Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type2 diabetes. It is also used to treat adults with heart failure and chronic kidney disease. It reversibly inhibits sodium-glucose co-transporter 2 (SGLT-2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.
Common side effects include hypoglycaemia (low blood sugar), urinary tract infections, genital infections, and volume depletion (reduced amount of water in the body). Diabetic ketoacidosis is a common side effect in people with type1 diabetes. Serious but rare side effects include Fournier gangrene.
It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. It is on the World Health Organization's List of Essential Medicines. In 2023, it was the 92nd most commonly prescribed medication in the United States, with more than 7million prescriptions. Dapagliflozin is available as a generic medication.
Medical uses Dapagliflozin is used along with diet, exercise, and usually with other glucose-lowering medications, to improve glycaemic control in adults with type2 diabetes. In addition, several clinical studies have demonstrated that dapagliflozin can slow the progression of kidney disease, lower the risk of kidney failure, and reduce the risk of death when used alongside standard treatments such as blood pressure medications. These benefits have been witnessed in patients with chronic kidney disease and/or heart disease, regardless of diabetes.
Guidelines including the European Society of Cardiology for Heart Failure and American Heart Association consider SGLT2 inhibitors such as dapagliflozin as standard therapy for people with heart failure with reduced ejection fraction, (LVEF < 40%). This is supported by two large, randomized, controlled trials and a 2023 systematic review and meta-analysis.
Evidence from multiple studies indicates that the addition of dapagliflozin and other sodium‑glucose cotransporter 2 (SGLT2) inhibitors to standard heart failure therapy can reduce the risk of worsening heart failure and hospitalisation for heart failure, regardless of the presence or absence of diabetes. A reduction in cardiovascular death is robust in heart failure with reduced ejection fraction (HFrEF), type 2 diabetes (T2DM), and chronic kidney disease (CKD), but less certain in heart failure with preserved ejection fraction (HFpEF) and acute myocardial infarction (MI). Large randomised controlled trials have shown that dapagliflozin significantly reduces worsening heart failure and heart failure hospitalisation across the spectrum of heart failure, including patients with reduced ejection fraction (LVEF <40%), mildly reduced ejection fraction (LVEF 41–49%) and preserved ejection fraction (LVEF ≥50%). Research shows that early initiation during hospitalization for acute heart failure appears safe in stable patients. Combined results of multiple trials also found that starting SGLT2 inhibitors in the hospital significantly lowers the risk of death from heart problems and prevents heart failure from getting worse. Dapagliflozin and other SGLT2 inhibitors may reduce hospitalisation for heart failure in Type 2 diabetic patients, with or without atherosclerotic cardiovascular disease,however evidence across these patient groups remains incomplete. Some meta-analyses and cohort studies have demonstrated consistent efficacy among SGLT2 inhibitors in reducing specific heart failure hospitalization, but there are no direct and definitive studies indicating the superiority of dapagliflozin over other SGLT2 inhibitors like empagliflozin and further studies are needed to support this claim
In the European Union, dapagliflozin is indicated in adults for treatment of: Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Insufficiently controlled type2 diabetes as an adjunct to diet and exercise As monotherapy when metformin is considered inappropriate due to intolerance In addition to other medicinal products for the treatment of type2 diabetes Symptomatic chronic heart failure Chronic kidney disease
In November 2021, the European Medicines Agency (EMA) stated that dapagliflozin should no longer be used to treat type1 diabetes.
Effects in nondiabetic chronic kidney disease In 2021, the US Food and Drug Administration (FDA) and the EMA expanded the indications for dapagliflozin to include the treatment of people who have chronic kidney disease, but do not have diabetes.
Clinical trials have shown these effects of such a treatment:
The DIAMOND trial (2017–2019) in treatment periods of six weeks showed no improvement of excess proteins in the urine (proteinuria), a significant deterioration of the kidney's filtration rate (reversible within 6 weeks after dapagliflozin discontinuation), and a significant mean loss of body weight of 1.5 kg.
