Summary

Type 1 diabetes results from autoimmune destruction of insulin-producing beta cells. There is a genetic predisposition to the disease, with the greatest contribution conferred by alleles present within the major histocompatibility complex (MHC; known as the human leukocyte antigen [HLA] region) on the short arm of chromosome 6. Whether the initiation of this immune response results from environmental triggers remains to be determined. Over years, immune infiltration into pancreatic islets leads to beta cell damage, impairment of cell function, and destruction of beta cells. This notion has led to clinical trials to arrest the progression of disease and potentially prevent or reverse the clinical syndrome.

Clinical trials using various immunologic agents have been conducted at multiple stages of the disease process. Primary prevention trials have been conducted in individuals with genetic predisposition who have not yet developed immunologic markers. Secondary prevention trials have been conducted in individuals with two or more type 1 diabetes-related autoantibodies, either during Stage 1 (normal metabolic function) or Stage 2 (abnormal metabolic function). Intervention trials, also referred to as tertiary prevention trials, have been conducted after diagnosis of hyperglycemia (Stage 3), mostly shortly after clinical onset of disease.

This article provides brief summaries of randomized controlled clinical trials that have been performed and mentions some nonrandomized pilot studies. Success has been limited in primary and secondary prevention trials, with one recent and notable exception (teplizumab). Some tertiary intervention trials have demonstrated improved beta cell function, but these studies have not permanently prevented the decline in beta cell function (eventually declining in parallel to controls). Future interventions with combinations of agents that can target multiple immunologic mechanisms may be needed, including strategies to improve regulatory immunity, as well as to replace and restore beta cell function.

Introduction

Type 1 diabetes is a progressive disease with a genetic predisposition, where a putative environmental trigger(s) initiates an immune response that results in pancreatic islet beta cell damage, impairment of beta cell function, and destruction of beta cells (1,2,3). Although initial characterization suggested a slow, linear progression of disease (1), more recent thought is that progression of type 1 diabetes is more variable, with waxing and waning of beta cell mass (Figure 1, solid line versus dotted line in Stages 1 and 2) (3,4). Moreover, the disease may be a consequence of imbalance between the immune system and the ability of the pancreatic beta cell to withstand attack (5).

FIGURE 1.

Stages of Type 1 Diabetes and Associated Reduction in Beta Cell Mass: Moving From a Linear Model of Beta Cell Loss to a More “Relapsing and Remitting” Model. Moving beyond the pioneering linear model of beta cell loss (solid line) by Dr. (more...)

A genetic basis for type 1 diabetes in association with human leukocyte antigens (HLA) was first described in the early 1970s (6), and subsequently, that relationship has been extensively characterized (7,8,9,10), with both HLA class II (10,11) and class I (12) contributing to genetic susceptibility and protection (13). Although multiple other genes have been identified (14,15), the HLA region remains the major contributor to genetic predisposition (16). In a study of the general population of Denver, Colorado, children born with the high-risk genotype HLA-DR3/4-DQ8 account for almost 50% of children who develop islet autoimmunity by age 5 years (17). Non-major histocompatibility complex (MHC) susceptibility genes may play a role in determining the rate of disease progression (17,18). More detail on genetic factors is described in the Diabetes in America article Genetics of Type 1 Diabetes (19).

An environmental or other acquired factor(s) that activates immunologically mediated destruction of beta cells has been suggested, but this (these) factor(s) has not been definitively identified (20,21). The role that the beta cell may play in its own demise, via endoplasmic reticulum (ER) stress and more, is a critical area of ongoing research (22). Moreover, the association between environmental factors and the course of the disease is complicated by observations that not only initiation of the disease process but also the rate of progression to clinical onset may be affected by environmental determinants. Further, metabolic decompensation at disease onset may be a consequence of unrelated or nonspecific environmental events that may, for example, induce inflammation in both the endocrine and exocrine pancreas. Observational cohort studies, such as The Environmental Determinants of Diabetes in the Young (TEDDY) study (23,24), are designed to ascertain environmental determinants that may trigger islet autoimmunity and affect the rate of progression to clinical onset in subjects with persistent islet autoimmunity. Please see the Diabetes in America article Risk Factors for Type 1 Diabetes for more discussion of putative environmental triggers of type 1 diabetes (25).

The immune response is initiated by antigen presentation in the context of HLA class II molecules with beta cell destruction mediated by T lymphocytes (26,27), resulting in a lymphocytic inflammatory response in pancreatic islets, called insulitis (28). Both effector CD4 (29) and cytotoxic CD8 (30) T lymphocytes are involved. These immune cells have the capacity to mediate damage both via cytokine effects, involving such cytokines as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α), or direct cytotoxic T lymphocyte-mediated lysis. This initial immune response, with continued lysis, creates the potential of a vicious cycle of inflammation, which also may engender secondary and tertiary immune responses that contribute to the impairment and eventual destruction of beta cells (3,5,26). This insidious process evolves over a variable amount of time—even many years in some individuals, particularly if diagnosed in adulthood. The eventual overt manifestation of clinical symptoms becomes apparent only when most beta cells have lost function and many have been destroyed.

