The onset of type 1 diabetes can be delayed!

Type 1 diabetes (T1D) is an autoimmune disorder caused by destruction of β cells in the Langerhans pancreatic islets by T-cell-mediated immune reaction leading to absolute insulin deficiency. β cell destruction may occur over months or years, and the symptoms start to appear when a significant amount of β cells are destroyed. In 2019, about 244,000 children and adolescents were diagnosed with T1D, and about 1.6 million adults. About 3-4% is an annual increase in the incidence of T1D over the past three decades. About 5-10% of all diagnosed diabetes globally is T1D. The global prevalence of T1D is estimated to be about 9.5%. T1D can affect any age group, but it is one of the most common chronic diseases of children. More severe clinical presentation is associated with childhood-onset of T1D, such as severe hyperglycemia or diabetic ketoacidosis (DKA). 

Researchers have spent huge effort to understand the mechanism of the disease and to improve its management. 

It is a multifactorial disease. It occurs in genetically susceptible individuals triggered by environmental factors. 

Genetic predisposition:

About 50% of familial T1D is associated with loci involving human leukocyte antigen (HLA) alleles DR and DQ on chromosome 6p21. In addition to HLA, the single nucleotide polymorphisms (SNPs) comprising the insulin gene (INS) is associated with about 10% of T1D. Other genes include protein tyrosine phosphatase non-receptor type 22 (PTPN22), cytotoxic T-lymphocyte–associated antigen (CTLA)-4 gene, interleukin-2 receptor alpha chain (IL2RA), and interferon induced with helicase C domain 1 (IFIH1) genes. The strongest genetic risk factors are HLA class II DRB1, -DQA1, and -DQB1 genotypes, especially HLA DR4-DQ8 and DR3-DQ2, which are found in 90% of children with T1D. Family history is strongly associated with T1D; however, the disease can develop in patients without family history and even without a history of autoimmune diseases. 

Environmental factors:

Potential factors that may trigger the autoimmune reaction against β cells in genetically susceptible individuals include infections (enteroviruses, influenza B, cytomegalovirus, coxsackie virus, rubella virus, mumps virus, and SARS-CoV-2 (COVID-19)), vaccinations, vitamin D levels, pollutants and toxins, gut microbiota composition, early life diet (cereal exposure and cow's milk), pregnancy and perinatal conditions, geographic distribution, and, of course, genetic predisposition. 

Geographic distribution: 

The highest incidence of T1D was reported in Finland and other Northern European nations, 400 times greater than the lowest level of incidence reported in China and Venezuela. 

Autoimmune reaction:

The immune-mediated β cell destruction is caused by autoantibodies against pancreatic β-cell autoantigens. The targeted antigens include insulin (IAA), antigens in the islet cell cytoplasm (ICA), insulinoma antigen 2/islet tyrosine phosphatase 2 (IA-2), glutamic acid decarboxylase isoform 65 (GAD65), and zinc transporter isoform 8 (ZnT8) antigens. The most commonly detected antigens in children are IAAs, while in adults it is GAD65. The higher the levels of detected antibodies, the greater the risk of T1D development. 

The classic symptoms of T1D are polyuria (excessive or abnormally large production or passage of urine), polydipsia (excessive thirst), polyphagia (abnormally strong sensation of hunger or desire to eat), lethargy (a state of unusual tiredness, lack of energy), and weight loss. Other presentations are the complications of the disease itself, such as DKA, in addition to perineal candidiasis and acute visual disturbances. A misdiagnosis of T2D may occur in adults when it is actually a delayed onset of T1D. Careful assessment must be performed. Measuring the levels of T1D pancreatic autoantibodies and performing pancreatic β-cell function through stimulated C-peptide levels can help to differentiate the two types of diabetes. 

The diagnostic criteria of T1D include the following:

• Fasting plasma glucose of ≥ 126 mg/dL on more than 1 occasion

• Plasma glucose of ≥ 200 mg/dL measured 2 hours after a 75-g oral glucose tolerance test (OGTT)

• Random plasma glucose of ≥ 200 mg/dL with classic symptoms of hyperglycemia

• HbA1c level of ≥ 6.5%  

Stages of T1D progression are:

The presymptomatic T1D can be divided into:

-Stage 1: B-cell autoimmunity has developed in normoglycemic individuals. No visible signs or symptoms.

-Stage 2: B-cell autoimmunity but have developed glucose intolerance. However, still no visible signs or symptoms. 

-Stage 3: symptomatic type 1 diabetes. The number of functioning pancreatic beta cells became low, and lifelong insulin therapy is required.

According to studies, 100% is the lifetime risk of progression from stage 1 and stage 2 to stage 3.

Management of T1D includes glycemic control (through lifelong insulin replacement), preventing the disease's complications, patient education, and improving their quality of life. 

