Immunosuppressive agents in diabetes treatment: Hope or despair?

Abstract

Exploration of immunosuppressive agents for the treatment of diabetes is a burgeoning field that has captured the attention of the medical community. The innovative approach of using these agents to combat diabetes is driven by their diverse capabilities to regulate the immune system, which is pivotal for disease pathogenesis. The primary objective is to enhance the management of blood glucose levels, which is a critical factor in the daily life of diabetic patients. This comprehensive review delves into the therapeutic horizons opened by immunosuppressive agents, particularly their potential impact on type 1 and type 2 diabetes mellitus, and their utility in the transplantation process. The complex etiology of diabetes, which involves a delicate interplay of genetic, environmental, and immunological factors, presents a multifaceted target landscape for these therapies. The agents discussed in the review, including CD3 inhibitors, cytotoxic T-lymphocyte-associated protein 4-immunoglobulin G, Janus kinase inhibitors, anti-thymocyte globulin, tumor necrosis factor-α inhibitors, CD20 inhibitors, alefacept, and alemtuzumab, each bring a unique mechanism to the table, offering a tailored approach to immune modulation. As research progresses, emphasis is being placed on evaluating the long-term efficacy and safety of these agents to pave the way for more personalized and effective diabetes management strategies.

Key Words: Immunosuppressive agents; Type 1 diabetes; Type 2 diabetes; Insulin resistance; Transplantation

Core Tip: The exploration of immunosuppressive agents for diabetes treatment is gaining attention. Diabetes' complex etiology offers multiple therapeutic targets. These agents regulate the immune system, which plays a crucial role in diabetes pathogenesis. The review examines their potential in type 1 diabetes, type 2 diabetes, and transplantation. The review aims to reveal the potential and limitations of these therapies by summarizing current research on immunosuppressive agents in diabetes treatment and prevention.

INTRODUCTION

Immunosuppressive agents have traditionally been used in the management of autoimmune diseases and transplant medicine to modulate the immune response of the body. The pathophysiological underpinnings of diabetes involve a complex interplay between the immune system and metabolic dysregulation. The advent of diabetes, characterized by an autoimmune destruction of insulin-producing β-cells in type 1 diabetes mellitus (T1DM) and progressive insulin resistance in type 2 diabetes mellitus (T2DM), has prompted an exploration of these agents for potential therapeutic benefits.

Clinical studies and trials have delved into the efficacy and safety profiles of some immunosuppressive agents in diabetes, with a focus on their effects on β-cell preservation, immune modulation, and overall metabolic health[1]. While some agents, such as teplizumab, have demonstrated promise and received Food and Drug Administration (FDA) approval to delay the onset of T1DM in at-risk individuals[2], others remain in the investigative stage, with ongoing research aimed at elucidating their long-term benefits and potential side effects. Moreover, immunosuppressant agents have been implicated in the onset of post-transplantation diabetes mellitus (PTDM), a complication attributed to their metabolic side effects[3], suggesting a complex relationship between immunosuppressants and diabetes. Currently, there is a lack of consensus regarding the clinical application of immunosuppressants across different types of diabetes and islet transplantation.

Considering the complexity of the pathogenesis of diabetes and the variety of therapeutic targets for immunosuppressants, a thorough investigation of the correlation between the two presents ample opportunities for scientific inquiry and clinical practice. This article provides an overview of the clinical studies on the use of immunosuppressants in the treatment and prevention of diabetes through a comprehensive survey of the literature on the intersection of immunosuppressants and diabetes. For this review, we searched PubMed and Cochrane databases for clinical studies on the use of immunosuppressants in treating or preventing diabetes, with a time span from 2000 to 2024. The immunosuppressants covered in this article include: CD3 inhibitors, cytotoxic T-lymphocyte-associated protein 4 (CTLA4) - immunoglobulin G (IgG), Janus kinase (JAK) inhibitors, anti-thymocyte globulin (ATG), tumor necrosis factor α (TNF-α) inhibitors, CD20 inhibitors, Alefacept and Alemtuzumab. The targets and application in diabetes of these immunosuppressants are listed in Table 1. Based on the clinical research data provided, we conducted an in-depth analysis of the safety and limitations of these drugs in the treatment or prevention of diabetes, including T1DM, T2DM, islet transplantation and PTDM.