The initial laboratory manifestation of this immune response to beta cell injury is seroconversion, i.e., the appearance of type 1 diabetes-related autoantibodies. These antibodies are not thought to mediate beta cell injury but to be markers of such injury. Type 1 diabetes-related autoantibodies were first described in the early 1970s, when islet cell antibodies (ICA) were identified by immunofluorescence (31). Subsequently, additional antibodies were identified with specific autoantigen targets, including insulin autoantibodies (IAA) and autoantibodies to glutamic acid decarboxylase (GAD), an aborted tyrosine phosphatase (islet antibody-2 or IA2), and the zinc transporter (ZnT8) (32), all components of beta cells. Seroconversion is an important marker of the type 1 diabetes disease process. Indeed, in longitudinal studies of birth cohorts identified by genetic screening, such as DAISY (Diabetes AutoImmunity Study in the Young) (33), BABYDIAB (34), and DIPP (DIabetes Prediction and Prevention study) (35), as well as the TEDDY study, if two or more autoantibodies appear, 61.6%–79.1% of children followed will progress to type 1 diabetes over the next 15 years (36,37,38). This finding has led to a new classification of type 1 diabetes (Figure 1), in which the presence of two or more autoantibodies defines Stage 1 type 1 diabetes (39).

During further evolution of the disease, progressive metabolic changes are observable (40). Lack of beta cell sensitivity to glucose—that is, failure of the beta cell to recognize glucose and appropriately secrete insulin—is an early defect (41), like that seen in type 2 diabetes (42). This defect may be manifested by loss of first-phase insulin response to intravenous glucose (43) and dysglycemia (abnormal glucose levels not reaching the threshold for clinical diagnosis), which defines Stage 2 type 1 diabetes. Dysglycemia typically refers to fasting glucose of 100–125 mg/dL (5.6–6.9 mmol/L), 2-hour oral glucose tolerance test (OGTT) glucose of 140–199 mg/dL (7.8–11.0 mmol/L), or 30, 60, or 90-minute OGTT glucose ≥200 mg/dL (≥11.1 mmol/L) (39). There is progression to symptomatic hyperglycemia (44), or Stage 3 type 1 diabetes (45) (defined as fasting glucose ≥126 mg/dL [≥7.0 mmol/L] or 2-hour OGTT glucose ≥200 mg/dL). Risk scores that consider several of these metabolic changes (e.g., glucose and C-peptide from OGTTs) have been developed (46,47) and validated (48,49,50), and these scores further help to distinguish progressors from non-progressors. After the clinical onset of type 1 diabetes, further progressive decline of beta cell function occurs (51).

If type 1 diabetes is an immunologically mediated disease, then immune intervention should alter the natural history of the disease and potentially abrogate the clinical syndrome. This concept has certainly been the case in animal models of type 1 diabetes (52,53,54). The first reported attempt at immune intervention in type 1 diabetes was in the late 1970s in a handful of subjects (55). In the 1980s, a number of small trials were conducted with a variety of immunologic agents (56). Then, stimulated by a provocative pilot study with cyclosporine (57), many studies have been conducted, mostly in recent-onset type 1 diabetes, in an attempt to interdict the disease process and preserve beta cell function (58,59). More and more studies have been conducted during the period prior to any evidence of autoimmunity (primary prevention) or after the development of type 1 diabetes-related autoantibodies (secondary prevention) (60). The goal of such primary and secondary interventions is to arrest the immune process and, thus, prevent or delay clinical disease.

This article describes significant progress made toward prevention of type 1 diabetes since the publication of the Diabetes in America, 3rd edition chapter Prevention of Type 1 Diabetes in 2018 (61). Table 1 lists both completed and ongoing primary and secondary prevention trials. Table 2 lists many contemporary intervention trials in subjects at clinical Stage 3 type 1 diabetes (tertiary prevention), mostly in recent-onset subjects, but some with established disease. Most studies listed in the tables are randomized controlled clinical trials, although a few pilot studies of significance are included.

TABLE 1.

Summary of the Results of Primary and Secondary Prevention Trials for Type 1 Diabetes Published Through April 2024

TABLE 2.

Summary of the Results of Intervention Studies in Recent-Onset Type 1 Diabetes Published Through April 2024

Primary Prevention Trials

Primary prevention trials (Table 1) have been conducted in birth cohorts identified by genetic screening for high-risk HLA haplotypes (e.g., DR3, DR4), with the interventions initiated at a time when there were neither signs of autoimmunity nor overt metabolic impairment. Since there is uncertainty as to whether those infants identified by genetic screening will progress to type 1 diabetes, any interventions evaluated must be extremely safe. Consequently, most primary prevention trials to date have involved dietary interventions directed at putative environmental triggers (62,63,64,65,66,67,68), although more recently, oral insulin antigen-specific therapy aimed at inducing early tolerance has been tested (69,70).

