ONGLYZA 5MG

Indications

• Type 2 diabetes mellitus as monotherapy
• Type 2 diabetes mellitus in combination with metformin
• Type 2 diabetes mellitus in combination with insulin or other antidiabetic medications

Mechanism of action

Saxagliptin works by inhibiting the DPP-4 enzyme, which is responsible for the degradation of incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). By inhibiting DPP-4, saxagliptin increases the levels of active GLP-1 and GIP, resulting in enhanced insulin secretion from pancreatic beta cells and decreased glucagon secretion from alpha cells. This dual action helps to lower blood glucose levels effectively.

Pharmacodynamics

Following administration, saxagliptin results in a significant increase in GLP-1 and GIP levels, up to 2- to 3-fold. The drug exhibits selective inhibition of DPP-4 enzyme activity for approximately 24 hours, which supports its once-daily dosing regimen. Saxagliptin decreases glucagon concentrations and enhances glucose-dependent insulin secretion from pancreatic beta cells, contributing to improved glycaemic control in patients with type 2 diabetes. It has a low potential for systemic side effects due to its selectivity for DPP-4 inhibition.

Pharmacokinetics

Saxagliptin has a molecular formula of C18H25N3O2. It is absorbed rapidly after oral administration, with peak plasma concentrations typically occurring within 2 hours. The drug is primarily eliminated through renal pathways, with dose adjustments recommended for patients with renal impairment. The half-life of saxagliptin is approximately 2.5 hours, and it forms active metabolites that also contribute to its antidiabetic effects. Saxagliptin does not significantly prolong the QTc interval.

Contra-indications

• Hypersensitivity to saxagliptin or any of its components
• History of pancreatitis

Adverse effects

• Headache
• Upper respiratory tract infection
• Nausea
• Diarrhea
• Constipation
• Hypoglycaemia when used with other antidiabetic agents

Interactions

• Antifungals (azoles) may increase saxagliptin exposure
• Cobicistat may increase saxagliptin exposure
• Crizotinib may increase saxagliptin exposure
• Grapefruit juice may increase saxagliptin exposure
• Idelalisib may increase saxagliptin exposure
• Imatinib may increase saxagliptin exposure
• Letermovir may increase saxagliptin exposure
• Mitotane may decrease saxagliptin exposure
• Nilotinib may increase saxagliptin exposure

Precautions

• Monitor renal function before treatment and periodically thereafter
• Use with caution in patients with a history of pancreatitis
• Consider potential for hypoglycaemia when combined with other antidiabetic medications

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether saxagliptin is excreted in human milk. Caution should be exercised when administered to a nursing woman.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Tablets 2.5 mg
• Tablets 5 mg

Mechanism of action

Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor antidiabetic for the treatment of type 2 diabetes. DPP-4 inhibitors are a class of compounds that work by affecting the action of natural hormones in the body called incretins. Incretins decrease blood sugar by increasing consumption of sugar by the body, mainly through increasing insulin production in the pancreas, and by reducing production of sugar by the liver. [Bristol-Myers Squibb Press Release] DPP-4 is a membrane associated peptidase which is found in many tissues, lymphocytes and plasma. DPP-4 has two main mechanisms of action, an enzymatic function and another mechanism where DPP-4 binds adenosine deaminase, which conveys intracellular signals via dimerization when activated. Saxagliptin forms a reversible, histidine-assisted covalent bond between its nitrile group and the S630 hydroxyl oxygen on DPP-4. The inhibition of DPP-4 increases levels active of glucagon like peptide 1 (GLP-1), which inhibits glucagon production from pancreatic alpha cells and increases production of insulin from pancreatic beta cells. Type 2 diabetes (T2D) is one of the major risk factors associated with Alzheimer's disease (AD). Recent studies have found similarities in molecular mechanisms that underlie the respective degenerative developments in the two diseases. Pharmacological agents, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, which increase the level of glucagon-like peptide-1 (GLP-1) and ameliorate T2D, have become valuable candidates as disease modifying agents in the treatment of AD. In addition, endogenous GLP-1 levels decrease amyloid beta (Abeta) peptide and tau phosphorylation in AD. The present study examines the efficacy of Saxagliptin, a DPP-4 inhibitor in a streptozotocin (STZ) induced rat model of AD. Three months following induction of AD by intracerebral administration of streptozotocin, animals were orally administered Saxagliptin (0.25, 0.5 and 1 mg/kg) for 60 days. The effect of the DPP-4 inhibitor on hippocampal GLP-1 levels, Abeta burden, tau phosphorylation, inflammatory markers and memory retention were evaluated. The results reveal an attenuation of Abeta, tau phosphorylation and inflammatory markers and an improvement in hippocampal GLP-1 and memory retention following treatment. This remarkable therapeutic effect of Saxagliptin mediated through DPP-4 inhibition demonstrates a unique mechanism for Abeta and tau clearance by increasing GLP-1 levels and reverses the behavioural deficits and pathology observed in AD. Saxagliptin inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both saxagliptin and its active metabolite (5-hydroxy saxagliptin) are more selective for inhibition of DPP-4 than for DPP-8 or DPP-9. Saxagliptin increases circulating levels of GLP-1 and GIP in a glucose-dependent manner. GLP-1 and GIP stimulate insulin secretion from pancreatic beta-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated). GLP-1 also decreases glucagon secretion from pancreatic alpha-cells, leading to reduced hepatic glucose production. Saxagliptin lowers fasting plasma glucose concentrations and reduces glucose excursions following a glucose load or meal in patients with type 2 diabetes mellitus.

Pharmacodynamics

Post-administration of saxagliptin, GLP-1 and GIP levels rise up to 2- to 3- fold. Because it is very selective of DPP-4 inhibition, there are fewer systemic side effects. Saxagliptin inhibits DPP-4 enzyme activity for a 24-hour period. It also decreased glucagon concentrations and increased glucose-dependent insulin secretion from pancreatic beta cells. The half maximal inhibitory concentration (IC50) is 0.5 nmol/L. Saxagliptin did not prolong the QTc interval to a clinically significant degree.