The rising healthcare costs due to T1D complications necessitated more research to improve the treatment and outcomes of the disease. Recently, the new approach is to early identify T1D at different stages and prevent or delay its progression, which is known as personalized medicine: 

"offering the right therapy at the right time for the right affected individual" 

Most patients do not have controlled blood glucose levels despite the presence of advanced insulin delivery devices and glucose monitoring technology. So, researchers focused on developing treatment that may delay or prevent the progression of T1D.

The FDA approved Teizeild (teplizumab) to delay the onset of stage 3 type 1 diabetes in adults and children ≥ 8 years of age with stage 2 type 1 diabetes, and the clinical history should not suggest type 2 diabetes!

The approval is based on a clinical trial that involved 76 patients with stage 2 T1D. In patients treated with teplizumab, the median time to develop stage 3 T1D was 50 months, with 45% of the 44 patients who received teplizumab developing T1D, compared to 25 months in patients who received placebo, with 72% of the 32 patients who received placebo developing T1D.

According to the American Diabetes Association (ADA), stage 2 is defined by the presence of two or more positive autoantibodies in addition to dysglycemia (through an oral glucose tolerance test (OGTT) or an alternative method). A recent study showed that a ≥10% increase in HbA1c was comparable to OGTT, defining the risk of stage 3 T1D progression. 

Teplizumab (Tzield) is a monoclonal antibody that was recently approved by the Food and Drug Administration (FDA) as the first preventative treatment for T1DM. 

The active ingredient of Tzield is teplizumab, a humanized anti-CD3 monoclonal antibody. 

Tzield is a monoclonal antibody that binds CD3 molecules that are present on the surfaces of T lymphocytes (for example, CD4 and CD8 cells) that are involved in the immune-mediated reaction in T1D leading to insulin deficiency.  Therefore, it slows the rate of pancreatic beta cell destruction and delays the onset of T1D. Teplizumab is not an immunosuppressive drug. It is an immune modulator treatment, as it balances the effector and regulatory T cells, reducing the effector function of T cells and increasing the number and function of regulatory T cells. 

Tzield is given as an infusion over 30 minutes for 14 days.

Premedication with a nonsteroidal anti-inflammatory drug (NSAID), antihistamine, and antiemetic before starting each dose, at least for the first 5 days of treatment. If there is an interruption in daily doses, it is recommended to continue the full 14-day course of treatment unless there is a contraindication of continuation, such as a severe acute hypersensitivity reaction.  Vital signs should be checked every 15 minutes during infusion.

-Having a serious infection. Due to the immunomodulating mechanism of the treatment, screening for active Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections should be performed before starting teplizumab. Prior to teplizumab, serology and viral load tests for hepatitis B/C, HIV, EBV, CMV, and TB testing (QuantiFERON Gold) are recommended.

-Recently receiving a vaccine, as TZIELD affects the work and effectiveness of vaccines. It is not recommended to receive an inactivated or messenger RNA vaccination during the teplizumab treatment period, within 2 weeks before starting teplizumab, and 6 weeks after completing teplizumab. Live-attenuated vaccinations are not recommended during the treatment period, within 8 weeks before starting the treatment, and up to 52 weeks after completing teplizumab. Also consider COVID-19 and influenza vaccines. 

-Pregnancy. TZIELD should not be received during pregnancy or at least 30 days before planned pregnancy to minimize the risk of exposure to the fetus. A reliable method of contraception should be considered. 

-Breastfeeding. It is recommended that lactating women should use pumping and discarding breast milk during and up to 20 days of receiving Tzield to minimize the effect on breastfed infants.

1-Headache

2-Rash:

Rash was reported in about 48% of patients who received teplizumab. It was mainly a self-limited, transient, pruritic, papular, and nonserious rash. Antihistamines or low-dose topical steroids as supportive treatment can be used to treat pruritus.

3-Lymphopenia (decrease in white blood cell counts): will be discussed later.

Serious reactions to TZIELD include cytokine release syndrome (CRS), lymphopenia, line infections, and hypersensitivity reactions. Concomitant infection, whether viral or bacterial illness, should also be excluded. 

1-Cytokine release syndrome (CRS):

This is usually observed in the first 5 days of TZIELD treatment; however, it can develop at any time during the treatment period and even up to 28 days following the last infusion dose. Symptoms include fever (which is the hallmark of CRS), headache, fatigue, nausea, muscle pain (myalgia), and joint pain (arthralgia). Elevated levels of liver enzymes in blood (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin are also observed. CRS is generally mild and can be tolerated. It is reported in about 5% of patients who received teplizumab. It is important to differentiate whether the fever is due to CRS or concomitant infection. 

To minimize the risk of CRS, premedication with antihistamines, NSAIDs, or acetaminophen and antiemetics, especially when nausea develops (e.g., ondansetron), 30 minutes before the first 5 doses of teplizumab and sometimes continued for longer periods.

