Saxagliptin; Uses, Dosage, Side Effects, Drug Interactions Saxagliptin is a potent, selective and competitive, cyanopyrrolidine-based, orally bioavailable inhibitor of dipeptidyl peptidase 4 (DPP-4), with hypoglycemic activity. Saxagliptin is metabolized into an, although less potent, active mono-hydroxy metabolite. Saxagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor which is used in combination with diet and exercise in the therapy of type 2 diabetes, either alone or in combination with other oral hypoglycemic agents. Saxagliptin is a relatively new medication and has yet to be implicated in causing clinically apparent liver injury. Saxagliptin is an oral hypoglycemic (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Saxagliptin (rINN) is an orally active hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. In April 2016, the U.S. FDA added a warning about increased risk of heart failure. This was based on data in an article that concluded “DPP-4 inhibition with saxagliptin did not increase or decrease the rate of ischemic events, though the rate of hospitalization for heart failure was increased. Although saxagliptin improves glycemic control, other approaches are necessary to reduce cardiovascular risk in patients with diabetes. Mechanism of Action of Saxagliptin 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 the 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. or 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 the AD. The present study examines the efficacy of Saxagliptin, a DPP-4 inhibitor in a streptozotocin(STZ) induced rat model of the 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 was 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 behavioral deficits and pathology observed in AD Indications of Saxagliptin Type 2 Diabetes Mellitus relatively modest risk of hypoglycemia, and does not cause weight gain Treatment of type 2 diabetes mellitus to improve glycemic control in combination with other agents or as monotherapy. Saxagliptin improved mean HbA1c levels (relative to placebo) in a 24-week trial in people with type 2 diabetes. Combination therapy with saxagliptin and metformin was more effective than saxagliptin or metformin monotherapy. When the relative benefits of increasing the dose of a sulfonylurea or adding saxagliptin were assessed in a study of 768 patients, combination treatments were shown to have a significantly greater impact on fasting blood glucose than increasing the tested glibenclamide dose alone Treatment of type 2 diabetes mellitus to improve glycemic control in combination with other agents or as monotherapy. Onglyza is indicated in adult patients aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control |as monotherapy In patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance As dual oral therapy in combination with metformin, when metformin alone, with diet and exercise, does not provide adequate glycaemic control. A sulphonylurea, when the sulphonylurea alone, with diet and exercise, does not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate. A thiazolidinedione, when the thiazolidinedione alone with diet and exercise, does not provide adequate glycaemic control in patients for whom use of a thiazolidinedione is considered appropriate. As triple oral therapy in combination with metformin plus a sulphonylurea when this regimen alone, with diet and exercise, does not provide adequate glycaemic control. |as combination therapy with insulin (with or without metformin), when this regimen alone, with diet and exercise, does not provide adequate glycaemic control. Stern, fixed-dose combination of saxagliptin and dapagliflozin, is indicated in adults aged 18 years and older with type 2 diabetes mellitus to improve glycaemic control when metformin and/or sulphonylurea (SU) and one of the monocomponents of Qtern do not provide adequate glycaemic control, when already being treated with the free combination of dapagliflozin and saxagliptin. Contra-Indications of Saxagliptin Low blood sugar Pituitary hormone deficiency Decreased Function of the Adrenal Gland Inadequate Vitamin B12 Excess Body Acid Extreme Loss of Body Water The habit of Drinking Too Much Alcohol Alcohol Intoxication Heart Attack Suddenly serious symptoms of heart failure Liver Problems Recent operation Fever Shock Severe Vomiting Severe Diarrhea Serious Lack of Oxygen in the