Saxagliptin; Uses, Dosage, Side Effects, Drug Interactions

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.

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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

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