Received 2023 Feb 21; Revised 2023 Apr 17; Accepted 2023 May 16; Issue date 2023 Jul-Aug.
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Challenges in Type 1 Diabetes Prevention
Individuals with type 1 Diabetes (T1D) and their families often struggle with the perceived quality of life. While treatments are advancing, managing T1D remains labor-intensive. The prospect of preventing T1D could have a profound global impact. Identifying the triggering antigen, avoiding environmental factors, and immune modifications are key strategies in delaying or preventing T1D. Barriers include the challenge of identifying at-risk populations and the absence of effective prevention methods. Recent progress in secondary prevention with Teplizumab offers hope, but preventive approaches may vary by region. This review explores preventive tactics for T1D, focusing on the Indian landscape.
Keywords: Indian perspective, prevention, teplizumab, type 1 diabetes
In addition to the points mentioned above, it is important to focus on promoting healthy lifestyle choices and behaviors to prevent the onset of chronic diseases. This can include regular physical activity, balanced diet, avoiding tobacco and alcohol consumption, and managing stress effectively.
Furthermore, healthcare providers need to be equipped with the necessary skills and knowledge to effectively manage chronic diseases, including proper diagnosis, treatment, and monitoring of patients. Continuous medical education and training programs are essential to ensure that healthcare professionals are up to date with the latest guidelines and practices in chronic disease management.
Strategies for Chronic Disease Prevention
Preventive approaches are categorized as primordial, primary, secondary, and tertiary. While primordial prevention might not apply to T1D due to population identification challenges, understanding T1D’s pathophysiology in stages facilitates targeted preventive actions.
Understanding the Progression of Type 1 Diabetes
| Before beginning | First step | Second step | Final step | |
|---|---|---|---|---|
| Factors that Increase Risk | Currently Present | ± | ± | ± |
| Beta-cell autoimmunity | is currently existing | It is currently present | It exists | It is evident now |
| Glycemic Condition |
| Normal |
| – |
| Abnormal Glucose Metabolism |
| High Blood Sugar Levels |
H3_2_ALT
Explanation of prevention stages related to type 1 diabetes
| Rank | Meaning in a broad sense | Interpretation within the context of type 1 diabetes |
|---|
| Subsequent |
| Identifying and treating diseases early |
| Stopping autoimmune response in people with multiple islet autoantibodies |
| Third Level |
| Handling current health conditions to avoid further issues |
| Treating symptoms of type 1 diabetes in a clinical setting |
In-depth understanding of vulnerable populations and suggested prevention methods is essential across different prevention levels.
P RIMARY PREVENTION
The group susceptible to T1D encompasses all children, as the factors contributing to the risk are not completely known. Genetic risk scores, based on HLA genotype and non-HLA gene loci, can identify up to half of new T1D cases. Different HLA alleles can increase or decrease the risk of T1D. The costs of genetic testing may pose a challenge for implementation in countries with low T1D incidence rates, such as India. Although identifying at-risk populations is complex, most preventive approaches are tested in familial cases.
Figure 1.
T1D develops in individuals with genetic predispositions when environmental factors trigger an autoimmune response. Primary prevention efforts focus on avoiding exposure to potential environmental triggers in high-risk groups. The identification of these triggers is still ongoing. Therapies that modulate immunity may prove useful in preventing T1D.
Attempts to use therapies with anti-inflammatory or immunity-modulating properties, such as docosahexaenoic acid, vitamin D, and high-dose nicotinamide, have not yielded successful results. However, antigen-specific treatments aimed at inducing immune tolerance through bystander suppression continue to be of interest to researchers. Bystander suppression involves exposing the immune system to an antigen similar to the target antigen to promote immune tolerance. While Type 1 diabetes is believed to develop through epitope spreading, the primary initiating antigen remains unidentified. Trials involving insulin administration to at-risk children have been carried out.
Summarizing the current status of primary prevention:
- Identifying new T1D cases is challenging
- Options for population-wide prevention are limited
- There is no established clinical guidance for primary prevention strategies
Secondary prevention for T1D aims to delay the onset of clinical disease in the early stages. Individuals with autoantibodies but no clinical diagnosis yet are targeted for secondary prevention. Strategies involve immunomodulation using agents like proinsulin, insulin, and GAD 65 to induce bystander suppression.
