Saxagliptin

Saxagliptin is an Antidiabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-4 (DPP-4) inhibitors.

Saxagliptin is approved for treating type 2 diabetes mellitus in adults, helping to control blood sugar levels. It is used to improve glycemic control by blocking the enzyme DPP-4. It works by raising the amounts of naturally occurring compounds called incretins, which help to control blood sugar.

Saxagliptin is rapidly absorbed from the gastrointestinal tract and reaches peak plasma levels within two hours. The liver is the chief site of drug metabolism, and its metabolites are eliminated in the urine and faeces. The half-life of elimination is around 2.5 hours.

Saxagliptin's most common side effects include hypoglycemia, headache, upper respiratory tract infection, urinary tract infection (UTI), and peripheral oedema.

Saxagliptin is available in the form of Oral Tablets.

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Saxagliptin is an Antidiabetic Agent belonging to the pharmacological class of Dipeptyl peptidase-4 (DPP-4) inhibitors.

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), two incretin hormones, are released at increased concentrations into the bloodstream in response to meals by the small intestine. Although the DPP4 enzyme immediately inactivates them, these hormones stimulate insulin release from pancreatic beta cells in a glucose-dependent manner. Additionally, GLP-1 reduces hepatic glucose synthesis by decreasing glucagon release from pancreatic alpha cells. GLP-1 concentrations are lower; however, the insulin response to GLP-1 still exists in type 2 diabetic individuals. In patients with type 2 diabetes mellitus, saxagliptin, a competitive DPP4 inhibitor, delays the inactivation of incretin hormones by raising their blood levels and lowering fasting and postprandial glucose concentrations in a glucose-dependent manner.

Saxagliptin is available in the form of Oral Tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily, generally with or without a meal.

Treatment of Type 2 diabetes mellitus

Saxagliptin can be used to treat Diabetes mellitus type 2 treatment. t helps improve blood sugar control by raising the levels of incretin hormones in the body, which stimulate insulin release and reduce the amount of glucose produced by the liver. Usually, Saxagliptin is used along with a healthy diet and regular exercise.

In Treatment of Type 2 diabetes mellitus

Saxagliptin helps increase the amount of insulin produced after a meal and stops the body from releasing too much glucose (sugar) into the blood. This way, it lowers the blood glucose levels in the body. It often only causes a single frequent adverse effect and is taken once each day.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus, it is either used as a monotherapy or in combination with other antihyperglycemic agents, including metformin, sulfonylureas, pioglitazone, or insulin, when those alone do not provide adequate glycemic control.

Orally: Saxagliptin is available as a tablet that can be taken orally. Saxagliptin should be taken on an empty stomach or with food. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 2.5mg, 5mg

Saxagliptin is available in the form of Oral Tablets.

Dose Adjustment in Adult Patients:

Diabetes Mellitus Type 2: 2.5-5 mg PO qDay

Dosing Considerations

Combination therapy: When used in conjunction, sulfonylurea or other insulin secretagogues may require a lower dose.

Strong CYP450 3A4/5 inhibitors shouldn't be coadministered with more than 2.5 mg PO daily.

Saxagliptin should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

While taking Saxagliptin, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Avoid consuming sugary foods and beverages, including cereals, snacks, and sweetened beverages, as they can lead to rapid spikes in blood glucose.

It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

Saxagliptin may be contraindicated in documented hypersensitivity (e.g., anaphylaxis, angioedema, exfoliative skin conditions)

