Mechanism of Action of Farxiga (Dapagliflozin)

Introduction

Dapagliflozin (trade name Farxiga) is a sodium–glucose co‑transporter 2 (SGLT2) inhibitor used in type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF). It lowers blood glucose by promoting renal excretion of glucose and also provides cardiovascular and renal benefits beyond glycemic control.

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Step-by-Step Mechanism of Action

1. Selective inhibition of SGLT2 in proximal renal tubule
   Dapagliflozin blocks the SGLT2 protein in the kidneys, reducing reabsorption of filtered glucose and sodium.
2. Increased urinary glucose excretion (UGE)
   Inhibition leads to excretion of 60–80 g of glucose per day, lowering plasma glucose and HbA₁c.
3. Osmotic diuresis and natriuresis
   Glucosuria draws water into the urine; concurrent sodium loss lowers plasma volume, blood pressure, and preload.
4. Weight loss and metabolic effects
   Caloric loss from glucosuria leads to weight reduction. Improved insulin sensitivity and cardiovascular outcomes follow.
5. Renoprotective and cardioprotective actions
   Mechanisms include reduced intraglomerular pressure, decreased albuminuria, and improved heart function via reduced preload, afterload, and energy utilization enhancement.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral (tablet)
Bioavailability	~78%
Time to Peak (Tmax)	~2 hours
Protein Binding	~91%
Metabolism	Hepatic via UGT1A9 to inactive glucuronide
Half-life	~12–13 hours
Excretion	~75% renal (mostly unchanged), rest fecal

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Clinical Uses

• Glycemic control in type 2 diabetes
• Reduces risk of cardiovascular death and hospitalization in HFrEF (with or without diabetes)
• Slows progression of chronic kidney disease (CKD)

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Adverse Effects

• Genitourinary infections: mycotic vaginal and urinary tract infections
• Volume depletion: hypotension, dizziness, especially in elderly or those on diuretics
• Euglycemic diabetic ketoacidosis (rare)
• Electrolyte changes: mild increases in LDL cholesterol and magnesium, possible slight potassium changes

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Comparative Analysis

Drug	SGLT selectivity	HbA₁c Reduction	Weight Loss	Cardiorenal Benefit
Dapagliflozin	SGLT2 > SGLT1	0.5–1.0%	2–3 kg	Yes
Canagliflozin	SGLT2 ≈ SGLT1	0.8–1.1%	2.5–3.5 kg	Yes
Empagliflozin	High SGLT2	0.7–1.0%	2–3 kg	Yes

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MCQs (15)

1. Dapagliflozin primarily inhibits which transporter?
   a) SGLT1 b) SGLT2 c) GLUT4 d) Na⁺/K⁺ ATPase
   Answer: b) SGLT2
2. Its glucose-lowering effect is due to:
   a) Enhanced insulin release b) Renal glucose excretion c) Intestinal glucose absorption blockade d) Hepatic gluconeogenesis inhibition
   Answer: b) Renal glucose excretion
3. Usual urinary glucose loss per day is around:
   a) 10 g b) 30 g c) 60–80 g d) 100 g
   Answer: c) 60–80 g
4. Common genitourinary side effect is:
   a) Pharyngitis b) Vaginal yeast infection c) Otitis media d) Dental caries
   Answer: b) Vaginal yeast infection
5. Dapagliflozin acts on which part of the nephron?
   a) Proximal tubule b) Loop of Henle c) Distal tubule d) Collecting duct
   Answer: a) Proximal tubule
6. Its effects on blood pressure are due to:
   a) Beta-blockade b) Natriuresis c) Vasodilation d) Calcium channel blockade
   Answer: b) Natriuresis
7. Rare but serious risk is:
   a) Lactic acidosis b) Euglycemic DKA c) Hyperthyroidism d) Bladder cancer
   Answer: b) Euglycemic DKA
8. Dapagliflozin metabolism occurs via:
   a) CYP3A4 b) UGT1A9 c) CYP2C9 d) Renal CYP enzymes
   Answer: b) UGT1A9
9. Protein binding is approximately:
   a) 50% b) 70% c) 91% d) 100%
   Answer: c) 91%
10. Weight loss is mainly due to:
    a) Appetite suppression b) Glucosuria and caloric loss c) Lipid malabsorption d) Increased exercise tolerance
    Answer: b) Glucosuria and caloric loss
11. A comparative SGLT2 inhibitor with similar benefit is:
    a) Metformin b) Sitagliptin c) Empagliflozin d) Liraglutide
    Answer: c) Empagliflozin
12. Primary route of elimination:
    a) Renal unchanged b) Biliary conjugates c) Fecal d) Pulmonary exhalation
    Answer: a) Renal unchanged
13. Dapagliflozin should be used with caution in patients with:
    a) CKD stage 3‑4 b) Hypothyroidism c) Liver cirrhosis d) Gastroenteritis
    Answer: a) CKD stage 3‑4
14. Electrolyte change may include mild:
    a) Hypomagnesemia b) Hyperkalemia c) Hypernatremia d) Hypocalcemia
    Answer: a) Hypomagnesemia
15. Dapagliflozin also reduces:
    a) LDL cholesterol b) Triglycerides c) Cardiovascular death & HF hospitalization d) Platelet aggregation
    Answer: c) Cardiovascular death & HF hospitalization

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FAQs

1. Is dapagliflozin effective in non-diabetic heart failure?
   Yes—it reduces hospitalization for HFrEF even in non-diabetic patients.
2. How often should renal function be monitored?
   Monitor eGFR at baseline and periodically, especially in CKD patients.
3. Can it cause hypotension?
   Yes, especially in elderly or volume-depleted individuals; monitor blood pressure.
4. Does it cause hypoglycemia?
   Unlikely when used alone; risk increases when combined with insulin or sulfonylureas.
5. Is dapagliflozin safe with ACE inhibitors or ARBs?
   Yes—often used together for cardiorenal protection.

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References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition
• KD Tripathi. Essentials of Medical Pharmacology, 8th Edition
• DrugBank: Dapagliflozin pharmacology summary
• StatPearls: SGLT2 inhibitor mechanisms and effects
• PubMed review: Cardiorenal benefits of dapagliflozin in T2DM and HF

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