Mechanism of Action of SGLT2Inhibitors

Introduction

SGLT2 inhibitors, also known as “gliflozins,” are a class of oral antidiabetic agents primarily used to manage type 2 diabetes mellitus. They also exhibit notable cardiovascular and renal protective effects, making them valuable in treating heart failure and chronic kidney disease, even in non-diabetic patients.

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Step-by-Step Mechanism of Action

1. Inhibition of SGLT2 in the Proximal Tubule
   These drugs selectively block the sodium-glucose co-transporter 2 (SGLT2) in the early segment of the proximal convoluted tubule of the nephron.
2. Reduced Glucose Reabsorption
   Normally, SGLT2 is responsible for reabsorbing approximately 90% of filtered glucose. Inhibition leads to increased urinary glucose excretion (glucosuria).
3. Osmotic Diuresis
   The excretion of glucose in the urine pulls water with it, resulting in increased urine volume (osmotic diuresis) and modest natriuresis (sodium excretion).
4. Caloric Loss and Weight Reduction
   Loss of glucose translates into a caloric deficit, contributing to modest weight loss in patients.
5. Improved Glycemic Control
   Blood glucose levels decrease due to reduced glucose reabsorption, which helps lower HbA1c levels.
6. Enhanced Erythropoiesis and Hematocrit
   Volume contraction and renal signaling promote erythropoietin release, leading to increased hematocrit and improved oxygen delivery.
7. Cardiovascular and Renal Protection
   These drugs reduce intraglomerular pressure, albuminuria, and myocardial stress, improving outcomes in heart failure and slowing the progression of CKD.

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Pharmacokinetic Parameters

Parameter	Value
Absorption	High oral bioavailability (~70–90%)
Tmax	~1 to 2 hours
Protein Binding	High (~86–99%)
Metabolism	Primarily glucuronidation (UGT enzymes)
Half-life	~12 to 13 hours
Excretion	Renal and fecal routes

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Clinical Uses

• Type 2 diabetes mellitus (T2DM)
• Heart failure with reduced ejection fraction (HFrEF)
• Chronic kidney disease (CKD), including non-diabetics

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Adverse Effects

• Genital mycotic infections
• Urinary tract infections
• Volume depletion, hypotension
• Euglycemic diabetic ketoacidosis (rare)
• Increased LDL cholesterol
• Rare risk of Fournier’s gangrene (especially with canagliflozin)

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Comparative Analysis

Drug	SGLT2 Selectivity	Key Features
Empagliflozin	High	Strong CV protection, once-daily dosing
Dapagliflozin	High	Broadest approved indications (DM, HF, CKD)
Canagliflozin	Moderate	Slight SGLT1 activity, amputation risk noted

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MCQs

1. SGLT2 inhibitors act on which part of the nephron?
   a) Distal tubule b) Loop of Henle c) Collecting duct d) Proximal tubule
   Answer: d) Proximal tubule
2. Primary action of SGLT2 inhibitors is:
   a) Increasing insulin secretion b) Reducing glucose reabsorption c) Enhancing glucose uptake d) Inhibiting hepatic gluconeogenesis
   Answer: b) Reducing glucose reabsorption
3. Which of the following is a common side effect?
   a) Hypernatremia b) Genital infections c) Bradycardia d) Hypercalcemia
   Answer: b) Genital infections
4. Glucosuria leads to:
   a) Fluid retention b) Hyponatremia c) Osmotic diuresis d) Metabolic alkalosis
   Answer: c) Osmotic diuresis
5. Cardiovascular benefit of SGLT2 inhibitors includes:
   a) Increased preload b) Reduced heart failure hospitalization c) Increased LDL d) Worsened ejection fraction
   Answer: b) Reduced heart failure hospitalization
6. Which drug has additional SGLT1 inhibition?
   a) Empagliflozin b) Dapagliflozin c) Canagliflozin d) Ertugliflozin
   Answer: c) Canagliflozin
7. Metabolism primarily occurs via:
   a) CYP3A4 b) Glucuronidation c) Sulfation d) Oxidation
   Answer: b) Glucuronidation
8. Which serious condition can occur despite normal blood glucose levels?
   a) Hyperosmolar coma b) Euglycemic ketoacidosis c) Lactic acidosis d) Hemolysis
   Answer: b) Euglycemic ketoacidosis
9. Albuminuria reduction is due to:
   a) Increased GFR b) Reduced intraglomerular pressure c) Enhanced filtration d) Sodium retention
   Answer: b) Reduced intraglomerular pressure
10. Which is a contraindication for SGLT2 inhibitors?
    a) Type 2 diabetes b) CKD stage 2 c) Type 1 diabetes d) Hypertension
    Answer: c) Type 1 diabetes

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FAQs

1. Can SGLT2 inhibitors be used in type 1 diabetes?
No, they are contraindicated due to the risk of euglycemic ketoacidosis.

2. Do they help in heart failure patients without diabetes?
Yes, especially in HFrEF and CKD, even in non-diabetics.

3. Is there a risk of hypoglycemia?
Minimal when used alone, but risk increases with insulin or sulfonylureas.

4. Do they require renal function monitoring?
Yes, efficacy decreases with low eGFR and dose adjustment may be needed.

5. Do they reduce weight?
Yes, through caloric loss from urinary glucose excretion.

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References

• PubMed: SGLT2 Inhibitor Review – PMC8720766
• PubMed: Cardiovascular & Renal Mechanisms – PMID: 39017631
• DrugBank: SGLT2 Inhibitors Overview
• StatPearls: SGLT2 Inhibitors
• MDPI: Pleiotropic Effects of SGLT2 Inhibitors