Bisoprolol + Dapagliflozin

Usage

Bisoprolol + Dapagliflozin is a fixed-dose combination medication primarily indicated for patients with Heart Failure with Reduced Ejection Fraction (HFrEF). It is also used to treat hypertension and/or stable coronary artery disease. Dapagliflozin component is indicated to improve glycemic control in adults with type 2 diabetes mellitus and to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure (HF). It also helps reduce the risks of worsening of kidney disease, end-stage kidney disease (ESKD), cardiovascular (CV) death, and hospitalization for heart failure (hHF) in patients with chronic kidney disease. It is important to note that dapagliflozin does not treat type 1 diabetes.

Pharmacological Classification:

• Bisoprolol: Beta-1 selective adrenergic receptor blocker (beta blocker), antihypertensive, antianginal.
• Dapagliflozin: Sodium-glucose co-transporter 2 (SGLT2) inhibitor, antidiabetic.

Mechanism of Action:

• Bisoprolol: Reduces heart rate and myocardial contractility by selectively blocking beta-1 adrenergic receptors, leading to decreased oxygen demand and workload on the heart.
• Dapagliflozin: Inhibits SGLT2 in the kidneys, reducing glucose reabsorption and increasing urinary glucose excretion, thus lowering blood glucose levels. The increased sodium delivery to the distal tubule enhances tubuloglomerular feedback, reducing intraglomerular pressure, potentially benefitting patients with HFrEF.

Alternate Names

This fixed-dose combination (FDC) medication does not have an international nonproprietary name (INN).

Brand Names: Corbis D (India).

How It Works

Pharmacodynamics:

• Bisoprolol: Decreases heart rate, blood pressure, and myocardial oxygen demand.
• Dapagliflozin: Lowers blood glucose levels independently of insulin secretion or action. Exerts osmotic diuresis and natriuresis, decreasing intravascular volume and blood pressure.

Pharmacokinetics:

• Bisoprolol: Well absorbed orally. Peak plasma concentration reached in 2-4 hours. Metabolized in the liver, eliminated renally and in feces. Half-life of 9-12 hours.
• Dapagliflozin: Well absorbed orally. Peak plasma concentration in 2 hours. Metabolized primarily via glucuronidation. Eliminated renally (75%) and in feces (15%). Half-life of 12.9 hours.

Mode of Action/Receptor Binding/Enzyme Inhibition:

• Bisoprolol: Selectively binds to and blocks beta-1 adrenergic receptors in the heart and kidneys.
• Dapagliflozin: Selectively inhibits SGLT2 in the proximal renal tubules.

Elimination Pathways:

• Bisoprolol: Renal and hepatic (CYP2D6 and CYP3A4).
• Dapagliflozin: Primarily renal, some fecal excretion.

Dosage

Standard Dosage

Adults:

The recommended starting dose is Dapagliflozin 10 mg + Bisoprolol fumarate 5 mg once daily for 1-2 weeks. If tolerated, increase to Dapagliflozin 10 mg + Bisoprolol fumarate 10 mg once daily for long-term treatment.

Children:

Use in children is not recommended as there is limited safety and efficacy data.

Special Cases:

• Elderly Patients: Initiate therapy at a lower dose and titrate cautiously based on tolerability.

• Patients with Renal Impairment: For eGFR ≥25 mL/min/1.73m² BSA, no dosage adjustment is generally needed for this FDC. Initiation is not recommended for eGFR <15 mL/min/1.73m². For patients on dialysis, this medication is contraindicated.

• Patients with Hepatic Dysfunction: Dosage adjustment is not required, but use with caution and close monitoring is recommended due to limited clinical experience.

• Patients with Comorbid Conditions: Dose adjustments may be required based on individual needs and the presence of conditions such as diabetes, hypertension, or other cardiovascular diseases.

Clinical Use Cases

The dosage of this combination is not specifically tailored to clinical scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. The dosage is adjusted according to the patient’s individual needs and their response to the treatment.

Dosage Adjustments

Dose adjustments are based on patient tolerability and renal function, particularly during the initial titration period. For patients with hepatic impairment, dosage adjustment isn’t needed, but caution is advised due to limited data.

Side Effects

Common Side Effects:

• Dizziness, lightheadedness
• Hypotension (low blood pressure)
• Hypoglycemia (low blood sugar) - especially when used with insulin or sulfonylureas
• Urinary tract infections (UTIs)
• Dehydration
• Nausea
• Genital infections

Rare but Serious Side Effects:

• Angioedema (swelling of the face, lips, tongue, or throat)
• Ketoacidosis (diabetic complication with high levels of blood acids called ketones)
• Kidney problems/failure
• Severe allergic reaction
• Fournier’s gangrene (a rare but serious infection of the genital area)

Long-Term Effects:

• Potential for chronic kidney disease progression if renal function is not monitored closely.