A 1994 meta-analysis demonstrated a correlation between onset of type 1 diabetes and either early introduction of cow’s milk formula or a brief period of breastfeeding (71). Consequently, two studies evaluated whether at the time of weaning, replacement of breast milk with a formula based on casein hydrolysate rather than conventional cow’s milk-based formula could abrogate autoimmunity (62,63). Eligible infants had HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes. A pilot study in Finland enrolled 230 infants (62). The investigators reported that the group assigned to casein hydrolysate formula had a reduced risk of development of beta cell autoimmunity (appearance of one or more of the type 1 diabetes-related autoantibodies). A hazard ratio (HR) of 0.54 (95% confidence interval [CI] 0.29–0.95) was reported; similarly, the hazard ratio adjusted for observed difference in duration of exposure to study formula was 0.51 (95% CI 0.28–0.91) (62). The larger Trial to Reduce IDDM in the Genetically at Risk (TRIGR), a multinational trial involving 77 centers in 15 countries, registered more than 5,000 newborns and randomized 2,159 with risk genotypes (approximately 45% of those screened) (63). After 7 years, the TRIGR Study Group found no difference in the rate of appearance of type 1 diabetes-related autoantibodies (63). In the group assigned to casein hydrolysate formula, 13.4% had two or more islet autoantibodies versus 11.4% among those randomized to the conventional formula (unadjusted HR 1.21, 95% CI 0.94–1.54). When adjusted for HLA risk, duration of breastfeeding, vitamin D use, study formula duration and consumption, and region of the world, the hazard ratio was 1.23 (95% CI 0.96–1.58). Nonetheless, TRIGR continued follow-up for >10 years because it was designed with a primary outcome of the development of type 1 diabetes. The frequency of type 1 diabetes development was similar between the casein hydrolysate formula group (8.4%) and the conventional formula group (7.6%, p=0.47) with an adjusted hazard ratio of 1.1 (95% CI 0.8–1.5, p=0.46) (68). Casein hydrolysate had no effect on progression through the stages of type 1 diabetes in the TRIGR study.

In earlier studies, to evaluate whether bovine insulin might be the component of cow’s milk that serves as a trigger for type 1 diabetes, the Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes (FINDIA) compared three formulas: cow’s milk-based formula (control), whey-based hydrolyzed formula, or whey-based FINDIA formula essentially free of bovine insulin, whenever breast milk was not available during the first 6 months of life (64). Of 5,003 infants screened, 1,113 were found eligible, 1,104 were randomized, and 908 provided at least one follow-up sample. By age 3 years, the group assigned to the FINDIA formula had a reduced risk of development of beta cell autoimmunity, defined as the appearance of one or more islet autoantibodies, in both the intention-to-treat analysis (odds ratio [OR] 0.39, 95% CI 0.17–0.91, p=0.03) and the actual treatment-received analysis (OR 0.23, 95% CI 0.08–0.69, p<0.01) for those in the FINDIA group when compared with the cow’s milk formula group (64).

The BABYDIET study, another randomized controlled trial, evaluated whether delayed exposure to gluten reduces the risk of type 1 diabetes autoimmunity (65). The rationale for the study was based on the investigators’ earlier prospective observational cohort demonstrating increased risk of islet autoimmunity in children who are exposed to gluten early in life (72). The BABYDIET trial randomized 150 infants with a first-degree relative with type 1 diabetes and an HLA risk genotype. They were assigned either to first gluten exposure at age 6 months (control group) or at age 12 months (late-exposure group) and were followed every 3 months until age 3 years and yearly thereafter. BABYDIET found that delaying gluten exposure until the age of 12 months was safe but did not reduce the risk for islet autoimmunity (3-year risk: 12% vs. 13%, p=0.6) (65), although the open-label nature and difficulty adhering to the dietary recommendations may have limited the outcome.

The Type 1 Diabetes TrialNet (TrialNet) Nutritional Intervention to Prevent (NIP) Type 1 Diabetes Pilot Trial assessed the feasibility of implementing a study to determine the effect of nutritional supplements with the omega-3 fatty acid docosahexaenoic acid (DHA), which has anti-inflammatory effects, during the last trimester of pregnancy and the first few years of life (66). NIP found that supplementation of infant diets with DHA was safe and resulted in an increased level of DHA in infant erythrocytes but did not find consistent reduction in inflammatory cytokines (66).

Based on putative observations that vitamin D administration in pregnancy may be protective of the subsequent development of diabetes in offspring of mothers with type 1 diabetes and that supplementation with vitamin D in infancy has been associated with decreased risk of type 1 diabetes (73,74), a group of Canadian investigators conducted a small pilot study. The group showed that it was possible to recruit infants from the general population for identification of HLA-associated risk status followed by enrollment before 1 month of age to a randomized controlled prevention trial of vitamin D supplementation (67). Therefore, they proposed a nationwide study (in Canada) to evaluate the hypothesis that vitamin D supplementation can decrease the risk of islet autoimmunity and type 1 diabetes. As of 2023, such a study has not been initiated.

