Type 1 diabetes mellitus - Emerging treatments

Immunotherapy

Type 1 diabetes is an autoimmune disease modulated by cytotoxic T cells. Several agents have been studied for treatment of new-onset disease. Nonantigen-specific systemic immunotherapies, including T-cell suppressors (cyclosporine), antiproliferative agents (methotrexate, azathioprine), and antithymocyte globulin have shown a strong tendency to adverse effects. Although cyclosporine use did reduce insulin requirements in the short term, it was associated with nephrotoxicity, and the effect on beta cells waned with treatment cessation. Antigen-specific vaccination with recombinant glutamic acid decarboxylase was shown to increase stimulated C-peptide in patients treated within 3 months of diagnosis.[131] Trials are under way to investigate treatment of type 1 diabetes with dendritic cells, mesenchymal stem cells, cord blood transfusion, and immunomodulators currently approved for use in other diseases, such as granulocyte colony stimulating factor or tumor necrosis factor-alpha inhibitors.[132][133]

Teplizumab

Teplizumab is a CD3-directed monoclonal antibody. One systematic review and meta-analysis found that teplizumab is associated with lower insulin use and higher AUC of C-peptide in early type 1 diabetic patients, with no significant effect on HbA1c levels.[134] One clinical trial in patients with new-onset diabetes showed that the decline in beta-cell function (measured by C-peptide) is slowed and insulin requirements for glycemic control are reduced.[135][136] In one study of patients who did not have diabetes, but who were at high-risk (≥2 type 1 diabetes auto-antibodies and dysglycemia), teplizumab delayed progression to clinical disease.[137] Teplizumab is approved by the Food and Drug Administration (FDA) to delay the onset of stage 3 type 1 diabetes in adults and children ≥8 years of age with stage 2 type 1 diabetes. The American Diabetes Association recommends that teplizumab should be considered to delay the onset of symptomatic type 1 diabetes in selected individuals ages ≥8 years with stage 2 type 1 diabetes, but notes that management should be in a specialized setting with appropriately trained personnel.[1] There are practical issues surrounding this therapy that currently limit its application in clinical practice, such as selecting eligible patients, infusion-administration, and patient following-up.

Pancreas and islet cell transplantation (donislecel)

The American Diabetes Association recognizes that successful pancreas and islet transplantation can normalize glucose levels and mitigate microvascular complications of type 1 diabetes.[1] However, it warns that these patients will require lifelong immunosuppression to prevent graft rejection or recurrence of autoimmune islet destruction, and suggests transplantation should be reserved for those undergoing/following renal transplant, recurrent ketoacidosis, severe hypoglycemia despite intensive glycemic management, or hypoglycemia unawareness.[1] Islet cell transplantation involves islet cells being prepared from a donor pancreas and injected into the portal vein.[138] The cells seed in the liver and produce insulin. Research in this field has been ongoing, with previously limited success.[139][140] However, in 2023, the Food and Drug Administration (FDA) approved donislecel, the first allogeneic (donor) pancreatic islet cellular therapy made from deceased donor pancreatic cells for the treatment of type 1 diabetes. Donislecel is approved for the treatment of adults with type 1 diabetes who are unable to approach target HbA1c because of current repeated episodes of severe hypoglycaemia despite intensive diabetes management and education. It must be used in conjunction with concomitant immunosuppression, and is administered as a single infusion into the hepatic portal vein. The safety and effectiveness of donislecel was evaluated in two nonrandomized, single-arm studies in which a total of 30 participants with type 1 diabetes and hypoglycemic unawareness received at least one infusion and a maximum of three infusions.[141][142] Overall, 21 participants did not need to take insulin for a year or more. However, five participants did not achieve any days of insulin independence. Adverse reactions associated with donislecel varied with each participant depending on the number of infusions they received and the length of time they were followed, and may not reflect the rates observed in practice. The most common adverse reactions included nausea, fatigue, anemia, diarrhea and abdominal pain. The majority of participants experienced at least one serious adverse reaction related to the procedure for infusing donislecel into the hepatic portal vein and the use of immunosuppressive medications needed to maintain the islet cell viability. These adverse events should be taken into account when considering donislecel use for each patient; the treatment is approved with patient-directed labeling to inform patients about its benefits and risks. There is no evidence to show a benefit of administration of donislecel in patients whose diabetes is well-controlled with insulin therapy or patients with hypoglycemic unawareness who are able to prevent current repeated severe hypoglycemic events using intensive diabetes management. Despite the potential advantages of donislecel treatment, its use remains controversial: questions have been raised over the ethics of commercializing the use of deceased donor islet cells, and while the FDA has designated this treatment as a biologic drug, some experts believe that it should be reclassified as a form of organ transplant.[143] Further, the requirement for donor cells limits its supply. Moreover, the studies did not involve renal transplant recipients and, therefore, questions about the long-term effects of immunosuppression in patients who would not otherwise need immunosuppression remain to be answered. Donislecel is not currently approved for use in the Europe.

