Immunosuppressive agents in diabetes treatment: Hope or despair?

Table 1 Immunosuppressive agents in diabetes treatment

Immunosuppressive agent class	Representative drugs in diabetes treatment	Target cell	Diabetes-specific studies or approvals
CD3 inhibitors	Teplizumab, otelixizumab	T-cells	Teplizumab: FDA-approved for delaying T1DM onset in specific populations; Otelixizumab: T1DM
CTLA4-Ig	Abatacept, belatacept	T-cells	Abatacept: T1DM; belatacept: T1DM, T2DM, islet or pancreas transplantation, prevention of PTDM
JAK inhibitors	Baricitinib, ruxolitinib, tofacitinib, upadacitinib	Various immune cells	Baricitinib: T1DM, T2DM; ruxolitinib: T1DM; tofacitinib: T1DM, T2DM; upadacitinib: T1DM
Immune globulin	ATG	T-cells	T1DM, islet or pancreas transplantation
TNF-α inhibitors	Adalimumab, Etanercept, Golimumab, Infliximab	Various immune cells	Adalimumab: T1DM, T2DM; etanercept: T1DM, T2DM, islet or pancreas transplantation; golimumab: T1DM; Infliximab: T1DM, T2DM
CD20 inhibitors	Rituximab	B cells	Rituximab: T1DM, T2DM; ofatumumab: T1DM
LFA-3/Ig	Alefacept	T cells	T1DM
Anti-CD52 antibody	Alemtuzumab	B and T cells	Islet or pancreas transplantation

FDA: Food and Drug Administration; T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; PTDM: Post-transplantation diabetes mellitus; ATG: Anti-thymocyte globulin; JAK: Janus kinase; TNF-α: Tumor necrosis factor α; CTLA4: Cytotoxic T-lymphocyte-associated protein 4; IgG: Immunoglobulin G; ATG: Anti-thymocyte globulin.

Table 2 Clinical research of immunosuppressive agents involved in type 1 diabetes mellitus