The Primary Oral Insulin Therapy (Pre-POInT) study was a pilot safety study across four countries of the use of oral insulin in children age 2–7 years at risk of developing type 1 diabetes (69). The study found that daily oral administration of 67.5 mg insulin is safe and can actively engage the immune system with features of immune regulation in children who are genetically at risk of developing type 1 diabetes. Pre-POInT was followed by the Pre-POInT-EARLY study in Germany, assessing the use of daily oral insulin (67.5 mg) in children age 6 months to 3 years (70). In this small study, the authors did not find a statistically significant difference in immune responses to insulin in the children who received oral insulin compared to the control group (70).

Secondary Prevention Trials

Secondary prevention trials (Table 1) are those conducted in individuals with Stage 1 (two or more islet autoantibodies with normoglycemia) or Stage 2 (islet autoantibodies and dysglycemia) type 1 diabetes (45). Most of these studies have been conducted in individuals who are first- or second-degree relatives of people with type 1 diabetes and who had been identified initially by screening for type 1 diabetes-associated autoantibodies. Because not all those with autoantibodies will progress to symptomatic disease (Stage 3), interventions to be evaluated have been selected cautiously to balance risk of therapy with risk of developing the disease. Initial studies tested nicotinamide (a vitamin B3 derivative) and insulin used in various routes of administration for its potential antigenic effects (to induce immune tolerance). This strategy was followed by GAD antigen therapy. With limited success, stronger therapeutics, such as anti-inflammatory and T lymphocyte-directed therapies, are now being studied.

Innate and Adaptive Immune Modulation Trials

TrialNet conducted three studies in relatives of individuals with type 1 diabetes using hydroxychloroquine (93), abatacept (94,95), and teplizumab (96,97) with the goal of preventing or delaying disease progression. The use of hydroxychloroquine, an antiparasitic and immunomodulatory agent, was proposed due to evidence of its suppression of inflammatory biomarkers and potential positive effect on insulin signaling. The TrialNet hydroxychloroquine study included first- or second-degree relatives with at least two type 1 diabetes-related autoantibodies and normal glucose tolerance (Stage 1 type 1 diabetes). The trial was stopped early, after enrollment of 275 participants, due to lack of beneficial effect on delay of glucose intolerance (Stage 2 type 1 diabetes) during interim analysis (93).

Eligibility for the TrialNet abatacept study (94) required at least two autoantibodies, one of which was not IAA (due to competing study enrollment), and normal glucose tolerance (Stage 1 type 1 diabetes). Abatacept, a therapeutic used in other autoimmune diseases, acts through attenuation of T cell activation via co-stimulation blockade. In this trial, the drug was given for 1 year. Overall, the hazard rate was not statistically significant (HR 0.702, 95% CI 0.452–1.09, p=0.11) (95).

Eligibility for the TrialNet teplizumab study (96,97) required at least two autoantibodies and dysglycemia during an OGTT (Stage 2 type 1 diabetes). Teplizumab is an anti-CD3 monoclonal antibody posited to modulate effector T cell phenotypes (96). In this landmark trial, the time to development of diabetes (Stage 3 type 1 diabetes) was delayed in the group randomized to teplizumab (median 48.4 months) compared to those who received placebo (24.4 months) (Figure 2). The hazard ratio for type 1 diabetes was 0.41 (95% CI 0.22–0.78, p=0.006) (96). However, the entire cohort was a very high-risk population—within the teplizumab arm, 43% of participants developed diabetes, and 72% in the placebo arm progressed. Extended follow-up further supported the delay of progression in this Stage 2 group, with median time to Stage 3 type 1 diabetes of 59.6 months in those who received teplizumab and 27.1 months for those who received placebo (rate of type 1 diabetes diagnosis HR 0.457, p=0.01) (97). Consequently, teplizumab has been approved by the U.S. Food and Drug Administration (FDA) for use in Stage 2 type 1 diabetes to delay progression to Stage 3 (98). Post hoc studies identified responder phenotypes that suggest that those without ZnT8 autoantibodies or without HLA-DR3 may be more likely to respond to teplizumab, although validation studies are needed to confirm this finding.

FIGURE 2.

TrialNet Teplizumab Trial in At-Risk Relatives Demonstrates Significant Delay in Diabetes Onset Compared to Placebo. Updated Kaplan-Meier Curve based on 923 days of follow-up (range 74–3,119 days). The hazard ratio for development of type 1 diabetes (more...)

Tertiary Prevention Trials

Tertiary prevention trials (Table 2) have been conducted in subjects with Stage 3 type 1 diabetes—this is typically classic symptomatic type 1 diabetes requiring insulin therapy (Figure 1), mostly recent-onset, but some with established disease. As noted, many early pilot trials with a variety of immune interventions (56,104) will not be discussed here. Rather, this discussion is confined to randomized controlled trials and studies that have either evaluated contemporary immunologic approaches or ones that offer special insights.

