Empagliflozin and Dapagliflozin

Mechanism

Pharmacological Class and Group

Cardioprotectors, nephroprotectors and antihyperglycemic agents belonging to the class of Sodium-Glucose Co-transporter Type 2 (SGLT2) Inhibitors.

Cardiovascular Mechanism of Action

Originally designed as diabetes drugs, SGLT2 inhibitors have revolutionized cardiovascular therapeutics. Its hemodynamic and cellular benefits in heart failure are largely independent of plasma glycemic control.

Mechanism of Cellular Cardioprotection and Hemodynamics of iSGLT2

1. Natriuresis and Selective Osmotic Diuresis of Interstitial Fluid: They competitively inhibit the SGLT2 transporter in the renal proximal tubule, promoting the urinary excretion of glucose and sodium in a coordinated manner. This induces a unique profile reduction in cardiac preload and afterload:

↓ Interstitial Volume ≫ ↓ Intravascular Volume Relief of congestion without activating the SNS or RAAS

Unlike classical diuretics (such as furosemide), SGLT2i preferentially depleted interstitial fluid without critically altering the effective intravascular volume of perfusion, minimizing reflex compensatory sympathetic activation and orthostatic hypotension.

2. Inhibition of the Cardiac Sodium-Hydrogen Exchanger (NHE1): SGLT2 i directly inhibits the NHE1 exchanger in ventricular myocytes. This decreases the concentration of free cytoplasmic sodium, which reduces mitochondrial calcium accumulation and optimizes ATP synthesis in the myocardium, improving myocardial contractility during diastole.

3. Shift of Metabolism towards Ketone Bodies: By inducing a moderate glucosuric caloric loss, they promote a slight increase in the plasma glucagon/insulin ratio, stimulating low-grade hepatic ketogenesis. The insufficient myocardium preferentially and more efficiently uses β-hydroxybutyrate as a primary energy substrate, optimizing mitochondrial oxygen consumption:

Myocardial metabolism of β-hydroxybutyrate ↑ Efficiency of ATP production per molecule of O₂

4. Hemodynamic Nephroprotection by Tubuloglomerular Feedback: They restore the sodium supply to the distal macula dense, inducing vasoconstriction of the afferent arteriole dilated by diabetes, which reduces intraglomerular filtration pressure and stops the progression of chronic kidney disease.

Pharmacokinetics

High Resolution Pharmacokinetics

• Absorption and Bioavailability: Excellent oral absorption quickly. Bioavailability greater than 78% for empagliflozin and 78% for dapagliflozin. The maximum plasma peak is reached in 1 to 2 hours.
• Distribution: High binding to plasma albumin (91% - 93%). Stable apparent volume of distribution of approximately 70 L.
• Metabolism: Exclusive phase II hepatic metabolism through glucuronidation by the action of the enzymes UGT1A9 and UGT2B7 to inactive metabolites. It does not present relevant interactions with cytochrome CYP450.
• Excretion: 54% in urine and 41% in feces.
• Half-life (t_1/2): It has a terminal elimination half-life of 12 to 13 hours, ideal for a single daily dosage in the morning.

Indicators and dose

Clinical Indications and Cardiovascular Uses

• Heart Failure with Reduced Ejection Fraction (HFrEF): Indicated in patients with or without diabetes to reduce mortality and hospitalizations (demonstrated by the DAPA-HF and EMPEROR-Reduced trials).
• Heart Failure with Preserved Ejection Fraction (HFpEF): First group of drugs with proven clinical benefit in this group (EMPEROR-Preserved and DELIVER trials).
• Chronic Progressive Kidney Disease: Indicated to delay the drop in glomerular filtration and the need for dialysis in patients with established albuminuria.

Dosage and Clinical Adjustment

• Heart Failure / Nephroprotection: Standardized fixed dose of 10 mg once a day orally in the morning, with or without food (applies to both Empagliflozin and Dapagliflozin). No dose titration is required.
• Renal Adjustment: No dose adjustment is required according to renal function, but it is not advisable to start treatment if the eGFR is less than 20 mL/min/1.73 m² in the case of empagliflozin, or less than 25 mL/min/1.73 m² in the case of dapagliflozin, due to the significant decrease in clinical efficacy.

Security

Absolute and Relative Contraindications

Absolute Contraindications

• Known hypersensitivity to SGLT2 inhibitors.
• End-stage renal failure or active dialysis: SGLT2i lose their diuretic and nephroprotective efficacy if the eGFR is less than 20 mL/min/1.73 m² (dapagliflozin is not started with filtrates < 25; empagliflozin is not started with < 20).

Relative Contraindications

• Predisposition to diabetic ketoacidosis.
• Severe recurrent infections of the urogenital tract.
• Previous arterial hypotension marked with extreme volume depletion in the elderly.

Adverse Effects and Toxicity

• Genital Fungal Infections (10%): Vulvovaginal candidiasis and balanitis due to glucose accumulation in the urinary outflow tract. They are treated with local antifungals and do not usually require discontinuation of the drug.
• Upper Urinary Infections: Moderate pyelonephritis (rare, < 1%).
• Euglycemic Diabetic Ketoacidosis (Very Rare, < 0.1%): Presents with symptoms of metabolic acidosis in the presence of normal serum glucose levels, usually triggered by surgeries or prolonged fasting.

Surgical Alert: Suspension of iSGLT2 before Major Surgeries

SGLT2i persistently decrease basal insulin secretion and promote cellular lipolysis. Faced with the metabolic stress of surgery or postoperative fasting, the energy balance is critically diverted towards progressive ketogenesis, triggering euglycemic diabetic ketoacidosis:

Use of iSGLT2 Strictly stop 3 days before scheduled surgery or prolonged fasting

The drug should be discontinued a minimum of 3 days prior to any major elective surgery and resumed only once full oral feeding has been safely established and the patient's hemodynamics are stabilized.

Relevant Drug Interactions

• Loop Diuretics (Furosemide): Volume synergism that can cause severe dehydration, hypotension and prerenal renal failure. Requires consideration of a dose reduction of basal loop diuretics of up to 25% to 50% when initiating SGLT2i.
• Insulin and Sulfonylureas: They increase the risk of severe de novo hypoglycemia in diabetic patients (but not in non-diabetic patients with heart failure).