Dapagliflozin

Dapagliflozin is an anti-diabetic agent belonging to the pharmacological class of Sodium-glucose cotransporter-2 (SGLT2) Inhibitors.

Dapagliflozin is approved to treat type 2 diabetes mellitus in adults, primarily by improving the control of glycemia by inhibiting renal glucose reabsorption, leading to high excretion of glucose through urine and reduced blood glucose levels.

Dapagliflozin is rapidly absorbed from the GI tract after being administered orally, reaching peak plasma concentrations in about 2 hours. It is primarily metabolized in the liver, with a half-life of approximately 12.9 hours. Dapagliflozin is eliminated chiefly through the kidneys, with about 75% excreted unchanged in the urine.

Dapagliflozin's most common side effects are fungal infection of the vagina, throat and nose passage inflammation, nasopharyngitis, and urinary tract infections.

Dapagliflozin is available in the form of injectable solutions.

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

Dapagliflozin is an anti-diabetic agent belonging to the pharmacological class of Sodium-glucose cotransporter-2 (SGLT2) Inhibitors.

The sodium-glucose cotransporter 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.

Dapagliflozin 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.

Management of type 2 diabetes mellitus is primarily done through the use of Dapagliflozin. To promote the elimination of extra glucose in the urine, it reduces the kidneys' ability to reabsorb glucose. This is commonly used with a nutritious diet and regular exercise to help treat diabetes mellitus type 2 since it lowers blood sugar levels.

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.

Dapagliflozin is indicated in adults for:

In conjunction with diet and exercise to help with glycemic management to lower the incidence of heart failure hospitalization in adults with several cardiovascular risk factors, existing cardiovascular disease, or type 2 diabetes mellitus.

To lessen the likelihood that persons with chronic kidney disease who are at the risk of progression may experience prolonged eGFR decline, end-stage kidney disease (ESKD), cardiovascular mortality, and hospitalization for HF.

In individuals with heart failure who have a decreased ejection fraction (NYHA class II–IV), to lower the risk of cardiovascular death and hospitalization for heart failure.

Not for the management of diabetic ketoacidosis or type 1 diabetes mellitus

Orally: Dapagliflozin can be taken orally, preferably in the morning, with or without food. Patients should ensure they maintain proper fluid intake to reduce the risk of hypotension. If a dose is missed, it should be taken as soon as possible, but patients should not double the following amount.

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

Dapagliflozin is available in the form of oral solutions.

Improve glycemic control

Initial: 5 mg orally qDay in the morning

Patients who can tolerate 5 mg per day and who need more glycemic control may be increased to 10 mg per day.

Lower the chance of heart failure hospitalization

10 mg orally qDay in AM

10 mg orally qDay

10 mg orally qDay

Not for the treatment of type 1 diabetes; in these individuals, there may be a higher risk of diabetic ketoacidosis

It is not advised to enhance glycemic control in persons with type 2 diabetes who have an eGFR of less than 45 mL/min/1.73 m2, as Dapagliflozin's mode of action may render it ineffective.

Patients with polycystic kidney disease or those undergoing or recently completing immunosuppressive therapy for kidney disease are not advised to use Dapagliflozin for chronic kidney disease (CKD); Dapagliflozin is likely to be unsuccessful in these populations.

Evaluate renal function, and then at regular intervals after that

Evaluate and adjust volume depletion as necessary.

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

While taking Dapagliflozin, avoid large meals and maintain regular meals with balanced macronutrient content to help stabilize blood sugar levels.

Limit alcohol consumption, as it can increase the risk of dehydration and Hypoglycemia when combined with Dapagliflozin.

As it may increase urination, leading to fluid loss, maintain adequate fluid intake to prevent dehydration, particularly in hot weather or during strenuous activities.

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.

The dietary restriction should be individualized as per patient requirements.

Dapagliflozin may be contraindicated in the following conditions:-

The adverse reactions related to Dapagliflozin can be categorized as:

Rash

Low blood sugar

Ketoacidosis

Perineal necrotizing fasciitis

Acute kidney injury and renal impairment

Pyelonephritis and urosepsis

Necrotizing fasciitis of the perineum

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

The most common side effects of Dapagliflozin include:

A Polyuria

Nausea

Vomiting

Dyslipidemia

Genital fungal infection

Nasopharyngitis is an inflammation of the nasal passages and throat.

Urinary tract infection

Pregnancy Category C. Use with caution if the benefits outweigh the risks.

It is not advised to use a medicine during the second or third trimester of pregnancy due to animal research that indicates adverse effects on the kidneys.

Pregnancy-related risks for significant birth abnormalities and miscarriages cannot be determined from the limited data available on pregnant women; poorly controlled diabetes throughout pregnancy carries risks for both the mother and the fetus.

In rat trials, when given at all tested doses at a time of renal development corresponding to the second and third trimesters of human pregnancy, rats developed unfavourable renal pelvis and tubule dilatations that were not reversible.

Maternal risks associated with poorly managed diabetes during pregnancy include diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, stillbirths, and delivery complications; fetal hazards include significant congenital disabilities, stillbirths, and morbidity related to macrosomia.

Dapagliflozin has been found in the milk of breastfeeding rats; however, the therapeutic significance of these data needs to be clarified due to species-specific changes in lactation physiology. No evidence is available regarding the drug's presence in human milk, effects on breastfed infants, or milk production.

Since human kidney maturation occurs in utero and throughout the first two years of life, when lactational exposure may appear, there may be a risk for growing human kidneys. It is advised to women that therapy is not recommended while nursing due to the possibility of significant adverse responses in breastfed infants.

As per FDA, safety and effectiveness in the pediatric population have yet to be established.

Dapagliflozin is generally safe and effective in geriatric patients with proper monitoring. Dosage adjustments might be necessary due to age-related changes. Potential side effects should be closely observed in this population.

Renal impairment

eGFR ≥45mL/min/1.73 m2: No dosage modification is necessary.

eGFR 25 to less than 45 mL/min/1.73 m2

T2DM: Not advised.

HF or CKD: There is no need to change the dosage.

eGFR <25 mL/min/1.73 m2

Starting is not advised.

To lower their risk of eGFR decline, ESKD, CV death, and HF hospitalization, patients with CKD or HF may continue taking 10 mg daily.

Dialysis with ESRD: Contraindicated.

Mild or moderate: No change in dose is necessary.

Severe: Not studied

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

Overconsumption of Dapagliflozin may include hypotension (low blood pressure), extreme thirst, frequent urination, dehydration, electrolyte imbalances and a risk of ketoacidosis.

There is no specific antidote or treatment for excessive intake of Dapagliflozin. However, immediate medical attention is essential. Dapagliflozin should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. In some cases, gastric lavage may be performed to remove unabsorbed Dapagliflozin.

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

In severe cases of overdose with associated kidney dysfunction, hemodialysis may be considered to remove Dapagliflozin from the bloodstream.

Dapagliflozin increases the amount of sodium delivered to the distal tubule while decreasing its reabsorption. This could affect several physiological processes, such as lowering the heart's pre- and afterload, downregulating sympathetic activity, and reducing intraglomerular pressure, which is thought to be mediated by an increase in tubuloglomerular feedback. 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.

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.

Bioavailability: 78%

Peak plasma time: 2 hr (fasting); ~3 hr (with high-fat meal)

Roughly 91% of Dapagliflozin is linked to proteins. Patients with renal or hepatic impairment do not have altered protein binding.

Protein-bound: 91%

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.

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.

Half-life: 12.9 hr

Excretion: 75% urine; 21% feces