Primary outcomes assessed in tertiary prevention trials, in the present day, focus on stimulated C-peptide production at the endpoint of the trial. Mean differences between treated and placebo groups at this timepoint are then compared for statistical significance. For the majority of trials, endogenous insulin (and C-peptide production) was stimulated by a standard liquid meal containing carbohydrate, protein, and fat (i.e., mixed meal tolerance test [MMTT]). Glucagon-stimulated C-peptide values have also been compared between treated and placebo groups. Several trials have used a measure of “remission” or “partial remission” to compare between treated and placebo groups. Remission has typically been the proportion who do not require exogenous insulin at a prespecified time point. The definition of partial remission, however, varies by trial; in general, this term refers to the proportion of individuals who require low doses of exogenous insulin and have a lower glycated hemoglobin (A1C) level. As trialists and participants weigh the potential benefits of such intervention trials, the risks are not inconsequential for some immunomodulatory therapies and are discussed below.

Non-antigen Specific Therapies

Therapeutics targeting the adaptive immune system in a non-antigen specific manner aim to transiently reduce inflammation and effector T cells, thus shifting the balance of immune cells toward a regulatory phenotype. In contrast, antigen-specific therapies in type 1 diabetes elicit a specific autoantigen-directed regulatory response, as described in the next section.

Mycophenolate Mofetil

TrialNet has conducted several studies with immunologic interventions in subjects with recently diagnosed type 1 diabetes. All studies enrolled subjects within 100 days of diagnosis (recent-onset Stage 3 type 1 diabetes) and measured beta cell function by C-peptide in response to serial MMTTs. One study evaluated the immunosuppressive agent mycophenolate mofetil, which impairs nucleic acid synthesis needed for lymphocyte proliferation, either alone or in combination with the anti-CD25 monoclonal antibody daclizumab, which targets the alpha chain of the interleukin-2 (IL-2) receptor expressed on T lymphocytes (122). The study enrolled 126 subjects age 8–45 years; it was stopped early by the Data and Safety Monitoring Board due to futility of the potential of seeing a beneficial treatment effect (122).

Anti-CD3 Intervention Studies

Extensive studies have been conducted with two anti-CD3 monoclonal antibodies targeting T lymphocytes—teplizumab and otelixizumab—which are humanized Fc-mutated (Fc receptor [FcR] nonbinding) monoclonal antibodies. The first study reported was a small study involving only 12 treated subjects and 12 untreated comparison subjects (123). Subjects received a single 14-day course of treatment with teplizumab within 6 weeks of diagnosis of Stage 3 type 1 diabetes and were found to have slower decline of beta cell function (by MMTT) at 1 year (123). In these and an expanded group of subjects (total of 21 treated, 21 untreated), sustained improvement of beta cell function was seen at 2 years (124). Meanwhile, the first randomized placebo-controlled trial with an anti-CD3 monoclonal antibody (125) included 80 subjects age 12–39 years. Within 4 weeks from diagnosis of Stage 3 type 1 diabetes, subjects were randomized to a 6-day course of either otelixizumab or placebo and followed for 18 months. Beta cell function measured using a hyperglycemic clamp followed by glucagon stimulation was found to be better in the otelixizumab than the placebo group, particularly in subjects with higher baseline insulin secretory response (125). After 4 years of follow-up, although beta cell function was not measured, the otelixizumab group had lower insulin requirements despite similar glycemic control as measured by A1C (126). Thus, the effects of a 6-day treatment course were evident 4 years later.

The results from these early Phase 2 studies with anti-CD3 treatment led to the initiation of Phase 3 clinical trials with both agents. However, the Phase 3 studies did not meet their primary outcome criteria. For teplizumab, the primary outcome was the combination of A1C <6.5% (<48 mmol/mol) and insulin dose <0.5 units/kg/day (127,128,129). This outcome measure was arbitrarily selected and highly criticized for several reasons. Moreover, by using a composite outcome that requires a subject to meet two criteria, the outcome became a dichotomous measure that dilutes the effect of two continuous variables—A1C and insulin dose. More importantly, when the conventional outcome measure of C-peptide was assessed, evidence of efficacy was observed both at 1 year (127) and 2 years (128) following two 14-day courses of teplizumab (at entry and at 26 weeks into the study). This effect was especially evident in subjects enrolled in the United States (who had lower A1C at entry and during the study), in younger subjects (age 8–17 years), in subjects enrolled within 6 weeks of diagnosis, and in subjects with higher levels of C-peptide at entry (127). For otelixizumab, the Phase 3 studies used a dose that was one-sixteenth (total of 3.1 mg over 8 days) that used in the positive Phase 2 study described in the previous paragraph (total of 48 mg) to avoid any side effects (130,131). Not only were side effects completely obviated, but beneficial effects were also obviated. This outcome highlights the challenge with significant dose reduction—all effective therapies are likely to have some side effects, and eliminating the side effects of a drug may also eliminate its potential benefits.

