Oral hypoglycemic drugs: Oral Antihyperglycemic Drugs

Antidiabetic drugs are used to manage blood glucose levels in individuals with diabetes mellitus, particularly type 2 diabetes mellitus. These drugs are broadly classified into insulin preparations and non-insulin (oral and injectable) antidiabetic agents .

1. Classification of Antidiabetic Drugs

A. Insulin Preparations

These are injectable agents used in both type 1 and type 2 diabetes mellitus. They replace or supplement endogenous insulin.

B. Non-Insulin Antidiabetic Agents

These are primarily used in type 2 diabetes mellitus and include oral and injectable medications. They work by different mechanisms to lower blood glucose levels.

Main classes include:

Insulin secretagogues
Insulin sensitizers
Alpha-glucosidase inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors
Sodium-glucose co-transporter 2 (SGLT2) inhibitors
Glucagon-like peptide-1 (GLP-1) receptor agonists (injectable)

2. Insulin Secretagogues

These agents stimulate pancreatic beta cells to secrete insulin. They include sulfonylureas and meglitinide analogues .

A. Sulfonylureas

Mechanism of Action:
They bind to and inhibit ATP-sensitive potassium channels on pancreatic beta cells, leading to calcium influx and subsequent insulin exocytosis.

Therapeutic Effects:

Increase endogenous insulin secretion
Reduce circulating glucagon levels
Improve insulin sensitivity in peripheral tissues

Examples and Generations:

Generation	Drug Names	Half-Life	Duration of Action	Notes
First	Tolbutamide	4–5 hours	6–8 hours	Safer in elderly
	Chlorpropamide	24–40 hours	20–60 hours	Can cause SIADH and disulfiram reaction
Second	Glipizide	2–4 hours	10–16 hours	Taken 30 minutes before meals
	Glyburide (Glibenclamide)	<3 hours	12–24 hours	Once daily dosing
	Glimepiride	5–9 hours	12–24 hours	Well tolerated, once daily

Adverse Effects:

Hypoglycemia (especially in elderly or patients with renal or hepatic impairment)
Weight gain
Gastrointestinal upset
Disulfiram-like reaction with alcohol (especially chlorpropamide)
Hyponatremia due to Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)
Secondary failure due to beta-cell exhaustion

Contraindications:

Type 1 diabetes mellitus
Pregnancy
Significant hepatic or renal dysfunction

Drug Interactions:

Increased effect with: Non-steroidal anti-inflammatory drugs, sulfonamides, fluconazole, warfarin
Decreased effect with: Thiazide diuretics, corticosteroids, enzyme inducers

B. Meglitinide Analogues

Examples: Repaglinide, Nateglinide

Mechanism of Action:
Similar to sulfonylureas, they block ATP-sensitive potassium channels in beta cells, but they have a rapid onset and short duration of action. This makes them effective for postprandial glucose control .

Pharmacokinetics:

Rapid absorption and onset
Short half-life (about 1 hour)
Metabolized by liver enzyme CYP3A4
Excreted via bile

Dosing: Taken before meals (usually three times daily)

Advantages:

Lower risk of hypoglycemia compared to sulfonylureas
Safe in patients with sulfonamide allergy

Adverse Effects:

Mild hypoglycemia
Weight gain
Gastrointestinal disturbances

3. Insulin Sensitizers

These agents enhance the body's sensitivity to insulin without stimulating insulin secretion.

A. Biguanides (e.g., Metformin)

Mechanism of Action:

Inhibits hepatic gluconeogenesis (glucose production by the liver)
Enhances peripheral insulin sensitivity
Reduces intestinal glucose absorption

Advantages:

First-line agent for type 2 diabetes mellitus
No weight gain; may induce weight loss
Does not cause hypoglycemia when used alone

Adverse Effects:

Gastrointestinal upset (nausea, diarrhea)
Risk of lactic acidosis (especially in renal impairment or alcohol abuse)

Contraindications:

Renal dysfunction (eGFR < 30 mL/min)
Liver failure
Heart failure
Severe infection or hypoxia

B. Thiazolidinediones (e.g., Pioglitazone, Rosiglitazone)

Mechanism of Action:
They activate peroxisome proliferator-activated receptor gamma (PPAR-γ), increasing transcription of insulin-responsive genes that enhance insulin sensitivity.

Adverse Effects:

Fluid retention and edema (may worsen heart failure)
Weight gain
Increased risk of bone fractures
Pioglitazone has a possible association with bladder cancer

4. Alpha-Glucosidase Inhibitors

Examples: Acarbose, Miglitol

Mechanism of Action:
They inhibit intestinal brush-border enzymes that digest complex carbohydrates, leading to delayed carbohydrate absorption and reduced postprandial glucose rise.

Adverse Effects: