Diabetes management can be a major factor in renal transplant aftercare – can DPP-4 therapy help improve outcomes?
Around one-third of renal transplants in the US are attributed to diabetes mellitus (DM) induced end-stage renal disease. Renal transplant survival rate has significantly improved compared to dialysis due to management advances; however, as essential treatments in post-renal transplant, calcineurin inhibitors (CNIs) are associated with increased diabetes risk in patients with renal transplants. Thus, many patients require diabetes treatment post-transplant, due to DM diagnosis either before or after transplant. Poor DM control is linked to worse outcomes in patient-survival post-transplant. It is also linked to poor glucose tolerance and is worse in patients with DM before renal transplant than patients who develop DM after transplant.
The ADA guidelines recommend Dipeptidyl Peptidase-4 (DPP-4) Inhibitors as a second-line therapy after metformin in individual patients, including patients who don’t have chronic kidney disease (CKD). DPP-4 inhibitors are associated with a reduced risk of hypoglycemia and have around 0.5-1% impact on A1C readings.
The study is a systematic review covering studies that reviewed the effect of DPP-4 in patients with renal transplants. Some studies were placebo-controlled trials, while others were retrospective observational trials. Around ten articles were reviewed in this systematic review.
One study showed that DPP-4 inhibitors had a similar outcome to placebo when comparing hypoglycemia risk in patients with CKD. However, they did not provide any significant renal protection compared to the placebo (P=0.58). Similarly, the rate of renal transplant or dialysis was not affected by DPP-4 inhibitors.
On the other hand, the potential benefit of DPP-4 inhibitors is their effect on glycemic control. A study comparing vildagliptin against placebo showed that after three months of vildagliptin, A1C was reduced from 5.7% to 5.6%. It was statistically significant compared to placebo (P=0.049). Another study showed that linagliptin significantly reduced insulin requirement when used as an add-on therapy compared to insulin alone (P=<0.05) in patients’ post-renal transplants. Also, linagliptin improved insulin resistance score significantly (HOMA-IR) compared to other conventional treatments (P=0.02) when initiated within 90 days post-transplant. Compared to the HOMA-IR with patients without post-transplant DM, the results showed no difference (P=0.395).
Also, sitagliptin was shown to increase insulin secretion in a patient with new-onset DM post-transplant. The study showed that insulin secretion improved significantly by 56.3% (P=0.005) after four weeks of sitagliptin. Furthermore, insulin sensitivity increased in those patients by 25.3% (P=0.006). Additionally, in patients with new-onset DM post-transplant, vildagliptin has been shown to significantly reduce the oral glucose tolerance test (-73.7mg/dL, P<0.01) and A1C (-0.6%, P=0.016) after three months compared to placebo. Similar outcomes were reported with sitagliptin and linagliptin when they were initiated after three months from transplant.
On the other hand, DPP-4 inhibitors did not significantly affect weight in patients with renal transplants. The change in BMI was not significant after two months of treatment (P=0.48). However, when sitagliptin was combined with metformin, it had more substantial weight reduction than metformin and insulin after three months of treatment. It had a 4kg reduction compared to the 0.8kg increase in the metformin/insulin group (P<0.05). In the metformin/sitagliptin group, BMI was significantly decreased after a year of treatment by -0.8kg/m2 (P<0.05).
In terms of safety outcomes, in general, DPP-4 inhibitors are tolerated by patients. Common reported side effects included mild GI symptoms and asymptomatic hypoglycemia. In renal transplant patients, nausea and diarrhea may change the level of immunosuppressant drugs, but the effect is not significant on tacrolimus and sirolimus. There is a potential risk in using cyclosporin with sitagliptin because of potential drug-drug interaction. However, there was no significant difference in cyclosporin dose with different DPP-4 inhibitors (linagliptin, sitagliptin, and vildagliptin) P=0.411. However, the study reported higher trough levels of cyclosporin with sitagliptin than vildagliptin (P=0.036).
One limitation is that some of the studies reviewed were not blinded, indicating a potential risk for bias. Based on the study results, individual patients with renal transplants may benefit from DPP-4 inhibitors, especially if they have inadequate glycemic control.
- DPP-4 inhibitors’ role in renal transplant is linked to their glycemic control, to reduce the risk of renal complications further.
- DPP-4 inhibitors did not provide direct renal protection compared to placebo.
- Although no practical significance was reported, sitagliptin interaction with cyclosporin may require close monitoring and dose adjustment to minimize tissue rejection risk.
Anderson, Sonya et al. “Review Of Newer Antidiabetic Agents For Diabetes Management In Kidney Transplant Recipients“. Annals Of Pharmacotherapy, 2020,
Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences