Dapagliflozin - Uses, Mechanism of Action, Precautions, and Side Effects

Overview:

Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor that is used to manage type 2 diabetes mellitus in adults. When used along with diet and exercise, this drug helps improve glycemic control. Dapagliflozin was approved by the food and drug administration (FDA) on January 8th, 2014.

How Does Dapagliflozin Work?

Dapagliflozin inhibits the sodium-glucose cotransporter 2 (SGLT2) in the kidney's proximal tubules. ASLT2 helps around 90 % of the glucose reabsorption in the kidneys, so its suppression allows the glucose to be removed in the urine. This glucose excretion leads to better glycemic control and weight loss in patients with type 2 diabetes mellitus.

Uses of Dapagliflozin:

Dapagliflozin is indicated:

• Type 2 Diabetes: In case one cannot take Metformin.

• Heart Failure: Dapagliflozin can reduce the risk of the heart becoming weaker.

Limitations:

• Dapagliflozin is not recommended in individuals with type 1 diabetes mellitus and for treating diabetic ketoacidosis.

Dosage Restrictions:

1. Route of Administration - Oral.

2. Dosage Strengths-

• 5 mg.

• 10 mg.

3. Dosage Forms -

• 5 mg Tablets - Yellow, biconvex, round, film-coated tablets with '5' embossed on one side and '1427' embossed on the other.

• 10 mg Tablets - Yellow, biconvex, diamond-shaped, film-coated tablets with '10' embossed on one side and '1428' embossed on the other side.

Special Considerations:

• Renal Impairment - Patients with renal impairment should undergo an evaluation of kidney function before and after starting with Dapagliflozin therapy. The drug should not be given in individuals with glomerular filtration rates less than 60 mL/min/1.73 m square. No adjustment of dose is needed in patients with mild kidney impairment. In case the estimated glomerular filtration rate is continuously less than 60 mL/min/1.73 m, Dapagliflozin should be discontinued.

Warnings and Contraindications:

Contraindications -

• History of hypersensitivity to Dapagliflozin.

• Severe kidney impairment.

• End-stage renal disease (ESRD).

• Patients on dialysis.

Warnings and Precautions:

• Hypotension - Dapagliflozin causes intravascular volume contraction. Hypotension can occur after starting Dapagliflozin in patients with impaired kidney functions, elderly patients, or patients on loop diuretics. Therefore, the volume status should be monitored and corrected if required before starting with Dapagliflozin therapy. In addition, signs and symptoms of hypotension should be monitored before starting with Dapagliflozin.

• Kidney Function Impairment - Dapagliflozin increases serum creatinine and reduces the estimated glomerular filtration rate. Elderly patients and patients with kidney impairment are more prone to such changes. In addition, side effects related to kidney function might occur after starting Dapagliflozin. Therefore, kidney function should be assessed and monitored from time to time after starting Dapagliflozin therapy.

• Hypoglycemia With Consequent Use With Insulin and Insulin Secretagogues - Insulin and insulin secretagogues have been found to cause hypoglycemia. Dapagliflozin can increase the risk of hypoglycemia or low blood sugar when given along with insulin or an insulin secretagogue. Hence, a reduced insulin or insulin secretagogue dose might be required to reduce the risk of hypoglycemia when combined with Dapagliflozin.

• Mycotic Infections - Dapagliflozin increases the risk of developing genital mycotic infections. Patients with a previous history of genital mycotic infection are more prone to developing genital mycotic infections.

• Increase in Low-Density Lipoprotein Cholesterol - Dapagliflozin has been found to increase low-density cholesterol.

• Bladder Cancer - Dapagliflozin should not be used in people with active bladder cancer.

For Patients:

What Is Type 2 Diabetes?

Type 2 diabetes is a common condition in adults in which the body does not use the hormone insulin, which regulates the sugar in the body the way it should. This is a long-term condition resulting in excess sugar in the blood. Individuals with type 2 diabetes have insulin resistance. This high blood sugar can lead to circulatory, nervous, and immune system disorders. The pancreas does not produce enough insulin, and the cells of the body cannot use the insulin, thereby taking up less sugar.

Why Is Dapagliflozin Prescribed for Type 2 Diabetes?

Dapagliflozin is administered to lower the blood sugar levels in people with type 2 diabetes. It is also used to decrease the risk of hospitalization due to heart failure in individuals with type 2 diabetes, along with diseases of the heart and blood vessels. It is a class of medication known as sodium-glucose cotransporter 2 (SGLT2) inhibitors. It reduces blood sugar by making the kidneys remove excess glucose in the urine. Dapagliflozin, along with lifestyle modifications, might help to manage type 2 diabetes. This drug also reduces the chances of getting diabetes-related complications such as a heart attack or stroke.

Facts One Should Know About Dapagliflozin -

How Should One Take Dapagliflozin?

• Dapagliflozin comes as a tablet that is to be taken orally.

• Dapagliflozin can be taken with or without food.

• It should be taken once a day.

• The doctor's directions should be carefully followed while taking the medication.

• Dapagliflozin should be taken at the same time every day.

What Should One Discuss With Their Doctor Before Beginning Dapagliflozin?

Before starting with Dapagliflozin therapy,

• Inform the doctor in case of any allergy to Dapagliflozin or any other medication.

• Inform the doctor about any prescription or non-prescription medication that one might take. For example, in case one is taking drugs such as Benazepril, Captopril, Enalapril, Fosinopril, Lisinopril, Moexipril, Perindopril, Ramipril, and Trandolapril, Azilsartan, Candesartan, Eprosartan, Irbesartan, Losartan, Olmesartan, Telmisartan; Aspirin, Ibuprofen, and Naproxen; diabetes medications such as Glimepiride, Glipizide, Glyburide, Repaglinide, and Tolbutamide; diuretics ('water pills'); and Insulin.

• If one is on dialysis, the doctor should be informed.

• The doctor should be informed about alcohol intake.

• Inform the doctor of conditions like heart failure, pancreatic diseases, surgeries, urinary tract infections, low blood pressure, fungal infections in the genital area, or kidney or liver disease.

• Inform the doctor about being pregnant, planning to conceive, or breastfeeding.

• Inform the doctor or dentist in case one is taking Dapagliflozin in case of surgery. The doctor might advise stopping Dapagliflozin three days before any surgery.

Is Dapagliflozin Safe?

Apart from diabetic ketoacidosis for individuals with type 2 diabetes, side effects of the medicine are rare.

Is Dapagliflozin Effective?

Dapagliflozin helps in controlling type 2 diabetes but does not cure it fully.

What Side Effects Can One Expect With Dapagliflozin?

Dapagliflozin changes the sugar levels of the body. It might cause the following side effects:

• Increased frequency of urination.

• Increased thirst.

• Burning while passing urine.

• Cloudy, red, pink, or brown urine.

• Foul-smelling urine.

• Reduced urine output.

• Pain in the pelvic or rectal area.

• Whitish, or yellowish, foul-smelling vaginal discharge.

• Vaginal itching.

• Redness, rashes, itching, pain, or swelling of the penis.

• Foul-smelling discharge from the penis.

• Fatigue, fever with pain, redness, and swelling of the genital area.

• Swelling of the legs and feet.

On experiencing the following side effects, Dapagliflozin should be immediately stopped:

1. Rashes.

2. Hives.

3. Itching.

4. Difficulty in breathing or swallowing.

5. Hoarseness of voice.

6. Nausea and vomiting.

7. Pain in the stomach area.

8. Fatigues.

9. Breathing difficulty.

Can One Stop Taking Dapagliflozin Without the Doctor's Approval?

Dapagliflozin should not be stopped without the doctor's permission.

Are There Any Dietary Restrictions to Consider When Taking Dapagliflozin?

Follow all the exercises and dietary recommendations given by the doctor. Have a healthy diet. One should drink enough fluids throughout while on the medication.

How Should One Store Dapagliflozin?

Dapagliflozin should be stored in a tightly sealed container away from kids. It should be stored at room temperature but not in the bathroom.

How Should One Dispose of Dapagliflozin?

Unused or expired medicine should be disposed of in a way such that pets, kids, and any other person cannot consume them. For example, it should not be thrown in the toilet. Instead, the medicine should be disposed of through a medicine take-back program after consulting with the pharmacist or the local garbage or recycling department.

What To Do in Case of Overdose?

In case of an overdose, the poison control team should be immediately contacted. Likewise, emergency services should be immediately contacted if the person has collapsed, had a seizure, has difficulty breathing, or is unconscious.

For Doctors:

Indications -

• Type 2 Diabetes Mellitus - Dapagliflozin is used along with diet and exercise to improve the glycemic content in people with type 2 diabetes.

• Heart failure.

• Chronic kidney disease.

What Is the Pharmacology of Dapagliflozin?

Description -

Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor that is used to manage diabetes mellitus type 2.

Components-

1. Active Ingredients -

• Dapagliflozin.

2. Inactive Ingredients -

• Microcrystalline cellulose.

• Anhydrous lactose.

• Crospovidone.

• Silicon dioxide.

• Magnesium stearate.

Clinical Pharmacology

Mechanism of Action -

The sodium-glucose cotransporter 2 (SGLT2) is expressed in the proximal tubules of the nephrons and is responsible for the maximum reabsorption of the filtered glucose from the tubules. Dapagliflozin is an inhibitor of SGLT2, thereby reducing filtered glucose's reabsorption and lowering the kidney threshold for glucose, thus increasing the removal of glucose from the urine.

Pharmacodynamics -

Dapagliflozin increases the amount of glucose removed from the urine in type 2 diabetic patients. 10 mg of Dapagliflozin administered for 12 weeks leads to the removal of around 70 grams of glucose in the urine per day for 12 weeks. This increased glucose excretion also resulted in increased urinary output.

Pharmacokinetics -

• Mean Cmax - Cmax is attained within two hours of fasting and decreased by 50 %.