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.

IMMUNOSUPPRESSIVE AGENTS IN T1DM

The pathophysiology of T1DM is characterized by the immune system mistakenly attacking and destroying pancreatic β-cells responsible for insulin production, leading to absolute insulin deficiency. Current treatment primarily involves exogenous insulin supplementation but fails to halt disease progression. Most clinical studies on immunosuppressive agent treatment for diabetes have primarily focused on the treatment of T1DM.

CD3 inhibitor

By engaging the CD3 element of the T-cell receptor complex, CD3 inhibitors intercept T cell activation pathways and play a central role in modulating the immune response in autoimmune conditions such as T1DM. Clinical studies have shown that CD3 inhibitors are effective in preserving β-cell function in patients with T1DM[4].

Teplizumab: Teplizumab, a CD3 inhibitor, is a novel monoclonal antibody therapy that has garnered significant attention for its potential in the treatment and prevention of T1DM. It has been approved by FDA to delay the onset of stage 3 T1DM in adults and pediatric patients aged 8 years and older with stage 2 T1DM. A phase 2, randomized, placebo-controlled, double-blind trial (TrialNet TN10 Study) revealed that teplizumab significantly delayed the onset of clinical T1DM in relatives at an increased risk of the disease. Participants treated with teplizumab experienced a median delay of approximately 2 years in the development of clinical diabetes compared with the placebo group[5]. Moreover, teplizumab inhibited swift metabolic decline and enhanced the metabolic status within 3 months post-treatment, with benefits lasting for a minimum of 6 months in the TrialNet TN10 study[6]. A follow-up study using TrailNet TN10 found that teplizumab treatment improved quantitative oral glucose tolerance test glucose area under the curve (AUC) values and insulin secretory dynamics, thereby resulting in a sustained delay in T1DM after a median follow-up of 742 days[7]. A phase 3, randomized, placebo-controlled study evaluated the safety and efficacy of teplizumab in the treatment of new-onset T1DM. Despite not meeting the primary endpoint of reduced insulin use and glycated hemoglobin (HbA1c) levels at 1 year, this study suggested the potential benefits of teplizumab in preserving β-cell function and reducing insulin needs, particularly in children and those treated early after diagnosis[8]. The Autoimmunity-Blocking Antibody for Tolerance (AbATE) trial treated new-onset T1DM with teplizumab for 2 weeks at diagnosis and after 1 year, and found that patients treated with teplizumab had a reduced decline in C-peptide and exogenous insulin use at 2 years[9]. The 7-year clinical and immunological follow-up of the AbATE trial revealed lasting benefits. It demonstrated a retarded decrease in C-peptide levels, indicating preserved β-cell function, and improvements in glycemic control and insulin requirements[10]. Recently, a phase 3, randomized, placebo-controlled trial assessed the effects of teplizumab in patients newly diagnosed with T1DM[11]. The study revealed that children and adolescents with newly diagnosed T1DM who received two 12-day courses of teplizumab had higher peak C-peptide levels at week 78 than those in the placebo group, suggested that teplizumab significantly slowed down the rate of β-cell function decline in patients with newly diagnosed T1DM. Nevertheless, no significant differences were observed between the groups in terms of insulin use, HbA1c levels, time in the target glucose range, or clinically significant hypoglycemic events. An integrated analysis of five clinical studies on teplizumab treatment for stage 3 T1DM demonstrated significant improvements in C-peptide levels during the first and second years after one or two courses of teplizumab therapy, accompanied by a notable reduction in insulin requirements[12]. A meta-analysis of eight randomized controlled trials of teplizumab in T1DM revealed that teplizumab decreased insulin use, accompanied by an increase in C-peptide levels, but did not affect HbA1c levels[13]. Hence, additional investigations are warranted to elucidate the effects of teplizumab on long-term blood glucose regulation.

