Dapagliflozin + Saxagliptin
Medicine Type :
Allopathy
Allopathy
Prescription Type:
Prescription Required
Prescription Required
Approval :
DCGI (Drugs Controller General of India)
DCGI (Drugs Controller General of India)
Schedule
Schedule H
Schedule H
Pharmacological Class:
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor, Therapy Class:
Antidiabetic Agent, Approved Countries
The United States, Canada, the United Kingdom, Germany, France and Australia.
Dapagliflozin + Saxagliptin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and Dipeptyl Peptidase-IV Inhibitors.
The combination of Dapagliflozin and Saxagliptin is approved for treating type 2 diabetes mellitus. It is combined to help manage blood sugar levels and enhance glycemic control in individuals with this condition.
After oral administration, dapagliflozin is quickly absorbed, mainly in the gastrointestinal tract. Moreover, Saxagliptin is readily absorbed when used orally. Both drugs are metabolized in the liver, mainly by the enzymes CYP3A4 and CYP2D6. Whereas Saxagliptin passes through elimination by both the renal and faecal pathways, dapagliflozin is primarily eliminated unaltered in the urine.
The common side effects of Dapagliflozin + Saxagliptin include upper respiratory tract infection, diarrhoea, genital infection, urinary tract infection, joint pain and hypoglycemia.
Dapagliflozin + Saxagliptin is available as a tablet for convenient administration.
Dapagliflozin + Saxagliptin is available in the United States, Canada, the United Kingdom, Germany, France and Australia.
Dapagliflozin + Saxagliptin is an Anti-diabetic Agent belonging to the pharmacological class of Sodium-glucose transport protein 2 (SGLT2) Inhibitors and Dipeptyl Peptidase-IV Inhibitors.
Dapagliflozin: The sodium-glucose co-transporter 2 (SGLT2), primarily found in the proximal tubule of the nephron, is inhibited by Dapagliflozin. Because SGLT2 supports 90% of the kidneys' reabsorption of glucose, its blockage permits the excretion of glucose in the urine. Patients with type 2 diabetes mellitus may greatly benefit from improved glycemic control and possible weight loss due to this excretion.
Saxagliptin: 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.
Data Onset of action of Dapagliflozin + Saxagliptin typically occurs within 2 hours after administration.
Data duration of action of Dapagliflozin + Saxagliptin effects generally lasts throughout the day.
The Data of Tmax (time to peak concentration) of Dapagliflozin + Saxagliptin generally reached approximately 1-4 hours after oral administration.
The Data of Cmax of Dapagliflozin + Saxagliptin is achieved within 2 hours following oral administration.
Dapagliflozin+ Saxagliptin is available in 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 a meal.
Dapagliflozin + Saxagliptin is used to treat type 2 diabetes to improve glycemic control. It helps lower blood glucose levels by promoting glucose excretion in the urine (Dapagliflozin) and inhibiting the breakdown of incretin hormones (Saxagliptin). This combination is administered to adults with inadequate glucose control through diet and exercise or as an adjunct to other anti-diabetic medications.
Dapagliflozin: For people with type 2 diabetes, the drug Dapagliflozin provides several benefits. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors like Dapagliflozin promote the excretion of extra glucose through the urine, which might improve blood sugar regulation and perhaps result in weight loss. 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.
Saxagliptin: Saxagliptin can be used to treat Diabetes mellitus type 2 treatment. 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.
Dapagliflozin+ Saxagliptin combination provides several therapeutic advantages to patients with type 2 diabetes. It effectively lowers blood glucose levels by dual mechanisms, promoting glycosuria and inhibiting glucose reabsorption in the kidneys. This combination supports weight loss, reduces the risk of hypoglycemia, and improves overall glycemic control.
In people with type 2 diabetes mellitus, Dapagliflozin + saxagliptin is indicated as an additive to diet and exercise to improve glycemic control whose dapagliflozin control is insufficient or if dapagliflozin and Saxagliptin are already being used.
Limitations on Use
Using dapagliflozin plus Saxagliptin to help patients with type 1 diabetes manage their blood sugar is not advised.
Orally: Dapagliflozin + Saxagliptin is a tablet that can be taken orally. It should be taken once daily in the morning with food, and 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.
Tablet: 5 mg dapagliflozin + 5 mg saxagliptin
Tablet: 10 mg dapagliflozin + 5 mg saxagliptin
Dapagliflozin + Saxagliptin is available in the form of Oral tablets.
Dosage Adjustment for Adult Patients
Type 2 Diabetes Mellitus
One tablet (10 mg/5 mg) PO per day in the morning, with or without food
Dosing Considerations
- If a patient has volume depletion, treat them before initiating medication.
- Evaluation of renal function before initiation and regularly afterwards
Limitations on Use
- Not recommended in cases of diabetic ketoacidosis or type 1 diabetes
- Only people who can handle 10 mg of dapagliflozin should use it.
Dapagliflozin + Saxagliptin should be used in treating type 2 diabetes mellitus, along with appropriate dietary restrictions.
Maintain adequate fluid intake to prevent dehydration, especially in hot weather or during physical activity.
Limit alcohol consumption. Excessive alcohol intake can increase the risk of hypoglycemia (low blood sugar) and may affect the effectiveness of these medications.
While taking this combination, it is advised to stay hydrated, consume a rich-balanced diet low in saturated fats and cholesterol—and drink plenty of vegetables, whole grains, fruits, and lean proteins in meals.
The dietary restriction should be individualized as per patient requirements.
Dapagliflozin + Saxagliptin may be contraindicated in the following conditions:-
- History of saxagliptin or dapagliflozin hypersensitivity, including anaphylaxis, oedema, or exfoliative skin problems.
- Patients with end-stage renal illness, moderate-to-severe renal impairment (eGFR <45 mL/min/1.73 m2), or dialysis recipients.
- Pancreatitis: Stop using Dapagliflozin + Saxagliptin immediately if pancreatitis exists.
- Heart Failure: In patients with established risk factors for heart failure, weigh the advantages and disadvantages of Dapagliflozin +Saxagliptin. Monitor out for symptoms and signs in patients.
- Arthralgia: Patients on DPP-4 inhibitors have been observed to experience severe and incapacitating arthralgia. Examine as a potential reason for excruciating joint pain, and stop using the medication if necessary.
- Bullous Pemphigoid: Patients using DPP-4 inhibitors have been reported to experience postmarketing bullous pemphigoid that necessitates hospitalization—instruct patients to report any blisters or erosions that appear. Stop using Dapagliflozin +Saxagliptin if a bullous pemphigoid is suspected.
- Macrovascular Outcomes: No clinical research has provided proof beyond a reasonable doubt that dapagliflozin plus Saxagliptin reduces macrovascular risk.
- Hypotension: Evaluate volume status and treat hypovolemia in individuals with low systolic blood pressure, the elderly, and those on loop diuretics before starting Dapagliflozin + Saxagliptin. Throughout therapy, monitor for any indications or symptoms.
- Ketoacidosis: Regardless of blood glucose level, patients exhibiting signs and symptoms of metabolic acidosis should be evaluated for ketoacidosis. When suspected, stop taking Saxagliptin and Dapagliflozin, get checked out, and be treated promptly. Before starting Saxagliptin + Dapagliflozin, consider taking into account your risk of ketoacidosis. When clinical circumstances are known to increase the risk of ketoacidosis, patients taking Dapagliflozin plus Saxagliptin may need to be closely monitored and have their medication temporarily stopped.
- Saxagliptin has been used to treat serious hypersensitivity responses, including anaphylaxis, angioedema, and exfoliative skin disorders. Postmarketing reports of these reactions have included urticaria and facial oedema. Stop taking Saxagliptin and Dapagliflozin as soon as possible. Check for other possible reasons. Start treating diabetes with alternate methods and with proper monitoring.
- Monitoring and treating genital mycotic infections are advised when necessary.
