Empagliflozin

Mechanism

Pharmacological Group

Highly selective inhibitor of sodium glucose cotransporter type 2 (SGLT2).

Mechanism of Action

Empagliflozin selectively blocks the SGLT2 transporter located in the S1 segment of the Proximal Convoluted Tubule (TCP). This transporter is responsible for reabsorbing 90% of the filtered glucose, along with sodium as a symporter. Blocking SGLT2 produces:

1. A massive and controlled glycosuria (excretion of approximately 60-80g of glucose per day).
2. A moderate initial natriuresis that contributes to blood pressure control and reduction of intravascular volume.
3. A mild osmotic diuresis, which preferentially reduces interstitial fluid over intravascular volume (attenuating fluid overload in HF without inducing the sympathetic reflex response caused by loop diuretics).

Molecular Mechanism · The Returned Tubuloglomerular "Feedback"

In conditions of chronic hyperglycemia (diabetes), TCP overadapts and increases the expression of SGLT2, reabsorbing massive amounts of sodium and glucose. As a result, an abnormally low amount of sodium chloride reaches the end of the loop, where the maculadensa is located. The macula mistakenly interprets this as a state of renal hypoperfusion and activates a vasodilatory response from the glomerular afferent arteriole to increase flow, causing glomerular hyperfiltration and chronic intraglomerular hypertension (the driver of diabetic nephropathy). By blocking SGLT2 with empagliflozin, the physiological supply of sodium to the macula dense is restored, stimulating the release of adenosine and achieving reflex vasoconstriction of the afferent arteriole. This immediately reduces intraglomerular pressure, providing powerful and unmatched long-term nephroprotection.

Pharmacokinetics

Key Pharmacokinetics

• Administration: Oral, once a day.
• Bioavailability: 78%, not modified by food in a clinically significant way.
• Protein binding: High (86%).
• Metabolism: Minor conjugation by uridine 5'-diphospho-glucuronosyltransferases (UGT2B7, UGT1A9) to inactive glucuronides. It has no significant CYP metabolism.
• Excretion: 54% eliminated through the kidneys (metabolite and free drug); 41% fecally.
• Half-life: 12 to 13 hours.

Indicators and dose

Clinical Indications

• Type 2 Diabetes Mellitus: Adjuvant glycemic control with proven cardiovascular risk reduction (EMPA-REG OUTCOME study).
• Heart Failure (with Preserved and Reduced Ejection Fraction): First choice to reduce the risk of hospitalization due to HF and cardiovascular death (EMPEROR-Reduced and EMPEROR-Preserved studies).
• Chronic Kidney Disease (with or without Type 2 Diabetes): Delay progression to terminal CKD or severe drop in filtration.

Dosage and Settings

• Hypertension / Heart Failure / Diabetes: 10 mg orally once a day in the morning. It can be increased to 25 mg/day in diabetes if well tolerated to improve glycemic control.
• Kidney adjustment:
  - eGFR 30 mL/min/1.73m²: No dose adjustment required.
  - eGFR < 30 mL/min/1.73m²: Initiating treatment for glycemic control is not recommended due to the drastic reduction of the glucosuric effect. However, in heart failure and CKD, the starting dose of 10 mg/day can be continued until the need for renal replacement therapy (dialysis) due to persistent nephroprotective benefits.

Security

Contraindications

• Absolute: Patients on dialysis or with absolute terminal renal failure (due to the total ineffectiveness of the glucosuric effect in the absence of renal filtration); history of hypersensitivity to the drug; predisposition to ketoacidosis.

Adverse Effects (ADR)

• Very common: Genitourinary fungal infections (vulvovaginitis due to Candida, balanitis) secondary to the constant presence of glucose in the lower genitourinary tract.
• Common: Transient polyuria, increased thirst, mild-moderate bacterial infections of the urinary tract.
• Serious / Rare: Euglycemic diabetic ketoacidosis (a class effect characterized by marked acidosis but with normal or slightly elevated blood glucose levels, making immediate diagnosis difficult; it is usually precipitated by fasting, dehydration or surgery), necrotizing fasciitis of the perineum (Fournier's gangrene).

Interactions

• Insulin and Secretagogues (Sulfonylureas): Marked hypoglycemic synergy. Requires preventive reduction of insulin or sulfonylurea doses to prevent severe hypoglycemia.
• Loop Diuretics: Natriuretic and hypovolemic synergy; Careful monitoring is advised to avoid orthostatic dehydration and severe hypotension.

Pregnancy and Breastfeeding

Category C / Not recommended. Animal studies revealed adverse effects on late kidney development during the second and third trimesters of pregnancy. Avoid its use. Contraindicated in breastfeeding.