Otelixizumab: Otelixizumab is another CD3-targeted monoclonal antibody designed to modulate the immune system with the aim of suppressing autoimmune attacks in conditions such as T1DM. A phase 2 placebo-controlled trial involving 80 individuals recently diagnosed with T1DM showed that administering otelixizumab (totaling 48-64 mg) over six successive days lowered insulin requirements and conserved β-cell functionality[14]. A follow-up study conducted on this research revealed that the 6-day course of otelixizumab treatment suppressed the rise in insulin requirements over a 48-month period, depending on their age and initial residual β-cell function[15]. However, a total dose of 48-64 mg of otelixizumab in the trial could cause reactivation of the Epstein-Barr virus in patients with new-onset T1DM. Therefore, a Durable Response Therapy Evaluation for Early or New-Onset T1DM (DEFEND-1) was conducted to explore the effects of low-dose otelixizumab on new-onset T1DM[16]. A multicenter, randomized, placebo-controlled trial found that treatment with 3.1 mg of otelixizumab administered over 8 days did not change the 2-hour C-peptide AUC, HbA1c level, glucose variability, or insulin dose. Another randomized, placebo-controlled, double-blind, multicenter study (DEFEND-2) also demonstrated that 3.1 mg otelixizumab was non-efficacious in adolescent T1DM[17]. A pharmacological study in recent-onset T1DM patients showed that the highest level of target engagement and modulation of CD3ɛ/TCR is attained with doses of 18 and 27 mg of otelixizumab[18]. To determine the optimal dose of otelixizumab for the treatment of T1DM, a randomized, single-blind, placebo-controlled study assessed the efficacy and safety of various doses of otelixizumab. The cumulative intravenous doses of otelixizumab administered were 9, 18, 27, and 36 mg over 6 days. The study revealed that a cumulative dose of 9 mg of otelixizumab maintained β-cell function over an 18-month period, with 18 mg identified as the maximum tolerated dose[19].

In summary, otelixizumab is an innovative therapeutic option for T1DM. Ongoing studies are attempting to clarify their roles and optimal use in clinical practice.

CTLA4-Ig

CTLA4-Ig is a sophisticated therapeutic fusion protein used in medical practice to modulate immune responses. CTLA4-Ig significantly inhibits the activation and proliferation of naïve T-cells, and presumably reduces autoimmune attacks against islet β-cells[20]. This not only theoretically allows for the preservation of remaining β-cells but also paves the way for new treatments to restore or maintain their insulin-secretion function.

Abatacept, the first CTLA4-Ig therapy approved by the FDA, primarily targets rheumatoid arthritis but shows potential in various autoimmune conditions, such as psoriatic arthritis, juvenile idiopathic arthritis, and lupus nephritis. A phase 2, multicenter, double-blind randomized controlled trial evaluated abatacept in recent-onset T1DM cases, involving 112 patients randomized to receive either 10 mg/kg abatacept (maximum 1000 mg/infusion) or placebo intravenous infusion on days 1, 14, and 28, and then monthly for 2 years (27 infusions total)[21]. The abatacept group displayed higher C-peptide levels, indicating delayed β-cell deterioration. After discontinuing abatacept for one year, a follow-up study with these patients showed that abatacept was likewise effective in delaying the β-cell function decline[22]. Recently, a phase 2, randomized, placebo-controlled, double-masked trial in antibody-positive participants with normal glucose tolerance was conducted to investigate the role of abatacept in T1DM progression in stage 1 relatives at risk[23]. Participants were given 14 of abatacept at 0, 2, 4 weeks, continuing every 28 ± 7 days for 12 months. The results indicated that one year of abatacept treatment did not significantly delay the progression to glucose intolerance in high-risk individuals, but it did affect immune cell subsets and preserved insulin secretion. Regarding safety and tolerability, abatacept is generally considered safe, with common side effects resembling those observed in other autoimmune disease treatments, including reactions at injection sites and mild infections[20].

Abatacept was designated as an orphan drug in 2013 for the treatment of T1DM patients with residual β-cell function; however, it has not been approved for this orphan indication[24], highlighting the need for further clinical trials to substantiate its efficacy and safety in the treatment of T1DM.

JAK inhibitors

The JAK/STAT pathway is involved in the regulation of insulin-secreting cells and insulin-target organ function, and is associated with the development of both T1DM and T2DM[25]. Widespread consensus acknowledges the hyperexpression of human leukocyte antigen class I (HLA-I) on pancreatic β-cells as a characteristic signature of T1DM development. JAK inhibitors reduce HLA-I via interferon pathway targeting in mouse models, suggesting potential in patient treatment to lower islet HLA-I hyperexpression, decrease β-cell immune visibility, and thereby hinder disease progression[26].