- Enhanced LDL-C: Adhere to regular care guidelines and continue to monitor.
- Bladder Cancer: Dapagliflozin clinical trials revealed an imbalance in the incidence of bladder malignancies. When a patient has a history of bladder cancer, they should utilize Dapagliflozin + saxagliptin cautiously and not at all in those who have immediate bladder cancer.
- Acute Kidney Injury and Renal Function Impairment: When oral intake is decreased, or fluid loss occurs, think about temporarily stopping. If acute renal injury develops, stop immediately and seek medical attention. Evaluate renal function while receiving treatment.
- Pyelonephritis and Urosepsis: Look for urinary tract infection signs and symptoms and treat quickly if necessary.
- Hypoglycemia: When starting Dapagliflozin + Saxagliptin, consider reducing the dose of the insulin secretagogue or insulin to lessen the risk of hypoglycemia.
- Male and female cases of necrotizing fasciitis of the perineum, often known as Fournier's gangrene, have been reported to be severe and potentially fatal. Evaluate individuals who appear with fever or malaise, erythema, oedema, or pain in the vaginal or perineal area. If suspected, start therapy as soon as possible.
Alcohol Warning
It is unsafe to consume Dapagliflozin + Saxagliptin with alcohol.
Breast Feeding Warning
There is insufficient scientific evidence regarding the use and safety of Dapagliflozin + Saxagliptin in breastfeeding.
Pregnancy Warning
Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus.
Food Warning
Avoid excessive intake of high-sugar or high-fat foods.
The adverse reactions related to Dapagliflozin + Saxagliptin can be categorized as:-
- Common Adverse Effects: Upper respiratory tract infection
- Less Common Adverse Effects: Upper respiratory tract infection, dyslipidemia, headache, diarrhoea, genital infection, renal impairment, hypoglycemia, increased serum inorganic phosphorus, hematocrit, and elevated creatine kinase.
- Rare Adverse Effects: Volume depletion, acute pancreatitis, decreased lymphocyte count, newly diagnosed bladder cancer.
Reports on post-marketing
Saxagliptin
Angioedema, anaphylaxis, and exfoliative skin disorders are instances of hypersensitivity responses.
Pancreatitis
Severe and disabling arthralgia
Bullous Pemphigoid Disease
Rhabdomyolysis
Dapagliflozin
Ketoacidosis
Acute kidney injury and impaired renal function
Urosepsis and pyelonephritis
Rash
Type 1 diabetes individuals suffering from diabetic ketoacidosis
The clinically relevant drug interactions of Dapagliflozin + Saxagliptin are briefly summarized here:
- Diuretics (e.g., Furosemide): Concomitant use of diuretics and Dapagliflozin can increase the risk of dehydration and low blood pressure. Monitor fluid balance and blood pressure regularly.
- Insulin and Insulin-Secretagogues (e.g., Sulfonylureas): Combining Dapagliflozin with insulin or insulin-secretagogues may increase the risk of hypoglycemia (low blood sugar). Dose adjustments may be needed.
- CYP3A4 Inhibitors (e.g., Ketoconazole): Saxagliptin is metabolized by the CYP3A4 enzyme. Co-administration with potent CYP3A4 inhibitors can increase Saxagliptin's blood levels. Dose adjustments may be necessary.
- Digoxin: There is a potential interaction between Saxagliptin and Digoxin, which can result in a slight increase in Digoxin levels. Monitor Digoxin concentrations when used concomitantly.
- Rifampin (and other strong CYP3A4 inducers): Co-administration with strong CYP3A4 inducers like Rifampin may reduce the effectiveness of Saxagliptin. An alternative anti-diabetic treatment may be considered.
The most common side effects of Dapagliflozin + Saxagliptin include:
Infection of the upper respiratory tract
Urinary tract infection
Low blood glucose, or hypoglycemia
Dyslipidemia
Headache
Diarrhea
Back pain
Genital infection
Hypoglycemia (low blood glucose level)
Dapagliflozin + Saxagliptin should be prudent in the following group of special populations.