Ref.	Study type	Disease	Treated drugs	Numbers of drug treated patients	Drug administration	Clinical outcome	Adverse events
Sherry et al[8]	Phase 3, multicenter, randomized study (Protégé study)	T1DM diagnosed within 12 weeks	Teplizumab	516	14-day full-dose group: A cumulative dose of 9034 μg/m2; 14-day low-dose group: A cumulative dose of 2985 μg/m2; 6-day full-dose group: A cumulative dose of 2426 μg/m2; All treatments were repeated at week 26	No significant differences were observed between the groups for the percentage of patients with insulin use of less than 0.5 U/kg per day and HbA1c of less than 6.5% at 1 year. Teplizumab decreased the use of exogenous insulin	The most common adverse event was rash
Herold et al[9]	Randomized, open-label study (AbATE Study)	T1DM diagnosed within 8 weeks	Teplizumab	52	A 14-day course of teplizumab was administered intravenously: Day 1, 51 μg/m2; day 2, 103 μg/m2; day 3, 206 μg/m2; day 4, 413 μg/m2; days 5-14, 826 μg/m2	Patients treated with teplizumab had a reduced decline in C-peptide at 2 years, and reduced the use of exogenous insulin in some patients with new-onset T1DM[9]. Patients who respond to teplizumab exhibited a sustained decrease in C-peptide levels over a period of up to 7 years[10]	Rash, transient upper respiratory infections, headache, and nausea
Herold et al[5]	Phase 2, randomized, placebo-controlled, double-blind trial (TrialNet TN10 Study)	Relatives of patients, who did not have diabetes but were at high risk	Teplizumab	44	Teplizumab was administered intravenously: Day 0, 51 μg/m2; day 1, 103 μg/m2; day 2, 206 μg/m2; day 3, 413 μg/m2; days 4-13, 826 μg/m2	Teplizumab extended the time to diagnosis of T1DM, with a lower percentage of patients in the teplizumab group being diagnosed with T1DM[5], and delayed rapid metabolic decline within 3 months[6]	Rash and transient lymphopenia
Ramos et al[11]	Phase 3, randomized, placebo-controlled trial (PROTECT Study)	Patients 8 to 17 years of age with stage 3 T1DM diagnosed within 6 weeks	Teplizumab	217	Two 12-day courses of teplizumab administered intravenously, separated by 26 weeks: Day 1: 106 μg/m2; day 2: 425 μg/m2; day 3-12: 850 μg/m2	Teplizumab maintained a clinically meaningful peak C-peptide level, with no differences in HbA1c	Headache, gastrointestinal symptoms, rash, lymphopenia, and mild cytokine release syndrome
Keymeulen et al[14]	Phase 2 placebo-controlled trial	T1DM had been treated with insulin for less than 4 weeks	Otelixizumab	40	First nine patients received a first dose of 24 mg, followed by infusions of 8 mg per day; the remaining 31 patients received six consecutive infusions of 8 mg of Otelixizumab	Residual β-cell function was better maintained with otelixizumab[14]. Otelixizumab suppressed the rise in insulin requirements over 48 months[15]	A moderate "flu-like" syndrome and transient symptoms of Epstein-Barr viral mononucleosis
Aronson et al[16]	Phase 3, multicenter, randomized, placebo-controlled trial (DEFEND-1)	T1DM diagnosed within 90 days	Otelixizumab	181	0.1 mg on day 1; 0.2 mg on day 2; 0.3 mg on day 3; and 0.5 mg/day on days 4-8, for a total dose of 3.1 mg	2-hour C-peptide AUC HbA1c, glucose variability, and insulin dose were not different in otelixizumab group	Adverse events were more common in the otelixizumab group, included headache, fever, rash, nausea
Ambery et al[17]	Randomized, placebo-controlled, double-blind, multi-centre study (DEFEND-2)	T1DM diagnosed within 90 days including adolescents	Otelixizumab	118	Intravenous infusion over eight consecutive days with a total dose of 3.1 mg	No significant difference in C-peptide secretion between groups at month 12	Higher incidence of adverse events in the otelixizumab group; most commonly headache, nausea, and fatigue
Keymeulen et al[19]	Randomized, single-blind, placebo-controlled study	T1DM diagnosed within 32 days	Otelixizumab	30	Intravenous infusion over 6 days in four dose cohorts (9, 18, 27, or 36 mg total dose)	Preservation of beta cell function observed with 9 mg dose; no beta cell function preservation observed at 18 and 27 mg doses	Dose-dependent adverse events including cytokine release syndrome and EBV reactivation