Two other studies with teplizumab are worth noting. In the Autoimmunity-Blocking Antibody for Tolerance in Recently Diagnosed Type 1 Diabetes (AbATE) Trial, conducted by the Immune Tolerance Network (ITN), efficacy was demonstrated (132), although this study was not blinded as the control group did not receive a placebo. The trial met the primary endpoint based on area under the curve (AUC) C-peptide from an MMTT, and the results from this trial and other successful new-onset type 1 diabetes randomized controlled trials are displayed in Figure 3. More importantly, however, subjects could be divided into two groups: “responders” and “non-responders” to treatment. Responders were those who maintained C-peptide better than the randomized but untreated comparison group at 24 months. This subgroup, which constituted 45% of subjects treated with teplizumab, maintained beta cell function for 2 years, whereas the non-responders lost beta cell function at a rate like the control group (132). In another teplizumab study, the Delay trial, subjects diagnosed with Stage 3 type 1 diabetes at least 4 but not more than 12 months before enrollment (thus “Delayed” compared to recent onset) were randomized to receive infusions of teplizumab or placebo (133). The decline of beta cell function slowed in the treated group, driven by beneficial effect in those treated within 4–8 months of diagnosis, as the effects were not significant in the subgroup treated 9–12 months after diagnosis. Another Phase 3 trial with teplizumab, the PROTECT study, which randomized 328 subjects, met its primary endpoint (134,135). At week 78, those treated with teplizumab not only had greater C-peptide AUC than placebo-treated (least-squares mean difference of 0.13 nmol/L, 95% CI 0.09–0.17, p<0.001), but also a greater frequency maintained “clinically meaningful peak C-peptide” ≥0.2 nmol/L (94.9% versus 79.2%, respectively).

FIGURE 3.

Visual Depiction of Seven New-Onset Type 1 Diabetes Randomized Clinical Trial Primary Endpoint Results (Area Under the Curve C-peptide). The therapeutic target for each drug is indicated above each set of graphs. ATG, anti-thymocyte globulin; AUC, area (more...)

Anti-thymocyte Globulin Intervention Studies

A small pilot study has evaluated the combination of low-dose ATG and pegylated granulocyte colony-stimulating factor (GCSF) (136). This study enrolled 25 subjects age 12–45 years with type 1 diabetes of 4–24 months duration, who were randomized 2:1 to active treatment or placebo. Subjects received intravenous ATG (or placebo) over 2 days, followed by subcutaneous GCSF every 2 weeks for six doses. At the end of 1 year, beta cell function was preserved, as measured by an MMTT. At the end of 2 years, the difference between groups was no longer statistically significant (137).

Most recently, TrialNet evaluated the efficacy of a polyclonal T cell-directed immunosuppressant ATG (Thymoglobulin) at low doses (2.5 mg/kg/course) to obviate the T cell-mediated immune destruction of the beta cell (138,139). In this trial, 89 individuals age 12–45 years were randomized in a 1:1:1 study design to receive ATG alone (two doses over 2 days), ATG and pegylated GCSF (six doses over 12 weeks), or placebo. In this study, C-peptide production (via an MMTT) was preserved in those who received low-dose ATG compared to placebo but not in the combination ATG+GCSF group compared to placebo at 1 year (138). Effector CD4 T lymphocytes were reduced, but regulatory T cells were preserved. This effect, along with lower A1C, was also seen in those treated with low-dose ATG 2 years after the initial therapy (139).

The ITN conducted an earlier study evaluating ATG (Thymoglobulin) at 6.5 mg/kg/course in recent-onset type 1 diabetes, the Study of Thymoglobulin to Arrest Type 1 diabetes (START) (140). In START, 58 subjects age 12–35 years with recent-onset Stage 3 type 1 diabetes were randomized in a 2:1 design to receive ATG or placebo over 4 days. There was no between-group difference in beta cell function at 1 year; however, ATG resulted in generalized depletion of T lymphocytes rather than the hoped-for specific depletion of effector memory T lymphocytes with preservation of regulatory T cells. Of note, post hoc analysis demonstrated a beneficial effect of this ATG dose at 2 years for those who were age >21 years (141).

Abatacept Intervention Study

TrialNet evaluated effects of the fusion protein abatacept (soluble CTLA4-Ig), which binds to CD80 and CD86, the ligands for CD28, a co-stimulatory molecule on T lymphocytes (142). In this study, 112 subjects age 6–45 years were randomized in a 2:1 design to receive either monthly infusions of abatacept or placebo for 2 years. After those 2 years, beta cell function was better maintained in the abatacept group than in the placebo group, although a progressive decline was seen in the abatacept group as well (142). After therapy was stopped, subjects were followed for an additional year, with the abatacept group maintaining a difference from the placebo group; a progressive parallel rate of decline was observed in both groups but shifted by 9.5 months in abatacept-treated subjects (143). Thus, the beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from the diagnosis of type 1 diabetes.

