Type 1 diabetes mellitus: Prevention and disease-modifying therapy

INTRODUCTION — One hundred years after its first clinical use, insulin remains the primary treatment for type 1 diabetes mellitus, but it does not modify the underlying autoimmune process. Furthermore, despite the advent of more physiologic insulin analogs, continuous glucose monitoring, and automated insulin delivery methods, most individuals living with type 1 diabetes do not meet the therapeutic targets that are associated with a lower risk of long-term complications [1,2]. Type 1 diabetes management is expensive, complicated, and exacts a mental and emotional toll on individuals with diabetes and their loved ones [3-6]. Therefore, alternative approaches that modify the natural history of type 1 diabetes, rather than solely treat hyperglycemia, could dramatically improve both quality of life and health outcomes for individuals with type 1 diabetes.

This topic will review strategies to prevent or delay clinical type 1 diabetes during preclinical stages of disease, as well as strategies to preserve insulin secretion after the onset of clinical disease. The pathophysiology and etiology of type 1 diabetes are discussed elsewhere, as are strategies for identifying and screening individuals at elevated disease risk. (See "Pathogenesis of type 1 diabetes mellitus" and "Type 1 diabetes mellitus: Disease prediction and screening".)

STAGES OF TYPE 1 DIABETES — Type 1 diabetes has a long preclinical period during which endogenous insulin secretion remains relatively stable, followed by a peridiagnostic period when secretion declines more rapidly [7-10]. (See "Type 1 diabetes mellitus: Disease prediction and screening", section on 'Stages of type 1 diabetes'.)

This long preclinical period comprises well-defined stages of disease progression, affording an opportunity to intervene with disease-modifying therapies. Virtually all individuals with preclinical disease progress to clinical type 1 diabetes (table 1).

●Stage 1 – Stage 1 diabetes is an asymptomatic period defined by seroconversion with the presence of at least two diabetes-related autoantibodies but preserved normoglycemia. This is considered the onset of type 1 diabetes.

●Stage 2 – Stage 2 diabetes is characterized by asymptomatic progression to dysglycemia.

●Stage 3 – Stage 3 diabetes is the onset of clinical disease and defined by glycemic criteria. Individuals with stage 3 diabetes usually but not uniformly have hyperglycemia-related symptoms.

In individuals with preclinical (stage 1 or stage 2) type 1 diabetes, the goal of disease-modifying therapies is to prevent or delay the onset of clinical disease. In individuals with clinical (stage 3) type 1 diabetes, the goal of disease-modifying therapy is to preserve beta cell function and insulin secretion.

PREVENTING OR DELAYING CLINICAL DISEASE IN HIGH-RISK INDIVIDUALS

Teplizumab — Teplizumab, a humanized anti-CD3 monoclonal antibody, is the only therapy with regulatory approval in the United States for delaying the onset of clinical type 1 diabetes in individuals with preclinical disease.

Clinical use — In the United States, teplizumab is approved for individuals aged 8 years and older who have stage 2 type 1 diabetes (≥2 diabetes-related autoantibodies and dysglycemia) (table 1) and is administered as a single 14-day course of daily intravenous infusions.

The implementation of teplizumab in clinical practice is evolving and varies regionally. For individuals who meet criteria for teplizumab therapy, the choice to initiate treatment should be individualized based on patient and family preferences and the availability of infrastructure to support treatment infusions.

The availability of teplizumab represents a paradigm shift in the treatment of type 1 diabetes; with enhanced understanding of disease pathogenesis and progression, type 1 diabetes can be identified and treated in its preclinical stages before the development of symptomatic hyperglycemia. Improved clinical systems to identify and monitor individuals with preclinical disease will be critical as other disease-modifying therapies become available and the use of these therapies expands in clinical practice. (See "Type 1 diabetes mellitus: Disease prediction and screening", section on 'Screening for diabetes-related autoantibodies'.)

Efficacy and side effects — Regulatory approval of teplizumab in the United States was based on a landmark prevention trial in which 76 individuals (median age 14 years) with stage 2 diabetes (≥2 diabetes-related autoantibodies, impaired glucose tolerance) and a relative with type 1 diabetes were randomly assigned to a single 14-day course of once-daily infusions of either teplizumab (n = 44) or placebo (n = 32) [11]. Over a median follow-up of approximately two years, teplizumab delayed the onset of clinical type 1 diabetes by a median of 24 months (figure 1), and 25 of 44 teplizumab recipients remained disease-free compared with 9 of 32 placebo recipients (57 versus 28 percent, respectively). In a follow-up analysis with a median 923 days of observation, teplizumab conferred a median delay in type 1 diabetes diagnosis of 32.5 months, and 50 percent of teplizumab recipients remained disease-free compared with 22 percent of placebo recipients (figure 2) [12]. The efficacy results of this small trial may differ from effectiveness in clinical practice.

Among clinical trial participants, the primary side effects of teplizumab treatment were transient lymphopenia, rash, headache, transient liver transaminase elevation, and nausea [11]. Lymphocyte count declined early during teplizumab treatment but self-resolved in all participants (figure 3). The teplizumab prevention trial was relatively small and of short duration, which limits conclusions about adverse events that are less common.

Therapies in development for preclinical disease — Studies are underway to test the efficacy of several immune-modulating treatments in individuals with both stage 1 (≥2 diabetes-related autoantibodies with normoglycemia) and stage 2 (≥2 diabetes-related autoantibodies and dysglycemia) type 1 diabetes (table 1). None of these therapies is available for clinical use.

●Antithymocyte globulin – Antithymocyte globulin (ATG) comprises animal-derived antibodies that deplete B cells and T cells. This treatment was shown to preserve insulin secretion in clinically overt (stage 3) type 1 diabetes, prompting design of a subsequent efficacy trial in individuals with preclinical disease [13]. (See 'Lymphocyte-directed therapies' below.)

●Abatacept – Abatacept is a cytotoxic T lymphocyte antigen 4 (CTLA4) immunoglobulin that blocks T cell costimulation. Abatacept can preserve beta cell function in clinically overt (stage 3) type 1 diabetes, and this finding led to a follow-up trial in individuals with preclinical (stage 1) disease. In the follow-up trial, abatacept improved beta cell function at 12 months compared with placebo; however, 12 months after treatment ended, beta cell function was the same in both groups. Abatacept also did not delay progression to stage 2 or stage 3 disease [14].

●Hydroxychloroquine – Hydroxychloroquine is a well-tolerated medication that is approved for the treatment of autoimmune conditions including rheumatoid arthritis and systemic lupus erythematosus. It is under investigation as a therapy to delay the progression of preclinical (stage 1) type 1 diabetes [15,16].

●Oral insulin – Oral insulin has been tested in multiple trials to delay or prevent progression to clinical (stage 3) disease in individuals with preclinical disease or high genetic risk for type 1 diabetes. None of the trials have demonstrated efficacy for the prevention or delay of type 1 diabetes, but post hoc analyses indicate that oral insulin may benefit selected individuals with high insulin autoantibody titers or those closer to clinical diagnosis. In the Diabetes Prevention Trial (DPT-1), 372 autoantibody-positive family members of people with type 1 diabetes were randomly assigned to daily oral insulin or placebo [17]. In the overall cohort, oral insulin did not prevent disease progression. In a post hoc analysis, oral insulin delayed the onset of clinical disease by 4.5 and 10 years in participants with insulin autoantibody titers ≥80 and ≥300 nU/mL, respectively [18,19]. In a subsequent trial, oral insulin similarly did not delay progression to clinical disease, but in an independently randomized cohort of 55 participants with low first-phase insulin secretion at baseline, oral insulin conferred a 31-month delay in disease progression [20].

Oral insulin also is being tested for primary prevention of islet autoimmunity and clinical type 1 diabetes in genetically at-risk children. In a trial in 25 genetically at-risk children who had not yet developed autoantibodies, oral insulin (67.5 mg daily) was safe and induced a regulatory immune response [21]. These preliminary data prompted a subsequent, ongoing trial [22].

●Intranasal insulin – Trials testing intranasal insulin have demonstrated that therapy is safe and elicits an immune response but is ineffective for delaying type 1 diabetes progression [23-25]. Additional studies are testing whether a higher dose or alternative dosing schedule may delay disease progression.

Therapies without benefit for preclinical disease

●Nicotinamide – Nicotinamide prevents autoimmune diabetes in nonobese diabetic (NOD) mice. However, in a trial in 552 individuals with preclinical type 1 diabetes (autoantibody positivity, relative with type 1 diabetes), daily treatment with extended-release nicotinamide (1.2 g/m²) over a course of five years had no effect on type 1 diabetes progression [26].

●Parenteral insulin – Early treatment with exogenous insulin was hypothesized to "rest" dysfunctional beta cells and reduce their immune-mediated destruction. An arm of the DPT-1 trial tested low-dose ultralente insulin in 339 participants with preclinical disease and high risk for progression. Therapy was safe and did not cause excessive hypoglycemia but did not delay progression to clinical disease [23].

PRESERVING INSULIN SECRETION IN CLINICAL DISEASE — At the time of diagnosis, most patients with type 1 diabetes still have clinically meaningful endogenous insulin production, which is measured as C-peptide. C-peptide is cosecreted with insulin in equimolar amounts and reflects endogenous insulin secretion in individuals treated with insulin therapy. The aim of immunotherapy in early clinical disease is to preserve remaining insulin secretion, which is associated with reduced glycemic variability, lower risk of long-term complications, and lower risk of hypoglycemia.

Clinical benefits of preserved insulin secretion — Historically, type 1 diabetes was thought to uniformly cause absolute deficiency of endogenous insulin, typically within a few years of diagnosis. However, endogenous insulin secretion persists in some individuals for years or even decades after diagnosis. For example, a T1D Exchange substudy of 919 individuals (aged 5 to 88 years) with variable disease duration (3 to 81 years, median duration 13 years) found that the overall frequency of detectable, nonfasting C-peptide (≥0.017 nmol/L [0.05 ng/mL]) was 29 percent [27]. In a separate cross-sectional analysis in 924 individuals with a median diabetes duration of 19 years, 80 percent of individuals had detectable post-meal urine C-peptide [28]. In cohorts of individuals with a mean duration of type 1 diabetes >50 years, the frequency of detectable C-peptide concentrations has ranged from 32 to 67 percent [29,30]. The variable frequency of detectable C-peptide concentrations across studies may in part reflect the substantial increase in assay sensitivity over time.

In individuals with type 1 diabetes, data from natural history studies, intervention studies, and transplant studies show that preserved beta cell function reduces the risk of long-term microvascular complications and severe hypoglycemia. However, the magnitude and duration of preserved insulin secretion needed to confer these benefits have not been clearly established. Preserved beta cell function may reduce risk of diabetes-related complications in part through improved glycemia; the extent to which preserved beta cell function and intensive glucose management provide independent and additive protection from risk of diabetes-related complications has not been clearly established.

Lower risk of diabetes-related complications — Preserved insulin secretion strongly associates with a reduced risk of diabetes-related microvascular complications. The protective effects of preserved insulin secretion were shown in a subgroup analysis from the Diabetes Control and Complications Trial (DCCT) that included 303 individuals with type 1 diabetes (duration one to five years) and preserved C-peptide production (stimulated C-peptide level >0.20 nmol/L [0.6 ng/mL]). In this subgroup, participants who were randomly assigned to intensive insulin therapy (three or more daily insulin injections or continuous subcutaneous insulin infusion) exhibited both a higher rate of preserved C-peptide response and a lower risk of retinopathy progression or microalbuminuria than those who received conventional therapy (one or two daily insulin injections) [31]. Moreover, within the group assigned to intensive insulin therapy, individuals who retained a C-peptide response had a 50 percent lower risk of retinopathy progression than those who lost C-peptide response during the study.

In cohorts of people living with type 1 diabetes for 50 years or longer, continued production of endogenous insulin is associated with relative protection from long-term diabetes-related complications including retinopathy, kidney disease, and vascular disease. Cross-sectional analyses have shown that among individuals with longstanding type 1 diabetes (mean duration >50 years), protection from diabetes-related complications is associated with lower daily insulin doses (approximately 0.5 units/kg body weight) [32,33], consistent with some degree of preserved insulin secretion. Notably, one of these studies also demonstrated that this relative protection from complications was not associated with current glycated hemoglobin (A1C) or longitudinal (over 15 years) A1C trends [33], suggesting that preserved insulin secretion may impart protection independent of glycemia.

Improved glycemia — In individuals with type 1 diabetes, clinical data suggest that preserved insulin secretion promotes overall glycemic management, reduced glycemic variability, and avoidance of hypoglycemia. In the DCCT, participants who were randomly assigned to intensive insulin therapy had a reduced risk of diabetes-related complications but a two- to three-fold greater risk of severe hypoglycemia compared with those who received conventional therapy [34]. However, in a subgroup analysis of 303 participants with preserved C-peptide production at baseline (stimulated C-peptide level >0.20 nmol/L [0.6 ng/mL]), those who retained a C-peptide response during intensive insulin therapy had both a lower A1C and a 65 percent lower risk of severe hypoglycemia than intensively treated participants who lost a C-peptide response [31].

Similarly, in an analysis from the Inducing Remission in New-Onset T1D with Alefacept (T1DAL) trial in individuals with newly diagnosed type 1 diabetes (aged 12 to 35 years), stimulated C-peptide level was inversely correlated with A1C, glycemic variability, and hypoglycemia after two years of follow-up [35]. These correlations were evident irrespective of treatment group assignment, further suggesting that preserved C-peptide, rather than the treatment intervention, was responsible for the observation [35].

Observational data from islet cell transplant studies provide indirect corroboration of the protective effects of preserved beta cell function on glycemia. In a study of 12 islet cell transplant recipients, stimulated C-peptide level was inversely correlated with mean interstitial glucose, glycemic variability, time spent outside the glucose target range, and hypoglycemia risk [36].

Degree of preserved insulin secretion needed for clinical benefit — Collective clinical data suggest that even minimal residual insulin secretion provides clinical benefit in individuals with type 1 diabetes, although specific benefits may require different thresholds of insulin secretion. For example, in a retrospective analysis of DCCT data that stratified participants in the intensive insulin therapy arm by stimulated C-peptide level, those with a stimulated C-peptide >0.04 nmol/L (0.12 ng/mL) at study entry exhibited reduced risk of retinopathy and diabetic kidney disease [37]. However, only those participants with a stimulated C-peptide level >0.2 nmol/L (0.6 ng/mL) experienced lower frequency of severe hypoglycemia [37]. An investigation of 677 islet cell transplant recipients followed for a mean of 4.6 years found that stimulated C-peptide >0.97 nmol/L (2.9 ng/mL) provided optimal protection from severe hypoglycemia [38]. In another analysis of DCCT data, any incremental increase in C-peptide above the point of detection (0.03 nmol/L [0.09 ng/mL]) was associated with lower A1C, lower daily insulin usage, fewer episodes of hypoglycemia, and lower risk of retinopathy [39].

Further supporting the protective effects of preserved insulin secretion, an analysis from a natural history cohort of 6076 people with type 1 diabetes found that nonfasting C-peptide level was inversely correlated with both incident retinopathy and frequency of severe hypoglycemia [40]. Notably, in this cohort, a continuous reduction in severe hypoglycemia risk was associated with C-peptide levels to the lower limit of detection (0.003 nmol/L [0.009 ng/mL]), markedly lower than the protective threshold observed in the DCCT intensive treatment cohort. The reduction in retinopathy risk also was associated with the lower A1C levels evident in individuals with preserved C-peptide.

Data from islet cell transplant studies also offer indirect evidence of the protective effects of even minimal endogenous insulin production. In a study of 23 individuals with type 1 diabetes who underwent islet cell transplant, minimal beta cell function after transplant was sufficient to abrogate severe hypoglycemia and impaired awareness of hypoglycemia, even when insulin production from the transplanted islets was inadequate to improve mean glucose, reduce glycemic variability, or enable insulin independence [41].

Promising investigational therapies to preserve insulin secretion — As in all other immune-mediated diseases, immunotherapy does not cure type 1 diabetes, but multiple therapies have demonstrated the potential to alter the natural history of disease. Since the 1980s, dozens of short-term therapies have been tested in new-onset (stage 3) type 1 diabetes. Although none is approved for clinical use in type 1 diabetes, several have demonstrated an acceptable risk profile and the capacity to modify the underlying disease and preserve insulin secretion.

Regardless of the therapy's mechanism of action, the results in trials with positive outcomes are similar: the rate of C-peptide decline differs between drug- and placebo-treated individuals soon after randomization, and C-peptide later declines in parallel in both groups [42]. These findings suggest that immunotherapy can modify the natural history of type 1 diabetes, as the early treatment benefit leads to a sustained increase in C-peptide in drug-treated groups compared with control groups. Further, this benefit endures for years after treatment. For example, two days of therapy with antithymocyte globulin resulted in greater insulin secretion than placebo two years after treatment (figure 4) [42]. (See 'Lymphocyte-directed therapies' below.)

Findings from several stage 3 trials suggest that treatment response is most evident during the time of more rapid loss of insulin secretion; such rapid loss is often seen in younger children or in those closer to clinical diagnosis.

Cytokine-directed therapies — A hallmark of type 1 diabetes pathophysiology is beta cell infiltration by CD4+ and CD8+ T cells. These lymphocytes can release cytokines that may variably facilitate beta cell destruction, beta cell repair, or tolerance of self-antigens; thus, targeting these cytokines or their downstream pathways represents a potential therapeutic strategy for preserving endogenous insulin secretion in type 1 diabetes. The pathophysiology of type 1 diabetes is reviewed in detail separately. (See "Pathogenesis of type 1 diabetes mellitus".)

●Anti-tumor necrosis factor (TNF) therapies – The anti-TNF agents etanercept and golimumab have been shown to transiently preserve insulin secretion in new-onset type 1 diabetes. Etanercept was tested in a pilot study in 18 individuals (aged 3 to 18 years) with type 1 diabetes diagnosed within 100 days who were randomly assigned to 24 weeks of etanercept or placebo injections [43]. At the end of treatment, stimulated C-peptide area-under-the-curve (AUC) increased 39 percent from baseline in the etanercept group but decreased by 20 percent in the placebo group. In a trial in 84 individuals (aged 6 to 21 years) recently diagnosed with type 1 diabetes, participants were randomly assigned to the anti-TNF agent golimumab or placebo [44]. After 52 weeks of treatment, golimumab treatment led to a higher stimulated C-peptide AUC than placebo (0.64 versus 0.43 pmol/mL, respectively), and this benefit was sustained for 52 weeks following treatment [45].