Orban et al[21]	Multicenter, double-masked, randomized controlled trial	T1DM diagnosed within 100 days	Abatacept	77	10 mg/kg, up to a maximum of 1000 mg/dose, intravenously on days 1, 14, 28, and monthly for a total of 27 infusions over two years	Adjusted C-peptide AUC was 59% higher at two years with abatacept vs placebo. Lower HbA1c but similar insulin use	No increase in infections or neutropenia
Russell et al[23]	Phase 2, randomized, placebo-controlled, double-masked trial	Stage 1 T1DM	Abatacept	101	Monthly infusions for 12 months, 10 mg/kg to a maximum of 1000 mg per infusion	Did not significantly delay progression to abnormal glucose tolerance or clinical diabetes	Well-tolerated, except for skin and connective tissue disorders which were higher with abatacept
van Lint et al[29,32]	ADR case reports	T1DM and T2DM	Tofacitinib, baricitinib, upadacitinib	Tofacitinib: 20, baricitinib: 19, upadacitinib: 4	No accurate dose	NA	Hypoglycaemia as a potential ADR associated with JAK inhibitor use
Fujita et al[30]	Case report	T1DM with rheumatoid arthritis and systemic sclerosis	Baricitinib	1	Baricitinib 4 mg/day	Decrease in required daily dose of insulin and HbA1c levels	NA
Waibel et al[27,28]	Phase 2, randomized, placebo-controlled trial	T1DM	Baricitinib	60	4 mg once per day orally for 48 weeks	Preserved β-cell function as estimated by mixed-meal-stimulated mean C-peptide level; lower daily insulin dose in the baricitinib group	Similar frequency and severity of adverse events in both groups; no serious adverse events attributed to baricitinib or placebo
Chaimowitz et al[31]	Case report	T1DM	Ruxolitinib	1	10 mg twice daily	Euglycemia achieved without insulin for over 1 year	NA
Gitelman et al[33,34]	Randomized, placebo-controlled, phase 2 trial	T1DM	ATG	38	6.5 mg/kg ATG over four days	No significant difference in preservation of β-cell function between ATG and placebo groups at 12 months. ATG did not preserve islet function in the majority at 24 months; older patients had significantly greater C-peptide AUCs at 24 months	Cytokine release syndrome and serum sickness in ATG group, with acute T cell depletion and slow reconstitution over 12 months; higher frequency of grade 3-4 adverse events in ATG group
Haller et al[35,36]	Randomized, single-blinded, placebo-controlled trial	T1DM	ATG and Pegylated G-CSF	17	ATG: 2.5 mg/kg intravenously, followed by pegylated G-CSF: 6 mg subcutaneously every 2 weeks for 6 doses	Tendency to preserve β cell function in T1DM patients[35]. No statistically significant differences in AUC C-peptide between ATG/GCSF and placebo groups at 24 months[36] or after 5 years[37]	Cytokine release syndrome in 14 subjects, serum sickness in 13 subjects. Few minor adverse events from the second year following treatment
Haller et al[38,39]	Three-arm, randomized, double-masked, placebo-controlled trial	T1DM diagnosed within 100 days	Low-dose ATG and GCSF	29 received ATG/GCSF, 29 received ATG	ATG: 2.5 mg/kg intravenously, followed by pegylated GCSF: 6 mg subcutaneously every 2 weeks for 6 doses; ATG alone: 2.5 mg/kg	The 1-year mean AUC C-peptide was significantly higher in the ATG group vs placebo. HbA1c was significantly reduced at 1 year in subjects treated with ATG and ATG/GCSF. After 2 years, ATG preserved C-peptide and reduced HbA1c more than placebo. ATG/GCSF did not show additional benefit over ATG alone	Common adverse events included serum sickness and cytokine release syndrome in the ATG/GCSF group
Foster et al[40]	Case series	Stage 2 T1DM	Low-dose ATG	6	2-day course (2.5 mg/kg)	50% did not progress to stage 3 within 18 months; those who progressed maintained HbA1c below target with low insulin requirements and robust C-peptide	Grade 1 cytokine release syndrome in 50%; Grade 3 Serum Sickness in 100%