- Pregnancy
Pregnancy Category C: Use with caution if the benefits outweigh the risks.
Advise females of the potential risk or threat to a fetus, especially during the second and third trimesters.
Adverse renal effects are shown in animal studies.
Animal data
When dapagliflozin was administered at exposure 15 times higher than the 10-mg clinical dose during a period of renal development corresponding to the late second and third trimesters of human pregnancy, adverse renal pelvic and tubular dilatations were observed in juvenile rats. These dilatations were not fully reversible.
During organogenesis or the first trimester of a human pregnancy, Saxagliptin did not exhibit any adverse effects.
- Nursing Mothers
It is unknown if it is present in human breast milk.
Rat milk that is nursing contains the medications saxagliptin and dapagliflozin. Since human kidney development is in utero and during the first two years of life, when lactational exposure may occur, there may be a risk to the developing human kidney.
Advise women that using dapagliflozin or Saxagliptin while nursing is not advised due to the possibility of severe adverse reactions in a breastfed child.
- Pediatric Use
As per FDA, safety and effectiveness in the pediatric population have yet to be established.
Dose Adjustment in Kidney Impairment Patient:
If your eGFR is <60 mL/min/1.73 m², refrain from starting
If the eGFR consistently drops to less than 60 mL/min/1.73 m², stop.
Lower than 45 mL/min/1.73 m²: Not recommended
Dose Adjustment in Hepatic Impairment Patients:
It may be administered to individuals who have liver impairment.
Severe decline of the liver: Evaluate each benefit-risk individually.
Signs and Symptoms
The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Dapagliflozin + Saxagliptin.
Overconsumption of Dapagliflozin + Saxagliptin could lead to severe hypoglycemia, dehydration, electrolyte imbalances, dizziness, weakness, confusion, and gastrointestinal distress.
Management
There is no specific antidote or treatment for excessive intake of Dapagliflozin + Saxagliptin. However, immediate medical attention is essential. Dapagliflozin + Saxagliptin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. Activated charcoal or gastric lavage may also be considered if the overdose is detected shortly after ingestion to reduce absorption.
Mild episodes of hypoglycemia can be effectively treated with oral glucose, whereas severe hypoglycemia with seizure, coma, or neurological impairment can be treated with glucagon or intravenous (IV) glucose.
Management typically involves supportive measures like maintaining vital signs, correcting electrolyte imbalances, and treating specific symptoms. The patient will also be continously monitored for several hours to ensure that blood sugar levels remain stable and that there are no further complications.
Pharmacodynamics
Dapagliflozin: Dapagliflozin increases the amount of sodium delivered to the distal tubule while decreasing its reabsorption. After receiving Dapagliflozin, both healthy individuals and patients with type 2 diabetes mellitus showed increases in the amount of glucose expelled in their urine, and in patients with type 2 diabetes mellitus, dapagliflozin dosages of 5 or 10 mg per day for 12 weeks led to an excretion of about 70 grams of glucose per day in the urine by Week 12. At a daily dose of 20 mg of Dapagliflozin, a near-maximum glucose excretion was noted. Dapagliflozin-induced increases in urine volume are also a consequence of this glucose excretion in the urine. The rise in urine glucose excretion for the 10 mg dose often returns to baseline three days after stopping Dapagliflozin. Dapagliflozin was not associated with a clinically significant lengthening of the QTc interval in a trial of healthy subjects at daily doses up to 150 mg (15 times the maximum amount advised). Moreover, in healthy individuals, a single amount of Dapagliflozin up to 500 mg (50 times the recommended maximum dose) did not cause a change in the QTc interval that was clinically significant.
Saxagliptin: 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.
Pharmacokinetics
Absorption
Dapagliflozin: When Dapagliflozin is taken orally, maximal concentration is attained during fasting for around two hours. AUC and Cmax grow in direct proportion to dosage. At 10 mg, the bioavailability is 78%. When taken with a high-fat meal, the AUC is unaffected, but Cmax and Tmax are slightly lowered. People can take Dapagliflozin with or without food.
