Medicines

Everything you need to know about Dapagliflozin mechanism of action

dapagliflozin mechanism of action Posted On
Posted By SUMIT SHARMA

Introduction 

Today, we will discuss a novel antidiabetic drug which has been popular for a few years. Yes, I am talking about dapagliflozin. Here, you will learn about dapagliflozin mechanism of action summary, uses, dosage, contraindications, side effects, etc.  

The prevalence of diabetes is being increased throughout the world. Our researchers are continuously working on it and trying to find an innovative therapeutic approach to control diabetes. 

Dapagliflozin has been found during research. It has a unique mechanism of action because it does not require the action of insulin

It removes your elevated blood glucose through the kidney via urine. 

Dapagliflozin has a lot of benefits. It not only controls your blood sugar level but also helps to reduce the progression of heart disease and kidney disease. 

In this post, we will talk about this potent antidiabetic drug and understand how dapagliflozin’s mechanism of action works in diabetes, heart disease and kidney disease.

Let’s get started right away.

 

What is the use of dapagliflozin?

Dapagliflozin is a newer antidiabetic drug that belongs to the gliflozin class family. This class is also called SGLT2 inhibitors.  

The full form of SGLT2 inhibitors is sodium-glucose cotransporter-2 inhibitors.

There are two more drugs in this class, i.e. Empagliflozin and Canagliflozin. 

Dapagliflozin was approved for medical use in 2014 by the US FDA with the brand name Farxiga. It was developed by AstraZeneca. 

It was marketed in European countries under the brand name Forxiga. The current role of dapagliflozin in following indications –

Dapagliflozin mechanism of action

 

Use of Dapagliflozin in T2DM

Dapagliflozin is the first novel SGLT2 inhibitor for the management of type 2 diabetes mellitus

This drug is considered a second-line agent to treat T2DM. It may be given as a first-line agent if metformin is contraindicated. 

Dapagliflozin is used with diet, exercise and other antidiabetic drugs to improve glycemic control. 

 

Use of Dapagliflozin in Heart Disease

In July 2020, researchers found the effect of dapagliflozin in NYHA class II to IV heart failure. 

Here, NYHA is a New York Heart Association that represents the stages of heart failure in classes.  

According to a recent study in August 2023, it has been shown that dapagliflozin significantly reduces all-cause mortality, death from cardiovascular problems, and hospitalisation due to heart failure. 

Therefore, dapagliflozin can be used as an off-label in heart failure patients if the patient does not have diabetes mellitus. But this drug could be the best choice if you have a heart failure with diabetes mellitus.

 

Use of Dapagliflozin in kidney disease

In April 2023, the effect of dapagliflozin was found to improve kidney outcomes in kidney disease. 

A study published in Kidney International Reports in 2022 stated that dapagliflozin reduces the risk of end-stage renal disease in patients with chronic kidney disease, whether diabetic or non-diabetic. 

 

How does dapagliflozin work in the body?

Dapagliflozin has a novel and unique mechanism of action. 

Mainly, typical antidiabetic drugs increase insulin secretion by working on the pancreas

On the contrary, this gliflozin drug is not dependent on the beta cells of the pancreas. Dapagliflozin directly works on the kidney and removes the excess glucose from your blood by the kidney via inhibiting the SGLT-2 transporter. 

Let’s understand this dapagliflozin mechanism of action summary in detail with basic concept – 

 

Physiology & function of SGLT-2 transporter

Usually, SGLT-2 is a transporter or pump that is present in your PCT (Proximal Convoluted Tubules) of the kidney’s nephron. 

SGLT-2 stands for sodium-glucose transport protein. The primary function of this transporter is to reabsorb (or reuptake) sodium and glucose into your blood.

Three main steps are involved in urine formation: filtration, reabsorption, and secretion. 

Your body filters your glucose in the nephron. Then, it reabsorbs 90% of glucose into your blood by a sodium-glucose pump and excretes the rest of the content. 

Dapagliflozin mechanism of action

Dapagliflozin mechanism of action in T2DM

In diabetes, having excessive glucose is not good. 

We already have a lot of antidiabetic drugs that need the action of insulin. However, researchers wanted to do something beyond insulin, where insulin is not required. 

Therefore, scientists have made an incredible molecule that is dapagliflozin. 

Dapagliflozin works on the kidney. The specialty of this molecule is that it restricts the re-entry of glucose into your blood. 

This drug stops the glucose reabsorption step in urine formation by inhibiting SGLT-2 (sodium-glucose transport protein-2).

This way, the dapagliflozin drug decreases your blood glucose level by excreting the glucose content via urine. 

That’s why dapagliflozin is called SGLT2  inhibitor. 

Dapagliflozin mechanism of action

Dapagliflozin mechanism of action in heart failure

Dapagliflozin works as an osmotic diuretic. Due to this osmotic diuretic mechanism, dapagliflozin protects the cardiovascular and helps in cardiac remodelling. 

