Dapagliflozin


Dapagliflozin, sold under the brand name Farxiga among others, is a medication used to treat type 2 diabetes and, with certain restrictions, type 1 diabetes. It is also used to treat adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.
The most common side effect in people with type 2 diabetes is hypoglycaemia, especially when used in combination with a sulphonylurea or insulin. The most common side effect in people with type 1 diabetes is genital infection, especially in women and a common side effect is diabetic ketoacidosis. It is of the gliflozin class.
It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. In 2017, it was the 259th most commonly prescribed medication in the United States, with more than one million prescriptions.

Medical uses

Dapagliflozin is used along with diet and exercise to improve glycemic control in adults with type 2 diabetes and to reduce the risk of hospitalization for heart failure among adults with type 2 diabetes and known cardiovascular disease or other risk factors. It appears less useful than empagliflozin.
In the US, it is also indicated for the treatment of adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.
In the European Union it is indicated in adults for the treatment of insufficiently controlled type 2 diabetes mellitus as an adjunct to diet and exercise
and for the treatment of insufficiently controlled type 1 diabetes mellitus as an adjunct to insulin in patients with BMI ≥ 27 kg/m2, when insulin alone does not provide adequate glycaemic control despite optimal insulin therapy.
One study found that it had no benefit on heart disease risk or overall risk of death in people with diabetes. Another study found that in heart failure with a reduced ejection fraction, dapagliflozin reduced the risk of worsening of heart failure or progression to death from cardiovascular causes, irrespective of diabetic status.

Adverse effects

Since dapagliflozin leads to heavy glycosuria it can lead to rapid weight loss and tiredness. The glucose acts as an osmotic diuretic which can lead to dehydration. The increased amount of glucose in the urine can also worsen the infections already associated with diabetes, particularly urinary tract infections and thrush. Rarely, use of a SGLT2 drug, including dapagliflozin, is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene.
Dapagliflozin is also associated with hypotensive reactions. There are concerns it may increase the risk of diabetic ketoacidosis.
Dapagliflozin can cause dehydration, serious urinary tract infections and genital yeast infections. Elderly people, people with kidney problems, those with low blood pressure, and people on diuretics should be assessed for their volume status and kidney function. People with signs and symptoms of metabolic acidosis or ketoacidosis should also be assessed. Dapagliflozin can cause serious cases of necrotizing fasciitis of the perineum in people with diabetes and low blood sugar when combined with insulin.
To lessen the risk of developing ketoacidosis after surgery, the FDA has approved changes to the prescribing information for SGLT2 inhibitor diabetes medicines to recommend they be stopped temporarily before scheduled surgery. Canagliflozin, dapagliflozin, and empagliflozin should each be stopped at least three days before, and ertugliflozin should be stopped at least four days before scheduled surgery.
Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.

Mechanism of action

Dapagliflozin inhibits subtype 2 of the sodium-glucose transport proteins which are responsible for at least 90% of the glucose reabsorption in the kidney. Blocking this transporter mechanism causes blood glucose to be eliminated through the urine. In clinical trials, dapagliflozin lowered HbA1c by 0.6 versus placebo percentage points when added to metformin.
Regarding its protective effects in heart failure, this is attributed primarily to haemodynamic effects, where SGLT2 inhibitors potently reduce intravascular volume through osmotic diuresis and natriuresis. This consequently may lead to a reduction in preload and afterload, thereby alleviating cardiac workload and improving left ventricular function.

Selectivity

The IC50 for SGLT2 is less than one thousandth of the IC50 for SGLT1, so that the drug does not interfere with intestinal glucose absorption.

Names

Dapagliflozin is the International nonproprietary name, and the United States Adopted Name.
There is a fixed-dose combination product dapagliflozin/metformin extended-release, called Xigduo XR.
In July 2016, the fixed-dose combination of saxagliptin and dapagliflozin was approved for medical use in the European Union and is sold under the brand name Qtern. The combination drug was approved for medical use in the United States in February 2017, where it is sold under the brand name Qtern.
In May 2019, the fixed-dose combination of dapagliflozin, saxagliptin, and metformin hydrochloride as extended-release tablets was approved in the United States to improve glycemic control in adults with type 2 diabetes when used in combination with diet and exercise. The FDA granted the approval of Qternmet XR to AstraZeneca. The combination drug was approved for use in the European Union in November 2019, and is sold under the brand name Qtrilmet.

History

In 2012, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion on the drug.
Dapagliflozin was found effective in several studies in participants with type 2 and type 1 diabetes. The main measure of effectiveness was the level of glycosylated haemoglobin, which gives an indication of how well blood glucose is controlled.
In two studies involving 840 participants with type 2 diabetes, dapagliflozin when used alone decreased HbA1c levels by 0.66 percentage points more than placebo after 24 weeks. In four other studies involving 2,370 participants, adding dapagliflozin to other diabetes medicines decreased HbA1c levels by 0.54-0.68 percentage points more than adding placebo after 24 weeks.
In a study involving 814 participants with type 2 diabetes, dapagliflozin used in combination with metformin was at least as effective as a sulphonylurea used with metformin. Both combinations reduced HbA1c levels by 0.52 percentage points after 52 weeks.
A long-term study, involving over 17,000 participants with type 2 diabetes, looked at the effects of dapagliflozin on cardiovascular disease. The study indicated that dapagliflozin's effects were in line with those of other diabetes medicines that also work by blocking SGLT2.
In two studies involving 1,648 participants with type 1 diabetes whose blood sugar was not controlled well enough on insulin alone, adding dapagliflozin 5 mg decreased HbA1c levels after 24 hours by 0.37% and by 0.42% more than adding placebo.
Dapagliflozin was approved for medical use in the European Union in November 2012. It is marketed in a number of European countries.
Dapagliflozin was approved for medical use in the United States in January 2014.
In 2020, the U.S. Food and Drug Administration expanded the indications for dapagliflozin to include treatment for adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure. It is the first in this particular drug class, sodium-glucose co-transporter 2 inhibitors, to be approved to treat adults with New York Heart Association's functional class II-IV heart failure with reduced ejection fraction.
Dapagliflozin was shown in a clinical trial to improve survival and reduce the need for hospitalization in adults with heart failure with reduced ejection fraction. The safety and effectiveness of dapagliflozin were evaluated in a randomized, double-blind, placebo-controlled study of 4,744 participants. The average age of participants was 66 years and more participants were male than female. To determine the drug's effectiveness, investigators examined the occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits. Participants were randomly assigned to receive a once-daily dose of either 10 milligrams of dapagliflozin or a placebo. After about 18 months, people who received dapagliflozin had fewer cardiovascular deaths, hospitalizations for heart failure, and urgent heart failure visits than those receiving the placebo.
In July 2020, the FDA granted AstraZeneca a Fast Track Designation in the US for the development of dapagliflozin to reduce the risk of hospitalisation for heart failure or cardiovascular death in adults following a heart attack.