The DAPA-CKD trial (2017–2020) showed in a median treatment period of 2.4 years of participants who had already been under ACE inhibitor or angiotensin II receptor blocker therapy that the events of a sustained decline of 50% in the kidney's filtration rate, kidney failure, or death occurred statistically around eight months later in the treatment group than in the placebo group. In the first 12–16 months of treatment, but the kidney filtration rate was worse in the treatment group than in the placebo group, being slightly less negative in the treatment group than in the placebo group only thereafter.
Adverse effects Since dapagliflozin leads to heavy glycosuria (sometimes up to about 70 grams per day), it can lead to rapid weight loss and tiredness. The glucose acts as an osmotic diuretic (this effect is the cause of polyuria in diabetes), 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 (candidiasis). Rarely, the use of an SGLT-2 inhibitor medication, including dapagliflozin, is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene.
Dapagliflozin is also associated with hypotensive reactions. SGLT2 inhibitors, including dapagliflozin, are associated with a small but important risk of diabetic ketoacidosis, including euglycaemic diabetic ketoacidosis, where ketone levels increase despite normal or only mildly elevated blood glucose levels. However, the DEPICT-1 and DEPICT-2 trials showed that dapagliflozin caused additional diabetic ketoacidosis events in the type 1 diabetic patients who received dapagliflozin. Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, fatigue, and trouble breathing.
Dapagliflozin can cause dehydration, serious urinary tract infections, and genital yeast infections. Elderly people and people with kidney dysfunction, low blood pressure, or who are on diuretic medications should have their volume status and kidney function assessed. Individuals with signs and symptoms of metabolic acidosis or ketoacidosis should also be assessed. Dapagliflozin can cause low blood sugar when combined with insulin.
To lessen the risk of developing ketoacidosis after surgery, the US FDA approved changes to the prescribing information for SGLT-2 inhibitors 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.
The glucose-lowering effect of dapagliflozin starts to diminish in people with chronic kidney disease with reduced kidney function (eGFR <45mL/min) and may not be as effective for glycemic control. However, studies have demonstrated a renoprotective effect in reducing kidney function decline, dapagliflozin can still be used to reduce kidney function decline regardless of diabetes status. Therefore, while dapagliflozin can be used in people with diabetes and chronic kidney disease to prevent kidney function decline, further interventions may be needed for glycemic control.
Chemistry The first synthesis of dapagliflozin was disclosed in a patent filed by Bristol Myers Squibb in 2002.
The two main carbon-containing fragments are combined by the reaction of an aryl lithium with a trimethylsilyl-protected gluconolactone. The trimethylsilyl groups are then removed by treatment with methanesulfonic acid in methanol. This gives an intermediate with an unwanted methoxy group at the anomeric centre, which is removed by reaction with triethylsilane in the presence of boron trifluoride etherate. This route, as well as others developed for the manufacture of the drug, have been reviewed.
Mechanism of action Dapagliflozin inhibits subtype2 of the sodium-glucose transport proteins (SGLT2), 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 combination with metformin, dapagliflozin at standard treatment dose of 10 mg daily lowered HbA1c by 0.54-0.84% (5.9-9.3 mmol/mol) when compared to metformin monotherapy in patients with inadequately controlled type2 diabetes and normal renal function.
Its protective effects in heart failure are 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 (1.1 versus 1390 nmol/L), so that the drug does not interfere with intestinal glucose absorption.
Names
Dapagliflozin is the international nonproprietary name (INN), and the United States Adopted Name (USAN).
The fixed-dose combination product, dapagliflozin/metformin extended-release, is sold under the brand name Xigduo XR.
In July 2016, the fixed-dose combination of saxagliptin and dapagliflozin was authorized 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 also 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 type2 diabetes when used in combination with diet and exercise. The FDA granted the approval of Qternmet XR to AstraZeneca. The combination drug was authorized 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 (CHMP) of the EMA issued a positive opinion on the drug. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
Dapagliflozin was found effective in several studies in participants with type2 diabetes. The main measure of effectiveness was the level of glycated haemoglobin (HbA1c), which indicates how well blood glucose is controlled.
In two studies involving 840 participants with type2 diabetes, dapagliflozin when used alone decreased HbA1c levels by 0.66% more than placebo (a dummy treatment) 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% more than adding placebo after 24 weeks.