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45-522: Sodium-dependent glucose cotransporters (or sodium-glucose linked transporter , SGLT ) are a family of glucose transporter found in the intestinal mucosa ( enterocytes ) of the small intestine (SGLT1) and the proximal tubule of the nephron ( SGLT2 in PCT and SGLT1 in PST ). They contribute to renal glucose reabsorption . In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along

90-545: A heart attack . 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. In April 2021,

135-497: A diverse range of substrates beyond glucose. Specific members of this family are specialized for the transport of: Each of these transporters plays a specific role in cellular metabolism and homeostasis, often utilizing sodium gradients for substrate transport similar to the glucose transporters in this family. The transport of glucose across the proximal tubule cell membrane involves a complex process of secondary active transport (also known as co-transport). This process begins with

180-589: A multicenter, double-blind study of 4,304 participants. 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. A generic version of dapagliflozin was approved by the US FDA in February 2022, but cannot be sold until October 2025. A generic version

225-434: 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

270-534: A placebo (inactive treatment). 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 hospitalization for heart failure or cardiovascular death in adults following

315-445: A randomized, double-blind, placebo-controlled study of 4,744 participants. The average age of participants was 66 years and more participants were male (77%) 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 mg of dapagliflozin or

360-661: A reduction in preload and afterload, thereby alleviating cardiac workload and improving left ventricular function. The IC 50 for SGLT2 is less than one-thousandth of the IC 50 for SGLT1 (1.1 versus 1390 nmol/L), so that the drug does not interfere with intestinal glucose absorption. Dapagliflozin is the International nonproprietary name (INN), and the United States Adopted Name (USAN). The fixed-dose combination product, dapagliflozin/metformin extended-release,

405-403: 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. The first synthesis of dapagliflozin was disclosed in

450-667: 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 medicine) used with metformin. Both combinations reduced HbA 1c levels by 0.52% after 52 weeks. 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. 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

495-430: A transporter. It has a low affinity for glucose and does not significantly contribute to glucose transport across cell membranes. Instead, SGLT3 acts as a glucose-gated ion channel, generating small depolarizing currents in response to extracellular glucose. This electrical signaling function suggests a role in glucose sensing and signaling pathways rather than in glucose transport. The SLC5 family includes transporters for

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540-1065: Is also associated with hypotensive reactions. Concerns exist that it may increase the risk of diabetic ketoacidosis . Dapagliflozin and other SGLT2 inhibitors increase the risk of diabetic ketoacidosis in type 2 diabetic patients. 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. 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

585-506: Is also considered as an option for people with heart failure with reduced ejection fraction with a LVEF <40%. 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. SGLT-2 inhibitors reduce

630-420: 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

675-446: 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 the existing treatment regimen. Dapagliflozin

720-578: Is 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 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

765-792: Is only found in kidney tubules and in conjunction with SGLT1 resorbs glucose into the blood from the forming urine. By inhibiting SGLT2, and not targeting SGLT1, glucose is excreted which in turn lowers blood glucose levels. Examples include dapagliflozin (Farxiga in US, Forxiga in EU), canagliflozin (Invokana) and empagliflozin (Jardiance). Certain SGLT2 inhibitors have shown to reduce mortality in type 2 diabetes. The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes , and FDA has not approved them for use in these patients. In August 1960, in Prague, Robert K. Crane presented for

810-437: 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

855-470: The Na/K ATPase on the basolateral membrane. This enzyme uses ATP to pump 3 sodium ions out of the cell into the blood while bringing 2 potassium ions into the cell. This action creates a sodium concentration gradient across the cell membrane, with a lower concentration inside the cell compared to both the blood and the tubular lumen. SGLT proteins utilize this sodium gradient to transport glucose across

900-447: The apical membrane into the cell, even against the glucose concentration gradient. This mechanism is an example of secondary active transport. Once inside the cell, glucose is then moved across the basolateral membrane into the peritubular capillaries by members of the GLUT family of glucose uniporters . SGLT1 and SGLT2 are classified as symporters because they move sodium and glucose in

945-487: The brush border membrane was [is] coupled to downhill Na+ transport cross the brush border. This hypothesis was rapidly tested, refined, and extended [to] encompass the active transport of a diverse range of molecules and ions into virtually every cell type. Dapagliflozin Dapagliflozin , sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes . It

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990-457: 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. The safety and effectiveness of dapagliflozin were evaluated in

1035-696: The EMA issued a positive opinion on the drug. Dapagliflozin was found effective in several studies in participants with type 2. The main measure of effectiveness was the level of glycated haemoglobin (HbA 1c ), which indicates how well blood glucose is controlled. In two studies involving 840 participants with type 2 diabetes, dapagliflozin when used alone decreased HbA 1c 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 HbA 1c levels by 0.54–0.68% more than adding placebo after 24 weeks. In

1080-406: 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. The efficacy of dapagliflozin to improve kidney outcomes and reduce cardiovascular death in people with chronic kidney disease was evaluated in

1125-454: The GLUT/SLC2 have been identified. On the basis of sequence similarities, the GLUT family has been divided into three subclasses. Class I comprises the well-characterized glucose transporters GLUT1-GLUT4. Class II comprises: Class III comprises: Most members of classes II and III have been identified recently in homology searches of EST databases and the sequence information provided by

