Dapagliflozin
Dapagliflozin, sold under the brand names Farxiga (US) and Forxiga (EU) among others, is a medication used to treat type 2 diabetes. It is also used to treat adults with certain kinds of heart failure and chronic kidney disease. 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 type 1 diabetic patients. Serious but rare side effects include Fournier gangrene. Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT-2) inhibitor and works by removing sugar from the body  with the urine. It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. It is on the World Health Organization's List of Essential Medicines. In 2019, it was the 310th most commonly prescribed medication in the United States, with more than 1million prescriptions. It is available as a generic medication. 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 more useful  than empagliflozin. In addition, dapagliflozin is 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. It is also indicated to reduce 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. In the European Union it 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. 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, use of an 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 (acid buildup in the blood) should also be assessed. Dapagliflozin can cause serious cases of necrotizing fasciitis of the perineum (Fournier gangrene) in people with diabetes and low blood sugar when combined with insulin. To lessen the risk of developing ketoacidosis (a serious condition in which the body produces high  levels of blood acids called ketones) 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. Use is not recommended in patients with eGFR < 45ml/min/1.73m, though data from 2021 shows the reduction in the kidney failure risks in people with chronic kidney disease using dapagliflozin . Mechanism of action. 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 clinical trials, dapagliflozin lowered HbA 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 IC for SGLT2 is less than one thousandth of the IC 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). 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 (CHMP ) of the European Medicines Agency (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), 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 HbA levels by 0.66 percentage points 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 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 (another type of diabetes medicines) used with metformin. Both combinations reduced HbA 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 (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 was not controlled well enough on insulin alone, adding dapagliflozin 5 mg decreased HbA 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 (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. 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 (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 milligrams of dapagliflozin or 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 hospitalisation for  heart failure or cardiovascular death in adults following a heart attack. In August 2020, it was reported that detailed results from the Phase III DAPA-CKD trial 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, 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 a multicenter, double-blind study of 4,304 participants. Research. 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.