Saxagliptin: 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
Dapagliflozin: Roughly 91% of Dapagliflozin is linked to proteins. Patients with renal or hepatic impairment do not have altered protein binding.
Saxagliptin: Saxagliptin and its active metabolite are limited regarding 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).
Metabolism
Dapagliflozin: UGT1A9 is the main enzyme involved in dapagliflozin metabolism, with CYP-mediated metabolism as a minor human clearance mechanism. Dapagliflozin undergoes much metabolism, primarily producing the inactive metabolite dapagliflozin 3-O-glucuronide. Dapagliflozin 3-O-glucuronide is the main drug-related component in human plasma, accounting for 61% of a 50 mg [14C]-dapagliflozin dosage.
Saxagliptin: 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.
Elimination
Dapagliflozin: Renal elimination is the primary method to eliminate dapagliflozin and its associated metabolites. After a single 50 mg dose of [14C]-Dapagliflozin, the amount of radioactivity excreted in the urine is 75%, whereas the amount in the faeces is 21%. Less than 2% of the dosage is eliminated as a parent drug in the urine. About 15% of the dosage is destroyed as a parent drug in stools. After taking 10 mg of Dapagliflozin, the mean plasma terminal half-life (t¬) for Dapagliflozin is about 12.9 hours.
Saxagliptin: 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.
Therapeutic benefits of a combination of Dapagliflozin + Saxagliptin
- The sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin increases glucose excretion in the urine by decreasing renal glucose reabsorption. A dipeptidyl peptidase-4 (DPP-4) inhibitor called Saxagliptin improves the way that incretin hormones work to release more insulin and secrete less glucagon.
- As dapagliflozin increases the excretion of glucose in the urine, it can cause calorie loss and mild weight loss. In addition to preventing weight gain, Saxagliptin also helps with weight loss. Combining the two helps people to control their blood sugar levels and maintain weight.
- Dapagliflozin has shown cardiovascular benefits by reducing the risk of major adverse cardiovascular events in some patients. Combining it with Saxagliptin may provide additional cardiovascular protection.
- Zhuang Y, Song J, Ying M, Li M. Efficacy and safety of dapagliflozin plus Saxagliptin vs monotherapy as added to metformin in the patients with type 2 diabetes: A meta-analysis. Medicine (Baltimore). 2020 Jul 24;99(30):e21409. doi: 10.1097/MD.0000000000021409. PMID: 32791755; PMCID: PMC7386974.
- Mathieu C,et al. Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes. Diabetes Care. 2015 Nov;38(11):2009-17. Doi: 10.2337/dc15-0779. Epub 2015 Aug 5. PMID: 26246458.
- Coppenrath VA, Hydery T. Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for Treatment of Type 2 Diabetes. Ann Pharmacother. 2018 Jan;52(1):78-85. Doi: 10.1177/1060028017731111. Epub 2017 Sep 8. PMID: 28884600.
- Del Prato S, Rosenstock J, Garcia-Sanchez R, Iqbal N, Hansen L, Johnsson E, Chen H, Mathieu C. Safety and tolerability of dapagliflozin, Saxagliptin and metformin in combination: Post-hoc analysis of concomitant add-on versus sequential add-on to metformin and of triple versus dual therapy with metformin. Diabetes Obes Metab. 2018 Jun;20(6):1542-1546. doi: 10.1111/dom.13258. Epub 2018 Mar 25. PMID: 29446523; PMCID: PMC5969059.
- Williams DM, Stephens JW. Combination therapy with Saxagliptin and dapagliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2015;16(15):2373-9. doi: 10.1517/14656566.2015.1088830. PMID: 26389773.
- https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209091s000lbl.pdf
- https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
- https://www.ema.europa.eu/en/documents/product-information/qtern-epar-product-information_en.pdf
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220756/
Published on: 2 Nov 2023 4:37 AM GMT