• Median Tmax - Tmax is prolonged by one hour.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

• Pharmacokinetic Changes - Orally administered Dapagliflozin is rapidly absorbed into the body, attaining peak plasma concentrations within two hours of administration.

A. Distribution -

• Steady-state Plasma Levels - 118 Liters.

• Time to Approach Steady-state Levels - Two hours.

• Binding to Plasma Proteins - 91 %.

B. Metabolism -

UGT1A9, CYP-mediated metabolism, mediates the metabolism of Dapagliflozin. It is significantly metabolized into Dapagliflozin 3-O-glucuronide, an inactive metabolite.

C. Excretion -

• Recovery of Dapagliflozin - 75.2 % of Dapagliflozin is recovered in urine, and 21 % is excreted in feces.

D. Elimination -

Dapagliflozin is primarily eliminated through the kidneys.

Special Considerations:

• Renal Impairment - There are limited data concerning Dapagliflozin treatment in patients with an estimated glomerular filtration rate of less than 25 mL/min/1.73 m square. Hence it is not advised to start Dapagliflozin treatment in patients with estimated glomerular filtration of less than 15 mL/min/1.73 m square. In addition, individuals with moderate renal impairment had side effects of increased parathyroid hormone levels and low blood pressure.

• Hepatic Impairment - There is significantly less data on treatment with Dapagliflozin in individuals with hepatic impairment. Dapagliflozin exposure is raised in individuals with severe hepatic impairment.

• Effects of Age, Gender, Race, and Body Weight - Age, gender, race, and body weight do not significantly affect the pharmacokinetics of Dapagliflozin; hence, dose adjustment is needed.

• Pediatric - The use of Dapagliflozin on pediatric patients has yet to be researched much.

Drug Interactions -

• Abatacept - The metabolism of Dapagliflozin is increased in combination with Abatacept.

• Aceclofenac - Dapagliflozin might increase the excretion rate of Aceclofenac, leading to reduced efficiency.

• Acyclovir - Dapagliflozin might increase Acyclovir's excretion rate, resulting in decreased efficiency.

What Have Clinical Trials Shown With Regard to Dapagliflozin?

A model-based approach to investigating the relationship between glucose-insulin dynamics and Dapagliflozin treatment effect in patients with type 2 diabetes -

• The glycemic control during the treatment with Dapagliflozin was characterized by the components representing the pharmacokinetics of Dapagliflozin, glucose-insulin homeostasis, kidney glucose absorption, and HbA1c formation. The study model was made with the help of PK variables, glucose, plasma insulin, and urinary glucose excretion (UGE) from a phase ll Dapagliflozin trial in individuals with T2DM. This model was used to predict Dapagliflozin-induced HbA1c reduction compared to data from the phase three trials.

Results -

The glucose-insulin-dapagliflozin model described plasma glucose and insulin levels, along with UGE with response to oral glucose tolerance tests and intake of food. The clinical trials showed that Dapagliflozin-mediated glycemic control is anticorrelated to steady-state insulin concentration and sensitivity. It also suggests that Dapagliflozin benefits individuals with insufficient glycemic control from insulin, which increases as insulin control reduces.

Patient Counseling Information -

• The patients should be informed about the risks and benefits of Dapagliflozin and alternate therapy modes.

• The patients should be enlightened about diet, physical activity, timely blood glucose monitoring, and HbA1c testing.

• The patients should be advised to take medical help for conditions such as fever, trauma, infection, or surgery, as the need for medication might change.

• Dapagliflozin should be taken as prescribed.

• If a dose is missed, the medication should be taken as soon as possible unless it is time to take the next dose. In such cases, the patient should skip the missed dose and continue with the scheduled dose.

• The patient should be instructed to take only one dose simultaneously.

• The patient should be told about the common side effects.

• If the patient is pregnant or plans to conceive, she should inform her doctor.

• If the patient is a breastfeeding mother, the doctor should be informed before beginning the treatment, as the drug might cause harm to the infant.

Administration Instructions -

• Dapagliflozin should be taken orally.

• It should be taken once a day.

• It can be taken in the morning, with or without food.

• For patients who are tolerating Dapagliflozin 5 mg well and require additional glycemic control, the dosage can be increased to 10 mg once a day under the doctor's supervision.

Complications or Side Effects -

The mild side effects include -

1) Thrush.

2) Back pain.

3) Increased frequency of urination.

4) Dizziness.

5) Mild skin rashes.

6) Low blood sugar or hypoglycemia leads to the following-

• Increased hunger.

• Trembling or shaking.

• Sweating.

• Confusion.

• Difficulty in concentration.

Serious side effects include -

1) Dehydration.

2) Urinary tract infection.

3) Diabetic Ketoacidosis - This happens when the body has low insulin and harmful substances called ketones accumulate.

4) Anaphylaxis Reactions -

• Development of an itchy, reddish, inflamed skin rash.

• Wheezing.

• Chest tightness.

• Troubled breathing.

• Swelling of the face, mouth, lips, tongue, or throat.