Blood Weakened Patient Injury Sepsis Syndrome X-Ray Study with Intravenous Iodine Contrast Agent Chronic kidney disease stage 3B (moderate) Chronic kidney disease stage 4 (severe) Chronic kidney disease stage 5 (failure) Kidney disease with a likely reduction in kidney function Pancreatitis Side Effects of Saxagliptin Most common physical weakness (asthenia) diarrhea gas (flatulence) symptoms of weakness, muscle pain (myalgia) upper respiratory tract infection low blood sugar (hypoglycemia) abdominal pain (GI complaints), lactic acidosis (rare) low blood levels of vitamin B-12 nausea,vomiting chest discomfort chills, dizziness bloating/abdominal distention constipation heartburn More common Abdominal or stomach discomfort cough or hoarseness decreased appetite diarrhea fast or shallow breathing fever or chills general feeling of discomfort lower back or side pain muscle pain or cramping painful or difficult urination Less common Abnormal stools bad, unusual, or unpleasant (after) taste change in taste difficulty with moving discoloration of the fingernails or toenails flu-like symptoms joint pain rash a runny nose sneezing stuffy nose swollen joints Drug Interactions of Saxagliptin Saxagliptin may interact with following drugs, supplements & may decrease the efficacy of the drug angiotensin-converting enzyme inhibitors (ACEIs; captopril, enalapril, ramipril) alcohol antipsychotic medications (e.g., chlorpromazine, haloperidol, olanzapine, birth control pills bupropion atorvastatin atypical antipsychotics (e.g., aripiprazole, clozapine, olanzapine; quetiapine, risperidone) “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole) barbiturates (e.g., pentobarbital, phenobarbital) crizotinib cyclosporine dabrafenib corticosteroids (e.g., dexamethasone, prednisone) diabetic drugs (e.g., glyburide, insulin, repaglinide, sitagliptin) digoxin diuretics (e.g., furosemide, hydrochlorothiazide) HIV protease inhibitors (e.g., atazanavir, indinavir, ritonavir, saquinavir) phenytoin quinolone antibiotics (e.g., levofloxacin, moxifloxacin) selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, sertraline paroxetine, trimethoprim vancomycin verapamil warfarin Pregnancy & Lactation of Saxagliptin FDA Pregnancy Category B Pregnancy This medication is not recommended for use during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately. Lactation It is not known if saxagliptin passes into breast milk. If you breastfeeding-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding. References DrugBank http://www.drugbank.ca/drugs/DB06335 http://www.drugbank.ca/drugs/DB06335#targets http://www.drugbank.ca/drugs/DB06335#enzymes http://www.drugbank.ca/drugs/DB06335#transporters EPA DSStox https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID7048580 https://www.webmd.com/drugs/2/drug-154914/saxagliptin-metformin-oral/details/list-contraindications https://online.epocrates.com/u/1035465/Onglyza/Contraindications+Cautions Human Metabolome Database (HMDB) http://www.hmdb.ca/metabolites/HMDB0015634 ClinicalTrials.gov https://clinicaltrials.gov/ LiverTox https://livertox.nlm.nih.gov/Saxagliptin.htm NCIt https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C75983 https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C75984 EU Community Register of Medicinal Products https://ec.europa.eu/health/documents/community-register/html/h545.htm https://ec.europa.eu/health/documents/community-register/html/h1108.htm https://ec.europa.eu/health/documents/community-register/html/h731.htm HSDB https://toxnet.nlm.nih.gov/cgi-bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+361442-04-8 WHO ATC https://www.whocc.no/atc/ https://www.whocc.no/atc_ddd_index/ European Chemicals Agency (ECHA) https://echa.europa.eu/information-on-chemicals/cl-inventory-database/-/discli/details/173742 European Chemicals Agency – ECHA https://www.echa.europa.eu/web/guest/information-on-chemicals/cl-inventory-database/-/discli/details/173742 FDA Medication Guides https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/200678s018lbl.pdf#page=47 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209091s000lbl.pdf#page=37 https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022350s018lbl.pdf#page=31 FDA Orange Book https://www.fda.gov/Drugs/InformationOnDrugs/ucm129662.htm PubMed Health http://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0012084/ Show More