●Interleukin (IL)-2 therapy – The IL-2 pathway regulates the expansion of regulatory T cells, and some clinical studies have implicated deficient IL-2 production or regulatory T cells in type 1 diabetes [46,47]. However, a trial of combination therapy with rapamycin and IL-2 was ended early when a transient worsening of beta cell function was observed, despite the anticipated treatment-induced increase in regulatory T cells [48]. This trial and others revealed IL-2's narrow therapeutic dosing window. Different dosing strategies and modified versions of IL-2 are being developed to stimulate the desired expansion of regulatory T cells while avoiding off-target effects.

●Anti-IL-12, anti-IL-23, and anti-IL-17 therapies – IL-12 and IL-23 contribute to the production of interferon (IFN) lambda and IL-17, key cytokines in the generation of pathogenic effector T cells in type 1 diabetes. Antibodies to IL-12, IL-23, and IL-17 are being tested in adults with new-onset type 1 diabetes.

●Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibition – The JAK/STAT signaling pathway plays myriad roles in immune function including the regulation of cytokine receptors. This pathway has been implicated in immune-mediated beta cell destruction in type 1 diabetes, and blockade of this pathway prevents and reverses diabetes in the nonobese diabetic (NOD) mouse model [49]. In a trial in 91 individuals (aged 10 to 30 years) with new-onset type 1 diabetes (diagnosed within 100 days), participants were randomly assigned to daily treatment with the oral JAK1/2 inhibitor baricitinib (n = 60) or placebo (n = 31) [50]. After 48 weeks of therapy, stimulated mean C-peptide level was greater with baricitinib compared with placebo (median 0.65 versus 0.43 nmol/L/min, respectively). A1C, frequency of hypoglycemia, and the percentage of time spent in the target glucose range (70 to 180 mg/dL [3.9 to 10 mmol/L]) were not significantly different between groups.

Lymphocyte-directed therapies — Several B cell- or T cell-directed immunotherapies have proven effective for preserving insulin secretion in new-onset clinical (stage 3) type 1 diabetes.

●Teplizumab – Teplizumab is an anti-CD3 monoclonal antibody that blocks activated T cells, has been tested in multiple trials in new-onset type 1 diabetes and, in the United States, is the only treatment approved for preclinical type 1 diabetes. (See 'Teplizumab' above.)

Trials in patients with clinical (stage 3) type 1 diabetes have demonstrated that teplizumab therapy preserves insulin secretion [51]. Adverse effects in these trials included lymphopenia, rash, nausea/vomiting, liver transaminase elevation, and headache, similar to those seen in trials in participants with preclinical diabetes. Adverse events requiring permanent study drug discontinuation occurred in 14.3 and 3.7 percent of participants in teplizumab-treated and control groups, respectively. The most common of these were laboratory abnormalities, including liver enzyme elevations, neutropenia, and lymphopenia. (See 'Efficacy and side effects' above.)

As examples of these trials:

•In a preliminary trial in 24 individuals with newly diagnosed (within six weeks) type 1 diabetes, teplizumab preserved insulin secretory capacity compared with placebo [52]. A difference in beta cell function between groups remained evident two years after treatment [53]. In a subsequent trial, 52 individuals with newly diagnosed type 1 diabetes who were previously treated with teplizumab underwent a second 14-day course of teplizumab administered 12 months after the first course [54]. After two years of follow-up, teplizumab delayed C-peptide loss by 15.9 months compared with no treatment. In a post hoc analysis, predictors of treatment response included lower A1C and lower insulin use at baseline [54]. Seven years after treatment, responders to teplizumab therapy continued to exhibit higher stimulated C-peptide production and more favorable immune phenotypes [55].

•In a phase III trial in 516 individuals with newly diagnosed type 1 diabetes, participants were randomly assigned to one of four treatment arms: a full- or low-dose, single course of 14 daily teplizumab infusions; a full-dose, single course of six daily teplizumab infusions followed by eight daily placebo infusions; or a placebo arm (14 daily placebo infusions) [56]. All treatments were repeated after six months. The study did not meet its primary endpoint, a composite of clinical measures including A1C and daily insulin dose, rather than the more standard endpoint of stimulated C-peptide [57]. Nonetheless, post hoc analysis demonstrated benefit of a 14-day course of teplizumab relative to placebo in subgroups including individuals with greater C-peptide production, lower insulin use, lower A1C at baseline, and randomization close to time of diagnosis [58], suggesting that administration of drug early in clinical disease could be more effective.

