• Introduction 

• Illustrated mechanism of action 

• Examples of Medication Brand Names (with Images)

• Indication

• Side Effects 

• Precautions & Contraindications 

• Monographs

• Reference 

SGLT2 inhibitors are a class of prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes. Medicines in the SGLT2 inhibitor class include canagliflozin, dapagliflozin, and empagliflozin. They are available as single-ingredient products and also in combination with other diabetes medicines such as Metformin. SGLT2 inhibitors lower blood sugar by causing the kidneys to remove sugar from the body through the urine. The safety and efficacy of SGLT2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients.

 1. Renal glucose handling:

The kidneys filter approximately 180 grams of glucose daily through the glomeruli. Normally, 100% of this glucose is reabsorbed in the proximal convoluted tubule (PCT) to prevent glucose loss in urine.

Glucose reabsorption occurs via two main transporters:

1. SGLT2: Located in the early proximal tubule (S1 segment), responsible for reabsorbing ~90% of filtered glucose.

2. SGLT1: Located in the late proximal tubule (S3 segment), reabsorbs the remaining ~10%.

2. Site of Action:

SGLT2 inhibitors selectively inhibit the SGLT2 transporter in the S1 segment of the proximal tubule.

3. Primary Effects:

1. Blocks glucose reabsorption in the early proximal tubule.

2. Leads to increased urinary glucose excretion (UGE) (can be up to 60–80 grams/day).

This causes:

• Reduction in blood glucose levels (independent of insulin).

• Mild osmotic diuresis and natriuresis (loss of sodium in urine).

• Reduction in body weight (due to caloric loss).

• Decrease in blood pressure (due to volume depletion).

4. Secondary Systemic Effects:

• Pancreatic β-cell rest (reduced glucose toxicity may improve insulin secretion).

• Improved insulin sensitivity (especially in peripheral tissues).

• Reduction in HbA1c by ~0.5–1%.

Cardiovascular benefits:

1. Reduce heart failure hospitalization.

2. Improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF).

Renoprotective effects:

1. Decrease intraglomerular pressure.

2. Slow progression of albuminuria and chronic kidney disease.

5. Unique Properties:

1. Insulin-independent mechanism: Makes them useful in patients with advanced β-cell failure.

2. Low risk of hypoglycemia when used alone.

3. Synergistic with other anti-diabetic agents.

As we know that SGLT-2 inhibitors primarily used to treat type 2 diabetes, but they also have emerging roles in managing heart failure and chronic kidney disease (CKD). 

So we will discuss how it affect on:

1_Type 2 Diabetes 

As a result of inhibtion of SGLT-2:

 1_Inhibition of SGLT-2

• 1. 1. 1. 1. ↓ Glucose reabsorption in kidneys

           2. ↑ Glucose loss in urine (~60–100 g/day)

  2_Plasma glucose decreases

• 1. 1. 1. 1. Lower fasting and postprandial glucose

           2. HbA1c reduced by ~0.5–1% 

  3_Osmotic diuresis

• 1. 1. 1. 1. Water follows glucose into urine → mild diuretic effect

           2. ↓ Blood pressure (avg 4–6 mmHg systolic)

  4_Weight loss

• 1. 1. 1. 1. Caloric loss due to glucose in urine (200–300 kcal/day)

           2. Average weight loss: ~2–3 kg over a few months

2_Heart Failure

While these drugs were designed to lower blood sugar, they turned out to have powerful heart-protective effects through several non-glycemic mechanisms. 

  1_Anti-inflammatory & Anti-fibrotic Effects

•      Less chronic inflammation and fibrosis in the myocardium
  
  

•      Preserves heart muscle architecture and function

  2_Metabolic Shift in Heart Cells

• 1. 1. 1. • SGLT-2 inhibitors promote a shift toward ketone body use as fuel

           • Ketones are more efficient for energy production in failing hearts

           •  Boosts cardiac energy supply without increasing oxygen demand

 3_ Volume Reduction

• 1. 1. 1. • The drug blocks SGLT-2 in the kidney → more glucose and sodium are excreted

           • Water follows → less fluid retention

           •  Heart has less preload → less stretch → improved function

3_Chronic Kidney Disease 

SGLT-2 inhibitors protect the kidneys by easing pressure on the glomeruli, reducing protein loss, lowering inflammation, and improving overall kidney structure. They are now a core part of CKD management — not just for diabetics. .They slow kidney damage even in patients without diabetes. 

