The Future of Treatment For Type 2 Diabetes

Although the treatment of type 2 diabetes (T2DM) has made impressive progress in the past few decades, researchers are constantly searching for new treatments. How to better control blood glucose and reduce diabetes-related complications has become a hot topic in the field of T2DM research.

Previously, The Lancet Diabetes Endocrinology published an in-depth review detailing novel therapeutic targets for T2DM, mechanisms of drug action, and corresponding hypoglycemic efficacy. It involves innovation with traditional insulin and a host of other new drugs in the pipeline.

Current status of treatment development of T2DM

In recent years, the prevalence of T2DM has been increasing rapidly worldwide, which has become a serious public health problem worldwide. The short-term goal of T2DM treatment is to control hyperglycemia, so hypoglycemic therapy is the main treatment for T2DM patients. In addition, healthy lifestyle intervention combined with other drugs to prevent complications related to diabetes treatment will help improve the quality of life and prolong the life of patients with T2DM.

It is noteworthy that along with the successful application of a large number of innovative treatments, such as continuous glucose monitoring, insulin pumps, oral hypoglycemic sodium-glucose co-transport protein 2 (SGLT2) inhibitors, and injectable glucagon-like peptide-1 (GLP-1) agonists, the proportion of patients with good glycemic management has not increased as expected, which may be partly influenced by the accessibility of drugs, patient education, and patient motivation. This may be partly influenced by factors such as drug accessibility, patient education and patient motivation, and innovation in treatment by improving the efficacy of glucose-lowering drugs and reducing serious drug-related side effects (such as weight gain and diabetic hypoglycemia) may help to overcome the current treatment dilemma of T2DM.

Hot Topics in T2DM Treatment Frontiers

Innovations in Insulin Formulation

Although this year marks the 100th anniversary of the discovery of insulin, scientists have not yet stopped exploring insulin dosage forms, injection devices, efficacy and safety.

Icodec insulin is a new long-acting basal insulin analogue that binds tightly but reversibly to albumin to continuously, slowly and steadily lower blood glucose. Based on its concentrated formulation, icodec insulin can be administered once a week by injection to patients with T2DM and is similar to once-daily insulin U100 in terms of glycemic control and safety.

In terms of "smart" delivery of insulin, recent discoveries include insulin analogs with a sugar-linked structure (e.g. MK-2640) and glucose-responsive subcutaneous insulin delivery devices. The former can bind to insulin receptors to exert hypoglycemic effects, or bind to mannose receptors to cause its own degradation and clearance; the latter is based on glucose-responsive vesicles or phenylboronic acid-glucose complex gel microspheres, which can regulate insulin release during hyperglycemia. "Smart insulin" is the future direction of insulin development, but it is still in the early exploration stage.

Challenge the New Force of Insulin Resistance

Adiponectin, a protein secreted by adipocytes, is closely associated with insulin resistance and obesity. In vivo and in vitro experiments have confirmed that adiponectin has anti-atherosclerotic, anti-diabetic, anti-inflammatory effects, and can prevent the progression of diabetes and cardiovascular diseases. We note that several studies targeting Adiponectin and its derivatives (e.g., PPARγ agonists) are currently underway, with varying levels of glycemic reduction observed with different therapies, but these studies are currently in the preclinical stage.

Fibroblast growth factor (FGF)-21 is mainly secreted by the liver and has long been recognized as an endocrine factor regulating fat and glucose metabolism and regulating insulin sensitivity. It is worth mentioning that the secretion of Adiponectin is mainly activated by FGF-21 and its derivatives. Preclinical studies have shown that exogenous FGF-21 can still reduce blood glucose and body weight in obese and insulin-resistant mice. At present, FGF21 and similar structural drugs (such as LY2405319, PF-05231023, BMS-986036 and AKR-001, etc.) have also shown efficacy in phase 1 and phase 2 clinical trials. Although the efficacy results in human and animal models are different, future exploration is expected.

