Immunosuppressive agents in diabetes treatment: Hope or despair?

Table 4 Clinical research of immunosuppressive agents involved in transplantation

Ref.	Study type	Disease	Treated drugs	Numbers of drug treated patients	Drug administration	Clinical outcome	Adverse events
Posselt et al[86]	Prospective clinical trial	Islet transplantation in T1DM Patients	Belatacept	5	A dose of 10 mg/kg IV (intravenously) on days 0, 4, 14, 28, 56, and 75 after transplant	All belatacept-treated patients achieved insulin independence after single transplants	No significant side effects
Froud et al[88]	Case series	T1DM received islet transplantation	Alemtuzumab, sirolimus, tacrolimus, mycophenolic acid	3	Alemtuzumab 20 mg IV on postoperative day-1 and day 0 of initial islet infusion. Sirolimus and Tacrolimus for 3 months, then switched to Mycophenolic Acid	Improved short and long-term outcomes with 2 out of 3 achieving insulin independence Stable insulin requirements, better Mixed Meal Stimulation Index, peak C-peptide, and HbA1c at 24 months	Well-tolerated with no increased incidence of infections
Tan et al[89]	Pilot trial type 1 diabetes with end-stage renal disease	T1DM and end-stage renal disease who received islet and kidney transplantation	Alemtuzumab, sirolimus, tacrolimus	7	Alemtuzumab 15 mg IV 24 hours before transplantation and again 24 hours after islet infusion as induction. Sirolimus and Tacrolimus without glucocorticoids for maintenance	4 out of 7 insulin independent at 1 year, the rest reduced insulin use significantly. Serum C-peptide levels increased post-transplant in all patients	No major procedure-related complications
Nijhoff et al[90]	Retrospective cohort study	T1DM (islet transplant after kidney transplant)	Alemtuzumab, basiliximab, tacrolimus, mycophenolate mofetil, prednisolone	13	Alemtuzumab 15 mg subcutaneously on the day of and the day after the first islet transplantation. Maintenance included tacrolimus, mycophenolate mofetil, and prednisolone.	62% insulin independence at 1 year, 42% at 2 years. Graft function 100% at 1 year, 92% at 2 years. HbA1c significantly improved from 7.4% to 6.2%	No significant adverse events reported related to Alemtuzumab.
Kaufman et al[92]	Single-center, retrospective, nonrandomized, sequential study	Pancreas-kidney transplantation	Alemtuzumab, ATG	88 (50 Alemtuzumab, 38 ATG)	Alemtuzumab: Single dose of 30 mg intraoperatively; Antithymocyte globulin: 1.0 mg/kg intraoperatively and postoperatively for a total dose of 6.0 mg/kg	Long-term patient and graft survival rates were similar between groups; Rejection rates were nearly equivalent	Viral infectious complications were statistically significantly lower in the Alemtuzumab group; Cost of Alemtuzumab induction was lower than Antithymocyte globulin
Bösmüller et al[93]	Prospective randomized trial	Combined kidney-pancreas transplantation	Alemtuzumab + tacrolimus or ATG + tacrolimus + Mycophenolate mofetil + steroids	30 (14 Alemtuzumab group, 16 ATG group)	Alemtuzumab 30 mg + Methylprednisolone 500 mg, followed by Tacrolimus monotherapy. ATG 8 mg/kg with Tacrolimus, Mycophenolate mofetil, and steroids	1-year patient survival 100% in both groups. Kidney and pancreas survival 93% Alemtuzumab group, 100% and 87% ATG group respectively	Infectious complications comparable in both groups with a higher incidence of severe infections in alemtuzumab group
Clatworthy et al[94]	Prospective Study	Combined kidney-pancreas transplantation	Alemtuzumab	21	Two 30 mg doses of alemtuzumab administered subcutaneously on days 0 and 1; conventional immunosuppression with tacrolimus and mycophenolate mofetil	patient survival 100%; pancreas and kidney graft survival 95% and 100% respectively	One patient required a laparotomy for small bowel obstruction, and a second required evacuation ofintraperitoneal hematoma, which was found to be colonized with Candida albicans
Gangemi et al[95]	Prospective phase 1/2 trial	T1DM with islet transplantation	Daclizumab, sirolimus, tacrolimus, etanercept, exenatide	Daclizumab + sirolimus + tacrolimus: 4, Daclizumab + sirolimus + tacrolimus + etanercept + exenatide: 6	Etanercept 50 mg intravenously before islet transplantation and 25 mg subcutaneously at 3, 7 and 10 days after transplant	The Etanercept group used a smaller number of islets to achieve insulin independence	Two subjects in etanercept resumed insulin: One after immunosuppression reduction during an infectious complication, the other with exenatide intolerance
Bellin et al[96]	Prospective study	Islet allotransplants in T1DM recipients	ATG, etanercept, cyclosporine, everolimus, mycophenolic acid, mycophenolate mofetil	6	Induction: ATG and etanercept; Maintenance: Cyclosporine and everolimus for the first year, then mycophenolic acid or mycophenolate mofetil	5 of 6 recipients were insulin-independent at 1 year, 4 continued at a mean of 3.4 years posttransplant; no severe hypoglycemia recurrence	Included aphthous ulcers, leukopenia, transient liver enzyme elevations, cholelithiasis, acute cholecystitis, kidney function decline, and need for antihypertensive and lipid-lowering medications
Vanrenterghem et al[98]	Phase 3 clinical trials	ESRD requiring kidney transplantation	Belatacept (MI and LI regimens), CsA	Belatacept MI: 219, Belatacept LI: 226, CsA: 221 in BENEFIT; Belatacept MI: 184, Belatacept LI: 175, CsA: 184 in BENEFIT-EXT	Belatacept was administered in two regimens (MI and LI) vs CsA	Belatacept-based regimens showed improved cardiovascular and metabolic risk profiles, including lower blood pressure, lower serum lipids, and reduced diabetes incidence compared to CsA at 12 months post-transplant	NA
Müller et al[99]	Single-center cohort study	PTDM in kidney transplant recipients	Tacrolimus-or belatacept-based immunosuppression	Tacrolimus: 67, belatacept: 26	No accurate dose	Tacrolimus group: 16% had diabetes, 36% had prediabetes. Belatacept group: No diabetes, 8% had prediabetes	Worse kidney function and lower magnesium levels in tacrolimus group

T1DM: Type 1 diabetes mellitus; HbA1c: Glycated hemoglobin; ATG: Anti-thymocyte globulin; NA: Not available; ESRD: End-stage renal disease; MI: More intensive; LI: Less intensive; CsA: Cyclosporine A; PTDM: Post-transplantation diabetes mellitus.