1. Reduce Hyperfiltration

• 1. 1. 1. • In early CKD and diabetes, the kidneys overwork—they hyperfilter blood.

           • This puts pressure on the glomeruli (kidney filters), leading to damage.

SGLT-2 inhibitors reduce sodium and glucose reabsorption → more sodium reaches the distal tubule → triggers tubuloglomerular feedback → afferent arteriole constriction → ↓ intraglomerular pressure → ↓ hyperfiltration 

2. Preserve Renal Function

• 1. 1. 1. • Slows down decline in eGFR (estimated glomerular filtration rate)

           • Reduces progression to dialysis or transplant

           • Seen in both diabetic and non-diabetic kidney disease

3. Natriuresis & Osmotic Diuresis

• Promotes excretion of sodium and glucose in urine

• ↓ Blood volume → ↓ blood pressure

• Helps reduce glomerular hypertension, a driver of CKD progression

4. Anti-inflammatory and Antifibrotic Effects

• Reduces renal inflammation and fibrosis

• Improves structural integrity of nephrons

5. Reduces Albuminuria

• • • • • Less protein leakage into the urine

        • Indicates protection of the glomerular filtration barrie

1. Genital and Urinary Tract Infections

•  More glucose in the urine creates a sweet, moist environment → perfect for yeast and bacteria.

• More common in women.

• Symptoms: Burning sensation, itching, unusual discharge, odor.

2. Dehydration & Low Blood Pressure (Hypotension)

•  Osmotic diuresis (loss of water and sodium in urine).

• Symptoms: Dizziness, lightheadedness, especially when standing up.

3. Frequent Urination (Polyuria)

•  Extra glucose pulls more water into the urine.

• Usually temporary and gets better as the body adjusts.

4. Euglycemic Diabetic Ketoacidosis (eDKA)

• Rare but serious complication.

• Can occur even if blood sugar is normal or mildly elevated.

5. Acute Kidney Injury

•  Due to volume depletion (too much water loss), especially in those on diuretics or with kidney disease.

• Usually reversible if detected early.
   

1. Volume Depletion or Hypotension

• 1. • Due to their diuretic effect, they can lower blood pressure and cause dizziness or fainting.

     •  Monitor hydration, especially in elderly patients or those on diuretics.

     •  Consider checking blood pressure regularly and adjusting other Anti-hypertensives.
       
       

2. Chronic Kidney Disease (CKD)

• • • SGLT-2 inhibitors are protective, but:

    •  Not effective for glucose-lowering at very low eGFR (< 30 mL/min/1.73 m²)

    • Some drugs (like dapagliflozin) are approved for CKD even at low GFR for kidney protection, but dose adjustment and careful monitoring are essential.

3. History of Genital or Urinary Infections

• 1. • Due to the risk of recurrent infections, especially genital mycotic infections

     •  Educate patients on early signs & hygiene

4. Major Surgery, Starvation, or Serious Illness

• 1. • Increased risk of euglycemic diabetic ketoacidosis (eDKA)

     • Temporarily stop the drug before surgery or during acute illness
       
       

5. Elderly Patients

• 1. • Higher risk of hypotension, dehydration, and renal impairment

     • Use lowest effective dose and monitor closely

1. https://sci-hub.se/10.1056/NEJMcibr1506573

2. https://www.sciencedirect.com/science/article/pii/S1551713622000344

3. https://www.kidney.org/kidney-topics/sglt2-inhibitors#:~:text=SGLT2%20inhibitors%20are%20medicines%20that,diabetes%20manage%20their%20blood%20sugar.

4. https://www.hcplive.com/view/10-years-of-sglt2-inhibitors-a-decade-of-redefining-cardiometabolic-care