If you have heart failure, dapagliflozin helps decrease the workload on your heart. 

This drug excretes sodium from your blood and creates a hyponatremic effect. Due to this effect, it decreases the preload and after-load effect on the heart. It also improves the ejection fraction of your heart. 

Once you start taking this drug. You will begin to feel improvement in the symptoms of heart failure, such as breathlessness, tiredness and swelling in your lower legs. 

Many studies suggest SGLT2 inhibitors have cardiovascular benefits, such as – 

 

Dapagliflozin mechanism of action in CKD

CKD stands for chronic kidney disease, where a person starts losing nephron cells, which stops the kidney’s function over time. 

It could be due to glomerulonephritis, type 2 diabetes, hypertension or cardiovascular disease.

Taking dapagliflozin block SGLT-2 protein helps to reduce inflammation and pressure in the kidneys. It protects against progressive kidney damage.

Dapagliflozin decreases the intraglomerular pressure by natriuresis effect (excretion of sodium in the urine), which further helps to reduce albuminuria

It also decreases inflammatory mediators, such as interleukin-6, nuclear factor-kB, and profibrotic factors. 

Dapagliflozin also acts as a nephroprotective drug with or without diabetes. 

dapagliflozin mechanism of action pdf

What are the most common side effects of dapagliflozin?

In addition to its therapeutic effects, dapagliflozin may produce some unwanted effects as well.

1. Frequent UTI (Urinary tract infection)

The diuresis effect of dapagliflozin may cause bacterial or fungal infections like genital mycotic infections –

  • Vulvovaginal candidiasis (vaginal fungal infection) 
  • Balanitis (pain, inflammation, and irritation in the penis)

 

So, you should maintain personal hygiene, especially in genital areas. 

 

2. Dehydration 

You may have dehydration due to glucosuria/glycosuria and the osmotic diuresis effect of gliflozin. You need to take a sufficient amount of water to avoid dehydration. 

 

3. Hypotension

The natriuresis effect (loss of sodium in the urine) of dapagliflozin may decrease your blood pressure level and cause a hypotensive effect. 

So, it is also a helpful drug if you have hypertension with type 2 diabetes. But you need to reduce the dose of your existing antihypertensive medications like ACE inhibitors, diuretics or others.

 

4. Weight loss

You will observe slight weight reduction during gliflozin therapy because you will be losing calories (or glucose) by the glucosuria effect. However, it may be beneficial for obese patients. 

 

5. Hypoglycemia 

Dapagliflozin may cause mild hypoglycemia if it is used in combination with insulin injection or sulphonylurea-like drugs

It would help if you reduce the dose of insulin or other oral hypoglycaemic agents while taking SGLT2 inhibitor drugs. 

 

6. Polyuria and polydipsia 

You may have an excessive thirst and frequent urination due to the osmotic diuretic effect of dapagliflozin. 

 

7. Risk of bladder cancer

As we know, urinary tract infection (UTI) is dapagliflozin’s most common side effect. This UTI may further contribute to bladder cancer.  

 

When not to use dapagliflozin?

Dapagliflozin is contraindicated in certain conditions –

 

1. Pregnancy and breastfeeding 

Dapagliflozin comes in category C medications

Currently, no data are available on the use of dapagliflozin in pregnant women. The researcher found reproductive toxicity in animals during dapagliflozin, especially in 2nd and 3rd trimesters. 

It was also found that dapagliflozin can be secreted in milk while breastfeeding.

Therefore, it would be best to avoid dapagliflozin in pregnancy and lactation. We already have insulin injections and metformin tablets as a safer option.   

 

2. Severe kidney disease (GFR<30ml/min)

Dapagliflozin drug should not be used for severe kidney damage, especially in stages 4 and 5 of CKD. 

At these stages, the GFR (Glomerular Filtration Rate) value decreases below 30 ml/min. 

This drug is not recommended in GFR 30 to 40 ml/min. You should strictly avoid dapagliflozin if someone has a GFR value of less than 30 ml/min. 

 

3. History of bladder cancer

You need to avoid dapagliflozin if a patient has active bladder cancer or a history of bladder cancer. 

 

4. History of ketoacidosis

You should avoid this drug if you have had ketoacidosis in the past because SGLT-2 inhibitors themselves cause ketoacidosis. 

In Feb 2022, a study reviewed the dapagliflozin is associated with diabetic ketoacidosis.

In this condition, your body starts to produce ketone bodies. Due to this, your blood becomes acidic (pH below 7). 

In ketoacidosis, you may feel burning while urinating, blood in urine, pain in the lower abdomen, and shortness of breath. If you observe these symptoms, you should stop this medicine immediately and contact your doctor. 

 

5. Allergic reaction

You should immediately discontinue this medicine if you feel a hypersensitive reaction to this dapagliflozin. 

 

How and when to take dapagliflozin? 