• Bullous Pemphigoid: Patients frequently recover with topical or systemic immunosuppressive therapy and stopping the DPP-4 inhibitor. Blisters or erosions that appear while a patient is receiving therapy should be reported by the patient. Stop therapy if bullous pemphigoid is suspected, and refer the patient to a dermatologist for a diagnosis with appropriate care.
• Severe and Disabling Arthralgia: Patients on DPP4 inhibitors have reported postmarketing cases of severe, incapacitating arthralgia. The duration from the start of medication therapy till the development of symptoms ranged from one day to years. When the drug was stopped, the signs of the patients improved. Continuing the same medication or a different DPP4 inhibitor caused symptoms to return in a small number of individuals. Consider DPP4 inhibitors a potential cause of severe joint discomfort and stop taking the medication if necessary.
• Heart Failure: In a cardiovascular trial (SAVOUR), more individuals on saxagliptin (3.5%) than placebo (2.8%) were hospitalised for heart failure. Participants in this study had known ASCVD or multiple risk factors. The risk was increased for the saxagliptin group (Hazard Ratio: 1.27). No matter the course of therapy, there was an increased risk for those with a history of heart failure or renal impairment. Before beginning treatment, weigh the advantages and disadvantages of saxagliptin in high-risk heart failure patients. Observe for heart failure symptoms, inform patients of the indicators, and report immediately. If heart failure occurs, take standard precautions and think about stopping saxagliptin.
• Pancreatitis: Patients should be monitored for pancreatitis symptoms and signs after starting saxagliptin. Saxagliptin should be stopped as soon as pancreatitis is detected, and the proper care should be started. The risk of developing pancreatitis while using saxagliptin is unclear in people with a history of the condition.
• There is an increased risk of hypoglycemia when combined with insulin or sulfonylurea. Sulfonylurea and/or insulin dosages should be regularly monitored and adjusted.
• Saxagliptin should be stopped if a significant hypersensitivity response is detected. You should also look for any further possible reasons and start a different diabetes treatment plan. Because it is uncertain if individuals who have already had angioedema from another dipeptidyl peptidase-4 (DPP4) inhibitor would be more susceptible to experiencing it with saxagliptin, it is advisable to exercise caution while treating such patients.

It is unsafe to consume Saxagliptin with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Saxagliptin in breastfeeding.

It is generally considered safe to use Saxagliptin during pregnancy.

The adverse reactions related to Saxagliptin can be categorized as

• Common Adverse Effects: Urinary tract infection, headaches, and nasopharyngitis.
• Less Common Adverse Effects: Hypoglycemia, Gastroenteritis, allergic reactions, Peripheral oedema, and pancreatitis.
• Rare Adverse Effects: Hypersensitivity, severe joint pain, bullous pemphigoid

Reports on Postmarketing

Anaphylactic responses, angioedema, and exfoliative skin disorders are signs of hypersensitivity reactions.

Pancreatitis

severe and debilitating arthralgia

Pemphigoid bullous

The clinically relevant drug interactions of Saxagliptin are briefly summarized here.

• Insulin or Insulin-Secreting Medications: Combining Saxagliptin with these medications may increase the risk of hypoglycemia. Dose adjustments may be necessary.
• Digoxin: Saxagliptin can increase the levels of digoxin in the blood. Monitoring digoxin levels and adjusting the dose may be needed.
• Thiazolidinediones (TZDs): Co-administration of Saxagliptin with TZDs may lead to fluid retention and heart failure. Close monitoring of fluid balance is essential.
• Sulfonylureas: Co-administration with sulfonylureas can also elevate the risk of hypoglycemia. Adjustments in medication dosage may be required.

The most common side effects of Saxagliptin include:

• Infection of the upper respiratory tract
• Infection of the urinary tract
• Headache
• Peripheral oedema
• Low blood sugar levels combined with sulphonylurea or insulin are known as hypoglycemia.

• Pregnancy

Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

There is insufficient data on saxagliptin's potential to cause severe birth abnormalities or miscarriages in pregnant women. Uncontrolled diabetes during pregnancy poses risks to both the mother and the foetus.

When saxagliptin was given to pregnant rats, pregnant rabbits, and lactating rats during the prenatal and postnatal periods and organogenesis, there were no adverse developmental consequences not caused by maternal toxicity.

Women with pre-gestational diabetes who have an HbA1c higher than seven are estimated to be at a background risk of 6% to 10% for severe birth abnormalities, while women with a HbA1c higher than ten have been reported to be at a background risk of up to 20% to 25%. It is uncertain what the suggested population's background miscarriage risk is. In clinically recognised pregnancies, the background risks of significant birth abnormalities and miscarriage are estimated to be 2% to 4% and 15% to 20%, respectively, in the general population of the United States.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, stillbirth, and delivery complications. Significant birth abnormalities, stillbirths, and macrosomia-related morbidity are more likely in foetuses with poorly managed diabetes.

Animal Data

Saxagliptin was given to pregnant rats and rabbits throughout the study's organogenesis phase, corresponding to the first trimester of a human pregnancy. Based on AUC, no adverse developmental effects were seen in either species at exposures 1503 and 152 times the therapeutic dosage of 5 mg in rats and rabbits, respectively. Following dosage in pregnant rats, saxagliptin passes through the placenta and enters the foetus.

Based on AUC, Saxagliptin was given to maternal rats in prenatal and postnatal development research from gestation day 6 to lactation day 21 at doses up to 470 times the 5 mg therapeutic dosage. No adverse developmental effects were observed.

• Nursing Mothers

There is no information on saxagliptin's presence in human milk, its effects on nursing infants, or its impact on milk production.

The milk of nursing rats contains saxagliptin. Along with the mother's clinical requirement for saxagliptin and any potential adverse effects of saxagliptin or the underlying maternal disease on the breastfed newborn, the developmental and health advantages of nursing should be considered.

• Pediatric Use

As per FDA, safety and effectiveness in the pediatric population under 18 years of age have not been established.

• Geriatric Use

In the seven double-blind, controlled clinical safety and effectiveness studies of saxagliptin, a total of 4,751 (42.0%) of the 11,301 patients randomised to saxagliptin were 65 years of age or older, and 1,210 (10.7%) were 75 years of age or older. Between participants over 65 and younger people, there were no general differences in safety or efficacy. Although this clinical experience has not revealed any variations in reactions between senior and younger patients, it cannot be ruled out that certain older people may be more sensitive.

Saxagliptin and its active metabolite are eliminated vai the renal pathway. t is essential to use caution when determining dosage for senior patients based on renal function since older patients are more likely to have diminished renal function.

Dose Adjustment in Kidney Impairment Patients:

CrCl 50 mL/min: No dosage adjustment is necessary.

CrCl 50 mL/min: 2.5 mg PO qDay maximum; required for hemodialysis patients with ESRD: provided post-dialysis, not to exceed 2.5 mg PO qDay.

Peritoneal dialysis for ESRD: Unknown

Dose Adjustment in Hepatic Impairment Patients:

There are no specific dosage adjustments provided.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Saxagliptin.

Overconsumption of Saxagliptin may lead to hypoglycemia (low blood sugar), leading to symptoms such as sweating, shakiness, confusion, fast heartbeat, and fainting.

Management

There is no specific antidote or treatment for excessive intake of Saxagliptin. However, immediate medical attention is essential. Saxagliptin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

In severe cases, especially if the person is unconscious or unable to swallow, intravenous glucose/ glucagon or carbohydrate-containing substances may be necessary.

Management typically involves supportive measures like intravenous fluids, electrolyte replacement, and symptomatic treatment such as antiemetic medications for nausea and vomiting.

The patient will continue to be monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

Saxagliptin causes GLP-1 and GIP levels to increase two to three times after treatment. Less systemic adverse effects are experienced due to its particular DPP-4 inhibition. For a total 24-hour period, saxagliptin blocks the DPP-4 enzyme. Additionally, it reduced glucagon levels and raised pancreatic beta cell release of glucose-dependent insulin. It has an IC50 of 0.5 nmol/L or half the maximum inhibitory concentration and it has shown that there was no clinically significant prolongation of the QTc interval by saxagliptin.

Cardiac Electrophysiology

Saxagliptin was not linked to a clinically significant prolonging of the QTc interval or heart rate at daily dosages up to 40 mg (8 times the MRHD) in a randomised, double-blind, placebo-controlled, 4-way crossover, active comparator research involving 40 healthy people and moxifloxacin.

