Sitagliptin pharmacology
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Sitagliptin Mechanism of Action and DPP-4 Inhibition
Sitagliptin is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which plays a key role in glucose regulation. By inhibiting DPP-4, sitagliptin increases the levels of active incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These hormones enhance insulin secretion and suppress glucagon release in a glucose-dependent manner, leading to improved blood sugar control in patients with type 2 diabetes mellitus (T2DM) 124. Sitagliptin’s action is primarily through the stabilization of these incretins, which results in increased insulin release after meals and reduced glucagon secretion from pancreatic alpha cells 124.
Pharmacokinetics and Dosing of Sitagliptin
Sitagliptin is well absorbed when taken orally, with a bioavailability of about 87%. It undergoes minimal hepatic metabolism and is mainly excreted unchanged in the urine (about 79-80%) 12. The drug has a terminal half-life of 8 to 14 hours, supporting a once-daily dosing regimen. Its pharmacokinetics are not significantly affected by food, and renal clearance is consistent across different doses . Doses of 100 mg daily are effective in inhibiting DPP-4 activity by more than 80% for 24 hours, resulting in a twofold increase in active GLP-1 levels 12.
Clinical Efficacy and Safety Profile
In clinical studies, sitagliptin has shown significant reductions in glycosylated hemoglobin (HbA1c) when used alone or in combination with other antidiabetic agents such as metformin or pioglitazone. The reduction in HbA1c ranges from about 0.5% to 0.9% depending on the treatment combination . Sitagliptin also improves markers of beta-cell function and is generally well tolerated, with a low risk of hypoglycemia and no significant weight gain 12.
Additional Pharmacological Effects: Anti-Inflammatory and Antioxidant Actions
Beyond its glucose-lowering effects, sitagliptin exhibits anti-inflammatory properties. It reduces the expression of proinflammatory cytokines and markers such as TNF-α, IL-6, and C-reactive protein, and suppresses the activity of inflammatory pathways like NF-κB 678910. Sitagliptin also enhances antioxidant defenses by activating the Nrf2 signaling pathway, which helps protect tissues from oxidative stress and inflammation 7910. These effects may contribute to its protective roles in conditions such as hepatic fibrosis, acute lung injury, and neuroinflammation 78910.
Novel Targets and Broader Therapeutic Potential
Recent research suggests that sitagliptin may also interact with targets beyond DPP-4, such as the angiotensin-converting enzyme 2 (ACE2). This interaction could have implications for improving insulin resistance, reducing oxidative stress, and modulating the ACE2/Ang-(1-7)/Mas receptor axis, which is relevant in both diabetes and conditions like COVID-19 . Additionally, sitagliptin has shown potential in reducing the survival and stemness of glioma cells and enhancing the effectiveness of chemotherapy in cancer models, indicating possible repurposing opportunities .
Conclusion
Sitagliptin is a DPP-4 inhibitor with well-established pharmacological properties for the management of type 2 diabetes. It effectively improves glycemic control by enhancing incretin hormone activity, is well tolerated, and has a favorable safety profile. Beyond its antidiabetic effects, sitagliptin demonstrates anti-inflammatory, antioxidant, and potential antifibrotic actions, and may interact with novel targets such as ACE2. These additional properties suggest broader therapeutic potential for sitagliptin in metabolic, inflammatory, and possibly oncological diseases.
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