The Use of Omarigliptin for the Treatment of Type 2 Diabetes

Omarigliptin is a new once-weekly dipeptidyl peptidase-4 (DPP-4) inhibitor developed for the treatment of type 2 diabetes. It is indicated to have favorable effects on glycosylated hemoglobin (HbA1c), fasting and postmeal plasma glucose. It potently but reversibly inhibits DPP-4 enzyme, which prolongs the circulating half-life of glucagon-like peptide-1 that increases insulin secretion in a glucose-dependent manner. Benefiting from glucosedependent insulin secretion, omarigliptin is associated with low risk of hypoglycemia. In contrast to the once-daily dipeptidyl peptidase-4 inhibitors (e.g., alogliptin, linagliptin, sitagliptin), once-weekly omarigliptin can improve patients' adherence and thus achieve optimal therapeutic efficacy. 

Mechanism

Dipeptidyl peptidase-4 (DPP-4) inhibitors to which Omarigliptin belongs are gaining attention as a novel class of antidiabetic agents based on the incretin effect. DPP-4 inhibitors achieve glycemic control through inhibition of the DPP-4 enzyme, which contributes to the rapid degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic polypeptide (GIP), both of which are released after food intake and then exert glucose-lowering effects through stimulating insulin secretion and by pancreatic β-cells and inhibiting glucagon secretion by pancreatic α-cells in a glucose-dependent manner. 

There are two major obstacles in developing GIP-based antidiabetic drugs, including rapid degradation by DPP-4 enzyme and severely low-incretin activity in patients with type 2 diabetes. GLP-1 is also rapidly inactivated by DPP-4 enzyme in the circulation, but its incretin effects are still largely retained in patients with type 2 diabetes. Therefore, DPP-4 inhibitors improve glycemic control in patients with type 2 diabetes in a glucose-dependent manner through inhibiting inactivation of GIP and GLP-1 and then exerting their various biological activities. Inhibition of DPP-4 can also reduce postprandial glucagon secretion from pancreatic α-cells and potentially will increase β-cell mass, induce small islets, and stimulate islet neogenesis.[1]

Insulin Resistance

The study by Sachiko Hattori aimed to determine whether weekly omarigliptin could improve inflammation and insulin resistance more effectively than daily sitagliptin and linagliptin. The results showed that weekly doses of omarigliptin decreased hsCRP and remnant lipoproteins and ameliorated insulin resistance more effectively than daily doses of the other two DPP4 inhibitors.

Daily doses of DPP4 inhibitors do not result in decreased plasma insulin levels or ameliorated insulin resistance in insulin-resistant, hyperinsulinemic individuals. Adipose tissue inflammation and insulin resistance closely correlate in obese persons and blocking systemic or adipose tissue macrophage inflammation improves insulin sensitivity in obese mice. A recent study has shown that DPP4 secreted by hepatocytes in obese mice promotes adipose inflammation and insulin resistance. Omarigliptin is a DPP4 inhibitor with a half-life that enables weekly dosing and it has a wide organ distribution including the liver. Therefore, it might decrease morning glucagon levels more effectively than daily DPP4 inhibitors. However, we did not measure values for glucagon, although it can lower FBG and insulin levels, and consequently decrease HOMA-IR. Omarigliptin might also decrease DPP4 secretion by hepatocytes that might promote adipose inflammation and insulin resistance. We found that omarigliptin tended to reduce liver transaminases, which could be due to reducing the amount of fat in the liver that might overexpress DPP4.

Remnant lipoproteins are thought to be atherogenic, and amounts of various remnant lipoproteins circulating in the blood are reflected in remnant-like particle cholesterol (RLP-C). Thus, high RLP-C levels are believed to constitute a significant independent risk factor for coronary artery disease (CAD) and to predict future coronary events in patients with confirmed CAD, as well as those with type 2 diabetes. The present study found that omarigliptin decreases RLP-C levels, which is closely associated with the amelioration of insulin resistance and inflammation.[2]

References

[1] Tan, Xueying. "Omarigliptin for the treatment of type 2 diabetes." Endocrine 54 1 (2016): 24–31.

[2] Hattori, Sachiko. "Omarigliptin decreases inflammation and insulin resistance in a pleiotropic manner in patients with type 2 diabetes." Diabetology and Metabolic Syndrome 12 (2020): 24.

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