Empagliflozin

Absorption

Following oral administration, peak plasma concentrations are reached in approximately 1.5 hours (Tmax). At steady-state, plasma AUC and Cmax were 1870 nmol·h/L and 259 nmol/L, respectively, following therapy with empagliflozin 10mg daily and 4740 nmol·h/L and 687 nmol/L, respectively, following therapy with empagliflozin 25mg daily. Administration with food does not significantly affect the absorption of empagliflozin.

Toxicity

Experience with empagliflozin overdose is limited - employ standard symptomatic and supportive measures, as well as gastric decontamination when appropriate. The use of hemodialysis in empagliflozin overdose has not been studied but is unlikely to be of benefit given the drug's relatively high protein-binding.

Description

Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, was originally discovered by Boehringer Ingelheim and codeveloped and co-marketed through research collaboration with Eli Lilly and Co. It was first approved by European Medicine Agency (EMA) in May 2014, followed by the approval of the US FDA in August 2014. SGLT2 inhibitors are anewclass of glucose-lowering agents developed for the treatment of type 2 diabetes mellitus, which have a mechanism of action that is independent of pancreatic b-cell function or the degree of insulin resistance. Consequently, SGLT2 inhibitors have the potential to be of use not only as standalone therapy but also in combination with any of the existing classes of glucose-lowering agents, including insulin. Empagliflozin selectively inhibits SGLT2, which in turn prevents glucose reabsorption by excreting excess glucose in the urine.

The Uses of Empagliflozin

Empagliflozin is a novel, potent and selective SGLT-2 inhibitor, improves glycaemic control and features of metabolic syndrome in diabetic rats.

Background

Empagliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), the transporters primarily responsible for the reabsorption of glucose in the kidney. It is used clinically as an adjunct to diet and exercise, often in combination with other drug therapies, for the management of type 2 diabetes mellitus.
The first known inhibitor of SGLTs, phlorizin, was isolated from the bark of apple trees in 1835 and researched extensively into the 20th century, but was ultimately deemed inappropriate for clinical use given its lack of specificity and significant gastrointestinal side effects. Attempts at overcoming these limitations first saw the development of O-glucoside analogs of phlorizin (e.g. remogliflozin etabonate), but these molecules proved relatively pharmacokinetically unstable. The development of C-glucoside phlorizin analogs remedied the issues observed in the previous generation, and led to the FDA approval of canagliflozin in 2013 and both dapagliflozin and empagliflozin in 2014. As the most recently approved of the "flozin" drugs, empagliflozin carries the highest selectivity for SGLT2 over SGLT1 (approximately 2700-fold). Empagliflozin was further approved by the EMA in March 2022 and Health Canada in April 2022, making it the first and only approved treatment in Europe and Canada for adults with symptomatic chronic heart failure regardless of ejection fraction.

Indications

Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes, either alone or in combination with metformin or linagliptin. It is also indicated to reduce the risk of cardiovascular death in adult patients with both type 2 diabetes mellitus and established cardiovascular disease, either alone or as a combination product with metformin.
An extended-release combination product containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 2020 for the improvement of glycemic control in adults with type 2 diabetes mellitus when used adjunctively with diet and exercise.
Empagliflozin is also approved to reduce the risk of cardiovascular mortality and hospitalization due to heart failure in adult patients with heart failure, either alone or in combination with metformin. It is also indicated in adults to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression.
Empagliflozin is not approved for use in patients with type 1 diabetes.

Pharmacokinetics

Empagliflozin lowers blood glucose levels by preventing glucose reabsorption in the kidneys, thereby increasing the amount of glucose excreted in the urine. It has a relatively long duration of action requiring only once-daily dosing. Patients should be monitored closely for signs and symptoms of ketoacidosis regardless of blood glucose level as empagliflozin may precipitate diabetic ketoacidosis in the absence of hyperglycemia. As its mechanism of action is contingent on the renal excretion of glucose, empagliflozin may be held in cases of acute kidney injury and/or discontinued in patients who develop chronic renal disease.
The overexcretion of glucose creates a sugar-rich urogenital environment which increases the risk of urogenital infections in both male and female patients - monitor closely for signs and symptoms of developing infection.

Metabolism

Empagliflozin undergoes minimal metabolism. It is primarily metabolized via glucuronidation by 5'-diphospho-glucuronosyltransferases 2B7, 1A3, 1A8, and 1A9 to yield three glucuronide metabolites: 2-O-, 3-O-, and 6-O-glucuronide. No metabolite represented more than 10% of total drug-related material.