Type 1 diabetes is an autoimmune disease modulated by cytotoxic T cells. Several agents have been studied for treatment of new-onset disease. Non-antigen-specific systemic immunotherapies, including T-cell suppressors (ciclosporin), antiproliferative agents (methotrexate, azathioprine), and anti-thymocyte globulin, have shown a strong tendency to adverse effects. Although ciclosporin 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. 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 tumour necrosis factor-alpha inhibitors.
One clinical trial of the anti-CD3 monoclonal antibody, teplizumab, in patients with new-onset diabetes shows that the decline in beta-cell function (measured by C-peptide) is slowed and insulin requirements for glycaemic control are reduced. In one study of patients who did not have diabetes, but who were at high-risk (≥2 type 1 diabetes auto-antibodies and dysglycaemia), teplizumab delayed progression to clinical disease. The US Food and Drug Administration has granted teplizumab breakthrough therapy designation for the prevention or delay of clinical type 1 diabetes in at-risk individuals, which may expedite the review process for approval of this drug.
Islet cell transplantation
Islet cells prepared from a donor pancreas are injected into the portal vein. The cells seed in the liver and produce insulin. Patients who undergo this procedure require immunosuppressive therapy afterwards. There is some initial success with this procedure but the long-term results remain disappointing. Even in the best centres, less than 50% of patients are free of insulin requirement at 1 year and only 10% at 5 years. The American Diabetes Association (ADA) recommends that this procedure be performed only within the context of a controlled research study at this time.
In June 2014, the US FDA approved a rapid-acting inhaled insulin. It can be administered before meals and should be used in combination with long-acting insulin. It can cause bronchospasm in patients with asthma and chronic obstructive pulmonary disease, and should not be used if these conditions are present. The most common side effects in a 24-week safety and efficacy trial were hypoglycaemia, cough, and throat infection. Long-term safety data are lacking. Moreover, it is available only in fixed doses of 4 or 8 units. Therefore, dose adjustments can be made only in multiples of 4 which may present difficulty in fine-tuning the dose in patients with type 1 diabetes. More experience is needed before inhaled insulin is routinely prescribed in type 1 diabetes.
Islet cell regeneration
Studies done in mouse models show that from the onset of insulinitis, there is a mass of beta cells within an inflammatory milieu that may be recoverable and serve as a future source of functioning beta cells. Several trials are under way to investigate mono- and combination therapies to arrest inflammation and possibly allow beta-cell regeneration.
A systematic review suggested that use of metformin in type 1 diabetes reduced insulin requirements but not HbA1c levels after 1 year of follow-up. Further research is indicated to better delineate the potential indications and benefits of this treatment in type 1 diabetes.
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 euglycaemic diabetic ketoacidosis in both type 2 and type 1 diabetes. Studies are ongoing to assess safety and efficacy of this class of medications in type 1 diabetes. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has approved the selective SGLT2 inhibitor dapagliflozin for use in patients with type 1 diabetes mellitus and a body mass index ≥27 kg/m² as an adjunct to insulin, when insulin alone does not provide adequate glycemic control despite optimal insulin therapy. In March 2019, the CHMP recommended that sotagliflozin, a dual inhibitor of SGLT1 and SGLT2, also be approved for the same indication. However, the US Food and Drug Administration (FDA) rejected approval of sotagliflozin for type 1 diabetes in March 2019. Patients must fulfil requirements to minimise the increased risk of diabetic ketoacidosis with both of these drugs.
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. The GLP-agonist liraglutide added to insulin improved glucose control in clinical trials with type 1 diabetes, but also increased the risk of both hypoglycaemia and hyperglycaemia with ketosis. Therefore, GLP-1 agonists should not routinely be used in type 1 diabetes.
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