An update of contemporary insulin therapy
Journal
Journal of diabetes investigation
Date Issued
2024-04-03
Author(s)
Abstract
A century has elapsed since the first formulated insulin made a debut. Progressive techniques and materials have overcome many problems of insulin therapy, including impurities, duration of action, antibodies against porcine or bovine insulin, and the expense of production1. Despite the advances in oral antidiabetic drugs (OADs), insulin injection remains the keystone therapy in type 1 diabetes, type 2 diabetes with significantly impaired renal function, pregnant women, pancreoprivic diabetes, hospitalized patients, and those who cannot take oral pills. According to the American Diabetes Association, the early initiation of insulin therapy is recommended in the presence of ongoing catabolism (weight loss), symptoms of hyperglycemia, or when the A1c levels are >10% (86 mmol/mol) or blood glucose levels are ≥300 mg/dL (16.7 mmol/L)2. Moreover, insulin therapy always plays a role in the treatment for individuals who suffer treatment failure with oral antidiabetic drugs. As type 2 diabetes is a progressive disease, a significant number of individuals will ultimately need a daily injection of insulin as a result of declining pancreatic beta-cell function. For example, a nationwide cohort study revealed that adolescents with type 2 diabetes mellitus progressively required more intensive treatment after 1 year on oral antidiabetic drugs, with the majority eventually needing insulin therapy3. A significant subset of people with adult diabetes exhibit a combination of traits seen in both type 1 and type 2 diabetes. They are recognized as having a slowly progressive autoimmune form of diabetes, yet they do not initially require insulin upon diagnosis. These individuals are classified as having adult latent autoimmune diabetes, constituting approximately 2–12% of all cases of diabetes4. Intermediate-acting and long-acting insulin are used as basal insulin, which is usually the beginning of insulin therapy. Common available insulin products are listed in Table 1. Insulin glargine and insulin degludec are deemed to be the most useful basal insulin currently. The DEVOTE Trial (Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients With Type 2 Diabetes at High Risk of Cardiovascular Events) was the first study to compare the cardiovascular safety of insulin degludec with insulin glargine U100 in patients with type 2 diabetes at high risk of cardiovascular events. Both insulins demonstrated comparable efficacy in the cardiovascular events outcome (hazard ratio 0.91; 95% CI 0.78–1.06). Degludec exhibited significantly reduced occurrences of severe hypoglycemia and nocturnal severe hypoglycemia (with rate ratios of 0.60; 95% CI 0.48–0.76 and 0.47; 95% CI 0.31–0.73, respectively)5. Another study assessing the effectiveness and safety of insulin glargine U300 and insulin degludec in managing glycemic control through continuous glucose monitoring also revealed no significant difference in the mean percentage of time within the target glucose range between glargine U300 and degludec (77.8 ± 19.2 vs 76.9 ± 18.3%, P = 0.848). In contrast, the mean percentage duration of hypoglycemia was notably reduced with glargine U300 compared with degludec (1.3 ± 2.7 vs 5.5 ± 6.4%, P = 0.002)6. A combined injectable therapy should be considered if the basal insulin has been adjusted to achieve a desirable fasting blood glucose level, and the A1c still exceeds the desired target. This strategy may involve the addition of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or a combination of glucose-dependent insulinotropic polypeptide and GLP-1 RA to the existing basal insulin or multiple insulin doses2. Fixed ratio combination products, such as insulin glargine U100 plus lixisenatide, are available to achieve better adherence for selected patients. Other considered options in combined therapy include degludec. It has a duration exceeding 40 h and can attain a steady plasma concentration for 3–5 days. In contrast to glargine and detemir insulins, degludec may be mixed with rapid-acting insulins without significantly altering the kinetics of either medication compared with other forms of basal insulin7. Insulin icodec is a novel basal insulin that has been designed for weekly subcutaneous administration. The implementation of this regimen will markedly reduce the need for weekly injections, leading to increased patient satisfaction and adherence. The ONWARDS (Once Weekly Insulin Icodec in Diabetes) trials demonstrated a more pronounced decrease in HbA1c levels among insulin-naïve patients and a similar effect in those already undergoing insulin treatment. Although the overall rate of combined clinically significant or severe hypoglycemia was significantly higher among the icodec group compared with the degludec group, the adverse effect of severe hypoglycemia did not increase8, 9. Basal insulin-Fc (LY3209590) is an investigational ultra-long-acting immunoglobulin G Fc-fusion insulin, also designed to be administered subcutaneously and weekly. In a phase 2 trial including 399 adults with type 2 diabetes, the basal insulin Fc (BIF) groups exhibited a comparable reduction in the HbA1C level with degludec (0.1% [90% CI –0.1 to 0.3]) despite higher fasting glucose targets in the BIF groups. The hypoglycemia event rates in the BIF groups were 25% lower than those of the degludec group. These findings suggest further investigation of BIF as a once-weekly insulin treatment for diabetic patients. More trials are required to address its safety and efficacy in the treatment of type 1 and type 2 diabetes10. The development of insulin treatment devices and continuous glucose monitoring facilitate diabetes control. Different treatment strategies, such as continuous subcutaneous insulin infusion plus glucose monitoring, and sensor-augmented pump (SAP) therapy are also under investigation11. Six type 1 diabetes patients underwent post-simultaneous kidney/pancreas or pancreas only transplant were studied. All of them were taking immunosuppressants and multiple daily insulin injections for hyperglycemia after surgery. Diabetes technologies were provided to help achieve better glucose control in those who had dysfunction of the pancreatic graft12. However, it is worth noting that insulin allergy and anti-insulin antibodies may cause severe adverse effects. A case of type 2 diabetes was reported as having severe diabetic ketoacidosis triggered by an allergic reaction to insulin and the presence of anti-insulin antibodies. In addition, other life-threatening events such as angioedema and anaphylaxis may also occur, although they are rare13. Additionally, there are concerns about how the changes in the structure of insulin to its analogs would increase mitogenic activities due to the enhanced affinity to the IGF-1 (Insulin-like Growth Factor) receptor and the prolonged residence on the receptors for insulin, leading to neoplastic consequences14. Few trials in the past have addressed this issue and have demonstrated conflicting results. A meta-analysis performed in 2023 compiled the risk of cancer among patients taking anti-diabetic medications. Positive associations were found between insulin secretagogues and pancreatic cancer (n = 5; RR = 1.26; 95% CI = 1.01–1.57), and between insulins and liver (n = 7; RR = 1.74; 95% CI = 1.08–2.80) and pancreatic cancers (n = 8; RR = 2.41; 95% CI = 1.08–5.36)15. However, due to the limited number of samples, further research is required to confirm such findings. This article highlights the integral role of long-acting insulin as a sole or combined regimen in the treatment of type 1 diabetes or type 2 diabetes after first-line agents have failed. Other novel agents such as basal insulin-Fc may be considered after the establishment of solid evidence supporting its benefits. Although neoplastic consequences such as pancreatic cancer may occur, more robust studies are required to verify such a hypothesis. The integration of the current insulin therapies with SAP and other continuous glucose monitoring devices allow close monitoring of glucose levels among patients, especially those under a combined regimen. This will foster opportunities for research and ensure a higher safety when administering insulin regimens. The authors declare no conflict of interest.
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journal article