SGLT-2 inhibitors

Mechanism of Action - The Sugar Spillers

• Primary Site: Proximal Convoluted Tubule (PCT) of the nephron.
• Action: Selectively inhibit the Sodium-Glucose Cotransporter 2 (SGLT-2).
  • SGLT-2 is responsible for reabsorbing ~90% of filtered glucose.
  • Inhibition blocks this reabsorption, leading to the excretion of glucose ($C_6H_{12}O_6$) in the urine.
• Key Effects:
  • Glycosuria: "Spilling" sugar into the urine.
  • Osmotic Diuresis: Water follows the excreted glucose, leading to increased urine output.
  • Natriuresis: Mild sodium loss as SGLT-2 is a sodium-glucose cotransporter.

⭐ Insulin Independent: SGLT-2 inhibitors lower blood glucose without relying on β-cell function or insulin sensitivity, making them effective at various stages of type 2 diabetes.

The Agents - Meet the '-gliflozins'

This class of oral hypoglycemics is easily identified by the common suffix '-gliflozin'. They are crucial not just for diabetes management but also for their significant cardiorenal benefits.

• Canagliflozin
• Dapagliflozin
• Empagliflozin

📌 Mnemonic: These agents make glucose 'flow' out in the 'zin' (urine).

⭐ Beyond glycemic control, Empagliflozin and Canagliflozin are proven to reduce major adverse cardiovascular events (MACE) and hospitalizations for heart failure in patients with established cardiovascular disease.

Clinical Uses - Cardio-Renal Superpowers

SGLT-2 inhibitors are indicated for Type 2 Diabetes, Heart Failure with reduced Ejection Fraction (HFrEF), and Chronic Kidney Disease (CKD), offering significant cardio-renal protection.

SGLT2["💊 SGLT-2 Inhibition
• Target proximal tubule• Block glucose uptake"]

GLUC["📋 Glucosuria & Natriuresis
• Sugar in urine• Sodium excretion"]

OSM["🔬 Osmotic Diuresis
• Water loss via urine• Lowers fluid volume"]

IGP["🔬 ⬇️ Intraglomerular P
• Tubuloglomerular FB• Afferent constriction"]

PRE["📋 ⬇️ Pre/Afterload
• Lower wall stress• Reduced BP/volume"]

RENAL["✅ Renal Protection
• Slower eGFR decline• Lower proteinuria"]

CV["✅ CV Protection
• ⬇️ HF admissions• CV mortality benefit"]

SGLT2 --> GLUC GLUC --> OSM GLUC --> IGP OSM --> PRE PRE --> CV IGP --> RENAL

style SGLT2 fill:#F1FCF5,stroke:#BEF4D8,stroke-width:1.5px,rx:12,ry:12,color:#166534 style GLUC fill:#FEF8EC,stroke:#FBECCA,stroke-width:1.5px,rx:12,ry:12,color:#854D0E style OSM fill:#FFF7ED,stroke:#FFEED5,stroke-width:1.5px,rx:12,ry:12,color:#C2410C style IGP fill:#FFF7ED,stroke:#FFEED5,stroke-width:1.5px,rx:12,ry:12,color:#C2410C style PRE fill:#FEF8EC,stroke:#FBECCA,stroke-width:1.5px,rx:12,ry:12,color:#854D0E style RENAL fill:#F6F5F5,stroke:#E7E6E6,stroke-width:1.5px,rx:12,ry:12,color:#525252 style CV fill:#F6F5F5,stroke:#E7E6E6,stroke-width:1.5px,rx:12,ry:12,color:#525252

> ⭐ **High-Yield:** In HFrEF patients, SGLT-2 inhibitors reduce the risk of cardiovascular death and hospitalization for heart failure, even in those **without** diabetes.

##  Adverse Effects - The Flozin Foes

*   **Genitourinary Infections:** Increased urinary glucose promotes the growth of bacteria and fungi, leading to:
    -   Vulvovaginal candidiasis
    -   Urinary Tract Infections (UTIs)
*   **Euglycemic Diabetic Ketoacidosis (eDKA):** A critical, life-threatening state of ketoacidosis *without* marked hyperglycemia (blood glucose often < **250** mg/dL).
*   **Hypotension:** Osmotic diuresis causes volume depletion, posing a risk for dizziness and falls, especially in the elderly.
*   **Fournier's Gangrene:** A rare but severe necrotizing fasciitis of the perineum requiring urgent intervention.
*   **Bone Fractures:** An increased risk has been associated specifically with Canagliflozin.

![Fournier’s Gangrene: Background, Signs, Causes, Treatment](https://ylbwdadhbcjolwylidja.supabase.co/storage/v1/object/public/notes/L1/Pharmacology_Endocrine_drugs_insulin_thyroid_medications_SGLT-2_inhibitors/085e3fe5-c0e5-44b2-ac77-88551072a85b.png)

> ⭐ **High-Yield:** Always consider **eDKA** in a patient on an SGLT-2i presenting with nausea, vomiting, or abdominal pain, even with near-normal blood glucose levels.

##  High-Yield Points - ⚡ Biggest Takeaways
> * SGLT-2 inhibitors, ending in **"-gliflozin,"** block glucose reabsorption in the **proximal convoluted tubule**.
> * They promote **glucosuria**, leading to modest **weight loss** and a low risk of **hypoglycemia**.
> * Offer significant **cardiovascular and renal benefits**, reducing MACE and slowing diabetic kidney disease progression.
> * Major side effects include **genitourinary infections** (e.g., UTIs, vulvovaginal candidiasis) from glucosuria.
> * Be aware of the risk for **euglycemic DKA** and **dehydration**.