In recent years, a number of new type 2 diabetes therapeutics have been launched, among which the new type 2 diabetes therapeutic drug —- Exenatide (trade name: Byetta), jointly developed by Eli Lilly and Company and Amylin, has attracted particular attention.
Exenatide is the first intestinal hypoglycemic analogue, a synthetic peptide consisting of 39 amino acids, which is similar to endogenous intestinal hypoglycemic peptide such as glucagon-like peptide-1 (GLP-1). The drug is a subcutaneous injection. It is a subcutaneously injected formulation.
As the first GLP-1 agonist, exenatide is a new class of hypoglycemic drug, but it has been marketed in Europe and the United States for 6 years, with tens of millions of prescriptions and rich clinical use experience. A series of clinical trials related to exenatide have shown that for patients with type 2 diabetes whose blood glucose is not well controlled with oral hypoglycemic drugs, the addition of exenatide can control blood glucose well.
Exenatide is similar to insulin in lowering blood glucose. In the traditional treatment strategy for type 2 diabetes, insulin therapy is usually started when two oral hypoglycemic drugs are still not lowering glucose.
How does exenatide compare to insulin? A study compared the glucose-lowering effect of exenatide with that of glargine insulin and diphasic menthol insulin and showed that exenatide could achieve similar glycemic control as insulin therapy; moreover, compared with glargine insulin and diphasic menthol insulin, exenatide could control postprandial blood glucose more strictly, with less hypoglycemic response and the advantage of weight reduction. Thus, exenatide is a good choice for overweight type 2 diabetic patients before receiving insulin therapy.
It is well known that type 2 diabetes is a progressive disease and as the disease progresses, it becomes more difficult for patients to control their blood glucose. Does the addition of exenatide just provide better glycemic control in the short term? Studies have confirmed that the hypoglycemic effect of exenatide persists steadily with the use of fixed doses. The investigators conducted further open extension trials of three large phase III clinical studies with up to 3 years of follow-up, showing that patients’ glycated hemoglobin levels remained significantly lower and stable for 3 years of exenatide treatment; and that patient age had no effect on the effect of exenatide (patients under or over 65 years of age benefited equally).
This suggests that the addition of a fixed dose of exenatide to oral hypoglycemic agents in patients with type 2 diabetes at different stages of the disease can result in a sustained and stable reduction in blood glucose. Based on the above evidence, exenatide has the advantage of sustained and effective glycemic control, and further exploration of its mechanism shows that the hypoglycemic effect of exenatide is inextricably linked to its role as a GLP-1 agonist that exerts the pleiotropic characteristics of GLP-1.
GLP-1 is an important class of enteroglucagon that plays an important role in the physiological regulation of blood glucose. When the body eats, GLP-1 is secreted by intestinal L cells under the stimulation of nutrients, stimulating insulin secretion and inhibiting glucagon secretion to exert hypoglycemic effects. More importantly, studies have shown that GLP-1 can act directly on pancreatic β-cells, reducing β-cell apoptosis and increasing their proliferation, thus protecting β-cells.
In addition, GLP-1 has the effect of reducing body weight by reducing food intake through central and gastrointestinal effects, which can further reduce β-cell load and benefit patients with type 2 diabetes.
Exenatide is now available in China and has become a new option for the treatment of type 2 diabetes. With the development of research and clinical application experience, the indications and dosage forms of exenatide are being updated. Recently, exenatide has been approved by the US Food and Drug Administration (FDA) for monotherapy initiation in patients with type 2 diabetes.
Another human GLP-1 analogue, liraglutide, will be available soon. In addition to the intervention of cardiovascular risk factors such as blood glucose, blood pressure and body weight, it has been shown that liraglutide can inhibit the expression of type 1 fibrinogen activator inhibitor (PAI-1) and type 1 vascular cell adhesion molecule (VCAM-1).
In contrast, studies by Noyan-Ashraf et al. in a mouse model of infarction confirmed that liraglutide pretreatment prevented cardiac rupture in mice with infarction, reduced mortality after cardiac rupture, and reduced infarct size 28 days after infarction. GLP-1 had positive effects on β-cell volume, endothelium, and heart, which are beneficial in preventing progression of type 2 diabetes. Of course, these promising findings require further studies to confirm whether they can produce long-term benefits against beta cells and cardiovascular disease.
Finally, let’s all look forward to more evidence to give guidance to clinicians and patients so that GLP-1 receptor agonists can be better used to benefit more patients with type 2 diabetes.