Mechanism of Action of Dapagliflozin

Introduction

Dapagliflozin is an oral sodium–glucose co-transporter 2 (SGLT2) inhibitor, used to treat type 2 diabetes mellitus (T2DM). Additionally, it offers benefits in heart failure and chronic kidney disease, independent of its glucose-lowering effects.

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Step-by-Step Mechanism of Action

1. Selective SGLT2 inhibition in proximal tubules
   Dapagliflozin specifically inhibits the SGLT2 transporter in the early proximal convoluted tubule of the kidney.
2. Reduced renal glucose reabsorption
   Normally responsible for about 90% of filtered glucose reabsorption, inhibition leads to elevated urinary glucose excretion (glucosuria).
3. Osmotic diuresis and natriuresis
   Excretion of glucose pulls water and sodium prematurely into the urine, decreasing plasma volume and blood pressure.
4. Improved glycemic control
   By lowering blood glucose via glucosuria, it helps reduce HbA1c without stimulating insulin secretion.
5. Weight reduction
   Caloric loss through urinary glucose excretion leads to modest weight loss.
6. Cardiorenal protective effects
   Volume reduction, decreased intraglomerular pressure, improved vascular function, and metabolic adaptations translate to reduced heart failure hospitalizations and slowed chronic kidney disease progression.

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Pharmacokinetic Parameters

Parameter	Value
Route	Oral, once daily
Bioavailability	~78%
Protein Binding	~91%
Metabolism	Glucuronidation (UGT1A9)
Half-life	~12.9 hours
Excretion	Metabolites excreted via urine and feces

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Clinical Uses

• Glycemic control in type 2 diabetes mellitus
• Treatment of heart failure with reduced ejection fraction (HFrEF)
• Management of chronic kidney disease (CKD) in diabetics and non-diabetics

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Adverse Effects

• Genital mycotic infections
• Urinary tract infections
• Volume depletion (e.g., hypotension, dizziness)
• Rare risk of euglycemic diabetic ketoacidosis
• Slight increase in LDL cholesterol; rare cases of Fournier’s gangrene

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Comparative Analysis

Agent	SGLT2 Selectivity	Key Benefits
Dapagliflozin	High	T2DM, heart failure, CKD, cardiovascular protection
Empagliflozin	Very high	Similar benefits; strongest CV data
Canagliflozin	Moderate	Adds modest SGLT1 inhibition; amputation risk noted

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MCQs

1. Dapagliflozin inhibits transporters in the:
   a) Distal tubule b) Loop of Henle c) Proximal tubule d) Collecting duct
   Answer: c) Proximal tubule
2. Primary metabolic effect is:
   a) Insulin release b) Glucosuria c) Hepatic gluconeogenesis d) Glucose absorption
   Answer: b) Glucosuria
3. Which effect contributes to blood pressure reduction?
   a) Vasodilation b) Natriuresis c) Beta-blockade d) ACE inhibition
   Answer: b) Natriuresis
4. The half-life of dapagliflozin is approximately:
   a) 1 hour b) 6 hours c) 12.9 hours d) 24 hours
   Answer: c) 12.9 hours
5. Weight loss with dapagliflozin is due to:
   a) Appetite suppression b) Caloric loss in urine c) Fat metabolism d) Increased exercise
   Answer: b) Caloric loss in urine
6. A serious but rare complication is:
   a) Euglycemic ketoacidosis b) Hypernatremia c) Hypokalemia d) Hepatic failure
   Answer: a) Euglycemic ketoacidosis
7. Metabolism of dapagliflozin is primarily through:
   a) CYP3A4 b) CYP2D6 c) Glucuronidation d) Renal unchanged
   Answer: c) Glucuronidation
8. Cardiorenal protection is due to:
   a) Beta-cell preservation b) Intraglomerular pressure reduction c) Increased preload d) Increased HDL
   Answer: b) Intraglomerular pressure reduction
9. Which infections are most common?
   a) GI b) Genital mycotic c) Respiratory d) Bloodstream
   Answer: b) Genital mycotic
10. Compared to canagliflozin, dapagliflozin:
    a) Inhibits SGLT1 b) Has higher UGT metabolism c) Has less risk of amputations d) Is injectable
    Answer: c) Has less risk of amputations

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FAQs

1. Is dapagliflozin suitable for non-diabetic patients with kidney disease?
Yes—it’s approved for CKD even in non-diabetics due to its nephroprotective effects.

2. Does it cause hypoglycemia?
Unlikely when used alone, but risk increases with insulin or sulfonylureas.

3. Should renal function be monitored?
Yes—efficacy and safety depend on kidney function; dose adjustments may be required.

4. How long does it take to show cardiovascular benefit?
Benefits on heart failure outcomes may appear within weeks to months of initiation.

5. Are genital infections preventable?
Good hygiene and prompt treatment can reduce the incidence.

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References

• PubMed: Dapagliflozin cardiorenal mechanisms – PMID 39017631
• DrugBank: Dapagliflozin information
• FDA Label: Dapagliflozin (Farxiga)
• StatPearls: SGLT2 Inhibitors Overview
• PMC Review: SGLT2 inhibitor metabolic effects