Oral hypoglycemic agents

Biguanides & Sulfonylureas - The Classic Duo

• Biguanides (Metformin)

  • MOA: Primarily ↓ hepatic gluconeogenesis and ↑ peripheral insulin sensitivity.
  • Clinical Pearl: First-line therapy in Type 2 DM; promotes weight neutrality or modest loss.
  • Adverse Effects: GI distress (diarrhea), ⚠️ lactic acidosis, vitamin B12 deficiency.

• Sulfonylureas (Glipizide, Glyburide)

  • MOA: Stimulate insulin secretion from pancreatic β-cells by closing ATP-sensitive K+ channels.
  • Adverse Effects: Hypoglycemia and weight gain.

⭐ Metformin is contraindicated in severe renal dysfunction (eGFR < 30 mL/min/1.73 m²).

TZDs & Meglitinides - The Sensitivity Tweakers

• Thiazolidinediones (TZDs): "-glitazones" (Pioglitazone, Rosiglitazone)

  • MoA: ↑ Insulin sensitivity via PPAR-γ activation, upregulating GLUT4 in adipose & muscle.
  • Adverse Effects: Weight gain, edema, ⚠️ fluid retention can exacerbate heart failure, ↑ risk of fractures.

• Meglitinides: "-glinides" (Repaglinide, Nateglinide)

  • MoA: Stimulate postprandial insulin release by closing β-cell KATP channels (distinct site from sulfonylureas).
  • Use: Taken with meals to control postprandial hyperglycemia; flexible dosing.
  • Adverse Effects: Hypoglycemia (less risk than SUs).

⭐ High-Yield: TZDs are contraindicated in patients with symptomatic heart failure (NYHA Class III/IV) due to the significant risk of fluid retention and edema.

DPP-4 & SGLT2 Inhibitors - The New Guard

• DPP-4 Inhibitors (-gliptins)

  • Mechanism: Inhibit DPP-4 enzyme → ↑ GLP-1 → glucose-dependent ↑ insulin & ↓ glucagon.
  • Drugs: Sitagliptin, Saxagliptin, Linagliptin.
  • A/E: Well-tolerated; rare risk of pancreatitis and severe joint pain. Weight neutral.

• SGLT2 Inhibitors (-gliflozins)

  • Mechanism: Block SGLT2 in the proximal tubule → ↓ glucose reabsorption → ↑ urinary glucose excretion.
  • A/E: Genital mycotic infections, UTIs, osmotic diuresis (hypotension), rare euglycemic DKA.
  • Benefits: Weight loss, ↓ BP.

⭐ SGLT2 inhibitors show significant cardiovascular and renal benefits, reducing mortality in heart failure and slowing diabetic kidney disease progression.

Alpha-glucosidase Inhibitors - The Gut Crew

• MOA: Competitively inhibit α-glucosidase enzymes in the intestinal brush border, slowing complex carbohydrate digestion and absorption.
• Agents: Acarbose, Miglitol.
• Primary Effect: ↓ Postprandial glucose spikes; no risk of hypoglycemia in monotherapy.
• Adverse Effects: Significant GI distress (flatulence, diarrhea, bloating).

⭐ If hypoglycemia occurs (due to concurrent therapy), treat with glucose (dextrose), not sucrose, as sucrose breakdown is blocked.

High‑Yield Points - ⚡ Biggest Takeaways

• Metformin is the first-line agent for T2DM; its most feared side effect is lactic acidosis, especially in patients with renal insufficiency.
• Sulfonylureas directly stimulate insulin release from β-cells, carrying a significant risk of hypoglycemia.
• Thiazolidinediones (TZDs) increase insulin sensitivity but are associated with weight gain, edema, and can exacerbate heart failure.
• SGLT-2 inhibitors provide cardiovascular benefits and promote weight loss by increasing urinary glucose excretion.
• GLP-1 agonists also offer cardiovascular protection and weight loss.