Islet cell regeneration

Despite between 85% and 95% of beta cells being lost in well-established type 1 diabetes, many people will retain modest numbers of insulin-positive beta cells.[144] These remaining functional cells may be viable candidates for regeneration.[144] Promotion of self-proliferation of the existing beta cells is desirable but extremely challenging, and stimulation methods to date have failed to produce meaningful effects.[144] Other regenerative methods that have been explored include the generation of functional beta cells from human pluripotent stem cells.[144] A key challenge associated with the transplantation of stem cell-derived beta cells is delivering them into an environment that can support long-term islet function, while also preventing rejection by the immune system.[144] Tissue engineering approaches such as enhancing vascularization may be beneficial and are in early-stage trials.[144]

Insulin sensitizers

One systematic review suggested that use of metformin in type 1 diabetes reduced insulin requirements but not HbA1c levels after 1 year of follow-up.[145] Further research is indicated to better delineate the potential indications and benefits of this treatment in type 1 diabetes.[146][147]

Sodium-glucose co-transporter 2 inhibitors

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are oral medications that reduce glucose in an insulin-independent manner, by inhibiting SGLT2 in the proximal renal tubule and blocking glucose reabsorption. They are associated with modest weight loss and blood pressure reduction. SGLT2 inhibitors are approved for use in individuals with type 2 diabetes. Several reports have highlighted the risk of euglycemic diabetic ketoacidosis (DKA) in both type 2 and type 1 diabetes.[148][149] However, a real-world study of SGLT2 inhibitors in combination with insulin in 199 patients with type 1 diabetes has shown promising results in improving glycemic control, reducing weight, and reducing the need for insulin.[150] One systematic review found that, the addition of dapagliflozin in adult patients with poorly controlled type 1 diabetes already on insulin treatment would lead to substantial reductions in HbA1c levels, body weight, and insulin dose.[151] Ketosis episodes and DKA were reported in 2.5% and 3.5% of patients, respectively.[150] Due to the increased risk of DKA and other complications, use of SGLT2 inhibitors for glycemic control in type 1 diabetes remains limited.[152] If used, the patient should be educated about the risk of ketoacidosis and given advice on risk mitigation and monitoring.[1] These agents may be used for secondary prevention of cardiovascular disease or renal disease while continuing intensive insulin therapy, based on studies showing benefits in patients with type 2 diabetes or those without diabetes.

Glucagon-like peptide-1 (GLP-1) agonists

GLP-1 is a gut peptide that increases insulin secretion and decreases glucagon secretion in a glucose-dependent manner. In patients with type 2 diabetes, GLP-1 receptor agonists increase levels of GLP-1 and lead to more glucose-dependent insulin secretion, less glucagon secretion, delayed gastric emptying, and increased satiety. The specific advantage of GLP-1 agonists is weight loss, which may be desirable in some patients with type 1 diabetes.[153] The GLP-agonist liraglutide added to insulin improved glucose control in clinical trials with type 1 diabetes, but also increased the risk of both hypoglycemia and hyperglycemia with ketosis. Therefore, GLP-1 agonists should not routinely be used in type 1 diabetes. One systematic review and meta-analysis found liraglutide to be a potentially beneficial adjunct to insulin patients with type 1 diabetes.[154]

Glucokinase activators

The glucose-phosphorylating enzyme glucokinase has a role in glucose homeostasis as a “glucose sensor” of pancreatic beta cells and as a regulatory step in the conversion of glucose to glycogen, as well as in gluconeogenesis in the liver.[155] The FDA has granted a breakthrough therapy designation to TTP399, a novel, oral, small-molecule, liver-selective glucokinase activator, as an adjunctive therapy to insulin for type 1 diabetes following positive trial data showing statistically significantly decreased HbA1c.[156]

Bionic pancreas

The bionic pancreas is a trial device that integrates an automated insulin delivery system with a fully closed loop system. It is initialized only on the basis of body weight, makes all dose decisions and delivers insulin autonomously, and uses meal announcements without carbohydrate counting. Trial data show that the bionic pancreas was associated with a greater reduction than standard care in the glycated hemoglobin level. There have been trials using dual hormone pumps, using insulin and glucagon along with continuous glucose monitoring, to improve glycemic control. This research is being conducted to design an artificial pancreas that mimics normal islet cell function.