The baricitinib in new onset T1DM (BANDIT) trial examined if baricitinib, which used in rheumatoid arthritis and alopecia, could help sustain β-cells in early (< 100 days) T1DM[27]. This phase 2, double-blind, randomized, placebo-controlled trial demonstrated that 48 weeks of baricitinib treatment at a dose of 4 mg once daily led to a significant elevation in C-peptide levels stimulated by a mixed meal, and a lower daily insulin requirement[28]. HbA1c levels and adverse events were similar between the two groups. This study indicates a potential benefit of baricitinib in preserving β-cell function, but the long-term effects require further exploration. Several studies have reported cases of baricitinib-induced hypoglycemia and decreased HbA1c levels in patients with T1DM[29,30].

The gain of function of signal transducer and activator of transcription 1 (STAT1) impairs the function of pancreatic β-cells, promotes autoimmune responses, thereby contributing to the development of T1DM. A 17-year old T1DM was diagnosed with STAT1 gain-of-function disease, after initiating treatment with the JAK inhibitor ruxolitinib at a dose of 10 mg twice daily, gradually reducing the insulin dosage and discontinuing insulin usage after 12 months of treatment (21 months post-T1DM diagnosis)[31]. This case suggests that JAK inhibitor therapy can reverse T1DM in young adults.

There have also been numerous reports of JAK inhibitors inducing hypoglycemia. As of January 12, 2021, the European Pharmacovigilance Eudravigiliance recorded 32 adverse drug reaction reports, implicating the occurrence of hypoglycemia in 32 diabetic patients following the use of the JAK inhibitors tofacitinib or baricitinib[32]. Updated through September 17, 2021, reports from EudraVigilance indicated 43 cases of hypoglycemia or decreased blood glucose levels in patients with T1DM or T2DM treated with JAK inhibitors, including baricitinib, tofacitinib, or upadacitinib[29]. In 15 of these patients, a decrease in blood glucose levels occurred within one month of initiating JAK inhibitor therapy. Attention should also be paid to adverse reactions to JAK inhibitors that induce hypoglycemia.

ATG

ATG is an immunosuppressive medication administered to animals immunized with human T cells. It prevents organ rejection in transplant patients and is used to treat patients with severe aplastic anemia. The 12-month results of a randomized, placebo-controlled, phase 2 trial showed that 6.5 mg/kg ATG over a course of 4 days did not preserve β-cell function in new-onset T1DM[33]. The 2-year follow-up of this trial showed that ATG did not preserve β-cell function, but preserved C-peptide secretion in older participants[34]. Considering the unsatisfactory outcomes of singular therapeutic approaches, researchers have investigated the prospects of employing ATG in combination with other therapies to maintain β-cell functionality in T1DM patients. In a randomized, single-blinded, placebo-controlled trial, patients with T1DM (duration of T1DM > 4 months and < 2 years) received 2.5 mg/kg ATG intravenously followed by 6 mg pegylated granulocyte colony-stimulating factor (G-CSF) subcutaneously every 2 weeks for 6 doses[35]. The ATG/G-CSF treatment group showed a higher C-peptide AUC than the placebo group, with the difference approaching statistical significance at 12 months (P = 0.05), indicating a preservative effect on β-cell function. At 24 months, the AUC of C-peptide was still higher than that of the placebo group, although the difference was not statistically significant[36]. The 5-year follow-up study showed no statistically significant differences were observed in the AUC of C-peptide levels between the ATG/GCSF treatment and placebo groups[37]. Subsequently, a three-arm, randomized, double-masked, placebo-controlled trial was performed to explore the role of low-dose ATG (2.5 mg/kg given as two separate intravenous infusions: 0.5 and 2 mg/kg) on new-onset T1DM (duration < 100 days)[38]. ATG monotherapy and combination therapy with GCSF, effectively decreased HbA1c levels; however, it is noteworthy that monotherapy with low-dose ATG significantly decelerated the decline in C-peptide levels. This finding suggests that low-dose ATG alone may have a preventive or mitigating effect on T1DM. Two-year follow-up data from the trial showed that the beneficial effects of ATG in improving C-peptide AUC and reducing HbA1c levels lasted for 24 months[39]. One study investigated the efficacy of low-dose ATG in slowing the progression of stage 2 T1DM[40]. Six children with stage 2 T1DM did not progress to clinical diabetes within 4 years after receiving ATG, while three other subjects developed stage 3 within 1-2 months post-treatment; however, they still exhibited near-normal HbA1c levels. Currently, a phase 2, multicenter, randomized, double-blind, placebo-controlled, multi-arm parallel group trial is underway to investigate the optimal dosage of ATG for the treatment of T1DM[41]. A study comparing the effectiveness of various treatments including rituximab, abatacept, teplizumab, alefacept, high-dose ATG, low-dose ATG, and low-dose ATG combined with G-CSF for T1DM, and revealed that low-dose ATG and teplizumab had the most significant effect on preserving C-peptide levels[42].

