Immunosuppressive agents in diabetes treatment: Hope or despair?

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.