Alefacept Intervention Study

In another ITN study, the Inducing Remission in New-Onset Type 1 Diabetes with Alefacept (T1DAL) trial, alefacept was used to target memory T lymphocytes (144). In this trial, 49 subjects age 12–35 years with recent-onset Stage 3 type 1 diabetes were randomized in a 2:1 design to receive either alefacept or placebo, given as two 12-week courses of monthly intramuscular injections separated by a 12-week hiatus. Because the manufacturer withdrew alefacept from production during the trial, enrollment was smaller than planned. Beta cell function was preserved in the alefacept group, i.e., it did not decline over 12 months, but the results of the primary outcome—C-peptide during the first 2 hours of the MMTT—just missed statistical significance (p=0.065). In contrast, the secondary outcome—C-peptide during the full 4 hours of the MMTT—indicated a significant difference in beta cell function (p=0.019) (144). At 24 months, both the 4-hour and the 2-hour C-peptide levels were greater in the alefacept group than the placebo group (145). Thus, had the study been fully enrolled, the primary outcome may have been met. Moreover, alefacept appeared to have a greater impact on central memory and effector memory T lymphocytes, with sparing of naïve and regulatory T lymphocyte populations. Taken together, these findings suggest that targeting memory T lymphocytes may be an attractive immunomodulatory approach. A study of a different CD2-targeting therapeutic is underway as of January 2024 (146).

Rituximab Intervention Study

A TrialNet study evaluated the anti-CD20 monoclonal antibody rituximab, which depletes B lymphocytes (147). In this study, 87 subjects age 8–40 years were randomized in a 2:1 design to receive either four weekly doses of rituximab or placebo. After 1 year, beta cell function was better maintained in the rituximab group than in the placebo group, although a progressive decline was observed in the rituximab group as well (147). Over 2 years, the rate of decline of C-peptide was parallel between groups but shifted by 8.2 months in rituximab-treated subjects (148). Thus, the effect of rituximab was transient, with no fundamental alteration of the disease process.

Ongoing Intervention Studies

Generally Recognized as Safe (GRAS) therapies are being studied in those with newly diagnosed type 1 diabetes, including probiotic supplementation (191,192) and omega-3 fatty acids plus vitamin D supplementation (193). Several provocative studies demonstrating at least transient preservation of beta cell function have been conducted, but no controlled studies have demonstrated sufficient sustained beta cell function, such that insulin therapy is not required. As new therapies are explored, immunotherapies that have demonstrated transient beta cell preservation continue to be studied; however, direct comparison of therapeutics is unlikely as head-to-head comparison trials are unfeasible. Statistical modeling of six trials in recent-onset type 1 diabetes, adjusted for age and baseline C-peptide production, identified ATG and teplizumab as drugs that produced the greatest improvement in C-peptide over their respective placebo groups at 1 and 2 years (Figure 4) (194).

FIGURE 4.

Statistical Comparison of Seven Treatments From Six New-Onset Type 1 Diabetes Randomized Controlled Trials. Cross-trial comparison of recent-onset type 1 diabetes intervention trials. Panels (A) One-year and (C) two-year percentage increase in C-peptide (more...)

Conclusions

Additional studies aimed at intervening in early type 1 diabetes are underway with a variety of approaches, some of which include: (1.) further study of teplizumab and ustekinumab in children and young adults; (2.) a probiotic in combination with teplizumab; (3.) T and B cell combination therapy with rituximab and abatacept; (4.) anti-CD40 antibody; (5.) low-dose IL-2; (6.) JAK (Janus kinase) pathway inhibitor; (7.) methyldopa to inhibit the binding pocket for DQ8 antigen presentation; (8.) intralymphatic delivery of GAD vaccine in HLA-DR3-DQ2-restricted individuals; and (9.) dendritic cell-based vaccines (134,197,198,199,200,201,202,203,204,205,206,207,208,209,210,211). A combination approach may be needed—one that combines an anti-inflammatory agent targeting innate immunity, with an immunomodulatory agent targeting adaptive immunity, with agents that stimulate regulatory immunity, and an agent that helps preserve beta cell health (212). Additionally, lifelong or repeated courses of therapy during the time of detectable C-peptide production may be required, like the model of treatment for other autoimmune diseases.

To promote drug development and timely advancement along the regulatory approval process, if agents tested in Stage 3 type 1 diabetes studies are found to be efficacious and safe, they can be brought to earlier disease (Stage 1 and Stage 2 type 1 diabetes). In addition, initiatives to screen and detect individuals at risk for type 1 diabetes should facilitate the ability to conduct larger Stage 1 and Stage 2 prevention studies. If only successful Stage 3 therapeutics are used in the at-risk population, there is the potential risk of missing an effective treatment. The key is understanding precise mechanisms leading to type 1 diabetes. Without that knowledge, therapeutic measures will be broad and nonspecific.