•In a phase III trial in children and adolescents with newly diagnosed (within six weeks) type 1 diabetes, participants were randomly assigned to two, 12-day courses of teplizumab (n = 217) or placebo (n = 111) [59]. At 78 weeks, teplizumab treatment preserved C-peptide production compared with placebo (least-squares mean difference in C-peptide AUC of 0.13 pmol/mL), and the rate of preserved C-peptide production (peak level ≥0.2 pmol/mL) was higher in the teplizumab group (94.9 versus 79.2 percent with placebo). The percentage of time spent in the target glucose range (70 to 180 mg/dL [3.9 to 10 mmol/L]) was not significantly different between groups (68.7 versus 64.6 percent with teplizumab and placebo, respectively). Mean daily insulin dose did not change in the teplizumab group (0.45 units/kg/day at baseline and 78 weeks) but increased numerically in the placebo group (0.38 and 0.6 units/kg/day at baseline and 78 weeks, respectively).

●Rituximab – Rituximab is an anti-CD20 monoclonal antibody that destroys B cells. In a trial in 87 adults and children with new-onset type 1 diabetes, rituximab treatment resulted in a modestly higher stimulated C-peptide AUC than placebo (0.56 versus 0.47 pmol/mL, respectively) one year after treatment initiation [60]. Adverse effects of rituximab included infusion reactions and the expected decline in B cells [60,61].

●Abatacept – Abatacept is a cytotoxic T lymphocyte antigen 4 (CTLA4) immunoglobulin that blocks T cell costimulation. In a trial in 112 adults and children with new-onset type 1 diabetes, stimulated C-peptide AUC was 59 percent higher in the abatacept group than in the placebo group after two years of treatment [62]. Reported adverse events did not differ between the two groups [62,63].

●Sequential treatment regimens with rituximab followed by abatacept – Post hoc analyses of trial data have suggested the possible synergistic benefit of sequential therapy with rituximab and abatacept [64,65]. In a proposed trial, treatment with rituximab will be followed by weekly subcutaneous injections of abatacept [66].

●Alefacept – Alefacept is an anti-CD2 therapy that generates anti-memory T cell effects. In a trial in 49 adolescents and adults with new-onset type 1 diabetes, alefacept treatment increased stimulated C-peptide AUC relative to placebo (0.015 versus -0.156 nmol/L, respectively) after one year of treatment [67]. Adverse events were similar in alefacept- and placebo-treated participants [67,68]. Early phase trials of siplizumab, an anti-CD2 monoclonal antibody similar to alefacept, are underway.

●Antithymocyte globulin – Antithymocyte globulin (ATG), which depletes activated B cells and T cells, was tested in a trial in 89 adolescents and adults with new-onset type 1 diabetes that simultaneously tested combination therapy with ATG and granulocyte colony-stimulating factor (GCSF) [42]. ATG treatment led to a higher stimulated C-peptide AUC than placebo (0.646 versus 0.406 nmol/L, respectively), whereas combination therapy did not confer benefit. Stimulated C-peptide AUC remained significantly higher in ATG-treated individuals two years after randomization (figure 4) [69].

Cellular therapies — Several trials have tested the infusion of cells intended to either regulate immune function or replace destroyed or dysfunctional beta cells. These therapies are designed to preserve or replace endogenous insulin secretion, respectively.

●Autologous regulatory T cells – Peripheral infusion of autologous regulatory T cells has been tested as monotherapy or in combination with low dose IL-2 [70-73].

●Dendritic cells – Antigen-specific dendritic cell treatments may promote tolerance of type 1 diabetes-specific antigens [74,75], and promising early studies have prompted further investigation.

●Stem cells – Stem cells include pluripotent embryonic cells, multipotent mesenchymal cells, or induced pluripotent cells. Mesenchymal stem cells (MSC) possess immunoregulatory properties, lack immunogenicity, and secrete factors that enhance local tissue repair [76]. The capacity of MSCs to modify disease course in type 1 diabetes has been investigated in small trials [77-79].

●Allogeneic islet cell transplantation – Allogeneic islet cell transplantation can impart insulin independence and is an effective therapy for patients with severe hypoglycemia. Limitations include a limited supply of human islet cell donors, need for lifelong immunosuppression, and lower rates of insulin independence compared with whole pancreas transplant [80-83]. Islet cell encapsulation is a promising investigational strategy to protect the islet cells from rejection and thereby circumvent the need for lifelong immunosuppression. (See "Pancreas and islet transplantation in diabetes mellitus", section on 'Islet transplantation'.)