TNF-α inhibitor

TNF-α can act as a double-edged sword in T1DM by either positively or negatively modulating the peripheral T cell tolerance to β-cell antigens[43]. A case of rheumatoid arthritis complicated with T1DM experienced severe hypoglycemia following separate administrations of both etanercept and adalimumab[44], suggesting that TNF-α inhibitors may affect blood glucose in T1DM patients.

Etanercept: A 24-week double-blind, randomized, placebo-controlled study investigated the role of etanercept in children with new-onset T1DM. This small study demonstrated that etanercept can preserve β-cell function, reduced A1C levels, and increased endogenous insulin production[45]. One patient with idiopathic arthritis and a family history of T1DM progressed to T1DM despite etanercept treatment, suggesting that etanercept therapy did not prevent the development of T1DM[43].

Golimumab: Golimumab is a TNFα inhibitor used for the treatment of autoimmune diseases, specifically rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. A phase 2, multicenter, placebo-controlled, double-blind, parallel-group trial (T1GER) investigated the effect of golimumab in the treatment of newly diagnosed T1DM in adolescents[46]. The results showed that at 52 weeks of subcutaneous golimumab administration, the C-peptide AUC was significantly higher compared to the placebo group, accompanied by a reduction in insulin usage, suggesting a protective effect on β-cell function. Two-year follow-up from the T1GER study demonstrated that, 52 weeks after the discontinuation of golimumab treatment, C-peptide AUC remains higher in the golimumab group, with lesser insulin usage, greater improvements in metabolic parameters, and fewer incidents of hypoglycemia, suggesting that β-cell function in T1DM was preserved for at least a year after stopping golimumab[47].

Infliximab: A patient with concurrent Crohn’s disease and T1DM displayed increased insulin secretion and reduced insulin requirements after treatment with Infliximab[48].

Adalimumab: Following treatment with adalimumab, a patient with rheumatoid arthritis exhibited elevated blood glucose levels and positive GAD antibodies, indicating the potential development of T1DM[49].

CD20 inhibitor

T1DM typically attributed to β-cell destruction by T lymphocytes, has intriguingly demonstrated responsiveness to therapeutic interventions targeting B lymphocytes through antibody therapies.

Rituximab: An early randomized, double-blind study revealed that the administration of rituximab in four doses (375 mg per square meter of body-surface area administered on days 1, 8, 15, and 22) led to significantly higher C-peptide AUC levels over one year in new-onset T1DM patients than the placebo group, accompanied by reduced HbA1c and insulin requirements[50]. A 2-year follow-up investigation revealed that at 30 months, neither the C-peptide AUC, insulin requirements, nor HbA1c levels showed significant differences between the rituximab and placebo groups[51]. This implies that short-term rituximab therapy alleviated the decline in C-peptide levels without altering the long-term prognosis of patients. Systems biology approaches have recently indicated that elevated T-cell counts in peripheral blood might predict a less favorable response to rituximab treatment[52], and a case report also illustrated that a patient with both ITP and T1DM experienced a temporary reversal of hyperglycemia symptoms following rituximab administration[53]. Recently, a phase 1/2, prospective, three-arm, randomized, open-label, single-blind, multicenter clinical study revealed that combination therapy of CD4⁺ CD25^high CD127^- T regulatory cells (Tregs) with rituximab surpassed Tregs monotherapy in preserving C-peptide levels and inducing disease remission[54]. Moreover, a follow-up study found that higher PD-1 receptors on T cells were associated with favorable outcomes, such as enhanced C peptide AUC values and decreased insulin requirement, and PD-1 receptor (+) might be an efficient marker of the combination therapy of rituximab and Tregs[55].

