Indications
Empagliflozin is indicated as an adjunct to diet and exercise for enhancing glycemic control in patients aged 10 years and older with type 2 diabetes. It can be used alone or in combination with metformin or linagliptin. Additionally, empagliflozin is prescribed to decrease the risk of cardiovascular death in adult patients who have both type 2 diabetes mellitus and established cardiovascular disease. This medication may be administered either on its own or combined with metformin. An extended-release formulation containing empagliflozin, metformin, and linagliptin was approved by the FDA in January 2020 to assist with glycemic control in adults with type 2 diabetes mellitus when used alongside diet and exercise. Furthermore, empagliflozin is approved to lower the risk of cardiovascular mortality and hospital admissions due to heart failure in adults experiencing heart failure. It is also indicated to mitigate the risk of a sustained decline in estimated glomerular filtration rate (eGFR), end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression. Importantly, empagliflozin is not approved for use in individuals with type 1 diabetes.
Pharmacodynamics
Empagliflozin functions by inhibiting glucose reabsorption in the kidneys, thereby enhancing glucose excretion through urine, which helps to lower blood glucose levels. This medication has a long duration of action, allowing for once-daily dosing. It is crucial to monitor patients for signs and symptoms of ketoacidosis, as empagliflozin may induce diabetic ketoacidosis even in the absence of hyperglycemia. Since its mechanism is linked to renal glucose excretion, empagliflozin may need to be paused in cases of acute kidney injury and might be discontinued in patients who develop chronic renal disease. Additionally, the increased glucose excretion results in a sugar-rich urogenital environment, heightening the risk of urogenital infections in both male and female patients, necessitating close monitoring for signs of infection.
Absorption
Upon oral administration, empagliflozin reaches peak plasma concentrations within approximately 1.5 hours (Tmax). At steady-state, following daily administration of 10 mg, the plasma area under the curve (AUC) was 1870 nmol·h/L and the maximum concentration (Cmax) was 259 nmol/L; for a daily dose of 25 mg, these values were 4740 nmol·h/L and 687 nmol/L, respectively. Importantly, the absorption of empagliflozin is not significantly influenced by food intake, allowing for flexible dosing relative to meals.
Metabolism
Empagliflozin undergoes limited metabolic transformation. The primary metabolic pathway is glucuronidation, facilitated by the enzymes 5'-diphospho-glucuronosyltransferases 2B7, 1A3, 1A8, and 1A9, which results in the formation of three glucuronide metabolites: 2-O-, 3-O-, and 6-O-glucuronide. Notably, no single metabolite constitutes more than 10% of the total drug-related material, indicating that the parent compound remains the predominant form in systemic circulation.
Mechanism of Action
Empagliflozin functions as a potent inhibitor of the sodium-glucose co-transporter-2 (SGLT2) located in the proximal tubules of the kidneys, effectively reducing blood glucose levels by increasing glucosuria. Empagliflozin achieves this by interrupting the usual process whereby approximately 90% of glucose filtered through the glomerulus is reabsorbed. Normally, the reabsorption occurs through a mechanism where Na+/K+-ATPase pumps create a sodium gradient across the basolateral membrane of proximal tubular cells, enabling SGLT2 on the apical membrane to facilitate the secondary active co-transport of sodium and glucose from the filtrate back into the bloodstream. By inhibiting this transporter, empagliflozin significantly enhances urinary glucose excretion. Beyond its glucose-lowering effect, empagliflozin also offers cardiovascular benefits, particularly in reducing the risk of heart failure. While the exact mechanisms behind these cardiovascular advantages are not fully understood, hypotheses include the inhibition of Na+/H+ exchangers in the myocardium and the proximal tubule, diuretic and natriuretic effects leading to reduced preload and blood pressure, the suppression of pro-fibrotic markers to prevent cardiac fibrosis, and a decrease in pro-inflammatory adipokines.
