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Jagpal et al. Vessel Plus 2018;2:24 I http://dx.doi.org/10.20517/2574-1209.2018.27 Page 9 of 14

treated patients. The results of this study confirmed the advantages of tacrolimus over ciclosporin.

Early studies used a combination of azathioprine and corticosteroids with either tacrolimus or ciclosporin.
Nevertheless, since its use in the first heart transplant operation, treatment with azathioprine has been
replaced in clinical practice by MMF due to its increased toxicity. An early investigation into the substitution
of MMF for azathioprine found that in 650 heart transplant patients, MMF was more effective in reducing
[18]
mortality and rejection and was associated with decreased toxicity . In the 2000’s, Kobashigawa and
colleagues further investigated this area. They found that a combination of tacrolimus and MMF offered
more advantages than ciclosporin and MMF in cardiac transplant patients, including fewer rejections and
an improved side effect profile. Post-transplant diabetic rates were greater among the tacrolimus and MMF
[35]
treated group, although this difference was not statistically significant . The PTDM results Kobashigawa
produced reflect similarity with the current study.

In the studies mentioned above, all patients are followed for a short time interval. Trials comparing triple
immunosuppressive strategies involving tacrolimus or ciclosporin with MMF and steroids over a long term
[36]
are rarely published. Guethoff et al. (2013) used prospective randomised trial to follow-up heart transplant
patients over 10 years. Long term analysis found a lower incidence of rejection in the tacrolimus group, but
[36]
there was no difference between groups in long-term survival .

Clinical trials have been principle to the success of heart transplantation. Despite the vast number of trials,
there is no single validated immunosuppression regimen. Nevertheless, protocols used worldwide in 2017 are
strongly influenced by the results of SYMPHONY study which demonstrated that a low dose of tacrolimus,
[37]
MMF and corticosteroids had the best allograft outcomes .
Since the superior rejection profile of tacrolimus has been established, research has been directed towards
the side effects produced by the two CNIs and the consequences of this. However, there is limited data
surrounding the onset of diabetes after tacrolimus or ciclosporin treatment in cardiac transplant patients.
[38]
A large European multicentre trial published by Grimm et al. (2006) revealed the incidence of PTDM
in heart transplantation was significantly higher in the tacrolimus group. Accordingly, more tacrolimus
[38]
patients required insulin therapy .

[38]
Grimm et al. ’s results highlighting the diabetogenic potential of tacrolimus, it should be noted that
published studies in this area have often failed to reach significance to due low patient numbers. A study by
[39]
Teebken et al. (2002) reflects this, as out of 32 heart transplant recipients, 4 patients treated with tacrolimus
developed PTDM compared with 1 patient treated with ciclosporin. The small sample size makes these
results difficult to statistically analyse and compare.

Corticosteroids are also associated with a greater risk of developing diabetes after heart transplantation.
Heart transplant recipients developing diabetes were found to be receiving higher mean doses of
[40]
prednisolone compared to those without the condition . Consequently, an increased number of studies
are considering the effect of corticosteroid-sparing and corticosteroid-free regimens on the development
[41]
of PTDM. Baran et al. (2002) have shown that tapering of and weaning patients from corticosteroid
treatment considerably lowered the incidence of diabetes.

Impact of PTDM on heart transplantation
PTDM has been a recognised complication of transplantation for several years, despite this, the importance
of the condition has been underestimated. In the general population, it is putative that diabetes increases risk
of cardiovascular disease (CVD). Nonetheless, the complications associated with diabetes were not thought
to be a concern for patients who had undergone heart transplantation. Initial studies into the effect of PTDM