Secondary prevention strategies focus on immunomodulation through different approaches. Studies have shown varying results, with some therapies delaying T1D onset in specific groups. The age at intervention and dosage of therapies may influence their effectiveness.
Therapies targeting T-cell immune responses show promise in regulating specific cells for secondary prevention or early-stage T1D. Ongoing research is exploring the effectiveness of immunotherapies in preventing T1D.
| Specific Antigen | Treatment | Mechanism of Action | Latest Development |
|---|---|---|---|
| CD3, T cell | Teplizumab[34] | Long-term reduction of T cell activation and increase in regulatory T cells | Demonstrated 24-month delay in T1D onset. FDA approved for secondary prevention |
| CD3, T cell | Otelixizumab[35] | Sustained decrease in T cell activation and higher levels of regulatory T cells over time | Also postponed T1D onset, but optimal dose linked to increased risk of EBV activation. Dosage studies in progress |
| CD2, T cell | Alefacept[36] | Elevated T regulatory cells compared to T effector cells | Observed immunological response and delayed decline in C-peptide levels in clinical trials. Alefacept group required less insulin, but no significant difference in HbA1c. More research needed |
| CTLA 4, T cell | Abatacept[37] | Inhibiting T cell activation by targeting CD80 and CD86 on antigen-presenting cells | Sustained higher C-peptide levels during treatment. Delayed decline in C-peptide after discontinuation by 9.6 months, similar to placebo group. Further investigations ongoing |
| CD 20, B cell | Rituximab[38] | Targeting B cell function | Not effective on its own. Current trials combining with abatacept |
| TNF alpha | Golimumab[39,40] | Aiming at reducing inflammation | Phase 2 research indicated reduced need for insulin. Await further findings |
Therapies targeting Interleukin 1, Interleukin 2, anti-thymocyte globulin, mTOR pathway, and alpha 1 antitrypsin have shown limited effectiveness or are still being studied. Teplizumab stands out as the sole FDA-approved therapy for preventing T1D.
The development of Teplizumab can be traced back to the mid-1970s when B-cell hybridoma technology paved the way for monoclonal antibody immunotherapy. Anti-CD3mAb has proven to be effective in treating T1D.
The first human monoclonal antibody, OKT3, was approved in 1986 for preventing transplant rejection. Despite its ability to block cytotoxic T cell function, its side effects restricted its use. Teplizumab, a humanized version of OKT3, binds to autoreactive T cells, prompting migration and exhaustion instead of depletion.
Studies on Teplizumab have demonstrated enhanced insulin production and lower levels of glycosylated hemoglobin in T1D patients. FDA approval was granted based on a 24-month delay in T1D onset. Ongoing trials are assessing its effectiveness in the treatment of T1D.
Information on prescribing Teplizumab is available for healthcare providers.
| Teplizumab, a CD3-directed antibody, is recommended for adults and children over 8 years old with Stage 2 T1D to postpone the development of Stage 3 type 1 diabetes. |
| Before starting teplizumab treatment, it is recommended to undergo a full blood count and liver enzymes tests. |
| Beforehand, administer these medications: |
| 1) Choose between NSAIDs or acetaminophen for pain relief. |
| 2) A medication for allergies, or |
| 3) Administer an antiemetic prior to each dose during the initial 5 days of the 14-day therapy regimen. |
| Important Notes and Safety Measures: |
| • It is advised to avoid using Teplizumab in individuals who have |
| 1) When the number of lymphocytes is below 1,000 lymphocytes/mcL |
| 2) Hemoglobin levels below 10 g/dL |
| 3) Thrombocytes below 150,000 platelets/mcL |
| 4) Neutrophil count below 1,500 neutrophils/mcL is considered low. |
| 5) If ALT or AST levels are higher than twice the upper limit of normal, or if bilirubin levels are higher than 1.5 times ULN |
| 6) Presence of recent EBV or CMV infection as shown by laboratory tests or clinical symptoms |
| 7) Exclusion criteria include any ongoing severe infection or persistent active infection |
| • Ensure that all necessary vaccinations are given prior to initiating teplizumab treatment |
| 1) Ensure live vaccines are given at least 8 weeks before the start of the treatment. |
| 2) It is recommended to administer inactivated vaccines or mRNA vaccines at least 2 weeks before starting the treatment. |
| Proper Dosage and How to Administer Teplizumab should be infused intravenously once a day for 14 days, based on the patient’s body surface area. |
| Avoid giving two doses in one day. |
| If a scheduled teplizumab infusion is missed, it is recommended to resume treatment by taking all remaining doses on consecutive days to finish the 14-day course. |
| Negative Effects: The most frequent negative effects (over 10%) included a decrease in lymphocytes, skin rash, a decrease in white blood cells, and headaches, as well as cytokine release syndrome and severe infections. |
The combination of Teplizumab with other cell replacement therapies is recommended for preventing T1D.
