Oral Antidiabetic Drugs - As Per KDT (K.D. Tripathi)

Classification of Oral Antidiabetic Drugs

I. Insulin Secretagogues (Increase insulin release)

• 1st Generation: Tolbutamide, Chlorpropamide, Tolazamide
• 2nd Generation: Glibenclamide (Glyburide), Glipizide, Gliclazide, Glimepiride

• Repaglinide, Nateglinide

II. Insulin Sensitizers (Reduce insulin resistance)

• Metformin (only available member; phenformin withdrawn due to lactic acidosis)

• Pioglitazone, Rosiglitazone (troglitazone withdrawn due to hepatotoxicity)

III. Alpha-Glucosidase Inhibitors (Delay carbohydrate absorption)

• Acarbose, Miglitol, Voglibose

IV. Incretin-Based Drugs

• Sitagliptin, Vildagliptin, Saxagliptin, Alogliptin, Linagliptin

• Exenatide, Liraglutide, Semaglutide (oral form of semaglutide now available)

V. SGLT-2 Inhibitors (Gliflozins) (Increase urinary glucose excretion)

• Canagliflozin, Dapagliflozin, Empagliflozin

VI. Others

• Amylin analogues: Pramlintide (injectable)
• Bile acid sequestrant: Colesevelam
• Dopamine agonist: Bromocriptine (Cycloset)

METFORMIN

Mechanism of Action

1. Primary action - Inhibition of hepatic gluconeogenesis: Metformin acts on mitochondria in hepatocytes, reducing intracellular ATP and increasing AMP. This activates AMP-activated protein kinase (AMPK), which suppresses hepatic glucose production (HGP). It also inhibits mitochondrial glycerol-3-phosphate dehydrogenase, altering the redox state and limiting gluconeogenesis.
2. Reduces hepatic glycogenolysis - lowers fasting blood glucose.
3. Slows intestinal absorption of glucose - reduces postprandial glucose rise.
4. Improves peripheral insulin sensitivity - increases glucose uptake and utilization in skeletal muscle, though the primary hepatic action dominates.
5. Blunts glucagon action on the liver.
6. Does not cause hypoglycemia in normoglycemic individuals because it does not stimulate insulin release.

Adverse Effects

• Nausea, vomiting, anorexia
• Diarrhea, abdominal cramps, bloating, metallic taste
• GI effects are dose-dependent, usually transient, and can be minimized by:
  • Starting at a low dose and titrating slowly
  • Taking the drug with meals
  • Using extended-release preparation

• Risk increases with conditions causing tissue hypoperfusion - sepsis, myocardial infarction, decompensated heart failure, severe hepatic disease
• Contraindicated when eGFR < 30 mL/min/1.73 m²
• Mechanism: inhibition of mitochondrial respiration leads to increased lactate production, especially when drug accumulates due to renal failure

• Long-term use reduces Vitamin B12 absorption by 20-30% (impairs ileal absorption by reducing Ca²⁺-dependent uptake)
• Can cause megaloblastic anaemia and peripheral neuropathy
• Periodic B12 monitoring recommended

• eGFR < 30 mL/min/1.73 m² (renal failure)
• Severe hepatic disease
• Decompensated heart failure / sepsis / shock
• Severe pulmonary disease
• Chronic alcohol abuse
• Before IV contrast procedures (temporarily hold)
• Pregnancy (though used off-label in PCOS)

Uses of Metformin

1. Type 2 diabetes mellitus - drug of first choice, initiated at diagnosis (preferred initial therapy per all major guidelines)
2. Prediabetes / Impaired glucose tolerance (IGT) - delays or prevents progression to frank T2DM
3. Polycystic Ovary Syndrome (PCOS) - reduces insulin resistance; improves:
   • Menstrual regularity and ovulation
   • Hyperandrogenism and hirsutism
   • Assists in fertility
4. Obesity-associated insulin resistance - helps in weight management
5. Prevention of macrovascular complications - UKPDS showed reduced cardiovascular events in obese T2DM patients
6. Metabolic syndrome - adjunct in managing components of metabolic syndrome
7. Anti-aging research (investigational) - AMPK activation has been linked to lifespan extension in animal models

Note on Advantages of Metformin