adjusted HR = 1.66 95% Cl = 1.42, 1.93), or mycophenolate mofetil or azathioprine (adjusted HR = 1.36 95% Cl = 1.09,1.69). 

Observational studies In a retrospective study of the effects of telaprevir based triple therapy (telaprevir in combination with peg interferon alfa (peg IFNa) + RBV on nine patients) four patients were hospitalised because of adverse events (bacterial pneumonia, tacrolimus overdosing with renal failure, infectious enteritis, exacerbated diabetes mellitus and raised liver enzymes) [76=]. Anaemia (n=4), thrombocytopenia (n=4) and skin reactions (n = 3) were also reported. 

A retrospective study of 33 heart transplant patients on tacrolimus (TAC) with everolimus, adverse events included hyperlipaemia (48.5%), hypertension (33.3%) and diabetes mellitus (36.4%) [17 ]. 

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