Beta cell support (eg, verapamil) — While most disease-modifying therapies for type 1 diabetes have targeted immune-mediated beta cell destruction, other therapies provide direct beta cell support or reduce beta cell stress. These treatments may be used in combination with immunotherapy in future trials [84].

The following therapies are in development to provide beta cell support:

●Verapamil is a calcium channel blocker with a long record of clinical use in hypertension and tachycardia syndromes. Although verapamil is widely available and inexpensive, its off-label use in type 1 diabetes should be avoided, as additional safety and efficacy data are needed in this population.

Verapamil reduces the expression of thioredoxin-interacting protein (TXNIP), which is toxic to beta cells. In a small trial in 32 adults with new-onset type 1 diabetes, verapamil treatment led to higher stimulated C-peptide AUC at 3 and 12 months compared with placebo [85].

A subsequent trial in 88 children and adolescents with newly diagnosed type 1 diabetes (aged 7 to 17 years, mean time from diagnosis 24 days) tested verapamil in conjunction with partially automated (hybrid closed-loop) insulin therapy. At one year, C-peptide AUC was 30 percent higher in participants treated with verapamil (0.65 versus 0.44 pmol/mL with placebo, adjusted between-group difference 0.14 pmol/mL), whereas intensive insulin therapy provided no additional benefit [86,87]. In the verapamil group, three participants developed abnormal electrocardiogram findings, including first- and second-degree heart block, and hypotension occurred in one participant. A European network is testing verapamil in a trial in adults with newly diagnosed type 1 diabetes.

●Tyrosine kinase inhibitors [88].

●Difluoromethylornithine (DMFO).

●Tauroursodeoxycholic acid.

Insulin antigen therapy — Anti-insulin antibodies often appear early in islet autoimmunity [89,90], making insulin, its precursors (eg, pre-proinsulin and proinsulin), and insulin components (eg, B-chain) attractive targets for antigen therapy. Most trials testing insulin in new-onset or longer standing type 1 diabetes have not demonstrated endogenous insulin preservation, but several have identified promising markers of therapeutic immune modulation, prompting further study [91-94]. Ongoing trials in new-onset type 1 diabetes will deliver insulin in a modified fashion, for example, as a component of a plasmid deoxyribonucleic acid (DNA), via genetically modified bacteria, or as a nanoparticle to augment immune system exposure to insulin antigens. Endpoints of these early studies include safety and detection of a therapeutic immune signal.

Therapies without demonstrated benefit after clinical diagnosis

●Microbiome modulation/probiotics – Some studies have suggested that the fecal microbiome changes after diagnosis of type 1 diabetes [95]. However, whether this apparent dysbiosis contributes to disease pathogenesis is unknown, as are the possible therapeutic effects of manipulating the fecal microbiome (eg, through transplant or probiotic supplementation). In trials in individuals with new-onset type 1 diabetes, neither fecal transplant nor prebiotic or probiotic supplementation have modified disease course [96-101], but this remains an area of active investigation.

●Cyclosporine – Cyclosporine was one of the earliest anti-lymphocyte agents tested to induce remission in new-onset type 1 diabetes. Although cyclosporine induced remission in children with newly diagnosed type 1 diabetes, treatment conferred kidney and other toxicities [102-104].

●Azathioprine – The antipurine agent azathioprine was tested in new-onset type 1 diabetes both as monotherapy and in combination with prednisone. Like cyclosporine, azathioprine caused significant side effects, and it failed to preserve endogenous insulin secretion [105-107].

●Mycophenolate mofetil – In a trial in 126 individuals with newly diagnosed type 1 diabetes (within three months), treatment with the antipurine agent mycophenolate mofetil, either as monotherapy or combined with anti-IL-2 therapy, did not affect stimulated C-peptide AUC at two years [108].

●Anti-IL-1, anti-IL-6, and anti-IL-8 therapies – To date, therapies that inhibit IL-1, IL-6, and IL-8 have proven ineffective for preserving insulin secretion in newly diagnosed type 1 diabetes [109-111].

●Anti-IL-21 and GLP-1 receptor agonist combination therapy – In a trial in 308 adults with newly diagnosed type 1 diabetes, participants were randomly assigned to treatment with placebo, anti-IL-21 therapy, the glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide, or both liraglutide and anti-IL-21 therapy [112]. After one year of treatment, only combination therapy preserved C-peptide production relative to placebo. However, six months after treatment cessation, both liraglutide groups tended toward greater loss of insulin secretion compared with the placebo and anti-IL-21 groups, suggesting that the initial benefit of GLP-1 agonist therapy may have been related to its known augmentation of insulin secretion, rather than to modification of the underlying disease.