The article points out that in addition to adiponectin and hepatocyte factor FGF-21, small molecule oral GLP-1 receptor agonists, GLP-1 pro-secretory agents and imeglimin, an innovative drug targeting mitochondrial bioenergetics, are also promising in the treatment of T2DM. At the same time, how to avoid side effects or complications associated with the treatment of T2DM is also a challenge to be faced in the future.

GLP-1 agonists belong to the entero-insulin class of drugs, which can bring additional benefits beyond glucose-lowering such as weight loss, lower systolic blood pressure, and improved lipid profile, and the results of studies such as LEADER, SUSTAIN-6, and REWIND suggest that the use of GLP-1 agonists may prevent kidney-related adverse events in patients with T2DM.

Small-molecule oral GLP-1 agonists will theoretically be more easily absorbed by diabetic patients. In preclinical animal models, small-molecule oral GLP-1 receptor agonists modulate islet β-cell cAMP levels in a glucose-dependent manner and stimulate insulin secretion and lower blood glucose, and the pharmacokinetic study data of such drugs in human trials are worth looking forward to.

In addition, GLP-1 agonists can act by stimulating the secretion of GLP-1 from intestinal L cells, and preclinical studies have shown that GLP-1 agonist drugs can improve abnormal glucose tolerance in test animals.

Imeglimin, a small molecule drug synthesized with metformin as a precursor, is currently approved in Japan for the treatment of T2DM. Imeglimin is expected to exert its blood glucose lowering effects by improving insulin secretion from pancreatic β-cells, enhancing insulin sensitivity, preventing high-fat diet-induced insulin resistance, and inhibiting hepatic gluconeogenesis.

In addition, changes in the intestinal hormonal milieu brought about by bariatric surgery offer the possibility of the application of single molecule peptides targeting multiple receptors (GLP-1, glucose-dependent insulinotropic polypeptide, glucagon or peptide YY). Therefore, dual or triple single-molecule peptide agonists targeting GLP-1 and other targets may also become a hot spot for future research.

Innovative therapies with limitations in application

Based on current evidence, peroxisome proliferator-activated receptors (PPARs) agonists, glucagon receptor agonists, glucokinase activators, and inhibitors of the glucocorticoid metabolizing enzyme 11β-hydroxysteroid dehydrogenase (11β-HSD) are unlikely to eventually be used in the clinic because the evidence of benefit and risk is not promising.

Prospective individualized treatment of T2DM

The article suggests that in the future, the choice of glucose-lowering drugs for patients with T2DM may depend on their specific phenotype (e.g., based on anthropometric or laboratory parameters) or even genotypic characteristics. Cluster analysis showed that the same subgroup of T2DM patients not only showed different susceptibility to specific diabetic complications, but also different disease progression in this group.

This suggests that the main pathophysiological mechanisms of disease onset may differ between patients in the same subgroup, and therefore the optimal treatment strategy may need to be different as well. In the future, genetic characteristics based on T2DM patients may predict the therapeutic efficacy of specific hypoglycemic agents as well as the occurrence of adverse events.

Conclusion

At present, scientists are trying to provide better glycemic control therapy for diabetic patients through a variety of innovative mechanisms, some of which are likely to eventually succeed and change the status of treatment and management of T2DM.

Smart insulin delivery agents, drugs that target impaired mitochondrial function (such as imeglimin), GLP-1 secretagogues, small-molecule oral GLP-1 receptor agonists, and single-molecule peptides that can simultaneously interact with multiple endocrine hormone receptors, the authors' team noted. It is expected to provide great help for improving blood glucose and weight control in patients with T2DM. In addition, therapies to improve risk factors and comorbidities associated with T2DM may become increasingly important in addition to glycemic control.

Huateng Pharma has three SGLT-2 inhibitors in development: Dapagliflozin, Canagliflozin and Empagliflozin that used to treat type 2 diabetes. We can also provide CDMO services with sufficient capacity.