Dapagliflozin causes polyuria due to its osmotic diuretic effect. So, taking one tablet in the morning with or without a meal is always better.

The dose of dapagliflozin depends on the severity of the disease and type of disease, such as – 

 

Dapagliflozin dose for type 2 diabetes mellitus

Dapagliflozin is considered a first-line agent if metformin is contraindicated. 

You may be prescribed this medicine at the disease’s initial or late stage. It can be used as a monotherapy or added to insulin/another oral hypoglycemic agent. 

The starting dose of dapagliflozin in T2DM is 5 mg, administered once daily. It can be increased up to 10 mg if clinically indicated. 

The maximum dapagliflozin dose per day is 10 mg. 

 

Dapagliflozin dose for heart disease 

The recommended dose of dapagliflozin is 10 mg once daily dosing in NYHA class II–IV heart disease.  

 

Dapagliflozin dose for chronic kidney disease 

The usual dose of dapagliflozin is 10 mg once daily in chronic kidney disease. 

Taking dapagliflozin increases serum creatinine and reduces eGFR. These changes may be more prevalent in elderly patients and patients with impaired renal function. 

So, it would help if you kept in mind GFR values. The normal eGFR value is 90 ml/min or more.  

  No dose adjustment Not recommended Contraindicated
eGFR values (ml/min/1.73m2) 45 or above 30 or less than 45 Less than 30

 

 

What dapagliflozin brands are popular in India?

Dapagliflozin is prominent in India with brand names of – 

  • Forxiga 5 mg or 10 mg tablet
  • Oxra 5 mg or 10 mg tablet
  • Dapaone 5 mg or 10 mg tablet
  • Sugaflo 5 mg or 10 mg tablet

Dapagliflozin mechanism of action

Dapagliflozin mechanism of action

Dapagliflozin is also available in combination with traditional antidiabetic drugs like – 

1. Dapagliflozin and metformin combination 

You can get this fixed dose combination of Dapagliflozin & Metformin HCL extended-release tablets with brand names of –

  • Gledepa met XR 10/500mg or 1000 mg 
  • Glucreta M 5/500 or 10/1000 
  • Dapaturn M 5 or 10 mg tablet ER
  • Dapanorm M 5/500 mg 

 

2. Dapagliflozin and vildagliptin combination

The FDC of dapagliflozin & vildagliptin sustain release tablet is available with brand names of – 

  • Jalra-DP 10mg/100mg
  • Daparyl V 10mg/100mg
  • Torglip D 10mg/100mg 
  • Zukanorm D 10mg/100mg

 

3. Dapagliflozin + vildagliptin + metformin combination

This triple FDC combination (Dapagliflozin + vildagliptin + metformin) is available with brand names of – 

  • Daparyl VM 10mg/500mg/100mg Tablet
  • Zomelis-DM Forte Tablet SR
  • Jalra Trio Tablet
  • Vylda-DM 100/10/1000 Tablet SR

 

What are the clinical benefits of dapagliflozin?

Dapagliflozin does not only improve your glycaemic control, but it also has many benefits like – 

  • Effective in heart failure (NYHA class II-IV)
  • Effective in chronic kidney disease if GFR is 45 mg/ml or above
  • Rarely cause hypoglycaemia 
  • Helps to reduce blood pressure
  • Helps in weight reduction
  • Reduce fatty liver content, especially NAFLD

 

Conclusion

Dapagliflozin is a potent, well tolerated and safest antidiabetic drug. 

In this post, we understood the dapagliflozin mechanism of action and how it works in diabetes. 

Besides its use in diabetes, dapagliflozin has a cardio-renal effect.

This medicine can be considered a rising star in treating diabetes patients. 

This was all about the dapagliflozin mechanism of action summary, uses, benefits, side effects, and contraindications. 

Please share this post on social media if you found it informative.

 

FAQ

Q1. Is dapagliflozin bad for the kidneys?

Dapagliflozin would be the right choice for kidney disease, whose GFR value is more than 45 ml/min. It can be contraindicated if GFR is less than 30 ml/min. 

Q2. Does dapagliflozin increase creatinine?

Dapagliflozin drug increases serum creatinine levels and reduces eGFR. You should avoid this medicine if you have a higher creatinine level or lower GFR value. 

Q3. How long does dapagliflozin take to work?

The onset of action of dapagliflozin is 2 hours. Your blood glucose levels will drop after about two hours of taking dapagliflozin. However, it may take up to a week to become fully effective.

Q4. Which is better, metformin or dapagliflozin?

Metformin is a first-line antidiabetic drug. Suppose metformin is contraindicated or ineffective. In that case, dapagliflozin may be a second-line option for the treatment of diabetes. 

Q5. What is a substitute for dapagliflozin?

If dapagliflozin is contraindicated or not tolerated. Then, you may go to other drugs of this class, such as Canagliflozin or Empagliflozin. 

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