Ofatumumab: Ofatumumab is a human anti-CD20 monoclonal antibody developed for the treatment of relapsing multiple sclerosis. A patient with T1DM who had poor long-term blood glucose control and LGI1 encephalitis showed a significant improvement in blood glucose levels and a reduction in insulin usage after one month of ofatumumab treatment[56]. This suggests that ofatumumab may have potential applications value in the treatment of T1DM.

Alefacept

Alefacept is a sophisticated immunomodulatory biological agent that specifically targets lymphocyte function-associated antigen-3 to modulate immune responses. A phase 2, multicenter, randomized, placebo-controlled, double-blind clinical trial (T1DAL study) examined the efficacy of alefacept in patients with newly diagnosed (within ≤ 100 days) T1DM. At the 12-month treatment mark, alefacept did not significantly enhance C-peptide levels[57]; however, after 12 months of follow-up, the AUC of C-peptide was notably higher in the alefacept group than in the placebo group[58]. Alterations in the frequencies of CD8+ T cell subsets demonstrated a positive correlation with changes in C-peptide levels[59], and islet-autoreactive CD4+ T cells might serve as a potential biomarker for the therapeutic response to alefacept in treating T1DM[60]. Patients with a higher frequency of CD4⁺ CD25⁺ CD127hi (127-hi) cells showed a better response to alefacept treatment[61].

IMMUNOSUPPRESSIVE AGENTS IN T2DM AND INSULIN RESISTANCE

T2DM, in contrast to T1DM, is characterized by a fundamentally distinct pathophysiological mechanism. Unlike in T1DM, inflammation in T2DM stems from a combination of metabolic stress, obesity, and a pro-inflammatory environment, creating a feedback loop that exacerbates insulin resistance and β-cell dysfunction, which consequently leads to diminished reliance on immunosuppressive therapies in its management strategy.

TNF-α inhibitor

TNF-α is a pro-inflammatory cytokine that can induce an inflammatory environment, promoting insulin resistance and islet inflammatory microenvironment, thereby accelerating the progression of T2DM. Therefore, TNF-α inhibition is speculated to improve T2DM by suppressing the inflammatory environment. A retrospective study revealed that in patients with T2DM who have either rheumatoid arthritis or Crohn's disease, treatment with etanercept or infliximab led to improvements in fasting blood glucose levels as well as HbA1c[62]. Recently, a cohort study revealed that patients exposed to anti-TNFα inhibitors, including infliximab, adalimumab, golimumab, etanercept, and certolizumab pegol, had a lower risk of developing T2DM compared to those unexposed to these agents; however, this difference was not statistically significant[63].

Infliximab: A case series report showed that in insulin resistant patients, insulin sensitivity improved following treatment with infliximab[64]. A T2DM patient with psoriatic arthritis, who had been undergoing long-term treatment with infliximab, experienced an increase in blood glucose levels after discontinuing infliximab use; when he resumed infliximab treatment, his fasting blood glucose level promptly decreased[65]. Another patient, who had psoriasis and psoriatic arthritis, along with impaired fasting glucose and impaired glucose tolerance, progressed to T2DM after discontinuing infliximab therapy[66]. A double-blind, randomized, controlled trial in new-onset, treatment-naïve, rheumatoid arthritis (the IDEA) demonstrated that the addition of infliximab to a methotrexate regimen significantly improved the insulin resistance index homeostasis model assessment for insulin resistance (HOMA-IR)[67].

Etanercept: There is considerable variation in the clinical research data regarding the use of etanercept in T2DM. Several studies have reported that patients with T2DM developed hypoglycemia after treatment with etanercept 25 mg[68,69] or 50 mg[70,71]. In a case series of patients with polymyalgia rheumatica and diabetes, reduced in fasting blood glucose levels were observed during etanercept treatment in combination with prednisone[72]. In contrast, an open-label parallel study revealed that subcutaneous injections of 25 mg etanercept twice weekly for four weeks led to a reduction in systemic inflammatory markers, interleukin-6 and C-reactive protein, but did not significantly improve insulin sensitivity[73]. A randomized, double-blind clinical trial also demonstrated that twice-weekly subcutaneous injections of 25 mg etanercept over a 2-week period did not improve insulin secretion or sensitivity in patients with psoriasis at risk of developing T2DM[74]. However, etanercept does not affect insulin sensitivity in patients with metabolic syndrome[75].

