Type 1 diabetes mellitus - Emerging treatments

Once-weekly insulin formulations

Once-weekly administration of basal insulin would help to reduce the significant burden of diabetes management. There are currently two once-weekly basal insulins in clinical development: insulin icodec and basal insulin Fc (BIF; also known as insulin efsitora alfa). Insulin icodec is an ultra long-acting basal iոѕuliո (half-life of 1 week) that has regulatory approval in some countries and regions, including Canada, Japan, Australia, China, and the European Union, but not in the US. A 52-week phase 3 trial (ONWARDS 6) compared once-weekly insulin icodec with once-daily insulin degludec in 582 adults with type 1 diabetes.[179] The primary endpoint, change in HbA1c at week 26, showed that insulin icodec was noninferior to insulin degludec. However, insulin icodec was associated with a statistically significant higher rate of clinically significant or severe hypoglycemia.[179] BIF is still under clinical development. A 52-week phase 3 randomized noninferiority trial (QWINT-5) compared once-weekly BIF with once-daily insulin degludec in adults with type 1 diabetes.[180] The primary outcome, change in HbA1c at week 26, showed that BIF was noninferior to insulin degludec. However, BIF was associated with a statistically significant higher rate of combined level 2/3 hypoglycemia over the 52 weeks, particularly in the first 12 weeks.[180]

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.[181] 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.[182][183][184] Abatacept is an immunotherapy already used to treat rheumatoid arthritis.[185] It is a cytotoxic T-lymphocyte associated protein immunoglobulin (CTLA4Ig) which prevents T-cell activation and has the potential to slow beta-cell loss in new-onset type 1 diabetes.[185] In a randomized, placebo-controlled phase 2 trial, adults and children with stage 1 type 1 diabetes (≥2 diabetes-related antibodies but normal glucose tolerance) received abatacept for 1 year.[185] The study found that abatacept did not significantly delay progression to stage 2 or 3 type 1 diabetes; however, it impacted immune cell subsets and preserved insulin secretion suggesting it may have a role as a disease modifying therapy in type 1 diabetes.[185]

Teplizumab

Teplizumab is a CD3-directed monoclonal antibody that has been approved by the Food and Drug Administration (FDA) and is recommended by the American Diabetes Association (ADA) to delay the onset of stage 3 type 1 diabetes in people 8 years of age and older with stage 2 type 1 diabetes.[1] It is also being investigated as a potential disease-modifying drug in new onset stage 3 type 1 diabetes. Teplizumab has been shown to be associated with lower insulin use and higher area under the curve (AUC) of C-peptide (indicating greater overall C-peptide secretion) in patients with early type 1 diabetes.[62][63][64][65] However, in one meta-analysis, it was found to impart higher risks of grade 3 or higher adverse events, adverse events leading to discontinuation, nausea, rash, and lymphopenia.[65] Trials with other drugs targeting 1) autoimmune responses, 2) antigen presentation, 3) glycemic dysregulation, and 4) beta-cell stress/dysfunction are underway.[48]

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, or for those with 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.[186] The cells seed in the liver and produce insulin. Research in this field has been ongoing, with previously limited success.[187][188] 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.[189][190] 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 immunosuppressants 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.[191] Further, the requirement for donor cells limits its supply. Donislecel is not currently approved for use in 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.[192] These remaining functional cells may be viable candidates for regeneration.[192] 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.[192] Other regenerative methods that have been explored include the generation of functional beta cells from human pluripotent stem cells.[192][193] 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.[192] Tissue engineering approaches such as enhancing vascularization may be beneficial and are in early-stage trials.[192]

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.[194] Further research is indicated to better delineate the potential indications and benefits of this treatment in type 1 diabetes.[195][196]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

SGLT2 inhibitors are oral drugs 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 by the FDA for use in individuals with type 2, but not type 1, diabetes. A real-world study of SGLT2 inhibitors in combination with insulin in 199 patients with type 1 diabetes showed promising results in reductions in HbA1c, weight, and insulin requirements.[197] Ketosis episodes and diabetic ketoacidosis (DKA) were reported in 2.5% and 3.5% of patients, respectively.[197] Systematic reviews have reported similar effects.[198][199][200] However, due to concern about increased risk of DKA, especially euglycemic DKA, use of SGLT2 inhibitors for glycemic control in type 1 diabetes remains limited.[201][202][203] If used, the patient should be educated about the risk of ketoacidosis and given advice on risk mitigation and monitoring.[1]