1170-478: 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. Clinical trials have 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

1215-461: 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. 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. The results of

1260-447: The amino and carboxyl termini exposed on the cytoplasmic side of the plasma membrane . GLUT proteins transport glucose and related hexoses according to a model of alternate conformation, which predicts that the transporter exposes a single substrate binding site toward either the outside or the inside of the cell. Binding of glucose to one site provokes a conformational change associated with transport, and releases glucose to

1305-519: The body). Diabetic ketoacidosis is a common side effect in people with type 1 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 2022, it was the 115th most commonly prescribed medication in the United States, with more than 5   million prescriptions. Dapagliflozin

1350-608: The energy from the sodium gradient created by the Na+/K+ ATPase to transport glucose against its concentration gradient. SGLT2, encoded by the SLC5A2 gene, is predominantly expressed in the S1 and S2 segments of the proximal renal tubule and is responsible for approximately 97% of glucose reabsorption in the kidneys under normal conditions. SGLT1, encoded by the SLC5A1 gene, is primarily expressed in

1395-516: The first time his discovery of the sodium-glucose cotransport as the mechanism for intestinal glucose absorption. Crane 's discovery of cotransport was the first-ever proposal of flux coupling in biology. Glucose transporter Most non- autotrophic cells are unable to produce free glucose because they lack expression of glucose-6-phosphatase and, thus, are involved only in glucose uptake and catabolism . Usually produced only in hepatocytes , in fasting conditions, other tissues such as

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1440-403: The first time his discovery of the sodium-glucose cotransport as the mechanism for intestinal glucose absorption. Crane 's discovery of cotransport was the first ever proposal of flux coupling in biology. Crane in 1961 was the first to formulate the cotransport concept to explain active transport. Specifically, he proposed that the accumulation of glucose in the intestinal epithelium across

1485-457: The intestines, muscles, brain, and kidneys are able to produce glucose following activation of gluconeogenesis . In Saccharomyces cerevisiae glucose transport takes place through facilitated diffusion . The transport proteins are mainly from the Hxt family, but many other transporters have been identified. GLUTs are integral membrane proteins that contain 12 membrane-spanning helices with both

1530-455: 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 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

1575-403: The late proximal tubule (S3 segment) and accounts for the remaining 3% of glucose reabsorption. In addition to SGLT1 and SGLT2, there are 10 other members in the human protein family SLC5A. SLC5A4, also known as SGLT3, is a member of the sodium-glucose cotransporter family. Unlike SGLT1 and SGLT2, which are efficient glucose transporters, SGLT3 functions primarily as a glucose sensor rather than

1620-451: The nephron (98% in PCT , via SGLT2). If the plasma glucose concentration is too high ( hyperglycemia ), glucose passes into the urine ( glucosuria ) because SGLT are saturated with the filtered glucose. The sodium-glucose linked transporters (SGLTs) are responsible for the active transport of glucose across cell membranes. SGLT1 and SGLT2 are the most well-studied members of this family. Both SGLT1 and SGLT2 function as symporters , utilizing

1665-582: The other side of the membrane. The inner and outer glucose-binding sites are, it seems, located in transmembrane segments 9, 10, 11; also, the DLS motif located in the seventh transmembrane segment could be involved in the selection and affinity of transported substrate. Each glucose transporter isoform plays a specific role in glucose metabolism determined by its pattern of tissue expression, substrate specificity, transport kinetics, and regulated expression in different physiological conditions. To date, 14 members of

1710-895: The presence of boron trifluoride etherate . This route, as well as others developed for the manufacture of the drug, have been reviewed. 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. 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 type 2 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

1755-619: 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. 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

1800-522: The risk of hospitalisation due to heart failure in people with or without atherosclerotic cardiovascular disease A small number of meta-analyses and cohort studies have shown that dapagliflozin is superior to others such as empagliflozin. 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. In 2021,

1845-484: The same direction across the membrane. To maintain this process, the Sodium–hydrogen antiporter plays a crucial role in replenishing intracellular sodium levels. Consequently, the net effect of glucose transport is coupled with the extrusion of protons from the cell, with sodium serving as an intermediate in this process. SGLT2 inhibitors, also called gliflozins , are used in the treatment of type 2 diabetes . SGLT2

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1890-472: The treatment group than in the placebo group. In the first 12-16 months of treatment, however, 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. 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

1935-582: The various genome projects . The function of these new glucose transporter isoforms is still not clearly defined at present. Several of them (GLUT6, GLUT8) are made of motifs that help retain them intracellularly and therefore prevent glucose transport. Whether mechanisms exist to promote cell-surface translocation of these transporters is not yet known, but it has clearly been established that insulin does not promote GLUT6 and GLUT8 cell-surface translocation. In August 1960, in Prague , Robert K. Crane presented for

1980-504: 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. In 2012, the Committee for Medicinal Products for Human Use (CHMP) of

2025-453: Was not controlled well enough on insulin alone, adding dapagliflozin 5 mg decreased HbA 1c 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,

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