Adverse Drug Reactions (ADR):

• Any signs of severe allergic reaction (difficulty breathing, swelling, hives)
• Signs of ketoacidosis (nausea, vomiting, abdominal pain, fruity breath)
• Worsening of kidney function (decreased urine output, swelling in legs/feet)

Contraindications

• History of hypersensitivity to dapagliflozin or bisoprolol.
• Type 1 diabetes mellitus.
• Diabetic ketoacidosis.
• Severe bradycardia.
• Second- or third-degree heart block (unless a permanent pacemaker is present).
• Cardiogenic shock.
• Decompensated heart failure.
• Sick sinus syndrome (unless a permanent pacemaker is present).
• Patients on dialysis.

Drug Interactions

• Diuretics: Increased risk of hypotension and dehydration.
• Insulin and Sulfonylureas: Increased risk of hypoglycemia.
• Other Antihypertensives: Additive hypotensive effects.
• Calcium channel blockers: Increased risk of bradycardia and hypotension.

Pregnancy and Breastfeeding

• Pregnancy: Not recommended during pregnancy, especially the second and third trimesters, due to potential risk to the fetus.

• Breastfeeding: Dapagliflozin is excreted in breast milk, bisoprolol may also pass into breast milk; therefore not recommended during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Bisoprolol: Beta-1 blocker; Dapagliflozin: SGLT2 inhibitor.
• Side Effects: Dizziness, hypotension, hypoglycemia, UTIs, dehydration.
• Contraindications: Type 1 diabetes, severe bradycardia, cardiogenic shock, patients on dialysis.
• Drug Interactions: Diuretics, insulin/sulfonylureas, other antihypertensives.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: Adults: Start with Dapagliflozin 10 mg + Bisoprolol 5 mg, then increase to 10 mg + 10 mg if tolerated.
• Monitoring Parameters: Blood glucose, blood pressure, renal function (eGFR, creatinine), electrolytes.

Popular Combinations

This FDC itself represents a popular combination. Dapagliflozin is also combined with metformin. Bisoprolol can be combined with other antihypertensives as needed.

Precautions

• General Precautions: Monitor renal function, electrolytes, and blood glucose regularly. Correct volume depletion before initiating therapy.
• Specific Populations: Use with caution in the elderly and in patients with renal impairment. Avoid in pregnant and breastfeeding women. Not for use in children.
• Lifestyle Considerations: Alcohol may increase the risk of hypoglycemia and potentiate the hypotensive effects of bisoprolol.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Bisoprolol + Dapagliflozin?

A: Initial dose: Dapagliflozin 10 mg + Bisoprolol 5 mg once daily. Maintenance dose (if tolerated): Dapagliflozin 10 mg + Bisoprolol 10 mg once daily.

Q2: In which patients is Bisoprolol + Dapagliflozin contraindicated?

A: Patients with type 1 diabetes, severe bradycardia, cardiogenic shock, decompensated heart failure, sick sinus syndrome (without a pacemaker), and patients on dialysis.

Q3: What are the most common side effects of this combination?

A: Dizziness, lightheadedness, hypotension, hypoglycemia (especially with concomitant insulin or sulfonylurea use), UTIs, and dehydration.

Q4: How does dapagliflozin work in heart failure?

A: It inhibits SGLT2, increasing urinary glucose and sodium excretion. This causes osmotic diuresis and reduces intravascular volume, preload, and afterload, improving cardiac function.

Q5: Can this FDC be used in patients with renal impairment?

A: It can be used in patients with mild to moderate renal impairment (eGFR ≥25 mL/min/1.73m² BSA). It is not recommended for initiation in patients with eGFR <15 mL/min/1.73m² or patients on dialysis.

Q6: Does this combination interact with other antidiabetic medications?

A: Yes, especially with insulin and sulfonylureas. Increased risk of hypoglycemia. Dosage adjustments might be necessary.

Q7: What are the monitoring parameters for patients on Bisoprolol + Dapagliflozin?

A: Blood glucose, blood pressure, renal function (eGFR and creatinine), and electrolytes should be monitored regularly.

Q8: What precautions should be taken when prescribing this medication to elderly patients?

A: Initiate at a lower dose (Bisoprolol 2.5 mg) and titrate cautiously according to tolerability due to increased risk of side effects such as hypotension and bradycardia.

Q9: Is this medication safe during pregnancy and breastfeeding?

A: No, it’s contraindicated during pregnancy and breastfeeding due to potential harm to the fetus/infant.

Q10: What patient education should be provided?

A: Inform patients about potential side effects, including hypotension, hypoglycemia, and UTIs. Advise them to rise slowly from sitting or lying positions, maintain adequate hydration, and report any signs of infection or worsening of symptoms. Educate patients about the importance of adherence to the prescribed regimen and regular monitoring.