Empagliflozin

In the United States, empagliflozin is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure; Diabetes Empagliflozin is indicated in adults with type2 diabetes and established cardiovascular disease to reduce the risk of cardiovascular death; and as an adjunct to diet and exercise to improve glycemic control in adults with type2 diabetes. In June 2023, the US Food and Drug Administration (FDA) expanded the indication, as an addition to diet and exercise, to improve blood sugar control in children 10 years and older with type2 diabetes. Empagliflozin has shown beneficial effects on cardiovascular morbidity and mortality in patients with type 2 diabetes. People started on empagliflozin may first see a decrease in kidney function before their glomerular filtration rate stabilises. Greatest benefit was demonstrated in those who had severe loss of kidney function, higher risk of kidney function worsening and background of diabetes. empagliflozin/metformin, and empagliflozin/linagliptin/metformin. Chronic Kidney Disease Although Jardiance was originally developed for treatment of type 2 diabetes, large-scale clinical trials have proven, that it provides significant renal and cardiovascular benefits for a much wider range of patients, including to those with chronic kidney disease even without type 2 diabetes. Empagliflozin helps patients with chronic kidney disease via several complimentary mechanisms: • Slows kidney function decline: Empagliflozin significantly slows the annual rate of decline in the estimated glomerular filtration rate (eGFR), a key measure of kidney function. • Reduces risk of major kidney events: Clinical trials have shown that empagliflozin reduces the risk of kidney disease progression, including a sustained drop in eGFR, the need for dialysis or transplant, or death from renal causes. • Beneficial across patient types: The kidney-protective effects of empagliflozin are consistent in patients with or without diabetes and across different levels of kidney function (eGFR) and albuminuria (excess protein in the urine). ==== Mechanism of action in CKD ==== While the exact mechanisms are still being studied, several factors contribute to empagliflozin's kidney benefits: • Reduces intraglomerular pressure: By inhibiting SGLT2 in the kidney tubules, empagliflozin increases sodium-ion delivery to the macula densa. • This triggers a tubuloglomerular feedback, which constricts the afferent arteriole and reduces pressure within the glomerulus. This protects the delicate filtering units of the kidney from damage. • Lower blood pressure: Empagliflozin can cause a modest reduction in blood pressure and weight, which further reduces stress on the kidneys. • Anti-inflammatory effects: Studies suggest that SGLT2 inhibitors like empagliflozin may have anti-inflammatory and anti-fibrotic effects, potentially protecting against kidney tissue damage. Key trial results (EMPA-KIDNEY) The landmark EMPA-KIDNEY clinical trial demonstrated the broad benefits of empagliflozin for people with CKD. • Reduced composite risk: Empagliflozin reduced the risk of the composite primary outcome (kidney disease progression or cardiovascular death) by 28% compared to a placebo. • Decreased hospitalizations: The trial also showed a 14% relative risk reduction for all-cause hospitalizations. • Consistent benefits: The benefits were observed consistently across different patient groups, including those with low albuminuria who were previously not thought to benefit as much from this class of medication. Considerations and side effects While generally well-tolerated, empagliflozin use in CKD patients should be monitored by a healthcare provider. • Initial eGFR drop: When starting treatment, patients may experience an initial, modest decline in eGFR, which is part of the drug's mechanism. After this initial "dip", the rate of kidney function decline slows significantly. • Contraindications: Empagliflozin is not recommended for patients with polycystic kidney disease or those on kidney dialysis. • Adverse effects: Common side effects include an increased risk of urinary tract infections and genital mycotic infections. The risk of dehydration may also increase, especially in elderly patients or those on a low-salt diet. == Contraindications ==

• History of a severe allergic reaction to empagliflozin • End-stage kidney disease • Diabetic ketoacidosis == Side effects ==

Common • Empagliflozin increases the risk of genital fungal infections. The risk is highest in people with a prior history of genital fungal infections. • Empagliflozin reduces systolic and diastolic blood pressure and can increase the risk of low blood pressure, which can cause fainting and/or falls. However, given that this conclusion is largely based on a single major trial, further research is recommended to establish long-term safety and efficacy in this population. Serious • Diabetic ketoacidosis, a rare but potentially life-threatening condition, may occur more commonly with empagliflozin and other SGLT-2 inhibitors. While diabetic ketoacidosis is usually associated with elevated blood glucose levels, in people taking SGLT-2 inhibitors diabetic ketoacidosis may be seen with uncharacteristically normal blood glucose levels, a phenomenon called euglycemic diabetic ketoacidosis. Symptoms of diabetic ketoacidosis include nausea, vomiting, abdominal pain, tiredness, and trouble breathing. When used by itself or in addition to metformin it does not appear to increase the risk of hypoglycemia. == Mechanism of action ==