Individuals with lower C peptide responses than the median have shown a positive response to Teplizumab, especially those with active autoimmunity. Those who are HLA-DR3 negative, DR4 positive, and anti-ZnT8 antibody negative also respond well to Teplizumab.
Further research is necessary to understand the effects of multiple Teplizumab infusions. The ongoing PROTECT phase 3 study is investigating the efficacy of two infusions six months apart.
Teplizumab can delay the onset of T1DM and offers hope for its complete prevention in the future. Efforts in secondary prevention focus on identifying the appropriate population for prevention.
Immunotherapies for secondary prevention have shown some preservation of beta cell function. BCG vaccination may help delay T1D onset, while immunosuppressive therapies have led to temporary remission with notable side effects.
Large studies are needed to evaluate the impact of Teplizumab in tertiary prevention. Efforts in islet cell transplantation and artificial pancreas development aim to enhance the quality of life for T1D patients.
Advancements in T1D therapies, including artificial pancreas technology, insulin algorithms, and improved insulins, offer promise for better T1D management in the future.
Despite a high number of T1D patients in India, the care standards do not match those of developed countries. Comparing T1D statistics and care standards across different nations can shed light on care disparities.
Identifying the appropriate population for prevention without widespread screening remains a challenge. The approval of Teplizumab has revitalized hopes for improved secondary prevention therapies for T1D.
| Germany | Finland | USA | India |
|---|
| Number of Type 1 Diabetes cases among individuals aged 0-19 | 35.1K | 5.4K | 157.9K | 229.4K |
| Incidence of new Type 1 Diabetes cases in individuals aged 0-19 | 3600 (3 per 10000) | 600 (7 per 10000) | 18,200 (2.6 per 10000) | 24,000 (0.8 per 10000) |
| Total population eligible for Primary prevention | 1.07 cr | 8.6 lakh | 7 cr | 30 cr |
| Life expectancy at age 10 for individuals with Type 1 Diabetes | Over 70 years | Over 70 years | 55-69 years | 25-39 years |
| Health expenditure per person in PPP dollars | 7032 | 4897 | 11702 | 191 |
Information sourced from the IDF Diabetes Atlas and T1D report indicates that the life expectancy of individuals with T1D is relatively lower compared to the general population and other nations. In India, screening children for T1D poses a challenge due to limited resources. The global cost of Teplizumab is considerably high, with Mital et al. proposing that the expense can be justified based on genetic markers. Presently, the cost stands at $193,900, equivalent to ₹15,869,987.88 in Indian rupees. Therefore, the focus in India should pivot towards enhancing the outcomes of T1D patients.
Key issues in India revolve around the lack of educational resources and limited access to insulin. Tailored solutions that cater to the unique conditions in India are necessary to address these challenges. Priority initiatives should concentrate on improving access to essential care items and implementing technology-based education for better T1D management.
Exciting progress has been made in the realm of T1D prevention therapies, offering hope for a life free of diabetes. Nevertheless, hurdles persist in identifying suitable candidates for these innovative treatments. Primary and secondary prevention strategies might be more viable in countries like Finland and Germany. In contrast, India is striving to elevate the outcomes for T1D patients and venture into novel prevention avenues.
No conflicting interests are present in this context.
For more in-depth exploration, a plethora of references are available, including studies focusing on dietary interventions, removal of bovine insulin from cow’s milk formulas, primary dietary interventions for reducing islet autoimmunity risks in children, and more. These resources provide a rich foundation for further research and analysis in the domain of T1D treatment and prevention.