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Pronunciation | /ˌdæpəɡlɪˈfloʊzɪn/ DAP-ə-glif-LOH-zin | ||
Trade names | Forxiga, Farxiga, others | ||
Other names | BMS-512148; (1S)-1,5-anhydro-1-C-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-D-glucitol | ||
AHFS/Drugs.com | Monograph | ||
MedlinePlus | a614015 | ||
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Routes of administration | By mouth | ||
Drug class | Sodium-glucose co-transporter 2 (SGLT2) inhibitor | ||
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Pharmacokinetic data | |||
Bioavailability | 78% (after 10 mg dose) | ||
Protein binding | ~91% | ||
Metabolism | UGT1A9 (major), CYP (minor) | ||
Metabolites | Dapagliflozin 3-O-glucuronide (inactive) | ||
Elimination half-life | ~12.9 hours | ||
Excretion | Urine (75%), feces (21%) [6] | ||
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ECHA InfoCard | 100.167.331 | ||
Chemical and physical data | |||
Formula | C21H25ClO6 | ||
Molar mass | 408.88 g·mol−1 | ||
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Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. [6] [7] [9] It is also used to treat adults with heart failure and chronic kidney disease. [10] [11] [7] 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. [12]
Common side effects include hypoglycaemia (low blood sugar), urinary tract infections, genital infections, and volume depletion (reduced amount of water in the body). [13] Diabetic ketoacidosis is a common side effect in people with type 1 diabetes. [14] Serious but rare side effects include Fournier gangrene. [15]
It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. It is on the World Health Organization's List of Essential Medicines. [16] In 2021, it was the 187th most commonly prescribed medication in the United States, with more than 2 million prescriptions. [17] [18] Dapagliflozin is available as a generic medication.
Dapagliflozin is used along with diet, exercise, and usually with other glucose lowering medications, to improve glycaemic control in adults with type 2 diabetes. Dapagliflozin, in addition to other SGLT2-inhibitors, was shown to reduce the rate of decline in kidney function and kidney failure in non-diabetic and type 2 diabetic adults when added to existing treatment regimen. [19] [20] [21] [22]
Dapagliflozin is also considered as an option for people with heart failure with reduced ejection fraction with a LVEF <40%. [23] It can be given regardless of current diabetes status, in addition to standard medical therapy. Recent studies have indicated that the use of dapagliflozin and other medications from the SGLT-2 inhibitor class can reduce the risk of worsening heart failure, death, and hospitalization from cardiovascular disease. [23] [24] SGLT-2 inhibitors reduce the risk of hospitalisation due to heart failure in people with or without atherosclerotic cardiovascular disease [25] [26] A small number of meta-analyses and cohort studies have shown that dapagliflozin is superior to others such as empagliflozin. [27] [28] [29]
In the European Union, dapagliflozin is indicated in adults:
In November 2021, the European Medicines Agency (EMA) stated that dapagliflozin should no longer be used to treat type 1 diabetes. [9]
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 don't have diabetes. [33] [34] Clinical trials had shown the following effects of such a treatment.
The DIAMOND trial (2017-2019) showed in treatment periods of 6 weeks 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. [35] [36]
The DAPA-CKD trial (2017-2020) showed in a median treatment period of 2.4 years of participants who had already been under ACE or ARB 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, however, the kidney's 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. [20] [36]
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, use of an SGLT-2 drug, including dapagliflozin, is associated with necrotizing fasciitis of the perineum, also called Fournier gangrene. [37]
Dapagliflozin is also associated with hypotensive reactions. Concerns exist that it may increase the risk of diabetic ketoacidosis. [38] Dapagliflozin and other SGLT2 inhibitors increase the risk of diabetic ketoacidosis in type 2 diabetic patients. [39] [40] However, the DEPICT-1 and DEPICT-2 trials showed that dapagliflozin caused additional diabetic ketoacidosis events in the Type I diabetic patients who received dapagliflozin. [41] Symptoms of ketoacidosis include nausea, vomiting, abdominal pain, fatigue, and trouble breathing. [42]
Dapagliflozin can cause dehydration, serious urinary tract infections, and genital yeast infections. [10] 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. [10] Individuals with signs and symptoms of metabolic acidosis or ketoacidosis should also be assessed. [10] Dapagliflozin can cause low blood sugar when combined with insulin. [10]
To lessen the risk of developing ketoacidosis after surgery, the FDA has 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. [42]
The glucose lowering effect of dapagliflozin starts to diminish in people with chronic kidney disease with a 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. [20] [43]
The first synthesis of dapaglifloxin was disclosed in a patent filed by Bristol Myers Squibb in 2002. [44]
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. [45]
Dapagliflozin inhibits subtype 2 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. [46] In combination with metformin, dapagliflozin at standard treatment dose of 10 mg daily lowered HbA1c by 0.54-0.84% when compared to metformin monotherapy in patients with inadequately controlled type 2 diabetes and normal renal function. [47] [48] [49]
Its protective effects in heart failure 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. [50]