Wilhelm-Benartzi et al[41]	Phase 2, multicenter, randomized, double-blind, placebo-controlled, multiarm parallel cohort trial	T1DM diagnosed within 3 to 9 weeks	ATG	82	Given intravenously over two consecutive days with varying doses (2.5 mg/kg, 1.5 mg/kg, 0.5 mg/kg and 0.1 mg/kg)	NA	NA
Tack et al[43]	Case report	T1DM with rheumatoid arthritis	Etanercept	1	25 mg, twice a week	No prevention or delay of T1DM development	NA
Boulton and Bourne[44]	ADR case report	T1DM with rheumatoid arthritis	Etanercept, Adalimumab, Infliximab	1	Etanercept: 25 mg, twice a week, Adalimumab, Infliximab: Dosages not specified	Etanercept or adalimumab caused hypoglycaemia, while infliximab did not cause the ADR	Hypoglycaemia after etanercept or adalimumab treatment
Mastrandrea L et al[45]	Pilot, randomized, placebo-controlled, double-blind study	3-18 years with T1DM	Etanercept	9	0.4 mg/kg up to a maximum dose of 25 mg/dose subcutaneously twice weekly for 24 weeks	Lower A1C, higher percent decrease in A1C from baseline and decreased insulin dose in the etanercept group; in etanercept group	Mild and self-resolving paresthesia, cold symptoms, and abdominal pain reported more frequently in the etanercept group
Quattrin et al[46]	Phase 2, randomized, placebo-controlled, double-blind, parallel-group trial (T1GER Study)	T1DM diagnosed within 100 days	Golimumab	56	An induction dose of 60 mg/m2 (< 45 kg) or 100 mg (≥ 45 kg) at weeks 0 and 2, followed by maintenance doses of 30 mg/m2 and 50 mg, respectively, at week 4 and every 2 weeks through week 52	Better endogenous insulin production and less exogenous insulin use in the golimumab group. Two-year follow up study showed that C-peptide AUC remained greater in golimumab group[47]	Hypoglycemic events reported in 13 participants (23%) in the golimumab group
Timper et al[48]	Case report	T1DM with Crohn’s disease	Infliximab	1	5 mg/kg administered intravenously at weeks 0, 2, and 6, and every 8 weeks thereafter	Increase in insulin secretion; decrease in insulin resistance; a1c levels remained below 6.0%	NA
Richez et al[49]	ADR case report	T1DM with rheumatoid arthritis	Adalimumab	1	40 mg/week	Development of T1DM with appearance of anti-GAD antibodies	elevated blood glucose levels and positive GAD antibodies
Pescovitz et al[50,51]	Randomized, double-blind, phase 2 study	T1DM diagnosed within 3 weeks to 3 months	Rituximab	57	375 mg/m² per infusion on days 1, 8, 15, and 22; total of 4 infusions	Higher mean AUC for C-peptide, lower glycated hemoglobin levels, less insulin required, slower decline in C-peptide levels at 1 year. Delayed decline in C-peptide by 8.2 months initially, no significant difference in AUC, insulin dose, and HbA1c after 30 months	More adverse events in rituximab group after first infusion, mostly grade 1 or 2, no increase in infections or neutropenia
Quintana et al[53]	Case report	T1DM and immune thrombocytopenia	Rituximab	1	dosage is not specified	Temporal reversal of hyperglycemia in T1DM with reduced insulin requirements	NA
Zieliński et al[54,55]	Randomized phase 1/2 clinical trial	T1DM in pediatric patients	Autologous Expanded CD4+ CD25highCD127-Tregs and/or Rituximab	Tregs: 13, Tregs+ Rituximab: 12	Rituximab: Four infusions of 375 mg/m2 body surface area on days 14, 22, 29, and 36	Combined therapy showed superiority in C-peptide levels and a higher proportion of patients in remission at 24 months	In Tregs + Rituximab group: Infections, upper respiratory tract infection, influenza
Chen et al[56]	Case report	Anti-LGI1 encephalitis and T1DM	Ofatumumab	1	Single subcutaneous injection of 20 mg	Significant improvement in blood glucose control; reduced insulin dosage	No significant adverse effects observed
Rigby et al[57,58]	Phase 2, multicenter, randomized, placebo-controlled, double-blind clinical trial	T1DM diagnosed within 100 days	Alefacept	33	Two 12-week courses of 15 mg intramuscular injections per week, separated by a 12-week pause	The 4-hour C-peptide AUC was significantly higher and daily insulin use was lower in the alefacept group at 12 and 24 months	87.9% of subjects in the alefacept group experienced an adverse event, compared to 93.8% in the placebo group