●Early intensive insulin therapy – Several trials have investigated the introduction of early, intensive insulin therapy in new-onset type 1 diabetes. While an early study demonstrated a benefit for preservation of C-peptide, subsequent trials testing this intervention have been negative [87,113-115].

●Glutamic acid decarboxylase 65 – Glutamic acid decarboxylase 65 (GAD-65) is an enzyme essential for the formation of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter that can be detected in neural and neuroendocrine cells including islet cells. GAD-65 treatment has been tested in multiple new-onset type 1 diabetes trials but overall has shown no benefit for preserving insulin secretion [116-118].

●Hematopoietic stem cell transplantation – Autologous hematopoietic stem cell transplantation (HSCT) entails ex vivo expansion of pluripotent stem cells with subsequent infusion into a patient who has undergone nonmyeloablative chemotherapeutic conditioning. Although therapy confers a high rate of insulin independence, the conditioning component of HSCT imparts significant risks, including life-threatening bone marrow aplasia and sepsis [119]. These risks render HSCT unlikely to be useful in type 1 diabetes.

●Dietary modification or supplementation – No dietary supplements have shown efficacy for preserving insulin secretion in new-onset type 1 diabetes, although high-quality studies are limited. Dietary approaches that have been investigated include avoidance of dietary gluten, vitamin D supplementation, and omega-3 fatty acid supplementation, none of which has demonstrated benefit after clinical diagnosis [120-123].

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●Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Need for disease-modifying therapies – Most individuals living with type 1 diabetes mellitus do not meet the therapeutic targets that are associated with a lower risk of long-term complications. Type 1 diabetes also exacts an emotional, cognitive, and financial toll on individuals, families, and society and continues to limit life expectancy. Therefore, alternative approaches that modify the natural history of disease could dramatically improve both quality of life and health outcomes for individuals with type 1 diabetes. (See 'Introduction' above.)

●Preclinical progression – Type 1 diabetes has a long preclinical period with well-defined stages of disease progression (table 1), affording an opportunity to intervene with disease-modifying therapies. Virtually all individuals with preclinical disease progress to clinical type 1 diabetes. These stages are as follows (see 'Stages of type 1 diabetes' above):

•Stage 1 – Stage 1 diabetes is an asymptomatic period defined by seroconversion with the presence of at least two diabetes-related autoantibodies but preserved normoglycemia.

•Stage 2 – Stage 2 diabetes is characterized by asymptomatic progression to dysglycemia.

•Stage 3 – Stage 3 diabetes is the onset of clinical disease and is defined by glycemic criteria. Individuals with stage 3 diabetes usually but not uniformly have diabetes-related symptoms.

●Teplizumab therapy – Teplizumab, a humanized anti-CD3 monoclonal antibody, is the only therapy with regulatory approval in the United States for delaying the onset of clinical type 1 diabetes in individuals with preclinical disease. (See 'Teplizumab' above.)

In the United States, teplizumab is approved for individuals aged 8 years and older who have stage 2 diabetes (≥2 diabetes-related autoantibodies and dysglycemia) (table 1) and is administered as a single 14-day course of daily intravenous infusions. The implementation of teplizumab in clinical practice is evolving and varies regionally. For individuals who meet criteria for teplizumab therapy, the choice to initiate treatment should be individualized based on patient and family preferences and the availability of infrastructure to support treatment infusions.

Adverse effects include transient lymphopenia, rash, anemia, and fever.

●Other strategies to prevent or delay type 1 diabetes onset – Other immune-modulating therapies are under investigation to prevent or delay the onset of type 1 diabetes in individuals at high risk for developing the disease. (See 'Therapies in development for preclinical disease' above.)

●Benefit of preserved insulin secretion after diagnosis – Preservation of endogenous insulin secretion after the clinical diagnosis of type 1 diabetes is associated with enduring benefits, including reduced risks of microvascular complications and severe hypoglycemia. (See 'Clinical benefits of preserved insulin secretion' above.)

●Strategies to preserve beta cell function after diagnosis – Many therapeutic strategies have been investigated for preserving beta cell function after the clinical diagnosis of type 1 diabetes. Although no immune-modulating therapies are approved for use in clinical (stage 3) type 1 diabetes, several have demonstrated a reasonable risk profile and the capacity to modify the underlying disease and preserve insulin secretion. (See 'Promising investigational therapies to preserve insulin secretion' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges David McCulloch, MD, who contributed to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges Massimo Pietropaolo, MD (deceased), who contributed to earlier versions of this topic.