EMPAGLOZINE

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, 15, 16, 13 for the management of type 2 diabetes mellitus.

The first known inhibitor of

SGLTs, phlorizin, was isolated from the bark of apple trees in 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 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 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. 22, 19.

Empagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in patients aged 10 years and older with type 2 diabetes.

It is used either alone or in combination with metformin or linagliptin. 16, 15, 18 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 with metformin. 18, 21 An extended-release containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 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. 18, 23 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. 21, 24 Empagliflozin is not approved for use in patients with type 1 diabetes.

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.

Following oral administration, peak plasma concentrations are reached in approximately 1.5 hours (T max ).

At steady-state, plasma AUC and C max were 1870 nmol-h/L and 259 nmol/L, respectively, following therapy with empagliflozin 10 mg daily and 4740 nmol-h/L and 687 nmol/L, respectively, following therapy with empagliflozin 25 mg daily.

Administration with food does not significantly affect the absorption of empagliflozin.

The estimated apparent steady-state volume of distribution is 73.8 L.

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.

Hover over products below to view reaction partners Empagliflozin Empagliflozin-2-glucuronide Empagliflozin-3-glucuronide Empagliflozin-6-glucuronide.

After oral administration of radiolabeled empagliflozin approximately 41.2% of the administered dose was found eliminated in feces and 54.4% eliminated in urine.

The majority of radioactivity in the feces was due to unchanged parent drug while approximately half of the radioactivity in urine was due to unchanged parent drug.

The apparent terminal elimination half-life was found to be 12.4 h based on population pharmacokinetic analysis.

Apparent oral clearance was found to be 10.6 L/h based on a population pharmacokinetic analysis.

Improve decision support & research outcomes With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates.

View sample adverse effects data in our new Data Library! See the data Improve decision support & research outcomes with our structured adverse effects data.

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.