Pharmacokinetics:

Absorption

After a 5 mg once-daily dosing, saxagliptin's median time to maximum concentration (Tmax) was 2 hours, but its active metabolites were 4 hours. Saxagliptin's Tmax increased by around 20 minutes after administration with a high-fat meal compared to when it was given under fasting settings. Compared to fasted settings, saxagliptin's AUC increased by 27% when administered with a meal. With or without meals, saxagliptin can be issued.

Peak plasma time: 2hr (saxagliptin); 4 hr (5-hydroxy saxagliptin)

Distribution

Saxagliptin and its active metabolite are very limited in the way of in vitro protein binding in human serum. The distribution of saxagliptin is thus not anticipated to be affected by variations in blood protein levels in various disease conditions (such as renal or hepatic impairment).

Vd: negligible

Metabolism

Cytochrome P450 3A4/5 (CYP3A4/5) is primarily responsible for the metabolism of saxagliptin. A DPP4 inhibitor that is also saxagliptin's primary metabolite has half the potency of the original drug. As a result, saxagliptin and its active metabolite's pharmacokinetics will be affected by potent CYP3A4/5 inducers and inhibitors.

Hepatic by CYP450 3A4/5 to an active metabolite (50% potency of parent compound)

Excretion

Saxagliptin is eliminated via the hepatic and renal pathways. A single 50 mg dosage of 14C-saxagliptin excreted 24%, 36%, and 75% of the dose as saxagliptin, its active metabolite, and total radioactivity, respectively, in the urine. The percentage of the saxagliptin dosage excreted in bile and/or unabsorbed medication from the gastrointestinal system was 22% of the supplied radioactivity in the faeces.

Half-life (elimination): 2.5 hr (saxagliptin); 3.1 hr (5-hydroxy saxagliptin)

Renal clearance: 7.2 L/hr

Excretion: Urine (75%); feces (22%)

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Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two-year trials on CD-1 mice and Sprague-Dawley rats were used to assess carcinogenicity. Based on AUC, saxagliptin did not increase the frequency of tumours in mice given oral doses of 50, 250, and 600 mg/kg up to 870 times (for males) and 1,165 times (for females) the therapeutic dosage of 5 mg/day. Based on AUC, saxagliptin did not increase the incidence of tumours in rats given oral doses of 25, 75, 150, and 300 mg/kg up to 355 (for males) and 2,217 (for females) times the therapeutic dosage of 5 mg/day.

Mutagenesis

Several genotoxicity studies, including the Ames bacterial mutagenesis, human and rat lymphocyte cytogenetics, rat bone marrow micronucleus, and DNA repair assays, revealed that saxagliptin was neither mutagenic nor clastogenic. In an Ames bacterial experiment, the saxagliptin active metabolite was not mutagenic.

Impairment of Fertility

Based on AUC, saxagliptin administration to rats did not impact ovarian function or the capacity to raise a litter at exposures up to 603 and 776 times the therapeutic dosage of 5 mg for males and females, respectively.

• Patients should be informed that severe pancreatitis has been linked to using saxagliptin after the drug's first approval. Before starting saxagliptin, patients should be questioned about any other pancreatitis risk factors they may have, such as alcoholism, a history of pancreatitis, gallstones, or hypertriglyceridemia.
• Patients should be advised to consult a healthcare professional if they have any odd symptoms or if any current symptoms persist or worsen.
• The risks, benefits, and alternatives of saxagliptin should be explained to patients. They must also comprehend the significance of adhering to dietary recommendations, exercising regularly, monitoring the sugar levels in their blood, and controlling hypo and hyperglycemia. Medication requirements may vary under stressful situations (fever, injury, infection, surgery), requiring quick medical attention.
• Patients should be informed that the long-term administration of saxagliptin postmarketing has been associated with significant allergic (hypersensitivity) events, including angioedema, anaphylaxis, and exfoliative skin disorders.
• Emphasised on the warning signs and symptoms of heart failure to patients. Before starting saxagliptin, individuals should be questioned about their history of heart failure and other risk factors, such as moderate to severe renal impairment.

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