From the Guidelines
Mechanism of Action of Sitagliptin
Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, exerts its mechanism of action by selectively and reversibly inhibiting the enzyme DPP-4, which is responsible for the inactivation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) 1.
- At a typical oral dose of 100mg once daily, sitagliptin increases the levels of active GLP-1 and GIP, leading to:
- Enhanced glucose-dependent insulin secretion
- Decreased glucagon secretion
- Improved glycemic control The inhibition of DPP-4 by sitagliptin has been shown to be dose-dependent, with maximal inhibition achieved at the recommended dose, and its effects on glucose metabolism are evident within 1-2 hours of administration, lasting for up to 24 hours 1.
Key Points
- Sitagliptin is a DPP-4 inhibitor that increases the levels of active GLP-1 and GIP, leading to improved glycemic control 1.
- The inhibition of DPP-4 by sitagliptin is dose-dependent, with maximal inhibition achieved at the recommended dose 1.
- Sitagliptin has a neutral effect on weight and minimal risk of hypoglycemia when used as monotherapy 1.
From the Research
Mechanism of Action of Sitagliptin
The mechanism of action of sitagliptin involves the inhibition of dipeptidyl peptidase-4 (DPP-4) enzyme, which is responsible for the inactivation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) 2, 3, 4, 5.
- Sitagliptin improves glycaemic control by increasing the active forms of these incretin hormones, leading to increased insulin secretion and decreased glucagon secretion 2, 5.
- The inhibition of DPP-4 activity by sitagliptin also reduces the liberation of bioactive dipeptides, such as His-Ala and Tyr-Ala, which are generated from the degradation of GLP-1 and GIP, respectively 3.
- The glucoregulatory action of sitagliptin is associated with increased vagus nerve activity and is diminished in mice lacking GLP-1 or GIP receptors 3.
- Sitagliptin has been shown to restore islet cell mass and function in a rodent model of type 2 diabetes, suggesting a potential role in disease modification 6.
Key Effects of Sitagliptin
- Improves glycaemic control by increasing active incretin hormones and insulin secretion, and decreasing glucagon secretion 2, 4, 5.
- Reduces hemoglobin A1c (HbA1c), fasting and postprandial glucose levels 2, 4, 5.
- Has a low incidence of hypoglycemia, similar to that of a placebo 2, 4.
- Is weight neutral, with no significant effect on body weight 2, 4, 5.