Dual SGLT1/2 inhibitors

Sotagliflozin is a dual SGLT1/2 inhibitor that is under investigation as an adjunctive therapy in type 1 ԁiаbeteѕ. A phase 3 trial studied the effects of sotagliflozin added to insulin therapy in 1402 patients with type 1 diabetes selected to be at low risk for DKΑ.[204] After 24 weeks, significantly more patients on sotagliflozin achieved an HbA1c below 7% without severe hypoglycemia or DKA compared with placebo (28.6% vs. 15.2%). Sotagliflozin also led to greater reductions in HbA1c, weight, systolic blood pressure, and daily insulin dose. There was no difference in severe hypoglycemia. However, a key finding was a higher rate of DKA in the sotagliflozin group compared with placebo (3.0% vs. 0.6%). The authors concluded that sotagliflozin, while improving glycemic control and other parameters, increased the risk of DKA in type 1 diabetes patients on insulin.[204]

Glucagon-like peptide-1 (GLP-1) receptor 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. While GLP-1 receptor agonists are not approved by the FDA for type 1 diabetes, they are sometimes used off-label. One of the main advantages of GLP-1 receptor agonists is weight loss, which may be desirable in some patients with type 1 diabetes.[205][206] Some studies suggest other potential benefits such as modest HbA1c improvements and reduced insulin needs.[206][207] However, significant safety concerns exist, primarily the increased risk of hypoglycemia and diabetic ketoacidosis. The GLP-1 receptor agonist liraglutide was investigated in adults with type 1 diabetes (ADJUNCT ONE and TWO studies).[208][209] It failed to demonstrate a reduction in HbA1c of more than 0.4% (which had been designated as the efficacy threshold by the regulators) compared with placebo, and there was an increase in risk for documented symptomatic hypoglycemia and ketosis.

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.[210] 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.[211]

Bionic pancreas

The bionic pancreas is a trial device that integrates an automated insulin delivery system with a fully closed loop system. It uses a continuous glucose monitor and automatically delivers both insulin and glucagon to regulate glucose levels. 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.[212] In one US crossover trial, 39 adults with type 1 diabetes were randomly assigned to use either the bionic pancreas or a conventional insulin pump for two 11-day periods.[213] During the study, participants continued with their normal activities, including diet and exercise. The researchers found that the bionic pancreas significantly improved blood sugar control compared to conventional insulin pump therapy. People using the bionic pancreas had lower average blood sugar levels and spent less time with very low blood sugar levels. However, some participants experienced nausea.[213] A similarly designed, 5-day crossover trial investigated the effectiveness of a bionic pancreas in managing type 1 diabetes in 20 adults and 32 adolescents.[214] In both groups, the bionic pancreas significantly lowered average glucose levels compared to using an insulin pump. There were no severe hурοglуcеmic events during the closed-loop period.[214] These studies suggest that the bionic pancreas may be a promising new approach for managing type 1 diabetes. However, more research is needed to determine the long-term safety and efficacy of this technology.

Verapamil

In preclinical studies, thioredoxin-interacting protein overexpression induces pancreatic beta-cell apoptosis and is involved in glucotoxicity-induced beta-cell death.[215] Calcium-channel blockers such as verapamil reduce these effects and may be beneficial to beta-cell preservation in type 1 diabetes.[215] A meta-analysis of two double-blind, placebo-controlled, randomized clinical trials of verapamil in newly diagnosed type 1 diabetes - one in adults and one in children/adolescents - showed a significant improvement in pancreatic C‑peptide secretion after 1 year of therapy and provided reassuring safety data.[215][216][217] Verapamil was well tolerated without any significant increase in treatment-emergent adverse events, severe adverse events, hypoglycemia, constipation, or headache.[216] However, concern has been raised over the potential adverse events and long-term safety associated with verapamil use in children and adolescents.[218] The meta-analysis authors concluded that verapamil should be actively investigated in future larger and longer studies to further assess its ability to promote endogenous beta-cell function in type 1 diabetes.[216]