T1DM: Type 1 diabetes mellitus; T2DM: Type 2 diabetes mellitus; HbA1c: Glycated hemoglobin; AUC: Area under the curve; EBV: Epstein-Barr virus; ADR: Adverse drug reaction; NA: Not available; JAK: Janus kinase; G-CSF: Granulocyte colony-stimulating factor; Tregs: T regulatory cells.

Table 3 Clinical research of immunosuppressive agents involved in type 2 diabetes mellitus or insulin resistance

Ref.	Study type	Disease	Treated drugs	Numbers of drug treated patients	Drug administration	Clinical outcome	Adverse events
Gupta-Ganguli et al[62]	Retrospective study	T2DM with rheumatoid arthritis or Crohn’s disease	Etanercept and infliximab	8	Etanercept: 50 mg each week by injection; Infliximab: Large intravenous bolus every 6-8 weeks	Average FBG decreased from 142 to 121 mg/dL; average HbA1c decreased from 6.5% to 5.5%; average TG decreased from 350 to 200 mg/dL	NA
Yazdani-Biuki et al[64]	Case series	Insulin resistance	Infliximab	5	Infliximab was administered at a dosage of 5 mg/kg every 8 weeks via Intravenous injection	Improvement in insulin sensitivity observed, particularly in obese patients; remission of type-II diabetes in the index case	NA
Yazdani-Biuki et al[65]	Case report	T2DM with psoriatic arthritis	Infliximab	1	Infliximab discontinued and then restarted due to disease activity. No accurate dose	Relapse of diabetes after stopping infliximab; normalization after resuming	NA
Ursini et al[66]	Case report	Psoriasis, psoriatic arthritis and impaired fasting glucose and impaired glucose tolerance	Infliximab	1	Infliximab was administered at a dosage of 5 mg/kg every 8 weeks via Intravenous injection	Developed to T2DM after discontinuation of infliximab	NA
Bissell et al[67]	Randomized controlled trial	Early rheumatoid arthritis	Infliximab	79	3 mg/kg (maximal dose 1000 mg) standard regime (weeks 0, 2, 6, 14, 22)	Greater improvement in HOMA-IR with the addition of infliximab to a methotrexate regimen	NA
Bonilla et al[68]	ADR case report	T2DM with rheumatoid arthritis	Etanercept	1	25 mg subcutaneously twice weekly	Hypoglycemia: Decrease in glycemia to 40-50 mg/dL in the morning after etanercept injection	Hypoglycemia
Cheung and Bryer-Ash[69]	ADR case report	T2DM with Psoriasis	Etanercept	1	25 mg twice weekly	Decrease in fasting blood glucose and HbA1c	Persistent hypoglycemia
Wambier et al[70]	ADR case report	T2DM with generalized pustular psoriasis	Etanercept	1	50 mg on day 33 and day 39	Decrease in blood glucose	Severe hypoglycemia after initiation of etanercept
Farrokhi et al[71]	ADR case report	T2DM with Psoriasis	Etanercept	1	Etanercept 50 mg twice weekly, subcutaneously	Improved glycemic control with decreased HbA1c and insulin requirements	Hypoglycemia
Corrao et al[72]	Case reports	Polymyalgia rheumatica with T2DM	Etanercept	9	25 mg twice weekly	Complete remission at 1-year follow-up	NA
Dominguez et al[73]	Randomized Double-Blind Clinical Trial	Psoriasis with risk factors for T2DM	Etanercept	6	Etanercept 25 mg twice weekly for 2 weeks	No significant difference in insulin secretion and sensitivity compared with control; fasting serum insulin levels decreased in etanercept group	Mild erythema at injection site in one patient
Martínez-Abundis et al[74]	Randomized, Placebo-Controlled Study	Metabolic Syndrome	Etanercept	28	Etanercept 50 mg subcutaneously once a week for 4 weeks	Significant decrease in C-reactive protein levels and increase in adiponectin levels	Well tolerated with no serious adverse events
Bernstein et al[75]	Randomized, Open-Label Study	T2DM with obese	Etanercept	10	Etanercept 25 mg subcutaneously twice weekly for 4 weeks	No improvement in vascular or metabolic insulin sensitivity despite decreased inflammatory markers	One case of cutaneous infection resolved with antibiotics
Pina et al[76]	Prospective Study	Non-diabetic patients with Psoriasis	Adalimumab	29	80 mg at week 0 followed by 40 mg every other week	Significant improvement of insulin sensitivity	NA
van Eijk et al[77]	Case report	Rheumatoid arthritis with T2DM	Adalimumab	2	No accurate dose	Decrease in fructosamine levels, indicating improved glycemic control	NA
Wu and Tsai[78]	Case report	T2DM with psoriasis	Adalimumab	1	40 mg every other week	Elevated blood glucose levels after adalimumab administration	Elevated serum sugar levels
Martinez-Molina et al[79]	Observational, Retrospective, Single-Center Study	T2DM with rheumatoid arthritis	Tofacitinib and baricitinib	Tofacitinib: 6; Baricitinib: 7	Various dosages based on patient needs	Baricitinib significant reduced HbA1c. Tofacitinib showed no significant difference in HbA1c at 6 months	Due to the increased risk of infections, special caution should be taken
Di Muzio et al[80]	6-month proof-of-concept, open, prospective, clinical study	T2DM with rheumatoid arthritis	Tofacitinib	40	No accurate dose	Progressive reduction of HOMA2-IR[80] and improving trend in insulin sensitivity[81]	No life-threatening adverse events, no cardiovascular or thromboembolic events
Terrec et al[82]	Retrospective, noncontrolled, single-center study	Kidney transplant recipients with T2DM	Belatacept	103	Conversion from CNIs to belatacept at least 6 months post-transplant. Initiation of belatacept consisted of 5 mg/kg on day 1, a second injection on day 14, a third on day 28, and then 1 injection every 4 weeks	HbA1c significantly decreased in patients	Two patients experienced acute cellular rejection; no patient suffered from graft loss. No specific adverse events related to the switch to belatacept
Klubo-Gwiezdzinska et al[84]	Prospective cohort study	Type B insulin resistance	Rituximab, steroids and cyclophosphamide	22	Rituximab: Two doses 2 weeks apart at 750 mg/m2	19 of 22 of patients achieved remission after 5 months	Two patients required therapy to prevent reactivation of latent viral hepatitis; one patient treated for latent tuberculosis; Neutropenia observed in 38.1% of patients
Osanami et al[85]	Case report	Type B insulin resistance	Rituximab, Hydroxychloroquine	1	Rituximab: 375 mg/m2 once weekly for 4 weeks	Remission of diabetes; Negative conversion of circulating insulin receptor antibodies after 7 months	NA

FBG: Fasting blood glucose; TG: Triglyceride; HOMA-IR: Homeostasis model assessment for insulin resistance; T2DM: Type 2 diabetes mellitus; HbA1c: Glycated hemoglobin; ADR: Adverse drug reaction; NA: Not available; CNIs: Calcineurin inhibitors.

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.