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. [51]
Dapagliflozin is the International nonproprietary name (INN), [52] and the United States Adopted Name (USAN). [53]
The fixed-dose combination product, dapagliflozin/metformin extended-release, is called Xigduo XR. [54] [55] [56]
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. [57] 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. [58] [59]
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. [60] The combination drug was approved for use in the European Union in November 2019, and is sold under the brand name Qtrilmet. [61]
In 2012, the Committee for Medicinal Products for Human Use (CHMP) of the EMA issued a positive opinion on the drug. [7]
Dapagliflozin was found effective in several studies in participants with type 2. [7] The main measure of effectiveness was the level of glycated haemoglobin (HbA1c), which gives an indication of how well blood glucose is controlled. [7]
In two studies involving 840 participants with type 2 diabetes, dapagliflozin when used alone decreased HbA1c levels by 0.66% more than placebo (a dummy treatment) after 24 weeks. [7] 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. [7]
In a study involving 814 participants with type 2 diabetes, dapagliflozin used in combination with metformin was at least as effective as a sulphonylurea (another type of diabetes medicines) used with metformin. [7] Both combinations reduced HbA1c levels by 0.52% after 52 weeks. [7]
A long-term study, involving over 17,000 participants with type 2 diabetes, looked at the effects of dapagliflozin on cardiovascular (heart and circulation) disease. [7] The study indicated that dapagliflozin's effects were in line with those of other diabetes medicines that also work by blocking SGLT2. [7]
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. [7]
Dapagliflozin was approved for medical use in the European Union in November 2012. [7] It is marketed in a number of European countries. [62]
Dapagliflozin was approved for medical use in the United States in January 2014. [63] [33]
In 2020, the US FDA 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. [10] 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. [10]
The results of the DAPA-HF and DECLARE-TIMI 58 clinical trials demonstrated the efficacy of dapagliflozin compared to placebo in improving survival in adults with heart failure with reduced ejection fraction by 17%. They both showed a reduction in the number of hospitalizations from worsening heart failure, cardiovascular death and all-cause mortality. [23] [64]
The safety and effectiveness of dapagliflozin were evaluated in a randomized, double-blind, placebo-controlled study of 4,744 participants. [10] The average age of participants was 66 years and more participants were male (77%) than female. [10] To determine the drug's effectiveness, investigators examined the occurrence of cardiovascular death, hospitalization for heart failure, and urgent heart-failure visits. [10] Participants were randomly assigned to receive a once-daily dose of either 10 mg of dapagliflozin or a placebo (inactive treatment). [10] 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. [10]
In July 2020, the FDA granted AstraZeneca a Fast Track Designation in the US for the development of dapagliflozin to reduce the risk of hospitalization for heart failure or cardiovascular death in adults following a heart attack. [65]
In August 2020, detailed results from the Phase III DAPA-CKD trial reportedly showed that dapagliflozin on top of standard of care reduced the composite measure of worsening of renal function or risk of cardiovascular or renal death by 39% compared to placebo (p<0.0001) in patients with chronic kidney disease stages 2–4 and elevated urinary albumin excretion. The results were consistent in patients both with and without type 2 diabetes. [66]
In April 2021, the FDA expanded the indications for dapagliflozin to include reducing the risk of kidney function decline, kidney failure, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease who are at risk of disease progression. [33] The efficacy of dapagliflozin to improve kidney outcomes and reduce cardiovascular death in people with chronic kidney disease was evaluated in a multicenter, double-blind study of 4,304 participants. [33]
In February 2023, the EU approved dapagliflozin for extended use to cover heart failure patients across the full spectrum of left ventricular ejection fraction (LVEF), including those with mildly reduced and preserved ejection fraction. [67] [68]
A generic version of dapagliflozin was approved by the US FDA in February 2022, [69] but cannot be sold until October 2025. [70] [71] A generic version was approved in Canada in May 2023. [72]
In January 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for a generic version of Forxiga, which has been authorized in the EU since November 2012. [73] Dapagliflozin Viatris was approved for medical used in the European Union in March 2023. [8]
A systematic review concluded that dapagliflozin reduced heart failure hospitalization, cardiovascular death, and all-cause mortality in people with HFrEF (i.e., congestive heart failure) and diabetes. [74]
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, fatigue and unexplained weight loss. Symptoms may also include increased hunger, having a sensation of pins and needles, and sores (wounds) that do not heal. Often symptoms come on slowly. Long-term complications from high blood sugar include heart disease, stroke, diabetic retinopathy which can result in blindness, kidney failure, and poor blood flow in the limbs which may lead to amputations. The sudden onset of hyperosmolar hyperglycemic state may occur; however, ketoacidosis is uncommon.
Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome. It is sometimes used as an off-label adjunct to lessen the risk of metabolic syndrome in people who take antipsychotics. Metformin is not associated with weight gain and is taken by mouth.
Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.
Valsartan, sold under the brand name Diovan among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It belongs to a class of medications referred to as angiotensin II receptor blockers (ARBs). It is a reasonable initial treatment for high blood pressure. It is taken by mouth.
Inhibitors of dipeptidyl peptidase 4 are a class of oral hypoglycemics that block the enzyme dipeptidyl peptidase-4 (DPP-4). They can be used to treat diabetes mellitus type 2.
Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.
Saxagliptin, sold under the brand name Onglyza, is an oral hypoglycemic of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. Early development was solely by Bristol-Myers Squibb; in 2007 AstraZeneca joined with Bristol-Myers Squibb to co-develop the final compound and collaborate on the marketing of the drug.
The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5A2 gene.
Remogliflozin etabonate (INN/USAN) is a drug of the gliflozin class for the treatment of non-alcoholic steatohepatitis ("NASH") and type 2 diabetes. Remogliflozin was discovered by the Japanese company Kissei Pharmaceutical and is currently being developed by BHV Pharma, a wholly owned subsidiary of North Carolina, US-based Avolynt, and Glenmark Pharmaceuticals through a collaboration with BHV. In 2002, GlaxoSmithKline (GSK) received a license to use it. From 2002 to 2009, GSK carried out a significant clinical development program for the treatment of type-2 diabetes mellitus in various nations across the world and obesity in the UK. Remogliflozin etabonate's pharmacokinetics, pharmacodynamics, and clinical dose regimens were characterized in 18 Phase I and 2 Phase II investigations. Due to financial concerns, GSK stopped working on remogliflozin and sergliflozin, two further SGLT2 inhibitors that were licensed to the company, in 2009. Remogliflozin was commercially launched first in India by Glenmark in May 2019.
Canagliflozin, sold under the brand name Invokana among others, is a medication used to treat type 2 diabetes. It is used together with exercise and diet. It is not recommended in type 1 diabetes. It is taken by mouth.
Empagliflozin, sold under the brand name Jardiance, among others, is an antidiabetic medication used to improve glucose control in people with type 2 diabetes. It is taken by mouth.
Gliflozins are a class of drugs in the treatment of type 2 diabetes (T2D). They act by inhibiting sodium/glucose cotransporter 2 (SGLT-2), and are therefore also called SGLT-2 inhibitors. The efficacy of the drug is dependent on renal excretion and prevents glucose from going into blood circulation by promoting glucosuria. The mechanism of action is insulin independent.
SGLT2 inhibitors are a class of medications that inhibit sodium-glucose transport proteins in the nephron, unlike SGLT1 inhibitors that perform a similar function in the intestinal mucosa. The foremost metabolic effect of this is to inhibit reabsorption of glucose in the kidney and therefore lower blood sugar. They act by inhibiting sodium/glucose cotransporter 2 (SGLT2). SGLT2 inhibitors are used in the treatment of type 2 diabetes. Apart from blood sugar control, gliflozins have been shown to provide significant cardiovascular benefit in people with type 2 diabetes. As of 2014, several medications of this class had been approved or were under development. In studies on canagliflozin, a member of this class, the medication was found to enhance blood sugar control as well as reduce body weight and systolic and diastolic blood pressure.
Ipragliflozin is a pharmaceutical drug for treatment of type 2 diabetes. Ipragliflozin, jointly developed by Astellas Pharma and Kotobuki Pharmaceutical, was approved in Japan on January 17, 2014, and in Russia on May 22, 2019.
Finerenone, sold under the brand name Kerendia and Firialta, is a medication used to reduce the risk of kidney function decline, kidney failure, cardiovascular death, non-fatal heart attacks, and hospitalization for heart failure in adults with chronic kidney disease associated with type 2 diabetes. Finerenone is a non-steroidal mineralocorticoid receptor antagonist (MRA). It is taken orally.
Ertugliflozin, sold under the brand name Steglatro, is a medication for the treatment of type 2 diabetes.
Sotagliflozin, sold under the brand name Inpefa among others, is a medication used to reduce the risk of death due to heart failure.
Dapagliflozin/metformin, sold under the brand name Xigduo XR amongst others, is a fixed-dose combination anti-diabetic medication used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. It is a combination of dapagliflozin and metformin and is taken by mouth. Dapagliflozin/metformin was approved for use in the European Union in January 2014, in the United States in February 2014, and in Australia in July 2014.
Canagliflozin/metformin, sold under the brand name Vokanamet among others, is a fixed-dose combination anti-diabetic medication used for the treatment of type 2 diabetes. It is used in combination with diet and exercise. It is taken by mouth.
Bexagliflozin, sold under the brand name Brenzavvy, is an antidiabetic medication used to improve glycemic control in adults with type 2 diabetes. It is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is taken by mouth.