Mechanism of Action of SGLT2 Inhibitors

Introduction

SGLT2 Inhibitors, or sodium-glucose co-transporter 2 inhibitors, are a newer class of oral antidiabetic drugs that reduce blood glucose levels by promoting urinary glucose excretion. Unlike insulin-dependent drugs, they work via the kidneys and help in both glycemic control and weight reduction.

Commonly used SGLT2 inhibitors include:

• Canagliflozin
• Dapagliflozin
• Empagliflozin
• Ertugliflozin

These drugs are now also used for cardiovascular protection and chronic kidney disease, in addition to type 2 diabetes management. Highly relevant for USMLE, NCLEX, GPAT, and NEET-PG prep.

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Stepwise Mechanism of Action of SGLT2 Inhibitors

1. Target site – Proximal convoluted tubule
   SGLT2 inhibitors act on the proximal renal tubules, where SGLT2 transporters reabsorb 90% of filtered glucose.
2. Inhibition of SGLT2 transporter
   These drugs selectively inhibit SGLT2, reducing glucose reabsorption from the renal tubule back into the bloodstream.
3. Increased urinary glucose excretion (UGE)
   Glucose is excreted in urine, leading to reduced plasma glucose levels and caloric loss.
4. Reduction in fasting and postprandial glucose
   Glycemic control improves independent of insulin, reducing risk of hypoglycemia.
5. Additional systemic benefits
   They also lead to weight loss, mild diuresis, reduced blood pressure, and cardioprotective and nephroprotective effects.

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Pharmacokinetic Parameters of SGLT2 Inhibitors

Drug	Bioavailability	Half-life	Metabolism	Excretion
Canagliflozin	~65%	10–13 hrs	Hepatic (UGT1A9/UGT2B4)	Renal (~33%)
Dapagliflozin	~78%	12–13 hrs	Hepatic (UGT1A9)	Renal (~75%)
Empagliflozin	~78%	12 hrs	Minimal hepatic metabolism	Renal (~55%)

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Clinical Uses of SGLT2 Inhibitors

• Type 2 diabetes mellitus
• Heart failure with reduced or preserved ejection fraction (HFrEF, HFpEF)
• Chronic kidney disease (CKD)
• Weight management (indirect benefit)
• Reduction in cardiovascular risk (e.g., empagliflozin in EMPA-REG OUTCOME trial)

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Adverse Effects of SGLT2 Inhibitors

• Genital and urinary tract infections (common due to glucosuria)
• Volume depletion, hypotension
• Diabetic ketoacidosis (euglycemic DKA – rare but serious)
• Increased urination (polyuria)
• Fournier’s gangrene (very rare)
• Fracture risk and amputation (canagliflozin – earlier warning, now revised)

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Comparative Analysis: SGLT2 Inhibitors vs Other Oral Antidiabetics

Feature	SGLT2 Inhibitors	Other Oral Drugs
Hypoglycemia risk	Very low	Moderate to high (sulfonylureas)
Weight impact	Weight loss	Neutral or weight gain
Insulin dependence	Independent	Mostly dependent
Cardiovascular benefit	Yes (empagliflozin, dapagliflozin)	Not consistent
Route of excretion	Renal	Mostly hepatic or mixed

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Practice MCQs

Q1. SGLT2 inhibitors reduce blood glucose primarily by:
a. Enhancing insulin sensitivity
b. Blocking glucose absorption in the intestine
c. Inhibiting renal glucose reabsorption ✅
d. Stimulating insulin secretion

Q2. Which transporter is blocked by SGLT2 inhibitors?
a. SGLT1
b. SGLT2 ✅
c. GLUT4
d. Na⁺/K⁺ pump

Q3. Where is the SGLT2 transporter located?
a. Loop of Henle
b. Distal tubule
c. Proximal convoluted tubule ✅
d. Collecting duct

Q4. Which of the following is NOT a known benefit of SGLT2 inhibitors?
a. Weight loss
b. Increased insulin production ✅
c. Cardiovascular protection
d. Lower blood pressure

Q5. What serious but rare complication can occur with SGLT2 inhibitors?
a. Diabetic retinopathy
b. Euglycemic ketoacidosis ✅
c. Thyroid cancer
d. Hypercalcemia

Q6. Which drug has the strongest evidence for cardiovascular benefit?
a. Sitagliptin
b. Glibenclamide
c. Empagliflozin ✅
d. Acarbose

Q7. The increased urination from SGLT2 inhibitors is due to:
a. Osmotic diuresis from glucose ✅
b. Water channel blockage
c. Increased ADH
d. Loop of Henle inhibition

Q8. The EMPA-REG OUTCOME trial showed that empagliflozin:
a. Raises LDL
b. Increases fracture risk
c. Reduces cardiovascular mortality ✅
d. Stimulates insulin release

Q9. Which patient population needs caution with SGLT2 inhibitors?
a. Obese individuals
b. Patients with low GFR ✅
c. Type 2 diabetics with good renal function
d. Non-diabetic hypertensives

Q10. Which of the following is a common side effect of SGLT2 inhibitors?
a. Hypoglycemia
b. Genital infections ✅
c. Hyperkalemia
d. Hepatitis

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FAQs

Q1: Can SGLT2 inhibitors be used in type 1 diabetes?
Not routinely. Risk of euglycemic ketoacidosis makes them unsuitable unless under special protocols.

Q2: Do SGLT2 inhibitors cause hypoglycemia?
No, unless combined with insulin or sulfonylureas.

Q3: Are they safe in kidney disease?
Yes, especially dapagliflozin and empagliflozin, which are FDA-approved for CKD.

Q4: Should SGLT2 inhibitors be taken with food?
They can be taken with or without food, usually once daily in the morning.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Review of Pharmacology – Sparsh Gupta
• ADA Guidelines
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK513321/