SGLT2 inhibitors in hypertension

Mechanism of Action - The Sugar Spillers

• Site of Action: Primarily targets the Sodium-Glucose Cotransporter 2 (SGLT2) in the early Proximal Convoluted Tubule (PCT).
• Core Function: Reversibly inhibits SGLT2, preventing the reabsorption of ~90% of filtered glucose.
• Primary Result → Glycosuria:
  • Forces excretion of glucose into the urine, acting as an "overflow valve."
  • 📌 Mnemonic: "-gliflozins" make glucose "flow" out.
• Blood Pressure Lowering Effects:
  • Osmotic Diuresis: Urinary glucose exerts an osmotic force, pulling water with it, which reduces plasma volume.
  • Natriuresis: Mild sodium excretion contributes to volume depletion.

⭐ The blood pressure reduction is largely independent of the glycemic-lowering effect, making SGLT2i effective even in patients without diabetes.

Pleiotropic Effects - More Than a BP Drug

SGLT2 inhibitors offer significant benefits beyond just blood pressure, impacting multiple organ systems through various mechanisms.

• Cardiovascular Protection:

  • Reduces risk of Major Adverse Cardiovascular Events (MACE).
  • Markedly improves outcomes in Heart Failure (both HFrEF & HFpEF), decreasing hospitalizations.
  • Mechanism: Natriuresis & osmotic diuresis → ↓ preload; improved cardiac metabolism & bioenergetics.

• Renal Protection:

  • Slows progression of chronic kidney disease (CKD), especially in diabetics.
  • Mechanism: Afferent arteriole vasoconstriction via tubuloglomerular feedback → ↓ intraglomerular pressure & hyperfiltration.

• Metabolic Benefits:

  • Modest weight loss (avg. 2-3 kg).
  • Improved glycemic control.

⭐ The cardiovascular and renal benefits are independent of diabetes status, a key indication for use in non-diabetic patients with HF or CKD.

The Agents - Meet the '-flozins'

• Common suffix: -gliflozin.
• Canagliflozin (Invokana): One of the first agents developed.
• Dapagliflozin (Farxiga): Broad approval for T2D, HFrEF, HFpEF, and CKD.
• Empagliflozin (Jardiance): Strong evidence for reducing CV mortality in T2D.
• Ertugliflozin (Steglatro): A newer agent in the class.

⭐ Empagliflozin and Dapagliflozin show significant reduction in heart failure hospitalizations and progression of renal disease, even in patients without diabetes.

Adverse Effects & Risks - The Fine Print

• Genitourinary Infections: Common due to glucosuria. Includes UTIs and vulvovaginal candidiasis (yeast infections).
• Volume Depletion: Osmotic diuresis can cause hypotension and acute kidney injury (AKI). Caution with diuretics or in elderly patients.
• Euglycemic Diabetic Ketoacidosis (eDKA): ⚠️ A rare but life-threatening emergency. Patients present with acidosis but blood glucose is often <250 mg/dL.
• Fournier's Gangrene: A rare but severe necrotizing fasciitis of the perineum.
• Bone Fractures: Increased risk noted, particularly with canagliflozin.

⭐ In a patient on an SGLT2 inhibitor presenting with nausea, vomiting, and malaise, maintain a high suspicion for euglycemic DKA, even with non-elevated blood glucose.

High‑Yield Points - ⚡ Biggest Takeaways

• SGLT2 inhibitors, ending in -gliflozin, lower blood pressure primarily via osmotic diuresis and natriuresis.
• They block the sodium-glucose cotransporter 2 in the kidney's proximal convoluted tubule.
• Strong indication for patients with concurrent type 2 diabetes, heart failure (HFrEF), and CKD.
• Proven to reduce cardiovascular mortality and hospitalizations for heart failure.
• Key side effects include genital mycotic infections, UTIs, and a rare risk of euglycemic DKA.