Ibuprofen, according to the researchers, is preferred to acetaminophen due to the lower risk of liver enzyme elevation in addition to being more effective. Gastrointestinal prophylaxis (prevention) with antacids may be needed to prevent the decreased appetite due to the continuous use of ibuprofen. 

Adequate hydration must be ensured to decrease the incidence of adverse reactions. Oral hydration is often sufficient; however, IV fluids (e.g., 0.9 NS 20 mL/kg IV bolus) may be used, especially for CRS and if there is poor oral intake.

To decrease the symptoms and signs of severe adverse reactions, a short course of glucocorticoids could be used. Moderate to severe CRS is an example of such an indication. 

-Elevation of liver enzymes was observed in about 25% of patients with or without CRS (56% in patients who experienced CRS). It was mainly transient, and recovery occurred within 1–2 weeks of teplizumab. Discontinuation of treatment was observed in 5.6% of the teplizumab patients compared to 0.9% of the control group. 

CBC, liver enzymes, bilirubin, and the clinical symptoms of the complication should be observed during and even after the treatment course. 

2-Decrease in blood cell count: 

A-Lymphopenia:

A decrease in the levels of lymphocytes. This may happen after the first dose of TZIELD, which affects the ability to fight infections. Lymphopenia was reported in about 80% of patients who received teplizumab in clinical trials. It becomes more severe at 4–5 doses of teplizumab and improves with continuation of treatment. This may be due to transient migration of lymphocytes from the bloodstream into tissues, and rapid recovery occurs, so it is not due to T-cell depletion. By the 6th week, it becomes normalized. 

B-Anemia was reported in approximately 27% of patients who received teplizumab compared to 21% of placebo-treated individuals based on clinical trials. Anemia was observed to recover within 2–4 weeks of treatment. Clinical trials showed that about 2% of individuals who received teplizumab discontinued the treatment when the hemoglobin (Hb) dropped to <8.5 g/dL. 

C-Thrombocytopenia (low platelet count) was reported in about 13% of patients who received the treatment, occurring on the 14th day of treatment and recovering within 2–4 weeks of teplizumab. When platelet count became less than 50,000/µL, teplizumab was discontinued according to clinical trials, and this was observed in about 1% of patients. 

D-Neutropenia was observed in about 40% of patients receiving teplizumab compared to 22% of placebo-treated patients. 

A Complete Blood Count (CBC) with differential is recommended prior to starting teplizumab to detect any underlying hematologic abnormalities and for monitoring. It is also recommended that patients receiving teplizumab wear masks during the seasonal infections. Contact between patients and their household partners should be avoided at least 2 weeks prior to treatment and until recovery from lymphopenia and neutropenia. 

3-Hypersensitivity reaction:

Anaphylaxis was observed in 0.1%, peripheral edema in 1.6%, angioedema in 0.3%, urticaria in 1.9%, and serum sickness in 0.1% of patients who received teplizumab. It is recommended to discontinue teplizumab if severe hypersensitivity reactions occur. Availability of resuscitation equipment, oxygen, epinephrine injection, glucocorticoids, bronchodilators, antihistamine medications, and other supplies to deal with any unexpected hypersensitivity reactions. Hypersensitivity reactions are emergency situations that require well-trained personnel.

4-Serious infections were reported in 3.5% of the teplizumab group compared to 2% in the control group, according to clinical trials. Reactivation of EBV (5.1%) and CMV (0.5%) was reported in the treatment group. However, most cases were asymptomatic and did not require antiviral therapy. 

Discontinuation of teplizumab should be done, and diagnostic testing (including serology and viral load for EBV and CMV) should be performed if signs of infection occur during the treatment course. 

-No malignancies have been reported to date, but further research is still required. 

-Hyperglycemia (high blood glucose level) may occur during the treatment course and usually improves with time.

To conclude, clinical trials found that teplizumab, the first FDA-approved disease-modifying agent for T1D, could delay the progression from stage 2 to stage 3 T1D by a median of 32.5 months (which is equal to 2 years and 8.5 months). This gives hope for T1D for a better quality of life. However, due to teplizumab's social and economic challenges as well as the possibility of serious adverse reactions, a careful risk-benefit assessment must be performed before initiating the treatment. Universal access to this treatment must be provided to all patients from different socioeconomic backgrounds and should be covered with health insurance, which may take some time for sure. Patients should be educated about signs and symptoms of stage 3 T1D, as well as the clinical symptoms and signs of teplizumab complications, especially CRS. Researchers exert great efforts to produce better treatments, and further research is ongoing.

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(2) TZIELD® (Teplizumab). 

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(4) First-in-class treatment to delay onset of type 1 diabetes. European Medicine Agency (EMA).

(5) Sanofi Canada. (May 5, 2025).  Health Canada has granted approval for Tzield®, the first and only disease-modifying therapy in autoimmune type 1 diabetes in Canada [Press release]. 

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(7) Treatment approved to delay progression of type 1 diabetes. Diabetes research & wellness foundation.

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