Adalimumab: A 6-month prospective study found that 6 months of adalimumab treatment (initial dose of 80 mg, followed by 40 mg every other week) improved insulin sensitivity in non-diabetic patients with psoriasis[76]. In two patients with rheumatoid arthritis and coexisting diabetes, significant reductions in fructosamine levels were observed after adalimumab treatment, suggesting that adalimumab may improve insulin resistance[77]. However, in a patient with psoriasis and T2DM, repeated use of adalimumab was associated with increased blood glucose levels[78], indicating a complex modulatory effect of adalimumab on glucose metabolism.

JAK inhibitors

JAK signaling is closely associated with T2DM. Recently, an observational, retrospective, single-center study investigated the effects of the JAK inhibitors tofacitinib and baricitinib, in T2DM patients with rheumatoid arthritis[79]. Baricitinib has been demonstrated to enhance insulin sensitivity and glucose absorption, and reduce the HbA1c level and dosage of oral antidiabetic drugs in T2DM patients. Tofacitinib, likewise functioning as a JAK inhibitor, did not exert any therapeutic effects on T2DM in this study. Other studies have reported divergent perspectives on the role of tofacitinib in the management of T2DM. A proof-of-concept, open, prospective, clinical study demonstrated that in patients with rheumatoid arthritis complicated by T2DM, treatment with tofacitinib significantly reduced HOMA2-IR and elevated HOMA2-β, indicating that tofacitinib can enhance insulin sensitivity in T2DM patients[80,81]. Therefore, the potential role of JAK inhibitors in T2DM warrants further investigation.

CTLA4-Ig

Studies on the CTLA4-Ig in patients with T2DM are limited. A retrospective, noncontrolled single study found that kidney transplant patients with T2DM had significant reductions in HbA1c levels when calcineurin inhibitors were switched to belatacept for at least 6 months after transplantation, indicating a substantial improvement in glycemic parameters[82].

CD20 inhibitor

B lymphocytes have been implicated in the pathogenesis of T2DM[83]; however, drugs targeting B lymphocytes have not been extensively investigated in T2DM. A few studies have explored the role of rituximab in specific types of insulin resistance. Type B insulin resistance is an uncommon autoimmune disease induced by a polyclonal autoantibody directed against the insulin receptor on the cell surface[84]. It is characterized by resistance to massive doses of insulin, severe hyper-catabolism and hyperandrogenism. A prospective cohort study analyzed the efficacy of combined immunosuppressive therapy in the management of type B insulin resistance[84]. Immunosuppressive therapies include rituximab, high-dose pulsed steroids and cyclophosphamide. The study found that 86.4% of patients achieved remission after 5 months of treatment with combined immunosuppressive therapy, and none of the enrolled patients died during the observation period (median, 72 months). The immunosuppressive agents have made type B insulin resistance with high mortality a treatable disease. A case report indicated that a patient concurrently diagnosed with B-type insulin resistance syndrome and systemic lupus erythematosus, experienced improvement in their diabetic condition after undergoing double-filtration plasmapheresis and rituximab treatment[85].

IMMUNOSUPPRESSIVE AGENTS IN TRANSPLANTATION

Islet transplantation

Islet transplantation for T1DM is limited by graft dysfunction, immunosuppressive drug toxicity, multi-donor requirements, and allosensitization risks.

Belatacept is another immunosuppressive agent belonging to the CTLA-4-Ig fusion protein class, designed as an evolution of abatacept for refined immunomodulation after organ transplantation, with a particular focus on kidney transplants. Immunosuppressive regimens based on belatacept were effective, well tolerated, and maintained long-term insulin independence during islet transplantation[86,87].

