Empagliflozin (and Dapagliflozin)

Mechanism

Pharmacological Class and Group

Gliflozins, classified pharmacologically as Sodium-Glucose Co-transporter Type 2 (SGLT2) Inhibitors.

Mechanism of Action

In the normal renal glomerulus, circulating glucose is freely filtered into Bowman's capsule. 90% of this glucose load is actively reabsorbed in the S1 and S2 segment of the proximal convoluted tubule (PCT) by the action of the high-capacity, low-affinity transporter SGLT2. The remaining 10% is reabsorbed in the distal S3 segments by the SGLT1 transporter.

Molecular and Cellular Mechanism

1. Selective and competitive inhibition of SGLT2: Empagliflozin binds with high affinity to the SGLT2 transporter expressed on the apical membrane of TCP cells, significantly reducing the active reabsorption of filtered glucose and sodium in a 1:1 stoichiometric manner.

2. Induction of Massive Glucosuria: By lowering the renal glucose reabsorption threshold from approximately 180 mg/dL to less than 40-80 mg/dL, it induces a net urinary glucose excretion of 60-80 g/day (equivalent to a net caloric caloric loss of approximately 240-320 kcal/day).

3. Natriuretic and Osmotic Effect: Blockade of coupled sodium reabsorption causes a net loss of free water and sodium. This reduces cardiac preload and afterload by selectively decreasing interstitial fluid volume without markedly depleting intravascular volume:

↓ Systolic blood pressure (3-5 mmHg) and ↓ Diastolic blood pressure (1-2 mmHg)

4. Restoration of Tubuloglomerular Feedback (Nephroprotection): Increased delivery of sodium chloride to the distal tubule stimulates the cells of the macula previa. This causes the local release of adenosine, inducing selective vasoconstriction of the afferent arteriole, which normalizes intraglomerular pressure, reduces initial hyperfiltration and preserves glomerular architecture in the long term.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: Rapid oral absorption. Bioavailability of 78%. The peak of maximum plasma concentration (T_max) is reached between 1 and 1.5 hours post-administration.
• Distribution: High binding to plasma proteins (mainly albumin) of 86%. Distribution volume of 73.8 L.
• Metabolism: Phase II hepatic metabolism primarily through glucuronidation by the enzymes uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3, UGT1A8 and UGT1A9 to form inactive metabolites. No significant interactions with the CYP450 system are identified.
• Excretion: Elimination of 54.4% in urine (mainly unchanged) and 41.2% in feces.
• Half-life (t_1/2): Elimination half-life of 12.4 hours, allowing once-daily dosing.

Indicators and dose

Clinical Indications and Off-Label Uses

• Type 2 Diabetes Mellitus: To improve glycemic control, with proven benefits in reducing cardiovascular morbidity and mortality.
• Heart Failure with Reduced, Mildly Reduced and Preserved Ejection Fraction (HFrEF, HFrEF, HFpEF): Priority indication to reduce the risk of cardiovascular death and hospitalizations due to heart failure.
• Chronic Kidney Disease (CKD): To slow the progression of renal dysfunction in patients with eGFR between 20 and 90 mL/min/1.73 m² and albuminuria 200 mg/g.
• Type 1 Diabetes Mellitus (off-label / restricted): As adjuvant therapy for weight reduction and glycemic lability (high risk of ketoacidosis).

Dosage and Clinical Adjustment

Empagliflozin:

• Initial Dose: 10 mg once daily, orally, administered in the morning, with or without food.
• Maximum Dose: 25 mg once daily (to optimize glycemic control if tolerated).

Adjustment in Kidney Failure:

• eGFR 30 to 45 mL/min/1.73 m²: No dose adjustment required. Reduced efficacy for glycemic control, but the benefits of nephroprotection and reduction of mortality due to heart failure remain intact.
• eGFR 20 to 29 mL/min/1.73 m²: It is not advisable to start treatment, but if the patient has already been receiving it and it is well tolerated, it can be continued with a dose of 10 mg/day.
• eGFR < 20 mL/min/1.73 m² or dialysis: Contraindicated for use.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Hypersensitivity to the drug or components of the formulation.
• Chronic dialysis or ESRD treatment: Empagliflozin loses glucosuriant efficacy at eGFR < 20 mL/min/1.73 m², so it should not be used in end-stage renal disease.

Relative Contraindications

• Personal history or predisposing factors for metabolic ketoacidosis (very low carbohydrate diets, prolonged fasting).
• Severe recurrent infections of the urogenital tract.
• Previous marked arterial hypotension or extreme volume depletion in older adults.

Adverse Effects (ADR) and Specific Toxicity

• Very common (>10%): Genitourinary fungal infections secondary to local hyperglycosuria (vulvovaginal candidiasis in women and balanitis in men). They are usually self-limited and respond to usual topical antifungals.
• Common (1%-10%): Polyuria, thirst, constipation, dysuria, increase in initial serum creatinine concentration by 10-15% (reversible after 2-4 weeks of use), mild dyslipidemia.
• Rare (0.01%-0.1%): Genitourinary tissue necrosis (Fournier's Gangrene), Euglycemic Diabetic Ketoacidosis.

Clinical Alert: Euglycemic Diabetic Ketoacidosis (Euglycemic DKA)

SGLT2 inhibitors promote urinary glucose excretion, maintaining normal or only slightly elevated blood glucose levels (< 200 mg/dL) during episodes of DKA. However, they drastically decrease insulin secretion and directly stimulate pancreatic alpha cells to increase glucagon secretion:

↑ Glucagon/Insulin Ratio Massive Lipolysis β-oxidation in hepatocytes Synthesis of Acetoacetic Acid and β-hydroxybutyrate

The patient may present nausea, vomiting, abdominal pain and dyspnea with normal blood glucose, which delays the diagnosis. The drug should be discontinued immediately before any major scheduled surgery (at least 3 days before the intervention) to mitigate this risk.

Drug Interactions of Clinical Relevance

• Loop diuretics (Furosemide) and thiazides: Pharmacodynamic synergism that can cause severe dehydration, profound orthostatic hypotension and acute renal failure. It requires close monitoring and even reduction of the basal diuretic.
• Insulin and Secretagogues (Sulfonylureas): High risk of severe hypoglycemia. It is advisable to reduce the basal insulin dose by 10-20% when starting treatment with SGLT2i.

Safety in Pregnancy and Breastfeeding

• Pregnancy: Not recommended. The use of SGLT2 inhibitors during the second and third trimester of pregnancy may alter fetal renal development, according to preclinical studies that demonstrate ectasia and hypoplasia of renal calyces.
• Breastfeeding: Contraindicated. It is unknown whether it is excreted in human milk, but due to the functional immaturity of the infant's kidneys and the potential for developmental effects, it should be avoided.