Empagliflozin is an inhibitor of the sodium glucose co-transporter-2 (SGLT-2), which is found almost exclusively in the proximal tubules of nephronic components in the kidneys. SGLT-2 accounts for about 90percent of glucose reabsorption into the blood. Blocking SGLT-2 reduces blood glucose by blocking glucose reabsorption in the kidney and thereby excreting glucose (i.e., blood sugar) via the urine. Of all the SGLT-2 Inhibitors currently available, empagliflozin has the highest degree of selectivity for SGLT-2 over SGLT-1, SGLT-4, SGLT-5 and SGLT-6. == History ==

It was developed by Boehringer Ingelheim, patented in 2005, and is co-marketed by Eli Lilly and Company. For cardiovascular death, the FDA based its decision on a postmarketing study it required when it approved empagliflozin in 2014, as an adjunct to diet and exercise to improve glycemic control in adults with type2 diabetes. Empagliflozin was studied in a postmarket clinical trial of more than 7,000 participants with type2 diabetes and cardiovascular disease. In the trial, empagliflozin was shown to reduce the risk of cardiovascular death compared to a placebo when added to standard of care therapies for diabetes and atherosclerotic cardiovascular disease. For heart failure, the safety and effectiveness of empagliflozin were evaluated by the FDA as an adjunct to standard of care therapy in a randomized, double-blind, international trial comparing 2,997 participants who received empagliflozin, 10 mg, once daily to 2,991 participants who received the placebo. The main efficacy measurement was the time to death from cardiovascular causes or need to be hospitalized for heart failure. Of the individuals who received empagliflozin for an average of about two years, 14% died from cardiovascular causes or were hospitalized for heart failure, compared to 17% of the participants who received the placebo. This benefit was mostly attributable to fewer participants being hospitalized for heart failure. The FDA granted the application for empagliflozin priority review, and approved the additional indication of heart failure in 2022. ==Legal status==

As of May 2013, Boehringer and Lilly had submitted applications for marketing approval to the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). Empagliflozin was approved in the European Union in May 2014, and was approved in the United States in August 2014. The FDA required four postmarketing studies: a cardiovascular outcomes trial, two studies in children, and a toxicity study in animals related to the pediatric trials. == Research ==

A meta-analysis of short-term randomized controlled trials has shown similar efficacy on glycemic control between empagliflozin 10mg and 25mg in people with type2 diabetes. While there may be a higher reduction in HbA1c with higher doses, this difference is more clinically significant when the patients' baseline HbA1c is ≥ 8.5%. Weight and blood pressure Empagliflozin causes moderate reductions in blood pressure and body weight. These effects are likely due to the excretion of glucose in the urine and a slight increase in urinary sodium excretion. In clinical trials, participants with type2 diabetes taking empagliflozin with other diabetic medications lost an average of 2% of their baseline body weight. Empagliflozin use has been associated with clinically meaningful weight loss, with a higher proportion of individuals achieving weight loss greater than 5% of their baseline weight compared to placebo. Empagliflozin has been shown to reduce systolic blood pressure by 3 to 5millimeters of mercury (mmHg) without changes in pulse rate. == Etymology ==

The name is a constructed term composed of three parts: 1. Empa- (The Prefix) This is a specific syllable chosen by the manufacturer to distinguish this molecule from others in the same class (like Dapagliflozin or Canagliflozin). It serves as a unique identifier for the specific drug developed by Boehringer Ingelheim and Eli Lilly. 2. -gli- (The Middle Stem) This is an abbreviation for Glucose or Glycemic. It indicates that the drug's mechanism of action involves the regulation of sugar (glucose). 3. -flozin (The Suffix) This is the official stem for the class of SGLT2 inhibitors. This suffix is a direct linguistic reference to the molecule Phlorizin (or Phloridzin), the natural substance that served as the prototype for this entire class of drugs. The Origin of "Phlorizin" (The "Apple" Connection) The word Phlorizin is of Greek origin, coined by French chemists in 1835. It describes exactly where they found the substance: • Phloios : meaning "Bark". • Rhiza meaning "Root". They named it this because they isolated the compound from the bark of the root of apple trees. == References ==