Next, it is essential to understand whether type 1 diabetes heterogeneity is related solely to age or other phenotypes. The development and validation of biomarkers to identify subtypes (e.g., latent autoimmune diabetes in adults [LADA]), or “endotypes,” of type 1 diabetes could allow for therapeutic selection based on an individual’s specific mechanism of disease, while also increasing efficacy (213,214). Given that the heterogeneity of type 1 diabetes has been well documented (3,214,215), more homogeneous study populations will be needed to achieve robust and durable outcomes in clinical trials. In addition, the field has not achieved equal representation of racial and ethnic minority populations in clinical trials or equitable health outcomes for these individuals (216). The risk of progressing to clinical type 1 diabetes can present with different risk factors (e.g., HLA, autoantibodies) in African American populations compared to Caucasian/Northern European populations (217). This concern is vital, as one disease-modifying therapy is unlikely to be effective for everyone at risk of or diagnosed with type 1 diabetes.

List of Abbreviations

A1C

glycated hemoglobin

AAT

alpha-1-antitrypsin

AHSCT

autologous hematopoietic stem cell therapy

ATG

anti-thymocyte globulin

BCG

Bacille Calmette-Guérin

CI

confidence interval

DAISY

Diabetes AutoImmunity Study in the Young

DENIS

German (Deutsch) Nicotinamide Diabetes Intervention Study

DHA

docosahexaenoic acid

DIAPREV-IT

Diabetes Prevention–Immune Tolerance

DIPP

DIabetes Prediction and Prevention Study

DPT-1

Diabetes Prevention Trial-Type 1

ENDIT

European Nicotinamide Diabetes Intervention Trial

FDA

U.S. Food and Drug Administration

FINDIA

Finnish Dietary Intervention Trial for the Prevention of Type 1 Diabetes

GABA

gamma aminobutyric acid

GAD

glutamic acid decarboxylase

GCSF

granulocyte colony-stimulating factor

GLP-1

glucagon-like peptide-1

GRAS

Generally Recognized As Safe

HLA

human leukocyte antigen

HR

hazard ratio

IA2

islet antibody-2

IAA

insulin autoantibodies

ICA

islet cell antibodies

IDDM

insulin-dependent diabetes mellitus

IL

interleukin

INIT

Intranasal Insulin Trial

ITN

Immune Tolerance Network

MMTT

mixed meal tolerance test

NIP

Nutritional Intervention to Prevent Type 1 Diabetes

OGTT

oral glucose tolerance test

OR

odds ratio

POInT

Primary Oral Insulin Therapy study

TEDDY

The Environmental Determinants of Diabetes in the Young

TNF

tumor necrosis factor

TrialNet

Type 1 Diabetes TrialNet

TRIGR

Trial to Reduce IDDM in the Genetically at Risk

ZNT8

zinc transporter 8

Conversions

A1C: (% x 10.93) - 23.50 = mmol/mol

C-peptide: ng/mL x 0.333 = nmol/L

Glucose: mg/dL x 0.0555 = mmol/L

Funding

Dr. Jacobsen is supported by funding from the NIH. Dr. Schatz is supported by funding from the NIH and an NIH/NCATS Clinical and Translational Science Award to the University of Florida. Dr. Herold is supported by funding from the NIH and JDRF. Dr. Skyler is supported by the Diabetes Research Institute Foundation.

Acknowledgment

This is an update of: Skyler JS, Krischer JP, Becker DJ, Rewers M: Prevention of Type 1 Diabetes. Chapter 37 in Diabetes in America, 3rd ed. Cowie CC, Casagrande SS, Menke A, Cissell MA, Eberhardt MS, Meigs JB, Gregg EW, Knowler WC, Barrett-Connor E, Becker DJ, Brancati FL, Boyko EJ, Herman WH, Howard BV, Narayan KMV, Rewers M, Fradkin JE, Eds. Bethesda, MD, National Institutes of Health, NIH Pub No. 17-1468, 2018, p. 37.1–37.21

Article History

Received in final form on May 25, 2024.

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Drs. Jacobsen and Schatz reported no conflicts of interest. Dr. Herold reported that he has consulted for Sanofi, Sonoma Biotherapeutics, and Vertex and is on the Scientific Advisory Board for NexImmune. He is listed as a co-inventor on a patent for use of teplizumab for delay/prevention of type 1 diabetes but receives no royalties. Dr. Skyler reported that he: is the Chair of the Strategic Advisory Committee for INNODIA, INNODIA-HARVEST, INNODIA-iVZW, and EDENT1FI; is currently on the Data and Safety Monitoring Boards for three studies of disease-modifying therapies for type 1 diabetes; and has consulted (in the last 12 months) with several companies developing disease-modifying or other therapies for type 1 diabetes, including 4Immune, Abvance, ActoBiotics, Adocia, Avotres, COUR, Imcyse, ImmunoMolecular Therapeutics, Kriya, Novo-Nordisk, Provention Bio, Sanofi, Signos, Vertex, and Viacyte.