Alemtuzumab is a precision therapy that relies on CD52 antigens expressed on B and T lymphocytes to orchestrate dual immunomodulatory effects through natural killer cells and the complement cascade. Case series have indicated that alemtuzumab-induction during islet transplantation is well-tolerated and may improve both short- and long-term outcomes[88]. A reduction in calcineurin levels may be beneficial for the survival of transplanted islets. The induction of alemtuzumab-supported islet transplantation correlated with an initial modification of the phenotype of islet-specific T cells. Alemtuzumab is also widely used in pancreas-kidney transplantation[89-91]. A single-center, non-randomized, retrospective, sequential study[92] and a prospective randomized trial[93] demonstrated that the use of alemtuzumab vs ATG as an induction immunosuppressant in pancreas-kidney transplant recipients showed no significant difference in efficacy and safety. In addition, subcutaneous administration of alemtuzumab, not only enhanced graft survival rates in pancreas-kidney transplantation, but also circumvented hypotension induced by the initial dose, thereby decreasing the incidence of venous thrombosis in pancreas transplantation[94].

A phase 1/2 trial found that etanercept combined with exenatide enhanced the functionality of islet grafts, and promoted insulin independence with a diminished need for islets[95]. Among the six patients who underwent islet transplantation and were treated with ATG and etanercept for induction, along with cyclosporine and everolimus for maintenance therapy, two attained insulin independence for an average duration of > 3 years[96].

Lower risk of PTDM

Traditional immunosuppressants, such as calcineurin inhibitors, tend to facilitate the development of PTDM[3]. Belatacept demonstrates fewer less detrimental metabolic effects following transplantation. Employing a strategy of reduced calcineurin inhibitor use with belatacept successfully reduced HbA1c levels in patients with PTDM[82], offering a new approach to long-term treatment for these patients. Compared with calcineurin inhibitors, belatacept can reduce the risk of PTDM by 50% during kidney transplantation[97]. Two phase 3 studies (BENEFIT and BENEFIT-EXT) of belatacept-based regimens in kidney transplant recipients found that the incidence of PTDM was lower in the belatacept group than in the cyclosporine A group[98]. Compared to tacrolimus, belatacept exhibited a reduced incidence of both diabetes and prediabetes states among kidney transplant recipients[99].

SAFETY AND LIMITATION OF THE IMMUNOSUPPRESSIVE AGENTS IN DIABETES TREATMENT

Drawing from the synthesis of the aforementioned studies, it is evident that select immunosuppressive agents exhibit potential in either the treatment or prevention of diabetes progression. Notably, the safety profile of these interventions appears favorable, with reports of severe adverse events being relatively infrequent (Tables 2, 3 and 4). During the treatment of diabetes, teplizumab and otelixizumab might cause rashes, transient upper respiratory infections, headaches, nausea, and symptoms similar to influenza, as well as transient symptoms of Epstein-Barr viral mononucleosis; CTLA4-Ig was generally considered safe, with common side effects including injection site reactions and mild infections; JAK inhibitors and TNF-α inhibitors might induce hypoglycemia; ATG treatment might cause cytokine release syndrome and serum sickness, as well as acute T cell depletion and slow reconstitution; CD20 inhibitors might lead to a higher number of adverse events after treatment, most of which are grade 1 or 2, without increasing the risk of infection or neutropenia; alefacept has a higher proportion of patients experiencing adverse events in the treatment group. Additionally, live vaccines should not be administered concurrently with abatacept or within three months after discontinuation, which will limit its application in children. Currently, teplizumab is the only immunosuppressive agent approved for the prevention and treatment of T1DM; however, the effects of other drugs, especially their long-term effects, are unclear. In the context of T2DM, high-quality studies on immunosuppressive agents are lacking and their efficacy remains unclear. Based on current research, it seems that immunosuppressive agents does not appear to supplant the existing pharmacotherapies for T2DM, such as oral antidiabetic drugs, GLP-1 analogs, and insulin.

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.

CONCLUSION

This review examines the potential of immunosuppressive agents in diabetes treatment, highlighting several promising options. Teplizumab is notable for delaying T1DM onset and preserving β-cell function. Baricitinib and abatacept also show efficacy in maintaining β-cell function, though long-term effects need further study. Low-dose ATG and golimumab reduce HbA1c and preserve β-cell function but may cause side effects like cytokine release syndrome and hypoglycemia. Rituximab has initial promise, especially in combination therapies. In T2DM, evidence for immunosuppressive agents is limited, with unclear efficacy and safety. Personalized treatment strategies are essential for future research. Further studies are needed to clarify long-term safety, optimal dosages, and the most effective agents for clinical use.